Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA.
G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis.
Sci Adv. 2022 Aug 5;8(31)
Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA.
G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis.
Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.
Sci Adv. 2022 Aug 5;8(31)
Brasanac J, Ramien C, Gamradt S, Tänzer A, Glau L, Ritter K, Patas K, Agorastos A, Wiedemann K, Demiraley C, Fischer F, Otte C, Weygandt M, Gold SM.
Immune signature of multiple sclerosis-associated depression.
Brain Behav Immun. 2021 Dec 1;S0889-1591(21)00625-5.
Brasanac J, Ramien C, Gamradt S, Tänzer A, Glau L, Ritter K, Patas K, Agorastos A, Wiedemann K, Demiraley C, Fischer F, Otte C, Weygandt M, Gold SM.
Immune signature of multiple sclerosis-associated depression.
| Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as „inflammatory depression“. As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n=132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of „inflammatory“ subtypes of depression. |
Brain Behav Immun. 2021 Dec 1;S0889-1591(21)00625-5.
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis
Med (N Y). 2021 Mar 12;2(3):296-312
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis
| MS is a chronic autoimmune disease of the CNS associated with serious physical and cognitive disability. MS manifests most commonly in young adults with a relapsingremitting disease course (RRMS), in which recurrent episodes (relapses) of neurological symptoms are followed by clinical remission. The majority of MS patients develop a progressive form of the disease, in which an irreversible buildup of disability occurs, regardless of relapses, either from its clinical onset (primary progressive MS [PPMS]) or after approximately 10–20 years of RRMS (secondary progressive MS [SPMS]).1 Mechanistically, the relapses observed in RRMS have been linked to episodic bouts of CNS invasion by peripheral immune cells that cause demyelinating lesions in the white matter.1 therefore, targeting of the peripheral immune system can suppress RRMS disease activity as exemplified by the anti-integrin alpha 4 (ITGA4, CD49d) antibody natalizumab.2 Natalizumab blocks the extravasation of immune cells in the CNS, preventing their migration beyond the BBB and strongly suppressing relapses. Notably, in contrast to RRMS, the same treatment strategies, including natalizumab, are not effective in progressive MS, pointing to a subsequent uncoupling of disease activity from the peripheral immune system.3 Thus, there is a major unmet clinical need to understand the sequence of events that eventually leads to continuous neurodegeneration and disability progression. The best starting point would be to explore the basis for the uncoupling of the peripheral immune response and disability progression. Although it remains largely unknown and might partly be attributed to primary neurodegeneration, it could be explained by chronic organization of peripheral immune cells behind the BBB, beyond the reach of many common therapeutic strategies. This is suggested by the observation that the onset of progressive MS is best correlated with cortical lesions that are pathologically characterized by lymphocyte collections adjacent to the graymatter. 4–6 However, it is enigmatic whether such colonization of the CNS begins during the RRMS phase and therefore could be prevented at an early stage of disease. Here, we interrogated the basis of progressive MS by designing a study to (1) systematically identify immune cells homing to the CNS in RRMS, (2) test whether these cells become resident in the CNS of progressive MS patients, and (3) investigate them as a potential therapeutic target. For this purpose, we determined the signature of CNShoming cells trapped in the blood of natalizumab-treated RRMS patients using a high-dimensional readout of combined single-cell RNA sequencing (scRNA-seq) and protein surface marker profiling. We then tracked these cells in independent cohorts of both untreated RRMS and untreated progressive MS patients and investigated their localization directly in the CNS of progressive patients using spatial RNA sequencing of MS brains. Finally, we describe their detailed characteristics and suggest a strategy for specific targetingwith a view to delay or prevent the progressive phase ofMS that drives irreversible disability and is untreatable to this day. |
Med (N Y). 2021 Mar 12;2(3):296-312
Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Nornig S, Bauer S, Wagner I,Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA.
Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.
J Exp Med. 2021 May 3;218(5).e20201290
Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Nornig S, Bauer S, Wagner I,Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA.
Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.
| Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk-associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications. |
J Exp Med. 2021 May 3;218(5).e20201290
Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger M, Steptoe A, Whooley MA, Otte C
Comorbid depression in medical diseases
Nat Rev Dis Primers. 2020 Aug 20;6(1):69
Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger M, Steptoe A, Whooley MA, Otte C
Comorbid depression in medical diseases
Depression is one of the most common comorbidities of many chronic medical diseases including cancer and cardiovascular, metabolic, inflammatory and neurological disorders. Indeed, the prevalence of depression in these patient groups is often substantially higher than in the general population, and depression accounts for a substantial part of the psychosocial burden of these disorders. Many factors can contribute to the occurrence of comorbid depression, such as shared genetic factors, converging biological pathways, social factors, health behaviours and psychological factors. Diagnosis of depression in patients with a medical disorder can be particularly challenging owing to symptomatic overlap. Although pharmacological and psychological treatments can be effective, adjustments may need to be made for patients with a comorbid medical disorder. In addition, symptoms or treatments of medical disorders may interfere with the treatment of depression. Conversely, symptoms of depression may decrease adherence to treatment of both disorders. Thus, comprehensive treatment plans are necessary to optimize care.
Nat Rev Dis Primers. 2020 Aug 20;6(1):69
Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM.
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.
Cell Rep. 2019 Oct 22;29(4):810-815
Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM.
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.
| Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track „private“ T cell clones associated with disease activity in autoimmunity. |
Cell Rep. 2019 Oct 22;29(4):810-815
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Nat Neurosci. 2019 Jun;22(6):887-896
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.Nat Neurosci. 2019 Jun;22(6):887-896
Pöttgen J, Moss-Morris R, Wendebourg J, Feddersen L, Lau S, Köpke S, Meyer B, Friede T, Penner I, Heesen C, Gold SM
Randomised controlled trial of a self-guided online fatigue intervention in multiple sclerosis
J Neurol Neurosurg Psychiatry. 2018 Sep;89(9):970-976
Pöttgen J, Moss-Morris R, Wendebourg J, Feddersen L, Lau S, Köpke S, Meyer B, Friede T, Penner I, Heesen C, Gold SM
Randomised controlled trial of a self-guided online fatigue intervention in multiple sclerosis
Fatigue is a major disabling symptom in many chronic diseases including multiple sclerosis (MS), but treatment options are limited.Here, we tested the effectiveness of a self-guided , interactive, online fatigue management programme (ELEVIDA) based on principles of cognitive behavioural therapy (CBT) and related psychotherapeutic approaches (eg, mindfulness) for reducing fatigue in MS. METHODS: Patients with MS and self-reported fatigue were recruited via the website of the German MS Society and assigned via an automated randomisation generator (1:1, no blocking or stratification) to a 12-week online intervention (ELEVIDA, n=139, 82% female, mean age 40.8, median patient determined disease steps (PDDS) 3.0) or a waitlist control group (n=136, 79% female, mean age 41.9, median PDDS 3.0). The primary outcome was the Chalder Fatigue Scale. Outcomes were assessed at baseline, at week 12 (postintervention) and at follow-up (week 24). RESULTS: Compared with the control group, significantly greater reductions in Chalder Fatigue Scale scores were seen in the ELEVIDA group at week 12 (primary endpoint, intention-to-treat analysis: between-group mean difference 2.74 points; 95% CI 1.16 to 4.32; p=0.0007; effect size d=0.53), with effects sustained at week 24 (intention-to-treat analysis: between-group mean difference 2.19 points; 95% CI 0.57 to 3.82; p=0.0080). CONCLUSIONS: Our trial provides evidence for the effectiveness of a self-guided , internet-based intervention to reduce fatigue in MS. Interventions such as ELEVIDA may be a suitable low barrier, cost-effective treatment option for MS fatigue.J Neurol Neurosurg Psychiatry. 2018 Sep;89(9):970-976
Stürner KH, Stellmann JP, Dörr J, Paul F, Friede T, Schammler S, Reinhardt S, Gellissen S, Weissflog G, Faizy TD, Werz O, Fleischer S, Vaas LAI, Herrmann F, Pless O, Martin R, Heesen C
A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).
J Neurol Neurosurg Psychiatry. 2018 Apr.;89(4):330-338
Stürner KH, Stellmann JP, Dörr J, Paul F, Friede T, Schammler S, Reinhardt S, Gellissen S, Weissflog G, Faizy TD, Werz O, Fleischer S, Vaas LAI, Herrmann F, Pless O, Martin R, Heesen C
A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).
OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial.J Neurol Neurosurg Psychiatry. 2018 Apr.;89(4):330-338
Heesen C, Haase R, Melzig S, Poettgen J, Berghoff M, Friedemann P, Zettl U, Marziniak M, Angstwurm K, Kern R, Ziemssen T, Stellmann JP
Perceptions on the value of bodily functions in multiple sclerosis.
Acta Neurol Scand. 2018 Mar;137(3):356-362
Heesen C, Haase R, Melzig S, Poettgen J, Berghoff M, Friedemann P, Zettl U, Marziniak M, Angstwurm K, Kern R, Ziemssen T, Stellmann JP
Perceptions on the value of bodily functions in multiple sclerosis.
BACKGROUND: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians‘ perceptions. METHODS: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed. RESULTS: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients‘ and physicians‘ ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016). CONCLUSION: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians.Acta Neurol Scand. 2018 Mar;137(3):356-362
Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, Friese MA.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Sci. Immunol. 2016 Sep 23;1(3):eaaf86665
Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, Friese MA.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activityregulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 asa universal switch in migDCs that may be exploited to selectively modify immune responses.Sci. Immunol. 2016 Sep 23;1(3):eaaf86665
Gold SM, Enck P, Hasselmann H, Friede T, Hegerl U, Mohr DC, Otte C
Control conditions for randomised trials of behavioural interventions in psychiatry: a decision framework.
Lancet Psychiatry. 2017 Sep;4(9):725-732
Gold SM, Enck P, Hasselmann H, Friede T, Hegerl U, Mohr DC, Otte C
Control conditions for randomised trials of behavioural interventions in psychiatry: a decision framework.
In psychiatry, comparative analyses of therapeutic options and the aggregation of data from clinical trials across different therapeutic approaches play an important role in clinical decision making, treatment guidelines, and health policy. This approach assumes that trials of pharmacological and behavioural therapies generally produce the same level of evidence when properly designed. However, trial design for behavioural interventions has some unique characteristics and control groups vary widely, which influence the effects observed in any given trial. In this Personal View, we review various control conditions typically used in psychiatry, outline their effect on the internal validity and expected effect size of a trial, and propose a decision framework for choosing a control condition depending on the risk to the patient population and the stage of development of the therapeutic intervention. We argue that the choice of control group and its justification need to be taken into consideration when comparing behavioural and pharmacological therapies.Lancet Psychiatry. 2017 Sep;4(9):725-732
Engler JB, Kursawe N, Solane ME, Patas K, Wehrmann S, Heckmann N, Lühder F, Reichart HM, Arck PC, Gold SM, Friese MA
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy
Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E181-E190.
Engler JB, Kursawe N, Solane ME, Patas K, Wehrmann S, Heckmann N, Lühder F, Reichart HM, Arck PC, Gold SM, Friese MA
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy
Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell–specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E181-E190.
Fischer A, Schröder J, Vettorazzi E, Wolf OT, Pöttgen J, Lau S, Heesen C, Moritz S, Gold SM.
An online programme to reduce depression in patients with multiple sclerosis: a randomised controlled trial.
Lancet Psychiatry 2015;2:217-23.
Fischer A, Schröder J, Vettorazzi E, Wolf OT, Pöttgen J, Lau S, Heesen C, Moritz S, Gold SM.
An online programme to reduce depression in patients with multiple sclerosis: a randomised controlled trial.
BACKGROUND: With a lifetime risk for major depressive disorder of up to 50%, depression is a common comorbidity in multiple sclerosis but remains widely underdiagnosed and untreated. We investigated the potential of a fully automated, internet-based, cognitive behavioural therapy programme, Deprexis, to reduce depressive symptoms in patients with multiple sclerosis. METHODS: For this randomised controlled trial, we recruited patients from an outpatient clinic in Hamburg, Germany. Patients aged 18-65 years were eligible for inclusion if they had multiple sclerosis and self-reported depressive symptoms. By use of a computer-generated randomisation sequence, we allocated 90 patients (1:1; no blocking or stratification) to either the intervention group or a waitlist control group for 9 weeks. The primary endpoint was the Beck Depression Inventory (BDI), as assessed by an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01663649. FINDINGS: 71 patients completed the trial: 35 patients in the intervention group and 36 patients in the control group. During the intervention, BDI scores decreased in the Deprexis group and increased in the control group, yielding a positive effect of Deprexis relative to the waitlist group (mean group difference -4·02 points [95% CI -7·26 to -0·79], p=0·015, effect size d=0·53). Worsening of depressive symptoms from below to above the clinical cutoff (BDI >13) occurred in three (7%) of 45 patients in the control group and no patients in the Deprexis group. We noted no adverse events with respect to new occurrence of suicidal ideation during the trial. INTERPRETATION: Psychological online-intervention programmes could be suitable for patients with multiple sclerosis who are unable to regularly attend therapeutic sessions because of mobility impairments. FUNDING: European Union and the Deutsche Forschungsgemeinschaft.Lancet Psychiatry 2015;2:217-23.
Briken S, Gold SM, Patra S, Vettorazzi E, Harbs D, Tallner A, Ketels G, Schulz KH, Heesen C.
Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.
Mult. Scler. 2014;20:382-90.
Briken S, Gold SM, Patra S, Vettorazzi E, Harbs D, Tallner A, Ketels G, Schulz KH, Heesen C.
Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.
BACKGROUND: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. OBJECTIVE: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. METHODS: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. RESULTS: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. CONCLUSION: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. TRIAL REGISTRATION: ISRCTN (trial number 76467492) http://isrctn.org.Mult. Scler. 2014;20:382-90.
Köpke S, Kern S, Ziemssen T, Berghoff M, Kleiter I, Marziniak M, Paul F, Vettorazzi E, Pöttgen J, Fischer K, Kasper J, Heesen C.
Evidence-based patient information programme in early multiple sclerosis: a randomised controlled trial.
J. Neurol. Neurosurg. Psychiatr. 2014;85:411-8.
Köpke S, Kern S, Ziemssen T, Berghoff M, Kleiter I, Marziniak M, Paul F, Vettorazzi E, Pöttgen J, Fischer K, Kasper J, Heesen C.
Evidence-based patient information programme in early multiple sclerosis: a randomised controlled trial.
OBJECTIVE: To evaluate the efficacy of an evidence-based patient information programme aiming to increase informed choice in patients with early multiple sclerosis (MS). BACKGROUND: Patients with early MS face a number of uncertainties concerning diagnosis, prognosis and effectiveness of immunotherapy. Prior studies suggest that evidence-based patient information combined with group education can promote informed choice in MS patients. METHODS: A 12-month, six-centre, double-blind randomised controlled clinical trial with 192 patients with a diagnosis of confirmed relapsing-remitting MS or clinical isolated syndrome in Germany. A 4-h interactive evidence-based educational programme was compared with a 4-h MS-specific stress management programme. The primary endpoint was informed choice after 6 months comprising risk knowledge and congruency between attitude towards immunotherapy and actual immunotherapy uptake. Secondary endpoints included autonomy preference, decision autonomy, decisional conflict and satisfaction, anxiety and depression, and number of immunotherapies. RESULTS: For the primary endpoint, a significant difference was shown with 50 of 85 (59%) participants in the intervention group achieving informed choice after 6 months compared with 18 of 89 (20%) in the control group (OR 0.2 (95% CI 0.1 to 0.4), p<0.001). Four weeks after the intervention, more participants in the intervention group showed good risk knowledge (difference between groups 39% (95% CI 26% to 53%), p<0.001). There were no significant differences between groups for attitude towards immunotherapy and for immunotherapy uptake. There were trends towards increased autonomy preference after the intervention and increased adherence to immunotherapies in the intervention group. CONCLUSIONS: The intervention significantly increased informed choice and relevant risk knowledge without negative side effects.J. Neurol. Neurosurg. Psychiatr. 2014;85:411-8.
Schattling B, Steinbach K, Thies E, Kruse M, Menigoz A, Ufer F, Flockerzi V, Brück W, Pongs O, Vennekens R, Kneussel M, Freichel M, Merkler D, Friese MA.
TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
Nat Med. 2012 Dec;18(12):1805-11
Schattling B, Steinbach K, Thies E, Kruse M, Menigoz A, Ufer F, Flockerzi V, Brück W, Pongs O, Vennekens R, Kneussel M, Freichel M, Merkler D, Friese MA.
TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.Nat Med. 2012 Dec;18(12):1805-11
Friese MA, Jakobsen KB, Friis L, Etzensperger R, Craner MJ, McMahon RM, Jensen LT, Huygelen V, Jones EY, Bell JI, Fugger L.
Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
Nat Med. 2008 Nov;14(11):1227-35
Friese MA, Jakobsen KB, Friis L, Etzensperger R, Craner MJ, McMahon RM, Jensen LT, Huygelen V, Jones EY, Bell JI, Fugger L.
Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.Nat Med. 2008 Nov;14(11):1227-35
Köpke S, Kasper J, Mühlhauser I, Nübling M, Heesen C.
Patient education program to enhance decision autonomy in multiple sclerosis relapse management: a randomized-controlled trial.
Mult. Scler. 2009;15:96-104.
Köpke S, Kasper J, Mühlhauser I, Nübling M, Heesen C.
Patient education program to enhance decision autonomy in multiple sclerosis relapse management: a randomized-controlled trial.
BACKGROUND: Contrary to strong recommendations for high-dose intravenous corticosteroid treatment for relapses in multiple sclerosis (MS), uncertainty remains about most aspects of relapse management. Oral corticosteroids administered by physicians or patients themselves or no corticosteroids also appear justifiable. OBJECTIVE: To evaluate an education program that aims to involve patients with MS in decisions on relapse management. METHODS: In three German MS centers, 150 patients with relapsing MS were randomly assigned to a single, 4-h group session or a standard information leaflet. The primary outcome measure was the proportion of relapses with oral or no corticosteroid therapy as an indicator of patient autonomy in treatment decision making. Other outcomes included perceived decision autonomy, quality of life, and disability status. RESULTS: In the intervention group (IG), 108/139 (78%) relapses were treated with oral or no corticosteroids compared with 101/179 (56%) in the control group; P < 0.0001. Patients‘ perceived autonomy of treatment decision making was significantly higher in the IG; P < 0.0001. Quality of life, disability status, and adverse events of corticosteroid therapies were comparable. CONCLUSION: The patient education program led to more autonomous decision making in patients with relapsing MS. Relevant changes in relapse management were observed.Mult. Scler. 2009;15:96-104.
Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L.
Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system.
Nat Med. 2007 Dec;13(12):1483-9
Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L.
Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system.
Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1-/- mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.Nat Med. 2007 Dec;13(12):1483-9
Wirth S, Schlößer A, Beiersdorfer A, Schweizer M, Woo MS, Friese MA, Lohr C, Grochowska KM.
Astrocytic uptake of posttranslationally modified amyloid-β leads to endolysosomal system disruption and induction of pro-inflammatory signaling.
Glia. 2024 Apr 17.
Wirth S, Schlößer A, Beiersdorfer A, Schweizer M, Woo MS, Friese MA, Lohr C, Grochowska KM.
Astrocytic uptake of posttranslationally modified amyloid-β leads to endolysosomal system disruption and induction of pro-inflammatory signaling.
The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-β (Aβ) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer’s disease (AD). While it is known that the posttranslational modifications of Aβ have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Aβ3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aβ3(pE)-42, but not Aβ1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Aβ3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology.Glia. 2024 Apr 17.
Holz A, Obi N, Ahrens W, Berger K, Bohn B, Brenner H, Fischer B, Fricke J, Führer A, Gastell S, Greiser KH, Harth V, Heise JK, Holleczek B, Keil T, Klett-Tammen CJ, Leitzmann M, Lieb W, Meinke-Franze C, Michels KB, Mikolajczyk R, Nimptsch K, Peters A, Pischon T, Riedel O, Schikowski T, Schipf S, Schmidt B, Schulze MB, Stang A, Hellwig K, Riemann-Lorenz K, Heesen C, Becher H.
Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).
BMC Neurol. 2024 Apr 13;24(1):123
Holz A, Obi N, Ahrens W, Berger K, Bohn B, Brenner H, Fischer B, Fricke J, Führer A, Gastell S, Greiser KH, Harth V, Heise JK, Holleczek B, Keil T, Klett-Tammen CJ, Leitzmann M, Lieb W, Meinke-Franze C, Michels KB, Mikolajczyk R, Nimptsch K, Peters A, Pischon T, Riedel O, Schikowski T, Schipf S, Schmidt B, Schulze MB, Stang A, Hellwig K, Riemann-Lorenz K, Heesen C, Becher H.
Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).
Background: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. Methods: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. Results: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. Conclusions: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.BMC Neurol. 2024 Apr 13;24(1):123
Schubert C, Schiffmann I, Farschtschi SC, Emile JF, Friese MA.
Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.
Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200233
Schubert C, Schiffmann I, Farschtschi SC, Emile JF, Friese MA.
Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.
Objectives: Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either BRAFV600E variant or other variants in the RAS-RAF-MEK-ERK pathway. The rarity and heterogeneity of the disease only enable therapy through pathophysiologic considerations. Methods: We present 2 histiocytosis cases without BRAF sequence variants that affect the CNS, one with Erdheim-Chester disease and the other with an unspecified histiocytosis, and their diagnostic and therapeutic challenges. Results: In both cases, comprehensive analysis of the RAS-RAF-MEK-ERK signaling pathway secured the diagnosis. Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular edema made it necessary to reduce cobimetinib dosage. Low-dose cobimetinib maintenance medication was successful in preventing recurrence of histiocytic disease. Discussion: CNS involvement of histiocytic disorders can lead to detrimental neurologic symptoms. MEK inhibitors are effective treatment options for some of these patients. Since side effects are common, according to our cases we propose a low-dose treatment of 20 mg per day to balance treatment effects with side effects. Classification of evidence: This case report provides Class IV evidence. This is a single observational study without controls.Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200233
Fischbach F, Richter J, Pfeffer LK, Fehse B, Berger SC, Reinhardt S, Kuhle J, Badbaran A, Rathje K, Gagelmann N, Borie D, Seibel J, Ayuk F, Friese MA, Heesen C, Kröger N.
CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.
Med. 2024 Mar 22:S2666-6340
Fischbach F, Richter J, Pfeffer LK, Fehse B, Berger SC, Reinhardt S, Kuhle J, Badbaran A, Rathje K, Gagelmann N, Borie D, Seibel J, Ayuk F, Friese MA, Heesen C, Kröger N.
CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.
Background: Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases. Methods: Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS. Findings: CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64. Conclusions: CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19+ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted.Med. 2024 Mar 22:S2666-6340
Wenzel L, Haker M, Heesen C, Kasper J, Köpke S, Rahn AC.
Evaluating Relapse Knowledge in People with Multiple Sclerosis: A Cross-Sectional Study on the Development and Validation of the Relapse Knowledge Questionnaire.
Mult Scler Relat Disord. 2024 Jan 12;83:105381
Wenzel L, Haker M, Heesen C, Kasper J, Köpke S, Rahn AC.
Evaluating Relapse Knowledge in People with Multiple Sclerosis: A Cross-Sectional Study on the Development and Validation of the Relapse Knowledge Questionnaire.
„Background: Multiple sclerosis (MS) knowledge is a prerequisite for active patient engagement in medical decision-making. Treatment of relapses in MS is a clinical field with many uncertainties and each acute relapse requires decisions regarding possible options for action, indicating the need for patient involvement. However, there is no validated instrument assessing relapse knowledge in people with MS. Our study aims to develop a valid MS relapse questionnaire for use as an outcome instrument for educational interventions. Methods: A multidisciplinary panel developed the relapse knowledge questionnaire (RKQ) based on a previously developed questionnaire. We tested the RKQ on MS patients for comprehensibility, usability and acceptance in qualitative think-aloud interviews and conducted a cross-sectional quantitative online survey to validate the questionnaire. People with suspected or confirmed relapsing-remitting MS and a recent relapse experience were eligible for inclusion. We checked normal distribution of the RKQ score and determined the item difficulty. Construct validity was analysed using correlational analysis. Results: The final RKQ consists of 10 items. After minor changes of the RKQ during pre-testing (n = 2), pilot testing (n = 10) confirmed the usability and acceptance of the instrument. The subsequent validation study (n = 203) resulted in a mean item difficulty of 0.44, ranging from 0.18 to 0.83. Seven items were particularly difficult and answered incorrectly by more than 50 % of participants. Construct validity of the RKQ was satisfactory. The RKQ score correlated only weakly with participants‘ degree of education (|rp|>0.1), years since diagnosis (|rp|>0.1), and the intention to receive corticosteroids (|rp|>0.1). Conclusion: This study indicates the validity of the RKQ and proposes that the RKQ is a suitable instrument to assess relapse knowledge in people with MS participating in educational interventions.“Mult Scler Relat Disord. 2024 Jan 12;83:105381
Therriault J, Woo MS, Salvadó G, Gobom J, Karikari TK, Janelidze S, Servaes S, Rahmouni N, Tissot C, Ashton NJ, Benedet AL, Montoliu-Gaya L, Macedo AC, Lussier FZ, Stevenson J, Vitali P, Friese MA, Massarweh G, Soucy JP, Pascoal TA, Stomrud E, Palmqvist S, Mattsson-Carlgren N, Gauthier S, Zetterberg H, Hansson O, Blennow K, Rosa-Neto P.
Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology.
Mol Neurodegener. 2024 Jan 7;19(1):2
Therriault J, Woo MS, Salvadó G, Gobom J, Karikari TK, Janelidze S, Servaes S, Rahmouni N, Tissot C, Ashton NJ, Benedet AL, Montoliu-Gaya L, Macedo AC, Lussier FZ, Stevenson J, Vitali P, Friese MA, Massarweh G, Soucy JP, Pascoal TA, Stomrud E, Palmqvist S, Mattsson-Carlgren N, Gauthier S, Zetterberg H, Hansson O, Blennow K, Rosa-Neto P.
Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology.
Background: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181, p-tau217 and p-tau231 with established immunoassay techniques. Methods: We measured p-tau181, p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau181, p-tau217 and p-tau231. P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity. Results: Mass spectrometry and immunoassays of p-tau217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau181 and p-tau231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays. Conclusions: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification.Mol Neurodegener. 2024 Jan 7;19(1):2
Braun B, Fischbach F, Richter J, Pfeffer LK, Fay H, Reinhardt S, Friese MA, Stellmann JP, Kröger NM, Heesen C, Häußler V.
Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life.
Mult Scler Relat Disord. 2023 Dec 27.
Braun B, Fischbach F, Richter J, Pfeffer LK, Fay H, Reinhardt S, Friese MA, Stellmann JP, Kröger NM, Heesen C, Häußler V.
Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life.
Background: Autologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. Methods: 20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. Results: Baseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8-15.7) years compared to 5.9 years (range 0.9-9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2-98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). Conclusion: aHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.Mult Scler Relat Disord. 2023 Dec 27.
Duchow A, Bellmann-Strobl J, Friede T, Aktas O, Angstwurm K, Ayzenberg I, Berthele A, Dawin E, Engels D, Fischer K, Flaskamp M, Giglhuber K, Grothe M, Havla J, Hümmert MW, Jarius S, Kaste M, Kern P, Kleiter I, Klotz L, Korporal-Kuhnke M, Kraemer M, Krumbholz M, Kümpfel T, Lohmann L, Ringelstein M, Rommer P, Schindler P, Schubert C, Schwake C, Senel M, Bergh FT, Tkachenko D, Tumami H, Trebst C, Vardakas I, Walter A, Warnke C, Weber MS, Wickel J, Wildemann B, Winkelmann A, Paul F, Stellmann JP, Häußler V; Neuromyelitis Optica Study Group (NEMOS).
Time to disability milestones and annualized relapse rates in NMOSD and MOGAD.
Ann Neurol. 2024 Apr;95(4):720-732
Duchow A, Bellmann-Strobl J, Friede T, Aktas O, Angstwurm K, Ayzenberg I, Berthele A, Dawin E, Engels D, Fischer K, Flaskamp M, Giglhuber K, Grothe M, Havla J, Hümmert MW, Jarius S, Kaste M, Kern P, Kleiter I, Klotz L, Korporal-Kuhnke M, Kraemer M, Krumbholz M, Kümpfel T, Lohmann L, Ringelstein M, Rommer P, Schindler P, Schubert C, Schwake C, Senel M, Bergh FT, Tkachenko D, Tumami H, Trebst C, Vardakas I, Walter A, Warnke C, Weber MS, Wickel J, Wildemann B, Winkelmann A, Paul F, Stellmann JP, Häußler V; Neuromyelitis Optica Study Group (NEMOS).
Time to disability milestones and annualized relapse rates in NMOSD and MOGAD.
Objective: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. Methods: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the EDSS. Results: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG- /MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95%CI 6.6 – 9.6) years, AQP4-IgG- /MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95%CI 10.4 – 27.6) years; EDSS 4: 11.9 (95%CI 9.7 – 14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95%CI 16.5 – 32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. Interpretation: AQP4-IgG+ NMOSD, AQP4-IgG- /MOG-IgG- NMOSD and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD.Ann Neurol. 2024 Apr;95(4):720-732
Wendlandt M, Kürten AJ, Beiersdorfer A, Schubert Ch, Samad K, Sauer J, Pinto MC, Schulz K, Friese MA, Gee CE, Hirnet D, Lohr C.
A2A adenosine receptor-driven cAMP signaling in olfactory bulb astrocytes is unaffected in experimental autoimmune encephalomyelitis.
Front Immunol. 2023 Nov 23:14:1273837
Wendlandt M, Kürten AJ, Beiersdorfer A, Schubert Ch, Samad K, Sauer J, Pinto MC, Schulz K, Friese MA, Gee CE, Hirnet D, Lohr C.
A2A adenosine receptor-driven cAMP signaling in olfactory bulb astrocytes is unaffected in experimental autoimmune encephalomyelitis.
„Introduction: The cyclic nucleotide cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger, which is known to play an important anti-inflammatory role. Astrocytes in the central nervous system (CNS) can modulate inflammation but little is known about the significance of cAMP in their function. Methods: We investigated cAMP dynamics in mouse olfactory bulb astrocytes in brain slices prepared from healthy and experimental autoimmune encephalomyelitis (EAE) mice. Results: The purinergic receptor ligands adenosine and adenosine triphosphate (ATP) both induced transient increases in cAMP in astrocytes expressing the genetically encoded cAMP sensor Flamindo2. The A2A receptor antagonist ZM241385 inhibited the responses. Similar transient increases in astrocytic cAMP occurred when olfactory receptor neurons were stimulated electrically, resulting in ATP release from the stimulated axons that increased cAMP, again via A2A receptors. Notably, A2A-mediated responses to ATP and adenosine were not different in EAE mice as compared to healthy mice. Discussion: Our results indicate that ATP, synaptically released by afferent axons in the olfactory bulb, is degraded to adenosine that acts on A2A receptors in astrocytes, thereby increasing the cytosolic cAMP concentration. However, this pathway is not altered in the olfactory bulb of EAE mice.“Front Immunol. 2023 Nov 23:14:1273837
Meyer-Arndt L, Brasanac J, Gamradt S, Bellmann-Strobl J, Maurer L, Mai K, Steward T, Spranger J, Schmitz-Hübsch T, Paul F, Gold SM, Weygandt M.
Body mass,neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.
J Neurol. 2023 Nov 27
Meyer-Arndt L, Brasanac J, Gamradt S, Bellmann-Strobl J, Maurer L, Mai K, Steward T, Spranger J, Schmitz-Hübsch T, Paul F, Gold SM, Weygandt M.
Body mass,neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.
Overweight and obesity can worsen disease activity in multiple sclerosis (MS). Although psychobiological stress processing is increasingly recognized as important obesity factor that is tightly connected to proinflammatory metabolic hormones and cytokines, its role for MS obesity remains unexplored. Consequently, we investigated the interplay between body mass index (BMI), neural stress processing (functional connectivity, FC), and immuno-hormonal stress parameters (salivary cortisol and T cell glucocorticoid [GC] sensitivity) in 57 people with MS (six obese, 19 over-, 28 normal-, and four underweight; 37 females, 46.4 ± 10.6 years) using an Arterial-Spin-Labeling MRI task comprising a rest and stress stage, along with quantitative PCR. Our findings revealed significant positive connections between BMI and MS disease activity (i.e., higher BMI was accompanied by higher relapse rate). BMI was positively linked to right supramarginal gyrus and anterior insula FC during rest and negatively to right superior parietal lobule and cerebellum FC during stress. BMI showed associations with GC functioning, with higher BMI associated with lower CD8+ FKBP4 expression and higher CD8+ FKBP5 expression on T cells. Finally, the expression of CD8+ FKBP4 positively correlated with the FC of right supramarginal gyrus and left superior parietal lobule during rest. Overall, our study provides evidence that body mass is tied to neuro-hormonal stress processing in people with MS. The observed pattern of associations between BMI, neural networks, and GC functioning suggests partial overlap between neuro-hormonal and neural-body mass networks. Ultimately, the study underscores the clinical importance of understanding multi-system crosstalk in MS obesity.J Neurol. 2023 Nov 27
Woo MS, Nilsson J, Therriault J, Rahmouni N, Brinkmalm A, Benedet AL, Ashton NJ, Macedo AC, Servaes S, Wang YT, Tissot C, Fernandez Arias J, Hosseini SA, Chamoun M, Lussier FZ, Karikari TK, Stevenson J, Mayer C, Ferrari-Souza JP, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.
14-3-3 ζ/δ-reported early synaptic injury in Alzheimer’s disease is independently mediated by sTREM2.
Neuroinflammation. 2023 Nov 24;20(1):278
Woo MS, Nilsson J, Therriault J, Rahmouni N, Brinkmalm A, Benedet AL, Ashton NJ, Macedo AC, Servaes S, Wang YT, Tissot C, Fernandez Arias J, Hosseini SA, Chamoun M, Lussier FZ, Karikari TK, Stevenson J, Mayer C, Ferrari-Souza JP, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.
14-3-3 ζ/δ-reported early synaptic injury in Alzheimer’s disease is independently mediated by sTREM2.
„Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer’s disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation. Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer’s disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.“Neuroinflammation. 2023 Nov 24;20(1):278
Winkler I, Engler JB, Vieira V, Bauer S, Liu YH, Di Liberto G, Grochowska KM, Wagner I, Bier J, Bal LC, Rothammer N, Meurs N, Egervari K, Schattling B, Salinas G, Kreutz MR, Huang YS, Pless O, Merkler D, Friese MA.
MicroRNA-92a-CPEB3 axis protects neurons against inflammatory neurodegeneration.
Sci Adv. 2023 Nov 24;9(47):eadi6855
Winkler I, Engler JB, Vieira V, Bauer S, Liu YH, Di Liberto G, Grochowska KM, Wagner I, Bier J, Bal LC, Rothammer N, Meurs N, Egervari K, Schattling B, Salinas G, Kreutz MR, Huang YS, Pless O, Merkler D, Friese MA.
MicroRNA-92a-CPEB3 axis protects neurons against inflammatory neurodegeneration.
Neuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are important modulators of neuronal stress responses, but knowledge about their contribution to neuronal protection or damage during inflammation is limited. Here, we constructed a regulatory miRNA-mRNA network of inflamed motor neurons by leveraging cell type-specific miRNA and mRNA sequencing of mice undergoing experimental autoimmune encephalomyelitis (EAE). We found robust induction of miR-92a in inflamed spinal cord neurons and identified cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) as a key target of miR-92a-mediated posttranscriptional silencing. We detected CPEB3 repression in inflamed neurons in murine EAE and human MS. Moreover, both miR-92a delivery and Cpeb3 deletion protected neuronal cultures against excitotoxicity. Supporting a detrimental effect of Cpeb3 in vivo, neuron-specific deletion in conditional Cpeb3 knockout animals led to reduced inflammation-induced clinical disability in EAE. Together, we identified a neuroprotective miR-92a-Cpeb3 axis in neuroinflammation that might serve as potential treatment target to limit inflammation-induced neuronal damage.Sci Adv. 2023 Nov 24;9(47):eadi6855
Gnirck AC, Philipp MS, Waterhölter A, Wunderlich M, Shaikh N, Adamiak V, Henneken L, Kautz T, Xiong T, Klaus D, Tomczyk P, Al-Bahra MM, Menche D, Walkenhorst M, Lantz O, Willing A, Friese MA, Huber TB, Krebs CF, Panzer U, Kurts C, Turner JE.
Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease.
Nat. Commun. 2023 Nov 15;14(1):7372
Gnirck AC, Philipp MS, Waterhölter A, Wunderlich M, Shaikh N, Adamiak V, Henneken L, Kautz T, Xiong T, Klaus D, Tomczyk P, Al-Bahra MM, Menche D, Walkenhorst M, Lantz O, Willing A, Friese MA, Huber TB, Krebs CF, Panzer U, Kurts C, Turner JE.
Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease.
Mucosal-associated invariant T (MAIT) cells have been implicated in various inflammatory diseases of barrier organs, but so far, their role in kidney disease is unclear. Here we report that MAIT cells that recognize their prototypical ligand, the vitamin B2 intermediate 5-OP-RU presented by MR1, reside in human and mouse kidneys. Single cell RNAseq analysis reveals several intrarenal MAIT subsets, and one, carrying the genetic fingerprint of tissue-resident MAIT17 cells, is activated and expanded in a murine model of crescentic glomerulonephritis (cGN). An equivalent subset is also present in kidney biopsies of patients with anti-neutrophil cytoplasmatic antibody (ANCA)-associated cGN. MAIT cell-deficient MR1 mice show aggravated disease, whereas B6-MAITCAST mice, harboring higher MAIT cell numbers, are protected from cGN. The expanded MAIT17 cells express anti-inflammatory mediators known to suppress cGN, such as CTLA-4, PD-1, and TGF-β. Interactome analysis predicts CXCR6 – CXCL16-mediated cross-talk with renal mononuclear phagocytes, known to drive cGN progression. In line, we find that cGN is aggravated upon CXCL16 blockade. Finally, we present an optimized 5-OP-RU synthesis method which we apply to attenuating cGN in mice. In summary, we propose that CXCR6+ MAIT cells might play a protective role in cGN, implicating them as a potential target for anti-inflammatory therapies.Nat. Commun. 2023 Nov 15;14(1):7372
Woo MS, Tissot C, Lantero-Rodriguez J, Snellman A, Therriault J, Rahmouni N, Macedo AC, Servaes S, Wang YT, Arias JF, Hosseini SA, Chamoun M, Lussier FZ, Benedet AL, Ashton NJ, Karikari TK, Triana-Baltzer G, Kolb HC, Stevenson J, Mayer C, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.
Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals.
Alzheimers Dement. 2024 Feb;20(2):1166-1174.
Woo MS, Tissot C, Lantero-Rodriguez J, Snellman A, Therriault J, Rahmouni N, Macedo AC, Servaes S, Wang YT, Arias JF, Hosseini SA, Chamoun M, Lussier FZ, Benedet AL, Ashton NJ, Karikari TK, Triana-Baltzer G, Kolb HC, Stevenson J, Mayer C, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.
Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals.
„Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers. Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18 F]AZD4694 and tau-PET with [18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals. Results: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen’s Kappa = 0.74, CI95% = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity. Discussion: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.“Alzheimers Dement. 2024 Feb;20(2):1166-1174.
Eisenhut K, Faber J, Engels D, Gerhards R, Lewerenz J, Doppler K, Sommer C, Markewitz R, Falk Kim K, Rössling R, Pruess H, Finke C, Wickel J, Geis C, Ratusnzny D, Pfeffer LK, Bittner S, Piepgras J, Kraft A, Klausewitz J, Nuscher B, Kümpfel T, Thaler FS; German Network for Research on Autoimmune Encephalitis (GENERATE).
Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.
Neurol Neuroimmunol Neuroinflamm 2023 Nov 1;11(1):e200176
Eisenhut K, Faber J, Engels D, Gerhards R, Lewerenz J, Doppler K, Sommer C, Markewitz R, Falk Kim K, Rössling R, Pruess H, Finke C, Wickel J, Geis C, Ratusnzny D, Pfeffer LK, Bittner S, Piepgras J, Kraft A, Klausewitz J, Nuscher B, Kümpfel T, Thaler FS; German Network for Research on Autoimmune Encephalitis (GENERATE).
Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.
Objectives: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation. Methods: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics. Results: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes. Discussion: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.Neurol Neuroimmunol Neuroinflamm 2023 Nov 1;11(1):e200176
Dalgas U, Riemenschneider M, Gold SM, Kalron A, Beckerman H, de Groot V, Dennett R, Edwards T, Pilutti LA, Freeman J.
The MoXFo initiative – study design: Considerations related to study design and methodology in exercise research for people with multiple sclerosis.
Mult Scler 2023 Oct 26
Dalgas U, Riemenschneider M, Gold SM, Kalron A, Beckerman H, de Groot V, Dennett R, Edwards T, Pilutti LA, Freeman J.
The MoXFo initiative – study design: Considerations related to study design and methodology in exercise research for people with multiple sclerosis.
„Background: Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleiotropic effects, but continued progression of the field requires better future designs and methodologies. Objectives: This paper outlines the work of the ‚Study design and methodology‘ group of the MoXFo (moving exercise research forward) initiative, and addresses critical aspects and future directions when defining the research question of interest, and subsequently, designing the study and exercise intervention in MS patients. Methods: The work is based on the formation of an international expert panel formed within the MoXFo initiative. We provide a structured and concise synthesis of exercise-specific MS research challenges and considerations when designing randomized controlled trials (RCTs). Results: Challenges and considerations are presented using the Patient population, Intervention, Comparator, Outcomes, Timing, Setting (PICOTS) framework, thereby forming a new and specific MS exercise PICOTS framework. Conclusion: We propose that researchers should carefully consider and align all elements of this MS exercise PICOTS framework when developing future research questions and study designs, ultimately improving the quality of new exercise studies in people with MS.“Mult Scler 2023 Oct 26
Rosenkranz SC, Ploughman M, Hvid LG, Zimmer P, Erickson K, Stellmann JP, Centonze D, Friese MA.
The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies.
Mult Scler 2023 Nov;29(13):1569-1577
Rosenkranz SC, Ploughman M, Hvid LG, Zimmer P, Erickson K, Stellmann JP, Centonze D, Friese MA.
The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies.
Background: As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established. Objective: Establish recommendations for future mechanistic exercise studies in MS. Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research. Results: We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies. Conclusion: The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches.Mult Scler 2023 Nov;29(13):1569-1577
Motl RW, Casey B, Learmonth YC, Latimer-Cheung A, Kinnett-Hopkins DL, Marck CH, Carl J, Pfeifer K, Riemann-Lorenz K, Heesen C, Coote S.
The MoXFo initiative – adherence: Exercise adherence, compliance and sustainability among people with multiple sclerosis: An overview and roadmap for research.
Mult Scler 2023 Oct 26
Motl RW, Casey B, Learmonth YC, Latimer-Cheung A, Kinnett-Hopkins DL, Marck CH, Carl J, Pfeifer K, Riemann-Lorenz K, Heesen C, Coote S.
The MoXFo initiative – adherence: Exercise adherence, compliance and sustainability among people with multiple sclerosis: An overview and roadmap for research.
We know very little about exercise adherence, compliance and sustainability in multiple sclerosis (MS), yet adherence is seemingly important for yielding immediate and sustained health benefits. This paper is focused on exercise adherence, compliance and sustainability in the context of informing research and practice involving MS. This focus is critical for clarifying terminology for future research and providing a roadmap guiding clinical research and practice. Our objective was accomplished through a narrative summary of the literature by a panel of experts on exercise adherence from the Moving Exercise Research in Multiple Sclerosis Forward (MoXFo) initiative and a concluding summary of the state of the literature and future research directions. The panel of experts identified three overall themes (Background and Importance; Understanding and Promoting Exercise Adherence, Compliance and Sustainability and Challenges to Exercise Adherence, Compliance and Sustainability) that represented a categorization of nine subthemes. These overall themes and subthemes formed the basis of our recommendations regarding future research broadly involving exercise adherence in MS. Overall, there is limited evidence on rates and determinants of exercise adherence and compliance in MS, and little is known about techniques and interventions for immediate and long-term exercise behaviour change.Mult Scler 2023 Oct 26
Kutzinski M, Krause N, Riemann-Lorenz K, Meyer B, Heesen C
Acceptability of digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study.
BMC Neurol. 2023 Oct 23;23(1):382
Kutzinski M, Krause N, Riemann-Lorenz K, Meyer B, Heesen C
Acceptability of digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study.
Background: Many persons with multiple sclerosis (pwMS) desire to learn how health behaviour changes (e.g., dietary adjustments, physical activity, improvements in stress management) might help them manage their disease. Previous research has shown that certain health behaviour changes can improve quality of life (QoL), fatigue and other MS outcomes. Digital health applications may be well suited to deliver relevant health behavioural interventions because of their accessibility and flexibility. The digital health application „levidex“ was designed to facilitate health behaviour change by offering evidence-based patient information and cognitive-behavioural therapy techniques to pwMS. By doing so, levidex aims to improve QoL and MS symptoms such as fatigue and mental health. Objectives: A previous study reported on the development of levidex; this non-randomised pilot study examined the feasibility (practicability and acceptability) of levidex in pwMS with moderate to severe disability. Furthermore, the intervention’s impact on empowerment, stress management, and relevant health behaviours (e.g., dietary behaviour, physical activity) was explored. Methods: levidex was originally developed for newly diagnosed pwMS in the first year after diagnosis and eventually modified to offer access to pwMS with moderate to severe disability. Participants (n = 43) with an Expanded Disability Status Scale between 3.5 and 7.5 and a disease duration of more than one year were eligible to participate. The intervention was used over a period of six months with measurement time points at baseline, month 3 and month 6. Results: Out of 38 participants who completed the six-month intervention period, 18 (47.4%) completed all 16 modules and 9 (23.7%) reached modules 13-16, the long-term maintenance part of levidex. Participants rated levidex positively in terms of practicability and acceptability and had only few points of criticism such as to include more physical exercise routine suggestions suitable for participants with severe impairment. Data on secondary endpoints showed no significant changes. Conclusion: This pilot study provided evidence for the practicability and acceptability of levidex, a digital health application designed to facilitate health behaviour change in pwMS with moderate to severe disability. Adequately powered randomised controlled studies with longer follow-up periods are needed to clarify the benefit of levidex in pwMS with moderate to severe disability.BMC Neurol. 2023 Oct 23;23(1):382
Daniel N, Bruns I, Casey B, Coote S, Daubmann A, Heesen C, Riemann-Lorenz K.
„Activity Matters was great – I now realize: if I move, I’m fitter.“: development and process evaluation of a web-based program for persons with multiple sclerosis.
Disabil Rehabil. 2023 Oct 20:1-10
Daniel N, Bruns I, Casey B, Coote S, Daubmann A, Heesen C, Riemann-Lorenz K.
„Activity Matters was great – I now realize: if I move, I’m fitter.“: development and process evaluation of a web-based program for persons with multiple sclerosis.
„Purpose: Research shows that persons with mild to moderate multiple sclerosis are less physically active than healthy controls even though they would benefit from it. This study focusses on the feasibility testing and process evaluation of the pilot study of Activity Matters, a twelve-week web-based program, from Ireland, to increase physical activity in this population. Materials and methods: The intervention was adapted to local circumstances in Hamburg, Germany and consists of eleven modules incorporating behavior change techniques. After feasibility had been confirmed, 43 persons with multiple sclerosis participated in a pilot study with a pre-post, single-group intervention design. Qualitative data was collected with questionnaires and semi structured interviews. Physical activity level and stage of change was measured quantitatively. Results: Participants had a mean age of 49.5 years (SD 9.29) and an average Patient Determined Disease Step Score of 2.2 (SD 1.47). Thirty-six participants answered the follow-up questionnaire. On average 9.8 modules were processed within 13 weeks. Each tool for behavior change was perceived as helpful except the chat group. Physical activity levels increased significantly from pre- to post intervention (p-value 0.042, Cohen’s d = 0.35). Conclusions: The results indicate that Activity Matters is feasible and satisfactory and may change activity levels.“Disabil Rehabil. 2023 Oct 20:1-10
Krause N, Derad C, von Glasenapp B, Riemann-Lorenz K, Temmes H, van de Loo M, Friede T, Asendorf T, Heesen C; POWER@MS1 study group.
Association of health behaviour and clinical manifestation in early multiple sclerosis in Germany – Baseline characteristics of the POWER@MS1 randomised controlled trial.
Mult Scler Relat Disord. 2023 Oct 5;79:105042
Krause N, Derad C, von Glasenapp B, Riemann-Lorenz K, Temmes H, van de Loo M, Friede T, Asendorf T, Heesen C; POWER@MS1 study group.
Association of health behaviour and clinical manifestation in early multiple sclerosis in Germany – Baseline characteristics of the POWER@MS1 randomised controlled trial.
Background: Receiving a multiple sclerosis (MS) diagnosis is a significant stressor. Therefore, highly individualised counselling is needed, especially in early MS. Modifiable risk factors (e.g. smoking and obesity) are gaining relevance in MS. Despite evidence for worse MS-related health outcomes, prevalence of adverse health behaviours, such as smoking and physical inactivity, is high across all MS stages. However, knowledge regarding health behaviours as well as their association with MS-related health outcomes among newly diagnosed PwMS in Germany is scarce. Currently, the efficacy of an interactive digital lifestyle management application intended to be used as an add-on to standard care among newly diagnosed PwMS in Germany is evaluated in an ongoing multicentre randomised controlled trial (RCT) (‚POWER@MS1‘). Objectives: To describe baseline disease characteristics and health behaviours of the POWER@MS1 cohort and investigate associations between MS characteristics, quality of life (QOL), health behaviours and intention to optimise health behaviour habits. Methods: This study included 234 persons with early MS from 20 study centres located across Germany who participate in the POWER@MS1 RCT. Participants were recruited by treating neurologists from different regions and health-care settings in Germany. Baseline data was obtained using paper-based questionnaires and a web-based healthy diet screener between July 2019 and end of March 2022 and analysed descriptively. Results: In this early MS cohort (mean disease duration 4 months), a screening tool showed severe symptoms of anxiety in 15 % of the participants. Better means for stress management appeared to be particularly relevant for the whole cohort. Moreover, 19 % were current smokers, 15 % were obese and 36 % were insufficiently physically active. On average, participants only moderately adhered to dietary guidelines for recommended intake of key food groups (e.g. vegetables, fruits and fatty marine fish). Higher EDSS scores were associated with approximately 20 % higher T2-lesion burden (rate ratio RR=1.2, p<0.001) and 13 % higher relapse rate (RR=1.13,p=0.02) per EDSS disability level. Moreover, a higher T2-lesion burden was associated with current smoking (RR=0.76, p=0.033), resulting in approximately 24 % less T2-lesions at disease onset among non-smokers. In addition, smoking was associated with unhealthier dietary habits according to lower diet scores (linear regression coefficient β=-1.27, p<0.001). Higher EDSS scores (β=0.19,p<0.001) and higher BMI (β=0.013,p=0.03) were associated with higher HAQUAMS (lower QOL). Further, lower diet scores (β=-0.044,p=0.039) were associated with lower QOL. Moreover, higher HAQUAMS (lower QOL) indicated a higher intention to optimise stress management (β=0.98,p<0.001), physical activity (β=0.74,p=0.046) and sleep behaviour (β=1.82,p<0.001). Further, higher intention to optimise stress management was accounted for by higher EDSS scores (β=0.39,p=0.004) and a higher number of T2-lesions (β=0.029,p=0.015) in this newly diagnosed MS cohort. Conclusion: Results indicate a clear need for modifications of health behaviours among newly diagnosed PwMS participating in POWER@MS1. Individualised psychological and health behaviour counselling appears to be an important factor in treatment, also for similar early MS cohorts and particularly in those who demonstrate a more severe disease in clinical and MRI metrics.Mult Scler Relat Disord. 2023 Oct 5;79:105042
Chorschew A, Kesgin F, Bellmann-Strobl J, Flachenecker P, Schiffmann I, Rosenthal F, Althoff P, Drebinger D, Arsenova R, Rasche L, Dorsch EM, Heesen C, Paul F, Stellmann JP, Schmitz-Hübsch T.
Translation and validation of the multiple sclerosis walking scale 12 for the German population – the MSWS-12/D.
Health Qual Life Outcomes. 2023 Oct 9;21(1):110
Chorschew A, Kesgin F, Bellmann-Strobl J, Flachenecker P, Schiffmann I, Rosenthal F, Althoff P, Drebinger D, Arsenova R, Rasche L, Dorsch EM, Heesen C, Paul F, Stellmann JP, Schmitz-Hübsch T.
Translation and validation of the multiple sclerosis walking scale 12 for the German population – the MSWS-12/D.
Background: Gait impairment is a relevant problem in persons with multiple sclerosis (pwMS). The Multiple Sclerosis Walking Scale 12 (MSWS-12) is a valid Patient Reported Outcome Measure (PROM) to evaluate walking ability in pwMS. The aim of this study was to provide a linguistically valid translation of MSWS-12 into German language (MSWS-12/D) and to evaluate its psychometric properties. Methods: The MSWS-12 was translated in a process modified from guidelines for the cross-cultural adaption of PROMs, and a pre-test was applied in a small sample of 20 pwMS to evaluate comprehensibility and acceptance. Psychometric properties (floor and ceiling effects, internal consistency, construct validity) were then assessed in 124 pwMS seen at academic MS centers. Construct validity was evaluated against Expanded Disability Status Scale (EDSS) and maximum gait speed in the Timed 25-Foot Walk (T25FW). Results: Although the sample covered a wide spectrum of symptom severity, the majority had rather low levels of disability (EDSS median 2.0) and 6.5% scored EDSS of 0. In this sample, MSWS-12/D showed floor effects (36% with score 0) and for internal consistency, a Cronbach’s alpha of 0.98 was calculated. MSWS-12/D score showed a relevant correlation to EDSS (ρ = 0.73) and T25FW speed (r=-0.72). Conclusion: We provide MSWS-12/D as a linguistically valid German version of MSWS-12. Psychometric properties (acceptance, floor and ceiling effects, internal consistency and construct validity) in pwMS were similar to those described for the original version. This indicates that MSWS-12/D can be applied as equivalent to the original version in German speaking pwMS. Results support the relevance of PROMs to capture patient perception of walking ability in addition to performance-based assessments such as maximum walking speed or maximum walking distance.Health Qual Life Outcomes. 2023 Oct 9;21(1):110
Goldin K, Riemann-Lorenz K, Daubmann A ,Pöttgen J, Krause N, Schröder H, Heesen C.
Health behaviors of people with multiple sclerosis and its associations with MS related outcomes: a German clinical cohort.
Front Neurol. 2023 Sep 13:14:1172419
Goldin K, Riemann-Lorenz K, Daubmann A ,Pöttgen J, Krause N, Schröder H, Heesen C.
Health behaviors of people with multiple sclerosis and its associations with MS related outcomes: a German clinical cohort.
Background: Health behaviors in persons with multiple sclerosis (pwMS) have been associated with MS-related disease outcomes. Objective: The aim of the study was to gain knowledge about current patient health behaviors in a convenience sample representative for pwMS presenting to a large university-based outpatient clinic and to investigate associations between modifiable risk factors with physical impairment, quality of life (QoL) and cardiovascular comorbidities. Methods: A questionnaire was administered at the MS Outpatient Clinic of the University Medical Center Hamburg Eppendorf asking for health behaviors regarding dietary habits assessed with the German adaptation of the validated Spanish short Diet Quality Screener (sDQS), level of physical activity assessed with the Godin Leisure Time Questionnaire (GLTEQ) and tobacco smoking. Participants were asked to report cardiovascular comorbidities using items from the Self-Report Comorbidity Questionnaire for Multiple Sclerosis. Additionally, cardiovascular risk factors like blood pressure, height and weight (to calculate BMI) and waist circumference were measured. MS specific clinical data, e.g., disease course, duration, disability and MS-specific QoL were collected from the clinical database. Descriptive analyses were performed and multivariate regression analyses for complete cases were carried out for each of the three outcome variables including all mentioned modifiable risk factors (dietary behavior, smoking, physical activity and BMI) as independent variables. Results: In this sample of 399 pwMS the mean age was 42 years (SD 12.8) with a mean disease duration since diagnosis of 7.4 years (SD 8.4) and a mean EDSS of 2.8 (SD 1.9). 24% were current smokers, 44% were insufficiently physically active and 54% did not follow a healthy dietary pattern. 49% of this relatively young clinical population was overweight and 27% reported one or more cardiovascular comorbidities. Most modifiable risk factors showed no convincing associations with MS-related disease outcomes in the multiple regression analyses. Conclusion: This clinical cohort of pwMS shows a high prevalence of critical health behaviors and comorbidities and emphasizes the need for monitoring, education and assistance for behavior change in this population.Front Neurol. 2023 Sep 13:14:1172419
Bayas A, Berthele A, Blank N, Dreger P, Faissner S, Friese MA, Gerdes LA, Grauer OM, Häussler V, Heesen C, Janson D, Korporal-Kuhnke M, Kowarik M, Kröger N, Lünemann JD, Martin R, Meier U, Meuth S, Muraro P, Platten M, Schirmer L, Stürner KH, Stellmann JP, Scheid C, Bergh FT, Warnke C, Wildemann B, Ziemssen T.
Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.
Ther Adv Neurol Disord. 2023 Sep 28;16:17562864231180730
Bayas A, Berthele A, Blank N, Dreger P, Faissner S, Friese MA, Gerdes LA, Grauer OM, Häussler V, Heesen C, Janson D, Korporal-Kuhnke M, Kowarik M, Kröger N, Lünemann JD, Martin R, Meier U, Meuth S, Muraro P, Platten M, Schirmer L, Stürner KH, Stellmann JP, Scheid C, Bergh FT, Warnke C, Wildemann B, Ziemssen T.
Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.
„Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.“Ther Adv Neurol Disord. 2023 Sep 28;16:17562864231180730
Gold SM, Friede T, Meyer B, Moss-Morris R, Hudson J, Asseyer S, Bellmann-Strobl J, Leisdon A, Ißels L, Ritter K, Schymainski D, Pomeroy H, Lynch SG, Cozart JS, Thelen J, Román CAF, Cadden M, Guty E, Lau S, Pöttgen J, Ramien C, Seddiq-Zai S, Kloidt AM, Wieditz J, Penner IK, Paul F, Sicotte NL, Bruce JM, Arnett PA, Heesen C.
Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.
Lancet Digit Health. 2023 Oct;5(10):e668-e678
Gold SM, Friede T, Meyer B, Moss-Morris R, Hudson J, Asseyer S, Bellmann-Strobl J, Leisdon A, Ißels L, Ritter K, Schymainski D, Pomeroy H, Lynch SG, Cozart JS, Thelen J, Román CAF, Cadden M, Guty E, Lau S, Pöttgen J, Ramien C, Seddiq-Zai S, Kloidt AM, Wieditz J, Penner IK, Paul F, Sicotte NL, Bruce JM, Arnett PA, Heesen C.
Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.
Background: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. Methods: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. Findings: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. Interpretation: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers.Lancet Digit Health. 2023 Oct;5(10):e668-e678
Brehm TT, Heyer A, Woo MS, Fischer M, von der Meirschen M, Wichmann D, Jarczak D, Roedl K, Schmiedel S, Addo MM, Lütgehetmann M, Christner M, Huber S, Lohse AW, Kluge S, Schulzer Zur Wiesch J.
Comparative analysis of characteristics and outcomes in hospitalized COVID-19 patients infected with different SARS-CoV-2 variants between January 2020 and April 2022 – A retrospective single-center cohort study.
J Infect Public Health. 2023 Nov;16(11):1806-1812
Brehm TT, Heyer A, Woo MS, Fischer M, von der Meirschen M, Wichmann D, Jarczak D, Roedl K, Schmiedel S, Addo MM, Lütgehetmann M, Christner M, Huber S, Lohse AW, Kluge S, Schulzer Zur Wiesch J.
Comparative analysis of characteristics and outcomes in hospitalized COVID-19 patients infected with different SARS-CoV-2 variants between January 2020 and April 2022 – A retrospective single-center cohort study.
Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the roll-out of vaccines and therapeutic agents, as well as the emergence of novel SARS-CoV-2 variants, have shown significant effects on disease severity. Methods: Patients hospitalized at our center between January 2020 and April 2022 were attributed to subgroups depending on which SARS-CoV-2 variant was predominantly circulating in Germany: (i) Wild-type: January 1, 2020, to March 7, 2021, (ii) Alpha variant: August 3, 2021, to June 27, 2021, (iii) Delta variant: June 28, 2021, to December 26, 2021, and (iv) Omicron variant: December 27, 2021, to April 30, 2022. Results: Between January 2020 and April 2022, 1500 patients with SARS-CoV-2 infections were admitted to the University Medical Center Hamburg-Eppendorf. The rate of patients who were admitted to the intensive care unit (ICU) decreased from 31.2% (n = 223) in the wild-type group, 28.5% (n = 72) in the Alpha variant group, 18.8% (n = 67) in the Delta variant group, and 13.4% (n = 135) in the Omicron variant group. Also, in-hospital mortality decreased from 20.6% (n = 111) in the wild-type group, 17.5% (n = 30) in the Alpha variant group, 16.8% (n = 33) in the Delta variant group, and 6.6% (n = 39) in the Omicron variant group. The median duration of hospitalization was similar in all subgroups and ranged between 11 and 15 days throughout the pandemic. Conclusions: In-hospital mortality and rate of ICU admission among hospitalized COVID-19 patients steadily decreased throughout the pandemic. However, the practically unchanged duration of hospitalization demonstrates the persistent burden of COVID-19 on the healthcare system.J Infect Public Health. 2023 Nov;16(11):1806-1812
Woo MS, Ufer F, Sonner JK, Belkacemi A, Tintelnot J, Sáez PJ, Krieg PF, Mayer C, Binkle-Ladisch L, Engler JB, Bauer S, Kursawe N, Vieira V, Mannebach S, Freichel M, Flockerzi V, Vargas P, Friese MA.
Calcium Channel ß3 subunit regulates ATP-dependent migration of dendritic cells.
Sci Adv. 2023 Sep;9(38):eadh1653.
Woo MS, Ufer F, Sonner JK, Belkacemi A, Tintelnot J, Sáez PJ, Krieg PF, Mayer C, Binkle-Ladisch L, Engler JB, Bauer S, Kursawe N, Vieira V, Mannebach S, Freichel M, Flockerzi V, Vargas P, Friese MA.
Calcium Channel ß3 subunit regulates ATP-dependent migration of dendritic cells.
Migratory dendritic cells (migDCs) continuously patrol tissues and are activated by injury and inflammation. Extracellular adenosine triphosphate (ATP) is released by damaged cells or actively secreted during inflammation and increases migDC motility. However, the underlying molecular mechanisms by which ATP accelerates migDC migration is not understood. Here, we show that migDCs can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated calcium channel subunit β3 (Cavβ3; CACNB3), which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. By contrast, CACNB3 does not regulate lipopolysaccharide-dependent migration. Mechanistically, CACNB3 regulates ATP-dependent inositol 1,4,5-trisphophate receptor-controlled calcium release from the endoplasmic reticulum. This, in turn, is required for ATP-mediated suppression of adhesion molecules, their detachment, and initiation of migDC migration. Thus, Cacnb3-deficient migDCs have an impaired migration after ATP exposure. In summary, we identified CACNB3 as a master regulator of ATP-dependent migDC migration that controls tissue-specific immunological responses during injury and inflammation.Sci Adv. 2023 Sep;9(38):eadh1653.
Salmen A, Hoepner R, Fleischer V, Heldt M, Gisevius B, Motte J, Ruprecht K, Schneider R, Fisse AL, Grüter T, Lukas C, Berthele A, Giglhuber K, Flaskamp M, Mühlau M, Kirschke J, Bittner S, Groppa S, Lüssi F, Bayas A, Meuth S, Heesen C, Trebst C, Wildemann B, Then Bergh F, Antony G, Kümpfel T, Paul F, Nischwitz S, Tumani H, Zettl U, Hemmer B, Wiendl H, Zipp F, Gold R.
Factors associated with depressive mood at the onset of multiple sclerosis – an analysis of 781 patients of the German NationMS cohort.
Ther Adv Neurol Disord. 2023 Sep 8;16
Salmen A, Hoepner R, Fleischer V, Heldt M, Gisevius B, Motte J, Ruprecht K, Schneider R, Fisse AL, Grüter T, Lukas C, Berthele A, Giglhuber K, Flaskamp M, Mühlau M, Kirschke J, Bittner S, Groppa S, Lüssi F, Bayas A, Meuth S, Heesen C, Trebst C, Wildemann B, Then Bergh F, Antony G, Kümpfel T, Paul F, Nischwitz S, Tumani H, Zettl U, Hemmer B, Wiendl H, Zipp F, Gold R.
Factors associated with depressive mood at the onset of multiple sclerosis – an analysis of 781 patients of the German NationMS cohort.
Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.Ther Adv Neurol Disord. 2023 Sep 8;16
Köhler-Forsberg O, Stiglbauer V, Brasanac J, Chae WR, Wagener F, Zimbalski K, Jefsen OH, Liu S, Seals MR, Gamradt S, Correll CU, Gold SM, Otte C.
Efficacy and Safety of Antidepressants in Patients With Comorbid Depression and Medical Disease: An Umbrella Systematic Review and Meta-Analysis.
JAMA Psychiatry. 2023 Dec 1;80(12):1196-1207.
Köhler-Forsberg O, Stiglbauer V, Brasanac J, Chae WR, Wagener F, Zimbalski K, Jefsen OH, Liu S, Seals MR, Gamradt S, Correll CU, Gold SM, Otte C.
Efficacy and Safety of Antidepressants in Patients With Comorbid Depression and Medical Disease: An Umbrella Systematic Review and Meta-Analysis.
Importance: Every third to sixth patient with medical diseases receives antidepressants, but regulatory trials typically exclude comorbid medical diseases. Meta-analyses of antidepressants have shown small to medium effect sizes, but generalizability to clinical settings is unclear, where medical comorbidity is highly prevalent. Objective: To perform an umbrella systematic review of the meta-analytic evidence and meta-analysis of the efficacy and safety of antidepressant use in populations with medical diseases and comorbid depression. Data sources: PubMed and EMBASE were searched from inception until March 31, 2023, for systematic reviews with or without meta-analyses of randomized clinical trials (RCTs) examining the efficacy and safety of antidepressants for treatment or prevention of comorbid depression in any medical disease. Study selection: Meta-analyses of placebo- or active-controlled RCTs studying antidepressants for depression in individuals with medical diseases. Data extraction and synthesis: Data extraction and quality assessment using A Measurement Tool for the Assessment of Multiple Systematic Reviews (AMSTAR-2 and AMSTAR-Content) were performed by pairs of independent reviewers following PRISMA guidelines. When several meta-analyses studied the same medical disease, the largest meta-analysis was included. Random-effects meta-analyses pooled data on the primary outcome (efficacy), key secondary outcomes (acceptability and tolerability), and additional secondary outcomes (response and remission). Main outcomes and measures: Antidepressant efficacy presented as standardized mean differences (SMDs) and tolerability (discontinuation for adverse effects) and acceptability (all-cause discontinuation) presented as risk ratios (RRs). Results: Of 6587 references, 176 systematic reviews were identified in 43 medical diseases. Altogether, 52 meta-analyses in 27 medical diseases were included in the evidence synthesis (mean [SD] AMSTAR-2 quality score, 9.3 [3.1], with a maximum possible of 16; mean [SD] AMSTAR-Content score, 2.4 [1.9], with a maximum possible of 9). Across medical diseases (23 meta-analyses), antidepressants improved depression vs placebo (SMD, 0.42 [95% CI, 0.30-0.54]; I2 = 76.5%), with the largest SMDs for myocardial infarction (SMD, 1.38 [95% CI, 0.82-1.93]), functional chest pain (SMD, 0.87 [95% CI, 0.08-1.67]), and coronary artery disease (SMD, 0.83 [95% CI, 0.32-1.33]) and the smallest for low back pain (SMD, 0.06 [95% CI, 0.17-0.39]) and traumatic brain injury (SMD, 0.08 [95% CI, -0.28 to 0.45]). Antidepressants showed worse acceptability (24 meta-analyses; RR, 1.17 [95% CI, 1.02-1.32]) and tolerability (18 meta-analyses; RR, 1.39 [95% CI, 1.13-1.64]) compared with placebo. Antidepressants led to higher rates of response (8 meta-analyses; RR, 1.54 [95% CI, 1.14-1.94]) and remission (6 meta-analyses; RR, 1.43 [95% CI, 1.25-1.61]) than placebo. Antidepressants more likely prevented depression than placebo (7 meta-analyses; RR, 0.43 [95% CI, 0.33-0.53]). Conclusions and relevance: The results of this umbrella systematic review of meta-analyses found that antidepressants are effective and safe in treating and preventing depression in patients with comorbid medical disease. However, few large, high-quality RCTs exist in most medical diseases.JAMA Psychiatry. 2023 Dec 1;80(12):1196-1207.
Renner A, Bätge SJ, Filser M, Lau S, Pöttgen J, Penner IK.
Non-pharmacological randomized intervention trial for the management of neuropsychological symptoms in outpatients with progressive multiple sclerosis
Appl Neuropsychol Adult. 2023 Aug 31;1-13
Renner A, Bätge SJ, Filser M, Lau S, Pöttgen J, Penner IK.
Non-pharmacological randomized intervention trial for the management of neuropsychological symptoms in outpatients with progressive multiple sclerosis
Purpose: Despite typically more pronounced cognitive and mental health issues in progressive disease courses of multiple sclerosis (PMS), rehabilitation research in this subgroup is rare. The efficacy of two non-pharmacological interventions with positive results from prior investigations was therefore examined in PMS specifically. Methods: Persons with PMS (pwPMS) received either computerized cognitive training (BrainStim), standardized cognitive-behavioral group sessions (Metacognitive Training [MaTiMS]), or a combination of both in an ambulatory setting. Neuropsychological assessment was conducted before and after the four-week intervention. Results: 37 participants (13 with primary/24 with secondary PMS, meanage = 52.87, SDage = 7.11, meanEDSS = 4.02, SDEDSS = 1.35) entered analyses. The BrainStim group improved in immediate and delayed verbal memory, recognition, verbal working memory, and perceived cognitive deficits while experiencing increased anxiety post-intervention. MaTiMS participants reported high program satisfaction and less cognitive difficulties at retest. The Combination group performed better in immediate and delayed verbal memory, and in information processing speed after training. Descriptive data further indicated positive effects on anxiety and depression in the MaTiMS and Combination group. Conclusions: While objective cognitive performance improved when explicitly trained, psychoeducative sessions contributed to subjective mental health. The combination of both approaches is thus suggested, considering the specific needs of pwPMS treated in an ambulatory setting.Appl Neuropsychol Adult. 2023 Aug 31;1-13
Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M.
Vagus nerve inflammation contributes to dysautonomia in COVID-19.
Acta Neuropathol. 2023 Sep;146(3):387-394.
Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M.
Vagus nerve inflammation contributes to dysautonomia in COVID-19.
Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction. We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.Acta Neuropathol. 2023 Sep;146(3):387-394.
Rosenkranz SC, Gutmann L, Has Silemek AC, Dorr M, Häußler V, Lüpke M, Mönch A, Reinhardt S, Kuhle J, Tilsley P, Heesen C, Friese MA, Brandt A, Paul F, Zimmermann H, Stellmann JP.
Visual function resits early neurodegeneration in the visual system in primary progressive multiple sclerosis.
J Neurol Neurosurg Psychiatry. 2023 Nov;94(11):924-933
Rosenkranz SC, Gutmann L, Has Silemek AC, Dorr M, Häußler V, Lüpke M, Mönch A, Reinhardt S, Kuhle J, Tilsley P, Heesen C, Friese MA, Brandt A, Paul F, Zimmermann H, Stellmann JP.
Visual function resits early neurodegeneration in the visual system in primary progressive multiple sclerosis.
Background: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood. Methods: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function. Results: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes. Conclusion: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system.J Neurol Neurosurg Psychiatry. 2023 Nov;94(11):924-933
Heesen C., Solaria A.
Editorial: Shared decision-making in neurology.
Front Neurol. 2023 Jun 6;14:1222433
Heesen C., Solaria A.
Editorial: Shared decision-making in neurology.
No abstract available.Front Neurol. 2023 Jun 6;14:1222433
Tilsley P, Strohmeyer IA, Heinrich I, Rosenthal F, Patra S, Schulz KH, Rosenkranz SC, Ramien C, Pöttgen J, Heesen C, Has AC, Gold SM, Stellmann JP.
Physical fitness moderates the association between brain network impairment and both motor function and cognition in progressive multiple sclerosis.
J Neurol. 2023 JOct;270(10):4876-4888.
Tilsley P, Strohmeyer IA, Heinrich I, Rosenthal F, Patra S, Schulz KH, Rosenkranz SC, Ramien C, Pöttgen J, Heesen C, Has AC, Gold SM, Stellmann JP.
Physical fitness moderates the association between brain network impairment and both motor function and cognition in progressive multiple sclerosis.
Background: Neurodegeneration leads to continuous accumulation of disability in progressive Multiple Sclerosis (MS). Exercise is considered to counteract disease progression, but little is known on the interaction between fitness, brain networks and disability in MS. Objective: The aim of this study to explore functional and structural brain connectivity and the interaction between fitness and disability based on motor and cognitive functional outcomes in a secondary analysis of a randomised, 3-month, waiting group controlled arm ergometry intervention in progressive MS. Methods: We modelled individual structural and functional brain networks based on magnetic resonance imaging (MRI). We used linear mixed effect models to compare changes in brain networks between the groups and explore the association between fitness, brain connectivity and functional outcomes in the entire cohort. Results: We recruited 34 persons with advanced progressive MS (pwMS, mean age 53 years, females 71%, mean disease duration 17 years and an average walking restriction of < 100 m without aid). Functional connectivity increased in highly connected brain regions of the exercise group (p = 0.017), but no structural changes (p = 0.817) were observed. Motor and cognitive task performance correlated positively with nodal structural connectivity but not nodal functional connectivity. We also found that the correlation between fitness and functional outcomes was stronger with lower connectivity. Conclusions: Functional reorganisation seems to be an early indicator of exercise effects on brain networks. Fitness moderates the relationship between network disruption and both motor and cognitive outcomes, with growing importance in more disrupted brain networks. These findings underline the need and opportunities associated with exercise in advanced MS.J Neurol. 2023 JOct;270(10):4876-4888.
Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Steinberg L, Steckelberg A, Heesen C, Rahn AC.
Knowledge and worries on motherhood choice in multiple sclerosis – a cross-sectional study on patient-reported outcome measures.
Mult Scler Relat Disord. 2023 Aug;76:104789
Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Steinberg L, Steckelberg A, Heesen C, Rahn AC.
Knowledge and worries on motherhood choice in multiple sclerosis – a cross-sectional study on patient-reported outcome measures.
Background: Since multiple sclerosis (MS) is often diagnosed in young women, pregnancy is a common topic for women with MS (wwMS). The study aimed to assess the measurement properties of two patient-reported outcome measures on motherhood choice in MS, and to explore the information and support needs of wwMS concerning motherhood.Methods: We conducted an anonymous web-based survey to validate the motherhood/pregnancy choice and worries questionnaire (MPWQ, 31 items plus up to 3 additional items) and the motherhood choice knowledge questionnaire (MCKQ, 16 items). We used mailing lists and social media for nationwide recruitment in Germany, and included women of childbearing age with relapsing-remitting MS, clinically isolated syndrome or suspected MS who were considering pregnancy or were pregnant. For the MPWQ, we assessed item difficulty, discriminatory power, and internal consistency (Cronbach’s alpha; CA). We analysed construct validity using the Leipzig Questionnaire of Motives to have a Child, the Decisional Conflict Scale, the Hospital Anxiety and Depression Scale, and the Pregnancy-Related Anxiety Questionnaire-revised 2. We studied the structural validity using exploratory factor analysis (EFA). The MCKQ was evaluated descriptively. We explored the information and support needs of wwMS on motherhood descriptively. We examined correlations between MCKQ, MPWQ and clinical characteristics and performed exploratory group comparisons considering the following binary variables: having children and being pregnant. Results: 325 wwMS started the survey; 232 wwMS met our inclusion criteria and were analysed. Their mean age was 30 years (SD 5). Most women had relapsing-remitting MS (n = 218; 94%), 186 (80%) had no children, and 38 (16%) were pregnant. Internal consistency was good for the worries subscale (CA>0.8), while it was unsatisfactory for the attitude and coping subscales (CA<0.7). The EFA did not support the three-scale structure (coping, attitude, and worries). Due to these findings, we decided to keep the worries scale without any subscale. The items from the coping scale and attitude scale could be assessed as additional descriptive items. Convergent and divergent construct validity of the MPWQ was satisfactory. 206 wwMS (89%) completed the MCKQ. On average, 9 of 16 (56%) items were answered correctly (range 2-15), and the questionnaire showed a good balance between easy and difficult items. Questions on immunotherapy, disease activity, and breastfeeding were the most challenging. WwMS were confident in getting pregnant and raising a child (n = 222; 96%). Most wwMS were worried about postpartum relapses (n = 200; 86%) and the long-term effects of pregnancy on disease evolution (n = 149; 64%). About half of the wwMS (n = 124; 54%) did not know where to find professional help and 127 (55%) had no strategies to cope with future impairments so that they could take care of a child. Conclusion: Our results support the suitability and acceptability of both questionnaires as potential patient-reported measures for assessment of knowledge and worries around motherhood/pregnancy in MS. The survey results highlight the need for evidence-based information on motherhood in MS to increase knowledge, reduce worries and support wwMS in making informed decisions.Mult Scler Relat Disord. 2023 Aug;76:104789
Mayer Ch, Woo MS,Brehm TT, Heyer A, Fischer M, Fischbach F, Bal LC, Addo MM, Kluge S,Thomalla G, Schweingruber N, Schulze zur Wiesch J.
History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS-CoV-2 infection with presumed Omicron variant: a retrospective observational study.
Eur J Neurol. 2023 Aug;30(8):2297-2304
Mayer Ch, Woo MS,Brehm TT, Heyer A, Fischer M, Fischbach F, Bal LC, Addo MM, Kluge S,Thomalla G, Schweingruber N, Schulze zur Wiesch J.
History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS-CoV-2 infection with presumed Omicron variant: a retrospective observational study.
Background and purpose: This study aimed to investigate if pre-existing neurological conditions, such as dementia and a history of cerebrovascular disease, increase the risk of severe outcomes including death, intensive care unit (ICU) admission and vascular events in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2022, when Omicron was the predominant variant. Methods: A retrospective analysis was conducted of all patients with SARS-CoV-2 infection, confirmed by polymerase chain reaction test, admitted to the University Medical Center Hamburg-Eppendorf from 20 December 2021 until 15 August 2022. In all, 1249 patients were included in the study. In-hospital mortality was 3.8% and the ICU admission rate was 9.9%. Ninety-three patients with chronic cerebrovascular disease and 36 patients with pre-existing all-cause dementia were identified and propensity score matching by age, sex, comorbidities, vaccination status and dexamethasone treatment was performed in a 1:4 ratio with patients without the respective precondition using nearest neighbor matching. Results: Analysis revealed that neither pre-existing cerebrovascular disease nor all-cause dementia increased mortality or the risk for ICU admission. All-cause dementia in the medical history also had no effect on vascular complications under investigation. In contrast, an increased odds ratio for both pulmonary artery embolism and secondary cerebrovascular events was observed in patients with pre-existing chronic cerebrovascular disease and myocardial infarction in the medical history. Conclusion: These findings suggest that patients with pre-existing cerebrovascular disease and myocardial infarction in their medical history may be particularly susceptible to vascular complications following SARS-CoV-2 infection with presumed Omicron variant.Eur J Neurol. 2023 Aug;30(8):2297-2304
Woo MS, Mayer C, Fischer M, Kluge S, Roedl 2, Gerloff C, Czorlich P, Thomalla G, Schulze zur Wiesch J, Schweingruber N.
Clinical surrogates of dysautonomia predict lethal outcome in COVID-19 on intensive care unit.
Neurol Res Pract. 2023 May 4;5(1):17
Woo MS, Mayer C, Fischer M, Kluge S, Roedl 2, Gerloff C, Czorlich P, Thomalla G, Schulze zur Wiesch J, Schweingruber N.
Clinical surrogates of dysautonomia predict lethal outcome in COVID-19 on intensive care unit.
Background: Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown. Methods: We retrospectively analyzed data collected during a single-center observational study (March 2020-November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity. Results: Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors. Conclusions: Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future.Neurol Res Pract. 2023 May 4;5(1):17
Thaler C, Sedlacik J, Forkert ND, Stellmann JP, Schön G, Fiehler J, Gellißen S.
Effect of geometric distortion correction on thickness and volume measurements of cortical parcellations in 3D T1w gradient echo sequences.
PLoS One. 2023 Apr 14;18(4):e0284440
Thaler C, Sedlacik J, Forkert ND, Stellmann JP, Schön G, Fiehler J, Gellißen S.
Effect of geometric distortion correction on thickness and volume measurements of cortical parcellations in 3D T1w gradient echo sequences.
More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient’s current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient’s treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.PLoS One. 2023 Apr 14;18(4):e0284440
Woo MS, Mayer C, Brehm TT, Andersen G, Weigel A, Löwe B, Lohse AW, Addo MM, Gerloff C, Knobloch JKM, Schulze zur Wiesch J, Friese MA.
Absence of self-reported neuropsychiatric and somatic symptoms after Omicron variant SARS-CoV-2 breakthrough infections.
Brain Commun. 2023 Mar 25;5(2):fcad092
Woo MS, Mayer C, Brehm TT, Andersen G, Weigel A, Löwe B, Lohse AW, Addo MM, Gerloff C, Knobloch JKM, Schulze zur Wiesch J, Friese MA.
Absence of self-reported neuropsychiatric and somatic symptoms after Omicron variant SARS-CoV-2 breakthrough infections.
Persistent somatic and neuropsychiatric symptoms have been frequently described in patients after infection with severe acute respiratory syndrome coronavirus 2 even after a benign clinical course of the acute infection during the early phases of the coronavirus severe acute respiratory syndrome coronavirus 2 pandemic and are part of Long COVID. The Omicron variant emerged in November 2021 and has rapidly become predominant due to its high infectivity and suboptimal vaccine cross-protection. The frequency of neuropsychiatric post-acute sequelae after infection with the severe acute respiratory syndrome coronavirus 2 Omicron and adequate vaccination status is not known. Here, we aimed to characterize post-acute symptoms in individuals with asymptomatic or mildly symptomatic breakthrough infection with severe acute respiratory syndrome coronavirus 2. These individuals had either proven infection with the Omicron variant (n = 157) or their infection occurred in 2022 where Omicron was the predominant variant of severe acute respiratory syndrome coronavirus 2 in Germany (n = 107). This monocentric cross-sectional study was conducted at the University Medical Center Hamburg-Eppendorf between 11 February 2022 and 11 April 2022. We employed questionnaires addressing self-reported somatic symptom burden (Somatic Symptom Scale 8) and neuropsychiatric symptoms including mood (Patient Health Questionnaire 2), anxiety (Generalized Anxiety Disorder 7), attention (Mindful Attention Awareness Scale) and fatigue (Fatigue Assessment Scale) in a cohort of hospital workers. Scores were compared between 175 individuals less than 4 weeks after positive testing for severe acute respiratory syndrome coronavirus 2, 88 individuals more than 4 weeks after positive testing and 87 severe acute respiratory syndrome coronavirus 2 uninfected controls. The majority (n = 313; 89.5%) of included individuals were vaccinated at least three times. After recovery from infection, no significant differences in scores assessing neuropsychiatric and somatic symptoms were detected between the three groups (severe acute respiratory syndrome coronavirus 2 uninfected controls, individuals less and more than 4 weeks after positive testing) independent of age, sex, preconditions and vaccination status. In addition, self-reported symptom burden did not significantly correlate with the number of vaccinations against severe acute respiratory syndrome coronavirus 2, time from recovery or the number of infections. Notably, in all three groups, the mean scores for each item of our questionnaire lay below the pathological threshold. Our data show that persistent neuropsychiatric and somatic symptoms after recovery from severe acute respiratory syndrome coronavirus 2 infection in fully vaccinated hospital workers do not occur more frequently than that in uninfected individuals. This will guide healthcare professionals in the clinical management of patients after recovery from breakthrough infections with severe acute respiratory syndrome coronavirus 2.Brain Commun. 2023 Mar 25;5(2):fcad092
Gold SM, Landray MJ, Medhurst N, Otte C.
Fast tracking informative clinical trials: lessons for mental health.
Lancet Psychiatry. 2023 Jun;10(6):376-378
Gold SM, Landray MJ, Medhurst N, Otte C.
Fast tracking informative clinical trials: lessons for mental health.
No abstract available.Lancet Psychiatry. 2023 Jun;10(6):376-378
Chae WR, Baumert J, Nübel J, Brasanac J, Gold SM, Hapke U, Otte C.
Associations between individual depressive symptoms and immunometabolic characteristics in major depression.
Eur Neuropsychopharmacol. 2023 Mar 24;71:25-40
Chae WR, Baumert J, Nübel J, Brasanac J, Gold SM, Hapke U, Otte C.
Associations between individual depressive symptoms and immunometabolic characteristics in major depression.
Inflammation and metabolic dysregulations are likely to underlie atypical, energy-related depressive symptoms such as appetite and sleep alterations. Indeed, increased appetite was previously identified as a core symptom of an immunometabolic subtype of depression. The aim of this study was 1) to replicate the associations between individual depressive symptoms and immunometabolic markers, 2) to extend previous findings with additional markers, and 3) to evaluate the relative contribution of these markers to depressive symptoms. We analyzed data from 266 persons with major depressive disorder (MDD) in the last 12 months from the German Health Interview and Examination Survey for Adults and its mental health module. Diagnosis of MDD and individual depressive symptoms were determined by the Composite International Diagnostic Interview. Associations were analyzed using multivariable regression models, adjusting for depression severity, sociodemographic/behavioral variables, and medication use. Increased appetite was associated with higher body mass index (BMI), waist circumference (WC), insulin, and lower high-density lipoprotein. In contrast, decreased appetite was associated with lower BMI, WC, and fewer metabolic syndrome (MetS) components. Insomnia was associated with higher BMI, WC, number of MetS components, triglycerides, insulin, and lower albumin, while hypersomnia was associated with higher insulin. Suicidal ideation was associated with higher number of MetS components, glucose, and insulin. None of the symptoms were associated with C-reactive protein after adjustment. Appetite alterations and insomnia were most important symptoms associated with metabolic markers. Longitudinal studies should investigate whether the candidate symptoms identified here are predicted by or predict the development of metabolic pathology in MDD.Eur Neuropsychopharmacol. 2023 Mar 24;71:25-40
Heesen C, Rahn AC.
The challenge of pregnancy in women with multiple sclerosis.
Lancet Neurol. 2023 Apr;22(4):288-289.
Heesen C, Rahn AC.
The challenge of pregnancy in women with multiple sclerosis.
No abstract available.Lancet Neurol. 2023 Apr;22(4):288-289.
Ufer F, Ziegler SM, Altfeld M, Friese MA.
Case report: JAK inhibition as promising treatment option of fatal RVCLS due to TREX1 mutation (pVAL235Glyfs*6).
Front Neurol. 2023 Feb 21;14:11118369
Ufer F, Ziegler SM, Altfeld M, Friese MA.
Case report: JAK inhibition as promising treatment option of fatal RVCLS due to TREX1 mutation (pVAL235Glyfs*6).
Introduction: Autosomal dominant mutations in the C-terminal part of TREX1 (pVAL235Glyfs*6) result in fatal retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) without any treatment options. Here, we report on a treatment of a RVCLS patient with anti-retroviral drugs and the janus kinase (JAK) inhibitor ruxolitinib. Methods: We collected clinical data of an extended family with RVCLS (TREX1 pVAL235Glyfs*6). Within this family we identified a 45-year-old woman as index patient that we treated experimentally for 5 years and prospectively collected clinical, laboratory and imaging data. Results: We report clinical details from 29 family members with 17 of them showing RVCLS symptoms. Treatment of the index patient with ruxolitinib for >4 years was well-tolerated and clinically stabilized RVCLS activity. Moreover, we noticed normalization of initially elevated CXCL10 mRNA in peripheral blood monocular cells (PBMCs) and a reduction of antinuclear autoantibodies. Discussion: We provide evidence that JAK inhibition as RVCLS treatment appears safe and could slow clinical worsening in symptomatic adults. These results encourage further use of JAK inhibitors in affected individuals together with monitoring of CXCL10 transcripts in PBMCs as useful biomarker of disease activity.Front Neurol. 2023 Feb 21;14:11118369
Baetge SJ, Filser M, Renner A, Raithel LM, Lau S, Pöttgen J, Penner IK.
Supporting brain health in multiple sclerosis: exploring the potential of neuroeducation combined with practical mindfulness exercises in the management of neuropsychological symptoms
Neurol Neurosurg Psychiatry. 2023 Sep;94(9):718-725.
Baetge SJ, Filser M, Renner A, Raithel LM, Lau S, Pöttgen J, Penner IK.
Supporting brain health in multiple sclerosis: exploring the potential of neuroeducation combined with practical mindfulness exercises in the management of neuropsychological symptoms
Objective: We aimed at examining the effects of a known metacognitive training in MS (MaTiMS) and its modification with an additional neuroeducational module and mindfulness-based exercises (MaTiMS-modified) on neuropsychiatric and cognitive outcomes in people with progressive multiple sclerosis (pwpMS). Exploratively, we investigated whether the modification may show an additional benefit. Methods: Both interventions were administered in small groups of ambulatory patients. Neuropsychological testing before and after the 3- to 4-week intervention phase comprised patient reported outcomes and cognitive tests. After 3, 6 and 12 months, participants completed online surveys. Analysis of change scores (between baseline and retest) with t-tests (Mann-Whitney U and Wilcoxon tests, respectively) and mixed ANCOVAs with repeated measures for comparison of both interventions were conducted. Results: A total of 65 pwpMS turned to a final sample of 50 (n = 15 excluded due to drop-outs, occurrence of relapse or steroid treatment). Change scores within MaTiMS revealed no significant effect on the PDQ-20 total score and only a significant effect on the subscale retrospective memory lasting 3 months with a moderate effect size. In contrast, MaTiMS-modified revealed a highly significant change in PDQ-20 total compared to baseline and significant improvements with small to moderate effect sizes on all PDQ-20 subscales (lasting until 3 months), in self-efficacy, stress, visuo-spatial working memory (moderate effect sizes), and fatigue (small effect size). While no interaction effect between time and group could be revealed, a significant main effect for time was found in PDQ-20 total. Conclusion: Both MaTiMS and MaTiMS-modified positively affected perceived cognitive deficits. However, our data speak in favor of additional benefits by adding neuroeducational and mindfulness-based exercises thus being valuable methods to support brain health including self-efficacy, perceived stress, and fatigue, even in patients with a chronic and progressive brain disease.Neurol Neurosurg Psychiatry. 2023 Sep;94(9):718-725.
Abu Heijleh AP, Huck K, Jähne K, Tan CL, Lanz TV, Epping L, Sonner JK, Meuth SG, Henneberg A, Opitz CA, Herold-Mende C, Sahm F, Platten M, Sahm K.
Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.
Int J Tryptophan Res. 2023 Feb 9:16:11786469231153111
Abu Heijleh AP, Huck K, Jähne K, Tan CL, Lanz TV, Epping L, Sonner JK, Meuth SG, Henneberg A, Opitz CA, Herold-Mende C, Sahm F, Platten M, Sahm K.
Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.
The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11+ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.Int J Tryptophan Res. 2023 Feb 9:16:11786469231153111
Hümmert MW, Stern C, Paul F, Duchow A, Bellmann-Strobl J, Ayzenberg I, Schwake C, Kleiter I, Hellwig K, Jarius S, Wildemann B, Senel M, Berthele A, Giglhuber K, Luessi F, Grothe M, Klotz L, Schülke R, Gingele S, Faiss JH, Walter A, Warnke C, Then Bergh F, Aktas O, Ringelstein M, Stellmann JP, Häußler V, Havla J, Pellkofer H, Kümpfel T, Kopp B, Trebst C.
Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).
Mult Scler. 2023 Jun;29(7):819-831
Hümmert MW, Stern C, Paul F, Duchow A, Bellmann-Strobl J, Ayzenberg I, Schwake C, Kleiter I, Hellwig K, Jarius S, Wildemann B, Senel M, Berthele A, Giglhuber K, Luessi F, Grothe M, Klotz L, Schülke R, Gingele S, Faiss JH, Walter A, Warnke C, Then Bergh F, Aktas O, Ringelstein M, Stellmann JP, Häußler V, Havla J, Pellkofer H, Kümpfel T, Kopp B, Trebst C.
Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).
Background: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). Objective: To assess cognitive performance and changes over time in NMOSD. Methods: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. Results: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. Conclusions: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.
Mult Scler. 2023 Jun;29(7):819-831
Krieg PF, Sonner JK, Kurelic R, Engler JB, Scharenberg MF, Bauer S, Nikolaev VO, Friese MA.
GPR52 regulates cAMP in T cells but is dispensable for encephalitogenic responses.
Front Immunol. 2023 Jan 24;13:1113348.
Krieg PF, Sonner JK, Kurelic R, Engler JB, Scharenberg MF, Bauer S, Nikolaev VO, Friese MA.
GPR52 regulates cAMP in T cells but is dispensable for encephalitogenic responses.
G-protein coupled receptors (GPCR) regulate 3′,5′-cyclic adenosine monophosphate (cAMP) levels in T cells. cAMP as ubiquitous second messenger is crucial for adequate physiology of T cells by mediating effector T cell (Teff) function as well as regulatory T cell (Treg)-mediated immunosuppression. Several GPCRs have been identified to be crucial for Teff and Treg function. However, the role of the orphan, constitutively active Gs-coupled GPCR GPR52 is unknown. Here we show that GPR52 regulates cAMP levels in T cells but does not affect T cell function. We found that stimulation of transfected HEK cells or primary T cells with a GPR52 agonist results in a rise of intracellular cAMP. However, neither Gpr52 deficiency nor pharmacological modulation of GPR52 by antagonists or agonists affected T cell activation, differentiation, and proliferation or Treg-mediated immunosuppression. Moreover, Gpr52 deletion did not modify the clinical disease course of experimental autoimmune encephalomyelitis (EAE). Our results demonstrate that a modulation of cAMP levels in T cells does not inevitably result in altered T cell function. While we could not identify an obvious role of GPR52 in in vitro T cell assays and in vivo CNS autoimmunity, it might regulate T cell function in a different context or affect the function of other GPR52-expressing cells.Front Immunol. 2023 Jan 24;13:1113348.
Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna-Katharina Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K Sonner, Jung H Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A Calabresi, Manuel A Friese, Ari J Green, Claudio Acuna, David H Rowitch , Sven G Meuth, Lucas Schirmer.
Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.
J Clin Invest. 2023 Apr 3;133(7):e164223
Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna-Katharina Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K Sonner, Jung H Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A Calabresi, Manuel A Friese, Ari J Green, Claudio Acuna, David H Rowitch , Sven G Meuth, Lucas Schirmer.
Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.
Multiple sclerosis (MS) is a progressive inflammatory-demyelinating disease of the central nervous system. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward rectifying) and oligodendroglial Kir4.1 (inward rectifying) potassium channels have important roles in regulating neuronal excitability at and around nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory-demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE) with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient mice. In summary, our findings indicate that neuron-oligodendrocyte compensatory interactions promote resilience through Kv7 and Kir4.1 channels and suggest pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
J Clin Invest. 2023 Apr 3;133(7):e164223
Martin W Hümmert, Franziska Bütow, Daria Tkachenko, Ilya Ayzenberg, Thivya Pakeerathan, Kerstin Hellwig, Luisa Klotz, Vivien Häußler, Jan-Patrick Stellmann, Clemens Warnke, Yasemin Goereci, Thorleif Etgen, Felix Luessi, Paul Bronzlik, Stefan Gingele, Ann-Sophie Lauenstein, Ingo Kleiter, Paulus S Rommer, Friedemann Paul, Judith Bellmann-Strobl, Ankelien Duchow, Florian Then Bergh, Refik Pul, Annette Walter, Hannah Pellkofer, Tania Kümpfel, Mosche Pompsch, Markus Kraemer, Philipp Albrecht, Orhan Aktas, Marius Ringelstein, Makbule Senel, Katrin Giglhuber, Achim Berthele, Sven Jarius, Brigitte Wildemann, Corinna Trebst; Neuromyelitis Optica Study Group (NEMOS)
Effects of the COVID-19 Pandemic on Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.
Neurol Neuroimmunol Neuroinflamm. 2023 Jan 24;10(2):e200082
Martin W Hümmert, Franziska Bütow, Daria Tkachenko, Ilya Ayzenberg, Thivya Pakeerathan, Kerstin Hellwig, Luisa Klotz, Vivien Häußler, Jan-Patrick Stellmann, Clemens Warnke, Yasemin Goereci, Thorleif Etgen, Felix Luessi, Paul Bronzlik, Stefan Gingele, Ann-Sophie Lauenstein, Ingo Kleiter, Paulus S Rommer, Friedemann Paul, Judith Bellmann-Strobl, Ankelien Duchow, Florian Then Bergh, Refik Pul, Annette Walter, Hannah Pellkofer, Tania Kümpfel, Mosche Pompsch, Markus Kraemer, Philipp Albrecht, Orhan Aktas, Marius Ringelstein, Makbule Senel, Katrin Giglhuber, Achim Berthele, Sven Jarius, Brigitte Wildemann, Corinna Trebst; Neuromyelitis Optica Study Group (NEMOS)
Effects of the COVID-19 Pandemic on Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.
Background and objectives: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). Methods: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. Results: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). Discussion: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients‘ satisfaction with medical care and HRQoL did not decrease.
Neurol Neuroimmunol Neuroinflamm. 2023 Jan 24;10(2):e200082
Jordan-Paiz A, Martrus G, Steinert FL, Kaufmann M, Sagebiel AF, Schreurs RRCE, Rechtien A, Baumdick ME, Jung JM, Möller KJ, Wegner L, Grüttner C, Richtert L, Thünauer R, Schroeder-Schwarz J, von Goudoever JB, Geijtenbeek TBH, Altfeld M, Pals ST, Perez D, Klarenbeek PL, Tomuschat C, Sauter G, Königs I, Schumacher U, Friese MA, Melling N, Reinshagen K, Bunders MJ.
CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation
Cell Mol Immunol. 2023 Feb;20(2):201-213
Jordan-Paiz A, Martrus G, Steinert FL, Kaufmann M, Sagebiel AF, Schreurs RRCE, Rechtien A, Baumdick ME, Jung JM, Möller KJ, Wegner L, Grüttner C, Richtert L, Thünauer R, Schroeder-Schwarz J, von Goudoever JB, Geijtenbeek TBH, Altfeld M, Pals ST, Perez D, Klarenbeek PL, Tomuschat C, Sauter G, Königs I, Schumacher U, Friese MA, Melling N, Reinshagen K, Bunders MJ.
CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation
Gastrointestinal infections are a major cause for serious clinical complications in infants. The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++ CD4+ T cells (TFH cells). We investigated the ontogeny of CXCR5+PD-1++ CD4+ T cells in human intestines. While CXCR5+PD-1++ CD4+ T cells were absent in fetal intestines, CXCR5+PD-1++ CD4+ T cells increased after birth and were abundant in infant intestines, resulting in significant higher numbers compared to adults. These findings were supported by scRNAseq analyses, showing increased frequencies of CD4+ T cells with a TFH gene signature in infant intestines compared to blood. Co-cultures of autologous infant intestinal CXCR5+PD-1+/-CD4+ T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells. Taken together, we demonstrate that functional TFH cells are numerous in infant intestines, making them a promising target for oral pediatric vaccine strategies.Cell Mol Immunol. 2023 Feb;20(2):201-213
Grochowska KM, Gomes GM, Raman R, Kaushik R, Sosulina L, Kaneko H, Oelschlegel AM, Yuanxiang P, Reyes-Resina I, Bayraktar G, Samer S, Spilker C, Woo MS, Morawski M, Goldschmidt J, Friese MA, Rossner S, Navarro G, Remy S, Reissner C, Karpova A, Kreutz MR.
Jacob-induced transcriptional inactivation of CREB promotes Aß-induced synapse loss in Alzheimer’s disease.
EMBO J. 2023 Feb 15;42(4):e112453
Grochowska KM, Gomes GM, Raman R, Kaushik R, Sosulina L, Kaneko H, Oelschlegel AM, Yuanxiang P, Reyes-Resina I, Bayraktar G, Samer S, Spilker C, Woo MS, Morawski M, Goldschmidt J, Friese MA, Rossner S, Navarro G, Remy S, Reissner C, Karpova A, Kreutz MR.
Jacob-induced transcriptional inactivation of CREB promotes Aß-induced synapse loss in Alzheimer’s disease.
Synaptic dysfunction caused by soluble β-amyloid peptide (Aβ) is a hallmark of early-stage Alzheimer’s disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Aβ suppresses the transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aβ elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons. Aβ-regulated trafficking of Jacob induces transcriptional inactivation of CREB leading to impairment and loss of synapses in mouse models of AD. The small chemical compound Nitarsone selectively hinders the assembly of a Jacob/LIM-only 4 (LMO4)/ Protein phosphatase 1 (PP1) signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest targeting Jacob protein-induced CREB shutoff as a therapeutic avenue against early synaptic dysfunction in AD.EMBO J. 2023 Feb 15;42(4):e112453
Heesen C, Rahn AC, Köpke S.
Communication with people with MS: A key role for evidence-based patient information.
Patient Educ. Couns. 2022 DE;105(12):3339-3340
Heesen C, Rahn AC, Köpke S.
Communication with people with MS: A key role for evidence-based patient information.
No abstract available.Patient Educ. Couns. 2022 DE;105(12):3339-3340
Woo MS, Brehm TT, Fischer M, Heyer A, Wichmann D, Jordan S, Nörz D, Lütgehetmann M, Addo MM, Lohse AW, Schmiedel S, Kluge S, Schulze zur Wiesch J.
Sotrovimab in Hospitalized Patients with SARS-CoV-2 Omicron Variant Infection: a Propensity Score-Matched Retrospective Cohort Study.
Microbiol Spectr. 2023 Feb 14;11(1):e0410322
Woo MS, Brehm TT, Fischer M, Heyer A, Wichmann D, Jordan S, Nörz D, Lütgehetmann M, Addo MM, Lohse AW, Schmiedel S, Kluge S, Schulze zur Wiesch J.
Sotrovimab in Hospitalized Patients with SARS-CoV-2 Omicron Variant Infection: a Propensity Score-Matched Retrospective Cohort Study.
In vitro data suggest the monoclonal antibody sotrovimab may have lost inhibitory capability against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. We aimed to provide real-life data on clinical outcomes in hospitalized patients. We retrospectively analyzed patients who were treated at the University Medical Center Hamburg-Eppendorf, Germany, between December 2021 and June 2022. Out of all 1,254 patients, 185 were treated with sotrovimab: 147 patients received sotrovimab monotherapy, and 38 received combination treatment with sotrovimab and remdesivir. We compared in-hospital mortality for the different treatment regimens for patients treated on regular wards and the intensive care unit separately and performed propensity score matching by age, sex, comorbidities, immunosuppression, and additional dexamethasone treatment to select patients who did not receive antiviral treatment for comparison. No difference in in-hospital mortality was observed between any of the treatment groups and the respective control groups. These findings underline that sotrovimab adds no clinical benefit for hospitalized patients with SARS-CoV-2 Omicron variant infections. IMPORTANCE This study shows that among hospitalized patients with SARS-CoV-2 Omicron variant infection at risk of disease progression, treatment with sotrovimab alone or in combination with remdesivir did not decrease in-hospital mortality. These real-world clinical findings in combination with previous in vitro data about lacking neutralizing activity of sotrovimab against SARS-CoV-2 Omicron variant do not support sotrovimab as a treatment option in these patients.Microbiol Spectr. 2023 Feb 14;11(1):e0410322
Lutfullin I, Eveslage M , Bittner S, Antony G , Flaskamp M, Luessi F , Salmen A, Gisevius B , Klotz L , Korsukewitz C , Berthele A , Groppa S , Then Bergh F , Wildemann B , Bayas A, Tumani H , Meuth SG , Trebst C , Zettl UK, Paul F ,Heesen C, Kuempfel T, Gold R , Hemmer B, Zipp F, Wiendl H , Lünemann JD , German Competence Network Multiple Sclerosis (KKNMS)
Association of obesity with disease outcome in multiple sclerosis.
J Neurol Neruosurg Psychiatry. 2023 Jan;94(1):57-61
Lutfullin I, Eveslage M , Bittner S, Antony G , Flaskamp M, Luessi F , Salmen A, Gisevius B , Klotz L , Korsukewitz C , Berthele A , Groppa S , Then Bergh F , Wildemann B , Bayas A, Tumani H , Meuth SG , Trebst C , Zettl UK, Paul F ,Heesen C, Kuempfel T, Gold R , Hemmer B, Zipp F, Wiendl H , Lünemann JD , German Competence Network Multiple Sclerosis (KKNMS)
Association of obesity with disease outcome in multiple sclerosis.
Background: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. Methods: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. Results: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. Conclusions: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.
J Neurol Neruosurg Psychiatry. 2023 Jan;94(1):57-61
Has Silemek AC, Nolte G, Pöttgen J, Engel AK, Heesen C, Gold SM, Stellmann JP
Topological reorganization of brain network might contribute to the resilience of cognitive functioning in mildly disabled relapsing remitting multiple sclerosis.
J Neurosci Res. 2023 Jan;101(1):143-161
Has Silemek AC, Nolte G, Pöttgen J, Engel AK, Heesen C, Gold SM, Stellmann JP
Topological reorganization of brain network might contribute to the resilience of cognitive functioning in mildly disabled relapsing remitting multiple sclerosis.
| Multiple sclerosis (MS) is an inflammatory and demyelinating disease which leads to impairment in several functional systems including cognition. Alteration of brain networks is linked to disability and its progression. However, results are mostly cross-sectional and yet contradictory as putative adaptive and maladaptive mechanisms were found. Here, we aimed to explore longitudinal reorganization of brain networks over 2-years by combining diffusion tensor imaging (DTI), resting-state functional MRI (fMRI), magnetoencephalography (MEG), and a comprehensive neuropsychological-battery. In 37 relapsing-remitting MS (RRMS) and 39 healthy-controls, cognition remained stable over-time. We reconstructed network models based on the three modalities and analyzed connectivity in relation to the hierarchical topology and functional subnetworks. Network models were compared across modalities and in their association with cognition using linear-mixed-effect-regression models. Loss of hub connectivity and global reduction was observed on a structural level over-years (p < .010), which was similar for functional MEG-networks but not for fMRI-networks. Structural hub connectivity increased in controls (p = .044), suggesting a physiological mechanism of healthy aging. Despite a general loss in structural connectivity in RRMS, hub connectivity was preserved (p = .002) over-time in default-mode-network (DMN). MEG-networks were similar to DTI and weakly correlated with fMRI in MS (p < .050). Lower structural (β between .23-.33) and both lower (β between .40-.59) and higher functional connectivity (β = -.54) in DMN was associated with poorer performance in attention and memory in RRMS (p < .001). MEG-networks involved no association with cognition. Here, cognitive stability despite ongoing neurodegeneration might indicate a resilience mechanism of DMN hubs mimicking a physiological reorganization observed in healthy aging. |
J Neurosci Res. 2023 Jan;101(1):143-161
Wenzel L, Heesen C, Peper J, Grentzenberg K, Faßhauer E, Scheiderbauer J, Thale F, Meyer B, Köpke S, Rahn AC.
An interacitive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2) – development, feasibility, and pilot testing of a complex intervention.
Front Neurol. 2022 Sep 23;13:914814
Wenzel L, Heesen C, Peper J, Grentzenberg K, Faßhauer E, Scheiderbauer J, Thale F, Meyer B, Köpke S, Rahn AC.
An interacitive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2) – development, feasibility, and pilot testing of a complex intervention.
Introduction: Despite the lack of high-quality evidence regarding its long-term effectiveness, intravenous corticosteroid therapy is recommended as the standard treatment of acute multiple sclerosis relapses in Germany. High financial expenses and the equivalent effectiveness of oral corticosteroid therapy contrast with this trend. There is an urgent need to provide patients with evidence-based and comprehensible information on relapse management and to actively involve patients in relapse treatment decisions. Web-based decision support on relapse management could be an effective measure to empower people with multiple sclerosis making informed treatment decisions. Objectives: To develop a web-based programme on relapse management for people with multiple sclerosis and evaluate the feasibility and acceptability of the intervention. Methods: The study followed the first two phases of the UK Medical Research Council Framework for complex interventions. The first phase involved the development of an interactive web-based programme on relapse management. The second phase focused on the feasibility and pilot testing of the programme with people with multiple sclerosis and experts with a professional background in multiple sclerosis. Data was obtained using questionnaires with closed- and open-ended questions as well as qualitative semi-structured telephone interviews. Quantitative data was analyzed descriptively, whereas qualitative data was clustered by topic. Results: Feasibility of the intervention programme was tested with 10 people with multiple sclerosis and 10 experts. Feasibility testing indicated good practicability and acceptance of the content. After revision, the programme was piloted with seven people with multiple sclerosis and three experts. The results showed good acceptance in both groups. Based on the feedback, a final revision was performed. Conclusion: Feasibility and pilot testing indicated good user-friendliness, acceptance, and practicability of the programme. The programme is currently evaluated in a randomized controlled trial (Registration Number on ClinicalTrials.gov: NCT04233970). It is expected that the programme will have a positive impact on patients‘ relapse management and strengthen their autonomy and participation.
Front Neurol. 2022 Sep 23;13:914814
Dannemann M, Milaneschi Y, Yermakovich D, Stiglbauer V, Kariis HM, Krebs K, Friese MA, Otte C; Estonian Biobank Research Team, Lehto K, Penninx BWJH, Kelso J, Gold SM.
Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes.
Transl Psychiatry. 2022 Oct5;12(1):433
Dannemann M, Milaneschi Y, Yermakovich D, Stiglbauer V, Kariis HM, Krebs K, Friese MA, Otte C; Estonian Biobank Research Team, Lehto K, Penninx BWJH, Kelso J, Gold SM.
Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes.
Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets.Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans.
Transl Psychiatry. 2022 Oct5;12(1):433
Fründt O, Fadhel M, Heesen C, Seddiq Zai S, Gerloff C, Vettorazzi E, Pöttgen J, Buhmann C.
Do Impulse Control Disorders Impair Car Driving Performance in Patients with Parkinson’s Disease?
J Parkinsons Dis. 2022;12(7):2261-2275
Fründt O, Fadhel M, Heesen C, Seddiq Zai S, Gerloff C, Vettorazzi E, Pöttgen J, Buhmann C.
Do Impulse Control Disorders Impair Car Driving Performance in Patients with Parkinson’s Disease?
Background: Based on data regarding the prevalence of Parkinson’s disease (PD), the prevalence of impulsive control disorders (ICD) in PD, and the percentage of PD patients driving a car, it has to be assumed that at least 50,000 PD patients with ICD in Germany actively drive a car. However, these patients might be at risk for unsafe driving due to ICD-related dysfunctions such as failure to resist an impulse or temptation, to control an act or other altered neurobehavioral processes. Objective: This study determines the influence of ICD on driving ability in PD. Methods: We prospectively compared driving simulator performance of 23 PD patients with and 23 matched patients without ICD. ICD had to be socially compensated and presence was defined clinically for primary and questionnaire-based (QUIP-RS) for post-hoc analyses. Furthermore, between-group comparisons of driving-relevant neuropsychological tests were executed. Results: Except from a lower blinking frequency when changing lanes, overall driving safety of patients with ICD did not differ significantly from those without-regardless of the clinical or QUIP-RS-based ICD definition. ICD severity did not correlate with driving performance, but the latter correlated significantly with mean reaction times and certain neuropsychiatric tests (MoCA, TMT-A, TAP-M „flexibility“ and DBQ „error“). Conclusion: Clinically compensated ICD does not seem to impair driving safety in PD patients. Rather, cognitive and attentional deficits appear to be clinical markers for driving uncertainty.
J Parkinsons Dis. 2022;12(7):2261-2275
Krause N, Riemann-Lorenz K, Rahn AC, Pöttgen J, Köpke S, Meyer B, Thale F, Temmes H, van de Loo M, Gold SM, Heesen C.
„That would have been the perfect thing after diagnosis“: development of a digital lifestyle management application in multiple sclerosis.
Ther Adv Neurol Disord. 2022 Sep 6;15:17562864221118729
Krause N, Riemann-Lorenz K, Rahn AC, Pöttgen J, Köpke S, Meyer B, Thale F, Temmes H, van de Loo M, Gold SM, Heesen C.
„That would have been the perfect thing after diagnosis“: development of a digital lifestyle management application in multiple sclerosis.
Background: A multiple sclerosis (MS) diagnosis urges decision-making on immunotherapies, while persons with MS (PwMS) need to develop a coping concept in parallel. At this stage, PwMS ask how they themselves may contribute to controlling the disease. Evidence suggests that maintaining a healthy lifestyle (e.g. physical activity and stress management) is a key factor for healthy aging and preserving activity, while data on MS are complex. Objectives: Following the Medical Research Council framework, this study aimed to develop and investigate the feasibility of a new digital health application that conveys evidence-based patient information about lifestyle factors in MS and engages PwMS in relevant behaviour change techniques. Methods: Based on a digital health application promoting lifestyle management in breast cancer survivors, an MS-specific adaptation (‚levidex‘) was developed. Feasibility was tested with 15 PwMS and eight MS experts. Subsequently, a six-week pilot study with eight PwMS was conducted. All participants provided feedback on practicability and acceptability via a questionnaire and took part in a semi-structured telephone interview. Levidex was revised after each test phase. Results: The final levidex tool includes 16 modules, 177 references and several other functions. Feasibility results showed that PwMS and MS experts perceived levidex as understandable (14 out of 15; 6 out of 8), trustworthy (15 out of 15; 8 out of 8), and relevant (10 out of 15; 8 out of 8). Interviews revealed potential for improvement regarding the length and complexity of some content. Piloting of the revised version confirmed good feasibility and high acceptance. Most participants felt inspired to initiate (7 out of 8) or had already implemented (5 out of 8) lifestyle changes after working with levidex. Conclusion: Results suggest that levidex is feasible and well-accepted by PwMS and MS experts. It might be a useful tool to support PwMS in adapting to their diagnosis and initiating health-promoting lifestyle changes.
Ther Adv Neurol Disord. 2022 Sep 6;15:17562864221118729
Sippel A, Riemann-Lorenz K, Pöttgen J, Wiedemann R, Drixler K, Bitzer EM, Holmberg C, Lezius S, Heesen C.
Validation of the German eHealth impact questionnaire for online health information users affected by multiple sclerosis.
BMC Med Inform Decis Mak. 2022 Aug 16;22(1):219
Sippel A, Riemann-Lorenz K, Pöttgen J, Wiedemann R, Drixler K, Bitzer EM, Holmberg C, Lezius S, Heesen C.
Validation of the German eHealth impact questionnaire for online health information users affected by multiple sclerosis.
Background: Persons with multiple sclerosis (MS) are confronted by an overwhelming amount of online health information, which can be valuable but also vary in quality and aim. Therefore, it is of great importance for developers and providers of eHealth information to understand its impact on the users. The eHealth Impact Questionnaire (eHIQ) has been developed in the United Kingdom to measure the potential effects of health and experimental information websites. This contains user’s general attitudes towards using the internet to gain health information and attitudes towards a specific health related website. The self-complete questionnaire is divided into two independently administered and scored parts: the 11-item eHIQ part 1 and the 26-item eHIQ part 2. This study aimed to validate the psychometric properties of the German version of the eHealth Impact Questionnaire (eHIQ-G). Methods: 162 people with multiple sclerosis browsed one of two possible websites containing information on MS and completed an online survey. Internal consistency was assessed by Cronbach’s alpha and structural validity by Confirmatory Factor Analysis. Construct validity was examined by assessing correlations with the reference instruments eHealth Literacy Questionnaire and the General Self-Efficacy Scale measuring related, but dissimilar constructs. Moreover, we investigated the mean difference of the eHIQ-G score between the two websites. Data were analyzed using SPSS and AMOS software. Results: The eHIQ-G subscales showed high internal consistency with Cronbach’s alpha from 0.833 to 0.885. The 2-factor model of eHIQ part 1 achieved acceptable levels of goodness-of-fit indices, whereas the fit for the 3-factor model of eHIQ part 2 was poor and likewise for the alternative modified models. The correlations with the reference instruments were 0.08-0.62 and as expected. Older age was related with lower eHIQ part 1 score, whereas no significant effect was found for education on eHIQ part 1. Although not significant, the website ‚AMSEL‘ reached higher mean scores on eHIQ part 2. Conclusions: The eHIQ-G has good internal consistency, and sufficient structural and construct validity. This instrument will facilitate the measurement of the potential impact of eHealth tools.
BMC Med Inform Decis Mak. 2022 Aug 16;22(1):219
Roig MB, Krotka P, Burman CF, Glimm E, Gold SM, Hees K, Jacko P, Koeig F, Magirr D, Mesenbrink P, Viele K, Posch M.
On model-based time trend adjustments in platform trials with non-concurrent controls.
BMC Med Res Methodol. 2022 Aug 15;22(1):228
Roig MB, Krotka P, Burman CF, Glimm E, Gold SM, Hees K, Jacko P, Koeig F, Magirr D, Mesenbrink P, Viele K, Posch M.
On model-based time trend adjustments in platform trials with non-concurrent controls.
Background: Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial’s efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends. Methods: We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model. Results: A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from a step function when patients are allocated to arms by block randomisation. However, if time trends differ between arms or are not additive to treatment effects in the scale of the model, the type 1 error rate may be inflated. Conclusions: The efficiency gained by using step function models to incorporate non-concurrent controls can outweigh potential risks of biases, especially in settings with small sample sizes. Such biases may arise if the model assumptions of equality and additivity of time trends are not satisfied. However, the specifics of the trial, scientific plausibility of different time trends, and robustness of results should be carefully considered.
BMC Med Res Methodol. 2022 Aug 15;22(1):228
Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA.
G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis.
Sci Adv. 2022 Aug 5;8(31)
Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA.
G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis.
Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.
Sci Adv. 2022 Aug 5;8(31)
Beckmann H, Heesen C, Augustin M, Blome C.
The 27-Item Multiple Sclerosis Quality of Life Questionnaire: A New Brief Measure Including Treatment Burden and Work Life.
Int J MS Care. 2022 Jul-Aug;24(4):147-153
Beckmann H, Heesen C, Augustin M, Blome C.
The 27-Item Multiple Sclerosis Quality of Life Questionnaire: A New Brief Measure Including Treatment Burden and Work Life.
Background: Treatment- and work-related aspects have been neglected in health-related quality of life (HRQOL) measures in multiple sclerosis (MS). We aimed to develop a brief instrument covering all important impairment-, activity-, participation-, and treatment-related aspects for use in research and practice. Methods: The 27-item Multiple Sclerosis Quality of Life Questionnaire (MS-QLQ27) was developed using open item collection, a multidisciplinary expert panel, and cognitive pretesting. It was evaluated for reliability, construct validity, and responsiveness in 100 patients presenting with relapse (84 at follow-up ~14 days later). Construct validity was analyzed by correlating the MS-QLQ27 with the disease-specific Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and generic HRQOL instruments. The Expanded Disability Status Scale (EDSS) was used to analyze known-groups validity. Responsiveness was determined as the correlation of changes in MS-QLQ27 scores with changes in validation criteria. Results: Internal consistency was high (Cronbach α = 0.94 at baseline and 0.93 at follow-up). Convergent validity was supported by direction and magnitude of associations with disease-specific and generic instruments. Correlations with change in convergent criteria were strong, indicating responsiveness. The HAQUAMS showed the strongest associations with the MS-QLQ27. The MS-QLQ27 showed the highest effect size compared with other patient-reported outcomes and the EDSS. It successfully distinguished between levels of disease severity. Conclusions: These results indicate that the MS-QLQ27 is a reliable, valid, and highly responsive instrument for assessing HRQOL during relapse evolution in MS. Its advantages are that it is brief yet comprehensive, covering work- and treatment-related aspects not addressed in previous measures.
Int J MS Care. 2022 Jul-Aug;24(4):147-153
Wisgalla A, Ramien C, Streitz M, Schlickeiser S, Lupu AR, Diemert A, Tolosa E, Arck PC, Bellmann-Strobl J, Siebert N, Heesen C, Paul F, Friese MA, Infante-Duarte C, Gold SM.
Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis.
Front Immunol. 2022 Jul 4;13:907994.
Wisgalla A, Ramien C, Streitz M, Schlickeiser S, Lupu AR, Diemert A, Tolosa E, Arck PC, Bellmann-Strobl J, Siebert N, Heesen C, Paul F, Friese MA, Infante-Duarte C, Gold SM.
Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis.
In multiple sclerosis (MS), relapse rate is decreased by 70-80% in the third trimester of pregnancy. However, the underlying mechanisms driving this effect are poorly understood. Evidence suggests that CD56bright NK cell frequencies increase during pregnancy. Here, we analyze pregnancy-related NK cell shifts in a large longitudinal cohort of pregnant women with and without MS, and provide in-depth phenotyping of NK cells. In healthy pregnancy and pregnancy in MS, peripheral blood NK cells showed significant frequency shifts, notably an increase of CD56bright NK cells and a decrease of CD56dim NK cells toward the third trimester, indicating a general rather than an MS-specific phenomenon of pregnancy. Additional follow-ups in women with MS showed a reversal of NK cell changes postpartum. Moreover, high-dimensional profiling revealed a specific CD56bright subset with receptor expression related to cytotoxicity and cell activity (e.g., CD16+ NKp46high NKG2Dhigh NKG2Ahigh phenotype) that may drive the expansion of CD56bright NK cells during pregnancy in MS. Our data confirm that pregnancy promotes pronounced shifts of NK cells toward the regulatory CD56bright population. Although exploratory results on in-depth CD56bright phenotype need to be confirmed in larger studies, our findings suggest an increased regulatory NK activity, thereby potentially contributing to disease amelioration of MS during pregnancy.
Front Immunol. 2022 Jul 4;13:907994.
Schubert C, Schulz K, Träger S, Plath AL, Omriouate A, Rosenkranz SC, Morellini F, Friese MA, Hirnet D.
Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation.
Front Cell Neurosci. 2022 Jun 30;16:912030
Schubert C, Schulz K, Träger S, Plath AL, Omriouate A, Rosenkranz SC, Morellini F, Friese MA, Hirnet D.
Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation.
Adenine nucleotides, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), as well as the nucleoside adenosine are important modulators of neuronal function by engaging P1 and P2 purinergic receptors. In mitral cells, signaling of the G protein-coupled P1 receptor adenosine 1 receptor (A1R) affects the olfactory sensory pathway by regulating high voltage-activated calcium channels and two-pore domain potassium (K2P) channels. The inflammation of the central nervous system (CNS) impairs the olfactory function and gives rise to large amounts of extracellular ATP and adenosine, which act as pro-inflammatory and anti-inflammatory mediators, respectively. However, it is unclear whether neuronal A1R in the olfactory bulb modulates the sensory function and how this is impacted by inflammation. Here, we show that signaling via neuronal A1R is important for the physiological olfactory function, while it cannot counteract inflammation-induced hyperexcitability and olfactory deficit. Using neuron-specific A1R-deficient mice in patch-clamp recordings, we found that adenosine modulates spontaneous dendro-dendritic signaling in mitral and granule cells via A1R. Furthermore, neuronal A1R deficiency resulted in olfactory dysfunction in two separate olfactory tests. In mice with experimental autoimmune encephalomyelitis (EAE), we detected immune cell infiltration and microglia activation in the olfactory bulb as well as hyperexcitability of mitral cells and olfactory dysfunction. However, neuron-specific A1R activity was unable to attenuate glutamate excitotoxicity in the primary olfactory bulb neurons in vitro or EAE-induced olfactory dysfunction and disease severity in vivo. Together, we demonstrate that A1R modulates the dendro-dendritic inhibition (DDI) at the site of mitral and granule cells and impacts the processing of the olfactory sensory information, while A1R activity was unable to counteract inflammation-induced hyperexcitability.
Front Cell Neurosci. 2022 Jun 30;16:912030
Basso L, Boecking B, Neff P, Brueggemann P, El-Ahmad L, Brasanac J, Rose M, Gold SM, Mazurek B
Negative Associations of Stress and Anxiety Levels with Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus.
Front Psychol. 2022 Jun 23;13:871822
Basso L, Boecking B, Neff P, Brueggemann P, El-Ahmad L, Brasanac J, Rose M, Gold SM, Mazurek B
Negative Associations of Stress and Anxiety Levels with Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus.
Background: Depression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects. Methods: This longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline (N = 41), treatment end, 7.8-week (N = 35), and 13.8-week follow-up (N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal). Results: Bootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (-0.21 [-0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/-) and HADS anxiety (-0.14 [-0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores (β = -6.22 [-12.18, -0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels (β = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed. Conclusion: We observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress-/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated.
Front Psychol. 2022 Jun 23;13:871822
Kaufmann M, Schaupp AL, Sun R, Coscia F, Dendrou CA, Cortes A, Kaur G, Evans HG, Mollbrink A, Navarro JF, Sonner JK, Mayer C, DeLuca GC, Lundeberg J, Matthews PM, Attfield KE, Friese MA, Fugger L.
Identification of early neurodegenerative pathways in progressive multiple sclerosis.
Nat Neurosci. 2022 Jul;25(7):944-955
Kaufmann M, Schaupp AL, Sun R, Coscia F, Dendrou CA, Cortes A, Kaur G, Evans HG, Mollbrink A, Navarro JF, Sonner JK, Mayer C, DeLuca GC, Lundeberg J, Matthews PM, Attfield KE, Friese MA, Fugger L.
Identification of early neurodegenerative pathways in progressive multiple sclerosis.
Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.
Nat Neurosci. 2022 Jul;25(7):944-955
Ghaidar D, Sippel A, Riemann-Lorenz K, Kofahl C, Morrison R, Kleiter I, Schmidt S, Dettmers C, Schulz H, Heesen C.
Experiences of persons with multiple sclerosis with rehabilitation: A qualitative study interview.
BMC Health Serv Res. 2022 Jun 11;22(1):770
Ghaidar D, Sippel A, Riemann-Lorenz K, Kofahl C, Morrison R, Kleiter I, Schmidt S, Dettmers C, Schulz H, Heesen C.
Experiences of persons with multiple sclerosis with rehabilitation: A qualitative study interview.
Background: Managing multiple sclerosis (MS) includes different treatment approaches. Rehabilitation is a key strategy in MS for improving functioning, activity and participation. As part of a larger study on overall patient experiences with different treatment approaches, this study aims to give an overview of different patients‘ experiences and perspectives on inpatient rehabilitation in MS. Methods: We conducted problem-centered interviews in 50 persons with MS in Germany, of whom most had relapsing-remitting MS. We used the maximum variation sampling method during recruitment. Data were analyzed thematically. Results: As a result of the analysis, three major themes were identified: 1) factors contributing to the decision-making concerning rehabilitation, 2) experience with the rehabilitation setting, 3) benefits of rehabilitation treatments. The treating physicians‘ attitude had a major impact on the decision to either opt for rehabilitation or not. Setting goals prior to rehabilitation was given a high priority. Exchanging experiences with other persons with MS presented a major benefit from rehabilitation while for some being separated from regular daily life resulted in a more ambiguous attitude ranging from appreciation of escaping daily hassles to substantial behavioral change management. Conclusion: Patients reported various experiences in the process of decision-making with regard to rehabilitation. Physicians´ advice, goal setting and the selection of the most suitable rehabilitation clinic were considered most relevant.
BMC Health Serv Res. 2022 Jun 11;22(1):770
Elkalhii-Wilhelm S, Sippel A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Arnade S, Kleiter I, Schmidt S, Heesen C.
Experiences of persons with Multiple Sclerosis with lifestyle adjustment: A qualitative interview study.
PLoS One. 2022 May 27;17(5):e0268988.
Elkalhii-Wilhelm S, Sippel A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Arnade S, Kleiter I, Schmidt S, Heesen C.
Experiences of persons with Multiple Sclerosis with lifestyle adjustment: A qualitative interview study.
Background: Persons with Multiple Sclerosis (pwMS) follow individual strategies to cope with this highly heterogeneous disease. As surveys show, lifestyle habits play an important role in pwMS. However, little is known about individual experiences of pwMS with different lifestyle adjustment strategies.
Objective: This study aims to describe and understand individual experiences of pwMS with lifestyle adjustments. Methods: Semi-structured interviews were conducted with 50 pwMS in Germany. Criteria for inclusion were age ≥ 18 years and a diagnosis of relapsing-remitting Multiple Sclerosis. Data were analyzed inductively and deductively according to a six-step thematic analysis. Results: The three main themes for experience-based lifestyle adjustments were: 1) nutrition and supplements, 2) exercise and physical activity, and 3) stress management. Influencing factors on the decision-making process such as active disease management, information and advice, desire for mental health and social support, and the wish for self-determination were identified. Impacts of starting or maintaining lifestyle habits included, for example, MS-specific, general, and mental health benefits, the development of coping strategies, social support, and barriers that led to a termination of lifestyle adjustments. Conclusion: This study provides a rich and nuanced amount of experiences of pwMS with lifestyle adjustments and leads to three important conclusions: 1) Further research is warranted to better describe the perceived effects of lifestyle habits on MS symptoms and progression, in particular with regard to nutrition and stress reduction; 2) patient education in MS should include the available evidence on lifestyle management and 3) patients need to be actively supported in changing their lifestyle behavior.
PLoS One. 2022 May 27;17(5):e0268988.
Steinberg L, Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Heesen C, Rahn AC.
Motherhood choice in multiple sclerosis (MoMS) development and piloting of patient-reported outcome measures.
Mult Scler Relat Disord. 2022 Jul;63:103831
Steinberg L, Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Heesen C, Rahn AC.
Motherhood choice in multiple sclerosis (MoMS) development and piloting of patient-reported outcome measures.
Background: Multiple sclerosis (MS) particularly affects women between the age of 20 and 40. Therefore, pregnancy is often an important issue for women with MS (wwMS), but misunderstandings, misinformation, and uncertainties about MS and pregnancy are common. We developed and pilot-tested two questionnaires, one on knowledge (MCKQ), and one on attitudes, coping strategies and worries (MPWQ) of wwMS regarding pregnancy. Methods: This mixed-methods study followed the MRC framework for the development and evaluation of complex interventions. Two questionnaires were developed based on an earlier questionnaire and a qualitative study, cognitively debriefed and pilot tested in a web-based survey. Qualitative data were analysed using thematic analysis. The psychometric analysis included item difficulty and reliability (for both questionnaires), convergent validity assessment and exploratory factor analysis (EFA) (for MPWQ). Results: The qualitative study (three focus groups and interviews with 15 wwMS overall and interviews with 4 experts) revealed several topics requiring evidence-based decision support. A multidisciplinary panel produced the 16-item MCKQ and the 39-item MPWQ. The cognitive debriefing of both questionnaires went smoothly. Of 128 wwMS who approached the survey, 95 (74%) completed the MCKQ and 89 (70%) the MPWQ. The mean age of wwMS was 36.7 years, 88% had a relapsing MS, and 32% had no children. Item difficulty, reliability and convergent validity were acceptable for both questionnaires. The EFA did not confirm the three-scale structure (attitude, worries and coping). Conclusion: The developed questionnaires fill a gap in self-reported measures of knowledge (MCKQ) and attitudes, worries, and coping strategies (MPWQ) of wwMS regarding motherhood. Further refinement of the MPWQ and validation in a larger sample is warranted before its large-scale use.
Mult Scler Relat Disord. 2022 Jul;63:103831
Ri Chae W, Nübel J, Baumert J, Gold SM, Otte C.
Association of depression and obesity with C-reactive protein in Germany: a large nationally representative study.
Brain Behav Immun. 2022 Jul;103:223-231
Ri Chae W, Nübel J, Baumert J, Gold SM, Otte C.
Association of depression and obesity with C-reactive protein in Germany: a large nationally representative study.
Introduction: Depression and obesity often occur comorbidly, and once both are present, they further increase the risk of developing other medical comorbidities, likely due to the underlying chronic low-grade inflammation. We investigated to what extent depression and obesity are associated with levels of high-sensitivity C-reactive protein (hsCRP) in a nationally representative sample of the German adult population. Methods: We analyzed data from the German Health Interview and Examination Survey for Adults (DEGS1, N = 7115), and its mental health module (DEGS1-MH; N = 4483). Two different depression measures were used: current depressive symptoms assessed by the self-administered German version of the Patient Health Questionnaire-9 and major depressive disorder (MDD) in the last 12 months assessed by a modified German version of the Composite International Diagnostic Interview. Obesity was defined by body mass index calculated from measured data. Associations with log(x+1)-transformed hsCRP levels were analyzed using multivariable linear regression models. Results: Obese participants with depressive symptoms had significantly higher hsCRP compared to non-obese participants with depressive symptoms adjusted for sociodemographic and behavioral variables and medication use. In non-obese individuals, depressive symptoms were inversely associated with hsCRP whereas MDD was not associated with hsCRP after adjustment for covariates. Additional analyses suggested symptom-specific associations of hsCRP as higher levels were linked to fatigue (β = 0.10, p < .001) while lower levels were linked to cognitive problems (β = -0.09, p < .001). Low SES, current smoking, lower levels of physical exercise, and the use of anti-inflammatory/anti-rheumatic medication and antidepressants were additional determinants of hsCRP in the fully adjusted models. Conclusions: Our data suggest that obesity status is more strongly associated with increased inflammation than depressive symptoms or MDD. The relationship between depression and hsCRP in our population-based sample is substantially influenced by obesity status as well as other medical factors, lifestyle, and socioeconomic status. Furthermore, our findings suggest that the association between hsCRP and depression is symptom-specific rather than generalized.
Brain Behav Immun. 2022 Jul;103:223-231
Heesen C, Mokry C, Salmen A, Hegen H, Mäurer M, Warnke C, Gehring K, Berthele A, Meier U.
German guideline for diagnosis and treatment of multiple sclerosis – a survey focusing neurologists in daily practise.
Mult Scler Relat Disord. 2022 Apr 25;63:103828
Heesen C, Mokry C, Salmen A, Hegen H, Mäurer M, Warnke C, Gehring K, Berthele A, Meier U.
German guideline for diagnosis and treatment of multiple sclerosis – a survey focusing neurologists in daily practise.
We performed a web-based survey among German-speaking neurologists to evaluate the acceptance of the 2021 German guideline in the diagnosis and treatment of multiple sclerosis. Based on 327 replies in total, the current survey largely reproduced the findings of an earlier, smaller survey on the prefinal consultation version of the guideline and confirmed high acceptance rates. Half of the participants were practising neurologists. Neurologists from MS centers with more than 500 patients per year (n=26) were more critical of the guideline. They reiterated some of the criticisms of the previous feedback, and, in particular, felt that safety aspects are overemphasized in the guideline, thereby superseding early aggressive therapy.
Mult Scler Relat Disord. 2022 Apr 25;63:103828
Sippel A, Scheiderbauer J, Eklund D, Arnade S, Schmidt S, Kleiter I, Morrison R, Kofahl C, Heesen C.
Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.
BMC Neurol. 2022 Apr 20;22(1):146
Sippel A, Scheiderbauer J, Eklund D, Arnade S, Schmidt S, Kleiter I, Morrison R, Kofahl C, Heesen C.
Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.
Background: A variety of management options (e.g., disease-modifying therapy, lifestyle interventions, rehabilitation) are available for persons with relapsing-remitting multiple sclerosis (MS). Besides coping with the diagnosis, persons with MS have to make complex decisions, e.g., regarding disease-modifying therapies. In addition to factual information, reports of patient experiences may support other patients in their decision-making. Therefore, we developed a website presenting patient experiences illustrated by video, audio and text files. This study aimed to test the acceptability and usability of a website with patient experiences with MS. Methods: A mixed-methods approach was applied. A total of 69 participants visited the German „Patient Experiences with MS (PExMS)“ website and among them, 50 persons with MS and 6 experts completed an online survey. In total, 18 participants took part in telephone interviews or focus groups. Data from the survey were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. Results: Both quantitative and qualitative responses suggest that the PExMS website was viewed positively by patients and experts. 94% of persons with MS agreed that the information was comprehensible and reliable. 54% felt encouraged to share their health problems with others after having studied the website. 74% claimed to use the website if they had to make a decision regarding their health. Qualitative responses deduced from the website fell into 5 key themes: (1) web design, appearance, and functionality, (2) content, (3) usability, (4) satisfaction, and (5) loyalty. The search for persons of similar age and with comparable experiences was a major driving force to navigate the website. The material on the website was perceived as diverse, covering both positive and negative experiences in daily living with MS. All participants greatly appreciated having access to other people’s experiences online and judged the material on the website as particularly helpful in decision-making for disease-modifying therapies. Conclusions: The findings suggest that the PExMS website might have the potential to be a useful source of audio-visual information for persons with MS. Given the lack of websites available to patients with experiential information, health care professionals may be encouraged to routinely inform patients about this website at regular appointments.
BMC Neurol. 2022 Apr 20;22(1):146
Brasanac J, Hetzer S, Asseyer S, Kuchling J, Bellmann-Strobl J, Ritter K, Gamradt S, Scheel M, Haynes JD, Brandt AU, Paul F, Gold SM, Weygandt M.
Central stress processing, T-cell responsitivity to stress hormones and disease severity in multiple sclerosis.
Brain Commun. 2022 Apr 4;4(2)
Brasanac J, Hetzer S, Asseyer S, Kuchling J, Bellmann-Strobl J, Ritter K, Gamradt S, Scheel M, Haynes JD, Brandt AU, Paul F, Gold SM, Weygandt M.
Central stress processing, T-cell responsitivity to stress hormones and disease severity in multiple sclerosis.
Epidemiological, clinical and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T-cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T-cell glucocorticoid signalling in patients versus healthy persons as a potential indicator of disease-specific CNS-immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T-cell glucocorticoid signalling across groups. This network’s activity was simultaneously linked to patients‘ lesion volume, clinical disability and information-processing speed. Complementary analyses revealed that T-cell glucocorticoid signalling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress processing and T-cell stress hormone sensitivity are related to key severity measures of multiple sclerosis.
Brain Commun. 2022 Apr 4;4(2)
Freund M, Schiffmann I, Rahn AC, Chard D, Lukas C, Scheiderbauer J, Sippel A, Heesen C.
Understanding Magnetic Resonance Imaging in Multiple Sclerosis (UMIMS): Development and Piloting of an Online Education Program About Magnetic Resonance Imaging for People With Multiple Sclerosis.
Front Neurol. 2022 Mar 28;13:856240
Freund M, Schiffmann I, Rahn AC, Chard D, Lukas C, Scheiderbauer J, Sippel A, Heesen C.
Understanding Magnetic Resonance Imaging in Multiple Sclerosis (UMIMS): Development and Piloting of an Online Education Program About Magnetic Resonance Imaging for People With Multiple Sclerosis.
Background: People with multiple sclerosis (pwMS) lack sufficient magnetic resonance imaging (MRI) knowledge to truly participate in frequently occurring MRI-related therapy decisions. An evidence-based patient information (EBPI) about MRI is currently lacking. Objective: The aim of this study was to develop an evidence-based online education program about limitations and benefits of MRI for pwMS. Ultimately, our goal was to improve MRI risk-knowledge, empower pwMS, and promote shared decision-making. Methods: The program’s contents were based on literature research and a previous pilot study. It was revised following 2 evaluation rounds with pwMS, MRI experts and expert patients. In a pilot study, n = 92 pwMS received access to the program for 4 weeks. User experiences and acceptance, MRI knowledge (MRI-RIKNO 2.0 questionnaire) and emotions and attitudes toward MRI (MRI-EMA questionnaire) were assessed. Results were compared to a previous survey population of n = 508 pwMS without access to the program. Results: Participants rated the program as easy to understand, interesting, relevant, recommendable, and encouraging. In comparison to pwMS without access to the program, MRI risk-knowledge and perceived MRI competence were higher. Conclusion: Satisfaction with the program and good MRI-risk knowledge after usage demonstrates the need and applicability of EBPI about MRI in MS.
Front Neurol. 2022 Mar 28;13:856240
Fearey BC, Binkle L, Mensching D, Schulze C, Lohr C, Friese MA, Oertner TG, Gee CE.
A glibenclamide-sensitive TRPM4-mediated component von CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis.
Sci Rep. 2022 Apr 9;12(1)
Fearey BC, Binkle L, Mensching D, Schulze C, Lohr C, Friese MA, Oertner TG, Gee CE.
A glibenclamide-sensitive TRPM4-mediated component von CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis.
The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE.
Sci Rep. 2022 Apr 9;12(1)
Röhling HM, Althoff P, Arsenova R, Drebinger D, Gigengack N, Chorschew A, Kroneberg D, Rönnefarth M, Ellermeyer T, Rosenkranz SC, Heesen C, Behnia B, Hirano S, Kuwabara S, Paul F, Brandt AU, Schmitz-Hübsch T.
Proposal for Post Hoc Quality Control in Instrumented Motion Analysis Using Markerless Motion Capture: Development and Usability Study.
JMIR Hum Factors. 2022 Apr 1;9(2)
Röhling HM, Althoff P, Arsenova R, Drebinger D, Gigengack N, Chorschew A, Kroneberg D, Rönnefarth M, Ellermeyer T, Rosenkranz SC, Heesen C, Behnia B, Hirano S, Kuwabara S, Paul F, Brandt AU, Schmitz-Hübsch T.
Proposal for Post Hoc Quality Control in Instrumented Motion Analysis Using Markerless Motion Capture: Development and Usability Study.
Background: Instrumented assessment of motor symptoms has emerged as a promising extension to the clinical assessment of several movement disorders. The use of mobile and inexpensive technologies such as some markerless motion capture technologies is especially promising for large-scale application but has not transitioned into clinical routine to date. A crucial step on this path is to implement standardized, clinically applicable tools that identify and control for quality concerns. Objective: The main goal of this study comprises the development of a systematic quality control (QC) procedure for data collected with markerless motion capture technology and its experimental implementation to identify specific quality concerns and thereby rate the usability of recordings. Methods: We developed a post hoc QC pipeline that was evaluated using a large set of short motor task recordings of healthy controls (2010 recordings from 162 subjects) and people with multiple sclerosis (2682 recordings from 187 subjects). For each of these recordings, 2 raters independently applied the pipeline. They provided overall usability decisions and identified technical and performance-related quality concerns, which yielded respective proportions of their occurrence as a main result. Results: The approach developed here has proven user-friendly and applicable on a large scale. Raters‘ decisions on recording usability were concordant in 71.5%-92.3% of cases, depending on the motor task. Furthermore, 39.6%-85.1% of recordings were concordantly rated as being of satisfactory quality whereas in 5.0%-26.3%, both raters agreed to discard the recording. Conclusions: We present a QC pipeline that seems feasible and useful for instant quality screening in the clinical setting. Results confirm the need of QC despite using standard test setups, testing protocols, and operator training for the employed system and by extension, for other task-based motor assessment technologies. Results of the QC process can be used to clean existing data sets, optimize quality assurance measures, as well as foster the development of automated QC approaches and therefore improve the overall reliability of kinematic data sets.
JMIR Hum Factors. 2022 Apr 1;9(2)
Dietmaier JM, von dem Knesebeck O, Heesen C, Kofahl C
Personality and its association with self-management in multiple sclerosis.
Mult Scler Relat Disord. 2022 May;61:103752
Dietmaier JM, von dem Knesebeck O, Heesen C, Kofahl C
Personality and its association with self-management in multiple sclerosis.
Background: In a healthcare system which aims to empower the patient, self-management becomes increasingly important. In Multiple Sclerosis, an effective self-management is associated with various favorable health-related outcomes like improvement in quality of life, the reduction of depression and anxiety symptoms, and reduced healthcare costs. This study investigates the association between the Big Five personality traits and self-management including activity in self-help groups. Methods: People with MS were recruited via several paths within Germany (e.g. medical practices, social events and the German MS society). The final study sample consisted of 682 participants who answered a multidimensional questionnaire. This comprised the Big-Five-Inventory-10 for personality, the Health Education Impact Questionnaire (heiQ) for self-management competencies, questions for participation in self-help groups, and socio-demographic and clinical variables. Results: Multivariate regression analyses showed that personality could explain a greater amount of variance of self-management than socio-demographic and clinical variables. Neuroticism was the strongest predictor and correlated negatively with all heiQ-dimensions of self-management. In contrast, in logistic regression analysis none of the Big Five traits became significant in predicting the activity in self-help groups. Conclusion: As expected, personality plays an important role regarding self-management. Ideally, a time-saving personality assessment should be considered in routine clinical practice to identify patients at risk; however, at a minimum, personality traits should be considered in consultations with their neurologists. They may need help to understand the benefits of effective self-management and should receive support to improve their self-management skills and to reduce their neuroticism to lower the risk of secondary complications.
Mult Scler Relat Disord. 2022 May;61:103752
Ambra MG, Pöttgen J, Anglada E, Menendez R, Hoyer J, Giordano A, Pakenham KI, Galan I, Solari A.
Cross-Country Adaptation of a Psychological Flexibility Measure: The Comprehensive Assessment of Acceptance and Commitment Therapy Processes.
Int J Environ Res Public Health. 2022 Mar 8;19(6):3150
Ambra MG, Pöttgen J, Anglada E, Menendez R, Hoyer J, Giordano A, Pakenham KI, Galan I, Solari A.
Cross-Country Adaptation of a Psychological Flexibility Measure: The Comprehensive Assessment of Acceptance and Commitment Therapy Processes.
Purpose: The Comprehensive assessment of Acceptance and Commitment Therapy (ACT) processes (CompACT) is a 23-item self-report questionnaire assessing psychological flexibility, which is the overarching construct underpinning the ACT framework. We conducted a two-phase project to develop validated versions of the CompACT in three languages: phase 1-cross-cultural adaptation; and phase 2-psychometric validation of the questionnaire for use in Italy, Germany and Spain. This article focuses on the first phase. Methods: We translated and culturally adapted the CompACT in the three target languages, following the ISPOR TCA Task Force guidelines. The process was overseen by a translation panel (three translators, at least two multiple sclerosis (MS) researchers and a lay person), ACT experts and clinicians from the research team of each country and the original CompACT developers. We debriefed the new questionnaire versions via face-to-face interviews with a minimum of four adults from the general population (GP) and four adults with MS in each country. Results: The translation-adaptation process went smoothly in the three countries, with some items (7 in Italy, 4 in Germany, 6 in Spain) revised after feedback from ACT experts. Cognitive debriefing showed that the CompACT was deemed easy to understand and score in each target country by both GP and MS adults. Conclusions: The Italian, German and Spanish versions of the CompACT have semantic, conceptual and normative equivalence to the original scale and good content validity. Our findings are informative for researchers adapting the CompACT and other self-reported outcome measures into multiple languages and cultures.
Int J Environ Res Public Health. 2022 Mar 8;19(6):3150
Heesen C, Rosenkranz SC.
Physical exercise in multiple sclerosis is not just a symptomatic therapy, it has a disease-modifying effect: No.
Mult Scler. 2022 May;28(6):861-862
Heesen C, Rosenkranz SC.
Physical exercise in multiple sclerosis is not just a symptomatic therapy, it has a disease-modifying effect: No.
Mult Scler. 2022 May;28(6):861-862
Schneider A, Fasshauer E, Scheiderbauer J, Warnke C, Köpke S, Kasper J, Toussaint M, Temmes H, Hemmer B, Schiffmann I, Rahn AB, Heesen C.
Development and evaluation of evidence-based patient information handbooks about multiple sclerosis immunotherapies.
Mult Scler Relat Disord. 2022 Apr;60:103728.
Schneider A, Fasshauer E, Scheiderbauer J, Warnke C, Köpke S, Kasper J, Toussaint M, Temmes H, Hemmer B, Schiffmann I, Rahn AB, Heesen C.
Development and evaluation of evidence-based patient information handbooks about multiple sclerosis immunotherapies.
Background: Multiple sclerosis treatment options are increasing. Evidence-based patient information (EBPI) are therefore crucial to enable patient involvement in decision making. Based on earlier work on decision support, patient information handbooks on 8 MS immunotherapies were developed, piloted and evaluated with support from the German Clinical Competence Network MS and the German MS Society. Methods: Handbooks were structured according to EBPI concepts. Drafts were commented by patient representatives and neurologists with an MS expertise. Executive boards of the German MS Society and the Competence Network as well as pharmaceutical companies‘ feedback was included. Handbooks were distributed among MS neurologists by the German MS Society. Evaluation followed applying a mixed methods approach with interviews, focus groups and surveys. One survey addressed persons with MS (pwMS) based on a questionnaire included in each handbook. Neurologists who received printed patient handbooks were invited to give feedback in a second survey. Results: Eight handbooks were developed providing absolute and relative risk information in numbers and figures as well as monitoring needs and drug fact boxes. Despite the high amount of information and the display of low absolute risk reduction rates of treatments, handbooks were overall appreciated by pwMS (n=107) and mostly also by physicians (n=24). For more than 70% of the pwMS the information was new, understandable and supportive for decision making. But patients felt uncomfortable with relative risk information. However, response rates in the evaluation were low, exposing the challenges when implementing EBPI into clinical care. Therefore, conclusions must be considered preliminarily. Conclusion: EBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.
Mult Scler Relat Disord. 2022 Apr;60:103728.
GENERATE
Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.
Brain. 2023 Feb 13;146(2):600-611
GENERATE
Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.
“ Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.Brain. 2023 Feb 13;146(2):600-611
Artmann A, Rahn AC, Köpke S, Thomalla G, Heesen C, Alegiani AC.
Risk communication in acute stroke patients – from qualitative data to a pilot randomised controlled trial.
Z Evid Fortbild Qual Gesundhwes. 2022 Apr;169:19-27
Artmann A, Rahn AC, Köpke S, Thomalla G, Heesen C, Alegiani AC.
Risk communication in acute stroke patients – from qualitative data to a pilot randomised controlled trial.
Objectives: The probability of recurring strokes in patients with atrial fibrillation is high. Within 1.8 years, 6.6 % of the patients suffered a new stroke. While effective secondary prevention options exist, low adherence challenges effective medical treatment. The aim of our study was to examine the risk understanding of acute stroke patients and to find the best way to communicate risk reduction. Materials and methods: Risk communication had three formats: a text, a pictogram, and a cube diagram. All three were developed on the basis of the criteria of evidence-based patient information. Patients who were admitted to the stroke unit and diagnosed with acute stroke, assessed the information material. Data on secondary prevention using acetylsalicylic acid were taken as an example, with no reference to actual patient treatment. In a first step, we interviewed a focus group to check the feasibility of the questionnaire (qualitative study). In the second step, the information material was tested in a pilot randomized controlled trial. Results: Acute stroke patients (qualitative study, n=13) understood the information and were interested in numerical risk communication. The visualized representations were superior in terms of understandability of the numbers communicated (pilot randomized controlled trial, n=60, 50 % correct answers for question 1, p value of 0.502, and 55 % correct answers for question 2, p value of 0.338). Stroke-related neurologic deficits, measured with the National Institute of Health Stroke Scale (NIHSS) on admission, revealed a significant influence on the number of correct answers to stroke risk questions, whereas the type of stroke and education did not. Conclusions: Acute stroke patients were able to understand risk communication. Visualization helped them capture information on stroke risk.
Z Evid Fortbild Qual Gesundhwes. 2022 Apr;169:19-27
Pöttgen J, Friede T, Lau S, Gold SM, Letsch C, Bender G, Flachenecker P, Heesen C, Penner IK.
Managing neuropsychological impairment in multiple sclerosis – Controlled study on a standardized metacognitive intervention (MaTiMS)
Mult Scler Relat Disord. 2022 Mar;59:103687.
Pöttgen J, Friede T, Lau S, Gold SM, Letsch C, Bender G, Flachenecker P, Heesen C, Penner IK.
Managing neuropsychological impairment in multiple sclerosis – Controlled study on a standardized metacognitive intervention (MaTiMS)
Objective: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system of potential autoimmune origin that is frequently associated with neuropsychiatric symptoms and cognitive deficits, as well as with fatigue, stress and psychosocial burden. In the present controlled multi-centre trial we investigated whether two specific neuropsychological interventions (1. metacognitive training (MaTiMS); 2. computerized working memory training (BrainStim) in combination with MaTiMS) applied as add-on therapies to real life standard rehabilitation lead to increased benefit in self-perceived cognitive deficits (the primary outcome) in MS patients compared to standard rehab. Methods: 288 adult persons in three German rehab centers with a confirmed diagnosis of MS were sequentially allocated to one of the three intervention groups. 249 (87%) participants completed the post assessment and 187 (63%) the online survey after 12 months. Perceived cognitive deficits, mood, fatigue, coping, and activity were evaluated by self-reports and neuropsychological tests at baseline and 4 weeks postintervention. All self-reports were additionally administered digitally at three, six, and twelve months from baseline. Results: We could not show differential effects on the primary outcome between the intervention groups and the control group (p=.369, p=.934). Immediately after each intervention we could show beneficial time effects in all three groups on self-perceived cognitive deficits as well as on most of the other outcomes. The reported effects were however not sustained at 6 months follow-up. Conclusions: Our findings could not show an additional effect of specific cognitive training on cognitive deficit perception in MS. However, findings indicate that MS rehabilitation may improve patient reported outcomes in the short term. They also underline the need for concepts to maintain rehabilitation gains when patients return back home.
Mult Scler Relat Disord. 2022 Mar;59:103687.
Brasanac J, Gamradt S, Otte C, Milaneschi Y, Monzel AS, Picard M, Gold SM.
Cellular specificity of mitochondrial and immunometabolic features in major depression.
Mol Psychiatry. 2022 May;27(5):2370-2371
Brasanac J, Gamradt S, Otte C, Milaneschi Y, Monzel AS, Picard M, Gold SM.
Cellular specificity of mitochondrial and immunometabolic features in major depression.
No abstract available.
Mol Psychiatry. 2022 May;27(5):2370-2371
Testud B, Delacour C, El Ahmadi AA, Brun G, Girard N, Duhamel G, Heesen C, Häußler V, Thaler C, Has Silemek AC, Stellmann JP
Brain grey matter perfusion in primary progressive multiple sclerosis: Mild decrease over years and regional associations with cognition and hand function.
Eur J Neurol. 2022 Jun;29(6):1741-1752.
Testud B, Delacour C, El Ahmadi AA, Brun G, Girard N, Duhamel G, Heesen C, Häußler V, Thaler C, Has Silemek AC, Stellmann JP
Brain grey matter perfusion in primary progressive multiple sclerosis: Mild decrease over years and regional associations with cognition and hand function.
Background: Extend and dynamic of neurodegeneration in progressive Multiple Sclerosis (MS) might be reflected by global and regional brain perfusion, an outcome at the intercept between structure and function. Here, we provide a first insight in the evolution of brain perfusion and its association with disability in primary progressive MS (PPMS) over several years. Methods: 77 persons with PPMS were followed over up to 5 years. Visits included a 3T MRI with pulsed Arterial spin labelling (ASL) perfusion, the Timed-25-Foot-Walk, 9-Hole-Peg-Test (NHPT), Symbol-Digit-Modalities-Test (SDMT) and Expanded Disability Status Scale (EDSS). We extracted regional cerebral blood flow surrogates and compared them to 11 controls. Analyses focused in cortical and deep gray matter, the change over time and associations with disability on regional and global level. Results: Baseline brain perfusion of patients and controls was comparable for the cortex (p=0.716) and deep grey matter (p=0.095). EDSS disability increased mildly (p=0.023) while brain perfusion decreased during follow up (p<0.001) and with disease duration (p=0.009). Lower global perfusion correlated with higher disability as indicated by EDSS, NHPT and Timed-25-Foot-Walk (p<0.001). The motor task NHPT showed associations with twenty gray matter regions. In contrast, better SDMT performance correlated with lower perfusion (p<0.001) in seven predominantly frontal regions indicating a functional maladaptation. Conclusion: Decreasing perfusion indicates a putative association with MS disease mechanisms such as neurodegeneration, reduced metabolism, and loss of resilience. A low alteration rate limits its use in clinical practice, but regional association patterns might provide a snapshot of adaptive and maladaptive functional reorganization
Eur J Neurol. 2022 Jun;29(6):1741-1752.
Hümmert MW, Schöppe LM, Bellmann-Strobl J, Siebert N, Paul F, Duchow A, Pellkofer H, Kümpfel T, Havla J, Jarius S, Wildemann B, Berthele A, Bergh FT, Pawlitzki M, Klotz L, Kleiter I, Stangel M, Gingele S, Weber MS, Faiss JH, Pul R, Walter A, Zettl U, Senel M, Stellmann JP, Häußler V, Hellwig K, Ayzenberg I, Aktas O, Ringelstein M, Schreiber-Katz O, Trebst C; Neuromyelitis Optica Study Group (NEMOS).
Costs and Health-Related Quality of Life in Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Disease: CHANGE NOM Study.
Neurology. 2022 Mar 15;98(11):e1184-e1196
Hümmert MW, Schöppe LM, Bellmann-Strobl J, Siebert N, Paul F, Duchow A, Pellkofer H, Kümpfel T, Havla J, Jarius S, Wildemann B, Berthele A, Bergh FT, Pawlitzki M, Klotz L, Kleiter I, Stangel M, Gingele S, Weber MS, Faiss JH, Pul R, Walter A, Zettl U, Senel M, Stellmann JP, Häußler V, Hellwig K, Ayzenberg I, Aktas O, Ringelstein M, Schreiber-Katz O, Trebst C; Neuromyelitis Optica Study Group (NEMOS).
Costs and Health-Related Quality of Life in Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Disease: CHANGE NOM Study.
| ObjectiveTo evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD).MethodsIn this multicenter cross-sectional study, data on consumption of medical and non-medical resources and work ability were assessed via patient questionnaires. Costs were analyzed in EUR for 2018 from the societal perspective. HRQoL was captured by the EuroQoL EQ-5D-5L questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database.ResultsTwo hundred twelve patients (80% women; median age 50 [19-83] years; median disease duration 7 [0-43] years; median Expanded Disability Status Scale [EDSS] 3.5 [0-8.5]; 66% Aquaporin-4 IgG, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for EUR (Euro) 59 574 (95% CI 51 225 to 68 293; USD [United States dollars] 70 297, 95% CI 60 445 to 80 586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65 to 0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%) and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ=0.56, 95% CI 0.45 to 0.65); in the EDSS 6.5-8.5 subgroup the mean annual costs were EUR 129 687 (95% CI 101 946 to 160 336; USD 153 031, 95% CI 120 296 to 189 196). The HRQoL revealed a negative correlation to disease severity (ρ=-0.69, 95% CI -0.76 to -0.61); in the EDSS 6.5-8.5 subgroup the EQ-5D-5L mean index value was 0.195 (95% CI 0.13 to 0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL.ConclusionThese German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and preserve quality of life. |
Neurology. 2022 Mar 15;98(11):e1184-e1196
Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, Appelt-Menzel A, Cubukova A, Barenberg J, Leu J, Hartmann K, Thies E, Littau JL, Sepulveda-Falla D, Zhang L, Ton K, Liang Y, Matschke J, Ricklefs F, Sauvigny T, Sperhake J, Fitzek A, Gerhartl A, Brachner A, Geiger N, König EM, Bodem J, Franzenburg S, Franke A,Moese S, Müller FJ,Geisslinger G, Claussen C, Kannt A, Zaliani A, Gribbon P, Ondruschka B, Neuhaus W, Friese MA, Glatzel M, Pless O.
The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2.
Stem Cell Reports. 2022 Jan 3;S2213-6711(21)00650-0.
Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, Appelt-Menzel A, Cubukova A, Barenberg J, Leu J, Hartmann K, Thies E, Littau JL, Sepulveda-Falla D, Zhang L, Ton K, Liang Y, Matschke J, Ricklefs F, Sauvigny T, Sperhake J, Fitzek A, Gerhartl A, Brachner A, Geiger N, König EM, Bodem J, Franzenburg S, Franke A,Moese S, Müller FJ,Geisslinger G, Claussen C, Kannt A, Zaliani A, Gribbon P, Ondruschka B, Neuhaus W, Friese MA, Glatzel M, Pless O.
The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2.
| Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients‘ brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling. |
Stem Cell Reports. 2022 Jan 3;S2213-6711(21)00650-0.
Rosenkranz SC, Häußler V, Kolster M, Willing A, Matschke J, Röcken C, Stürner K, Leypoldt F, Tolosa E, Friese MA.
Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.
Brain Commun. 2021 Dec 16;4(1)
Rosenkranz SC, Häußler V, Kolster M, Willing A, Matschke J, Röcken C, Stürner K, Leypoldt F, Tolosa E, Friese MA.
Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.
| Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression. |
Brain Commun. 2021 Dec 16;4(1)
Fleischer V, Ciolac D, Gonzalez-Escamilla G, Grothe M, Strauss S, Molina Galindo LS, Radetz A, Salmen A, Lukas C, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Kümpfel T, Zettl UK, Knop M, Tumani H, Wiendl H, Gold R, Bittner S, Zipp F, Groppa S, Muthuraman M; German Competence Network Multiple Sclerosis (KKNMS).
Subcortical volumes as early predictors of fatigue in multiple sclerosis.
Ann Neurol. 2021 Dec 30
Fleischer V, Ciolac D, Gonzalez-Escamilla G, Grothe M, Strauss S, Molina Galindo LS, Radetz A, Salmen A, Lukas C, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Kümpfel T, Zettl UK, Knop M, Tumani H, Wiendl H, Gold R, Bittner S, Zipp F, Groppa S, Muthuraman M; German Competence Network Multiple Sclerosis (KKNMS).
Subcortical volumes as early predictors of fatigue in multiple sclerosis.
| Objective: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after four years by applying structural equation modeling (SEM). Methods: This multi-center cohort study included 601 treatment-naive MS patients after the first demyelinating event. All patients underwent a standardized 3T MRI protocol. A subgroup of 230 patients with available clinical follow-up data after four years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis. Results: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient]=0.763, p=0.003 [left]; s=0.755, p=0.006 [right]), putamen (s=0.614, p=0.002 [left]; s=0.606, p=0.003 [right]) and pallidum (s=0.606, p=0.012 [left]; s=0.606, p=0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s=0.605, p=0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p=0.008 [left]; p=0.007 [right]) and pons (p=0.0001). Interpretation: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. |
Ann Neurol. 2021 Dec 30
Thaler C, Hartramph I, Stellmann JP, Heesen C, Bester M, Fiehler J, Gellißen S
T1 Relaxation Times in the Cortex and Thalamus Are Associated With Working Memory and Information Processing Speed in Patients with Multiple Sclerosis
Front Neurol. 2021 Dec 3;12:789812
Thaler C, Hartramph I, Stellmann JP, Heesen C, Bester M, Fiehler J, Gellißen S
T1 Relaxation Times in the Cortex and Thalamus Are Associated With Working Memory and Information Processing Speed in Patients with Multiple Sclerosis
| Background: Cortical and thalamic pathologies have been associated with cognitive impairment in patients with multiple sclerosis (MS). Objective: We aimed to quantify cortical and thalamic damage in patients with MS using a high-resolution T1 mapping technique and to evaluate the association of these changes with clinical and cognitive impairment. Methods: The study group consisted of 49 patients with mainly relapsing-remitting MS and 17 age-matched healthy controls who received 3T MRIs including a T1 mapping sequence (MP2RAGE). Mean T1 relaxation times (T1-RT) in the cortex and thalami were compared between patients with MS and healthy controls. Additionally, correlation analysis was performed to assess the relationship between MRI parameters and clinical and cognitive disability. Results: Patients with MS had significantly decreased normalized brain, gray matter, and white matter volumes, as well as increased T1-RT in the normal-appearing white matter, compared to healthy controls (p < 0.001). Partial correlation analysis with age, sex, and disease duration as covariates revealed correlations for T1-RT in the cortex (r = -0.33, p < 0.05), and thalami (right thalamus: r = -0.37, left thalamus: r = -0.50, both p < 0.05) with working memory and information processing speed, as measured by the Symbol-Digit Modalities Test. Conclusion: T1-RT in the cortex and thalamus correlate with information processing speed in patients with MS. |
Front Neurol. 2021 Dec 3;12:789812
Mayer-Arndt L, Schmitz-Hübsch T, Bellmann-Strobl J, Brandt A, Haynes J, Gold SM, Paul F, Weygandt M.
Neural Processes of Psychological Stress and Relaxation Predict the Future Evolution of Quality of Life in Multiple Sclerosis
Front Neurol 2021 Nov 23;12:753107.
Mayer-Arndt L, Schmitz-Hübsch T, Bellmann-Strobl J, Brandt A, Haynes J, Gold SM, Paul F, Weygandt M.
Neural Processes of Psychological Stress and Relaxation Predict the Future Evolution of Quality of Life in Multiple Sclerosis
Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363-1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL (t = 3.68, p family-wise error [FWE]-corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an αFWE = 0.1 level (t = 3.37, p FWE = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale (t = -3.62, p FWE = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors.Keywords: functional magnet resonance imaging (fMRI); multiple sclerosis; neuropsychiatric symptoms; psychological stress; quality of life.
Front Neurol 2021 Nov 23;12:753107.
Brasanac J, Ramien C, Gamradt S, Tänzer A, Glau L, Ritter K, Patas K, Agorastos A, Wiedemann K, Demiraley C, Fischer F, Otte C, Weygandt M, Gold SM.
Immune signature of multiple sclerosis-associated depression.
Brain Behav Immun. 2021 Dec 1;S0889-1591(21)00625-5.
Brasanac J, Ramien C, Gamradt S, Tänzer A, Glau L, Ritter K, Patas K, Agorastos A, Wiedemann K, Demiraley C, Fischer F, Otte C, Weygandt M, Gold SM.
Immune signature of multiple sclerosis-associated depression.
| Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as „inflammatory depression“. As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n=132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of „inflammatory“ subtypes of depression. |
Brain Behav Immun. 2021 Dec 1;S0889-1591(21)00625-5.
Lagrèze W, Küchlin S, Ihorst G, Grotejohann B, Beisse F, Volkmann M, Heinrich S, Abrecht P, Ungewiss J, Wörner M, Hug M, Wolf S, Diem R, Tone study group (Stellmann, Heesen, Rosenkranz).
Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study
Front Neurol 2021 Nov 23;12:753107.
Lagrèze W, Küchlin S, Ihorst G, Grotejohann B, Beisse F, Volkmann M, Heinrich S, Abrecht P, Ungewiss J, Wörner M, Hug M, Wolf S, Diem R, Tone study group (Stellmann, Heesen, Rosenkranz).
Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study
Background: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial.Methods: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571.Findings: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 μm (SD 14·91) in the erythropoietin group and 14·65 μm (15·60) in the placebo group (adjusted mean treatment difference 1·02 μm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae.Interpretation: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis.Funding: German Federal Ministry of Education and Research (BMBF).
Front Neurol 2021 Nov 23;12:753107.
Ringelstein M, Ayzenberg L, Lindenblatt G, Fischer K, Gahlen A, Novi G, Hayward-Könnecke H, Schippling S, Rommer P, Kornek B, Zrzavy T, Biotti D, Crion J, Audoin B, Berthele A, Giglhuber K, Zephir H, Kümpfel T, Berger R, Röther J, Häußler V, Stellmann J, Whittam D, Jacob A, Kraemer M, Gueguen A, Deschamps R, Bayas A, Hümmert M, Trebst C, Haarmann A, Jarius S, Wildemann, Grothe M, Siebert N, Ruprecht K, Paul F, Collongues N, Marignier R, Levy M, Karenfort M, Deppe M, Albrecht P, Hellwig K, Gold R, Hartung H, Meuth S, Kleiter I, Aktas O.
Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders
Neurol Neuroimmunol Neuroinflamm 2021 Nov 16;9(1):e1100.
Ringelstein M, Ayzenberg L, Lindenblatt G, Fischer K, Gahlen A, Novi G, Hayward-Könnecke H, Schippling S, Rommer P, Kornek B, Zrzavy T, Biotti D, Crion J, Audoin B, Berthele A, Giglhuber K, Zephir H, Kümpfel T, Berger R, Röther J, Häußler V, Stellmann J, Whittam D, Jacob A, Kraemer M, Gueguen A, Deschamps R, Bayas A, Hümmert M, Trebst C, Haarmann A, Jarius S, Wildemann, Grothe M, Siebert N, Ruprecht K, Paul F, Collongues N, Marignier R, Levy M, Karenfort M, Deppe M, Albrecht P, Hellwig K, Gold R, Hartung H, Meuth S, Kleiter I, Aktas O.
Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders
Background and objectives: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).Methods: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.Results: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.Discussion: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.
Neurol Neuroimmunol Neuroinflamm 2021 Nov 16;9(1):e1100.
Gamradt S, Hasselmann H, Taenzer A, Brasanac J, Stiglbauer V, Sattler A, Sajitz-Hermstein M, Kierszniowska S, Ramien C, Nowacki J, Mascarell-Maricic L, Wingenfeld K, Piber D, Ströhle A, Kotsch J, Paul F, Otte C, Gold SM.
Reduced mitochondrial respiration in T cells of patients with major depressive disorder
iScience 2021 Oct 16;24(11):103312.
Gamradt S, Hasselmann H, Taenzer A, Brasanac J, Stiglbauer V, Sattler A, Sajitz-Hermstein M, Kierszniowska S, Ramien C, Nowacki J, Mascarell-Maricic L, Wingenfeld K, Piber D, Ströhle A, Kotsch J, Paul F, Otte C, Gold SM.
Reduced mitochondrial respiration in T cells of patients with major depressive disorder
Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.
iScience 2021 Oct 16;24(11):103312.
Dürr M, Nissen G, Sühs K, Schwenkenbecher P, Geis C, Ringelstein N, Hartung H, Friese MA, Kaufmann M, Malter M, Madlener M, Thaler F, Kümpfel T, Senel M, Häusler M, Schneider H, Bergh F, Kellinghaus C, Zettl U, Wandinger K, Melzer N, Gross C, Lange P, Dreyhaupt, Tumani H, Leypoldt F, Lewerenz J.
CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis
Neurol Neuroimmunol Neuroinflammn 2021 Oct 25;8(6):e1086.
Dürr M, Nissen G, Sühs K, Schwenkenbecher P, Geis C, Ringelstein N, Hartung H, Friese MA, Kaufmann M, Malter M, Madlener M, Thaler F, Kümpfel T, Senel M, Häusler M, Schneider H, Bergh F, Kellinghaus C, Zettl U, Wandinger K, Melzer N, Gross C, Lange P, Dreyhaupt, Tumani H, Leypoldt F, Lewerenz J.
CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis
Background and objectives: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.Methods: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.Results: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.Discussion: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.
Neurol Neuroimmunol Neuroinflammn 2021 Oct 25;8(6):e1086.
Sippel A, Riemann-Lorenz K, Scheiderbauer J, Kleiter I, Morrison R, Kofahl C, Heesen C.
Patients experiences with multiple sclerosis disease-modifying therapies in daily life – a qualitative interview study
BMC Health Serv Res 2021 Oct 22;21(1):1141.
Sippel A, Riemann-Lorenz K, Scheiderbauer J, Kleiter I, Morrison R, Kofahl C, Heesen C.
Patients experiences with multiple sclerosis disease-modifying therapies in daily life – a qualitative interview study
Background: Besides coping with a disease with many uncertainties, people with relapsing-remitting multiple sclerosis face complex decisions concerning disease-modifying therapies (DMTs). In an interview study, we aimed to assess patients‘ experiences with DMTs.Methods: Problem-centred interviews were conducted with 50 people with relapsing-remitting multiple sclerosis in Germany using maximum variation sampling and covering all licensed DMTs. Data were analysed thematically using deductive and inductive categories.Results: 47 of 50 patients had treatment with at least one of the approved DMTs. The main themes were: (1) starting a DMT, (2) switching to another DMT, (3) discontinuing a DMT, and (4) multiple sclerosis without starting a DMT. Different intercorrelated factors influenced the decision-making processes for or against a DMT. Individual experiences with DMTs in daily life contained the effort in administration, success, and failure of DMTs, coping strategies and well-being without DMTs. The decision-making process for or against a DMT and the use of those treatments can be understood as a constant, continually shifting process, complicated by different factors, which change over time. Experiences with DMTs were characterized by attempts to handle uncertainty and to (re)gain control and integrate adaptivity into one’s life.Conclusions: The study provides a rich and nuanced amount of patients‘ experiences with DMTs. The findings demonstrate the importance for practitioners to look at current life circumstances of patients with multiple sclerosis when recommending a DMT and to promote and enable patients to make informed decisions.Keywords: Decision making; Multiple sclerosis; Patient experiences; Qualitative study; Thematic analysis; Web-based experiential information.
BMC Health Serv Res 2021 Oct 22;21(1):1141.
Kurelic R, F.Krieg P, Sonner J, Bhaiyan G, Ramos G, Frantz S, Friese MA, Nikolaev V.
Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
Front Pharmacol 2021 Oct 5;12:748798.
Kurelic R, F.Krieg P, Sonner J, Bhaiyan G, Ramos G, Frantz S, Friese MA, Nikolaev V.
Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically.
Front Pharmacol 2021 Oct 5;12:748798.
Huang Y, Peng K, Popejoy A, Hu J, Nowicki T, Gold SM, Quintana-Murci L, Fuentes-Guajardo M, Shugay M, Greiff V, Burkhardt A, Alachkar H, Mangul S.
Ancestral diversity is limited in published T cell receptor sequencing studies
Immunity 2021 Oct 12;54(10):2177-2179.
Huang Y, Peng K, Popejoy A, Hu J, Nowicki T, Gold SM, Quintana-Murci L, Fuentes-Guajardo M, Shugay M, Greiff V, Burkhardt A, Alachkar H, Mangul S.
Ancestral diversity is limited in published T cell receptor sequencing studies
No abstract available
Immunity 2021 Oct 12;54(10):2177-2179.
Wenzel L, Heesen C, Scheiderbauer J, van de Loo M, Köpke S, Rahn Ac.
Evaluation of an interactive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2): study protocol for a process evaluation accompanying a randomised controlled trial
BMJ Open 2021 Oct 1;11(10):e046874.
Wenzel L, Heesen C, Scheiderbauer J, van de Loo M, Köpke S, Rahn Ac.
Evaluation of an interactive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2): study protocol for a process evaluation accompanying a randomised controlled trial
Introduction: Process evaluations accompanying complex interventions examine the implementation process of the underlying intervention, identify mechanisms of impact and assess contextual factors. This paper presents the protocol for a process evaluation conducted alongside the randomised controlled trial POWER@MS2. The trial comprises the evaluation of a web-based complex intervention on relapse management in 188 people with multiple sclerosis conducted in 20 centres. The web-based intervention programme focuses on relapse treatment decision making and includes a decision aid, a nurse-led webinar and an online chat. With the process evaluation presented here, we aim to assess participants‘ responses to and interactions with the intervention to understand how and why the intervention produces change.Methods and analysis: A mixed methods design is used to explore the acceptance of the intervention as well as its use and impact on participants. Participants are people with multiple sclerosis, neurologists, nurses and stakeholders. Quantitative semistandardised evaluation forms will be collected throughout the study. Qualitative semistructured telephone interviews will be conducted at the end of the study with selected participants, especially people with multiple sclerosis and neurologists. Quantitative data will be collected and analysed descriptively. Based on the results, the qualitative interviews will be conducted and analysed thematically, and the results will be merged in a joint display table.Ethics and dissemination: The process evaluation has received ethical approval from the Ethical Committee of the University of Lübeck (reference 19-024). Findings will be disseminated in peer-reviewed journals, at conferences, meetings and on relevant patient websites.Trial registration number: NCT04233970.
BMJ Open 2021 Oct 1;11(10):e046874.
Heestermans M, Naudin C, Mailer R, Konrath S, Klaetschke, Jämsä A, Frye M, Deppermann C, Paula G, Kuta P, Friese M, Gelderblom M, Sickmann A, Preston R, Nofer J, Rose-Jahn S, Butler L, Salomon O, Stavrou E, Renné T.
Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
Nat Commun 2021 Sep 22;12(1):5596.
Heestermans M, Naudin C, Mailer R, Konrath S, Klaetschke, Jämsä A, Frye M, Deppermann C, Paula G, Kuta P, Friese M, Gelderblom M, Sickmann A, Preston R, Nofer J, Rose-Jahn S, Butler L, Salomon O, Stavrou E, Renné T.
Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
Nat Commun 2021 Sep 22;12(1):5596.
Giovannelli J, Ciron J, Cohen M, Kim H, Kim S, Stellmann J, Kleiter I, McCreay M, Greenberg B, Deschamps R, Audoin B, Maillart E, Papeix C, Collongues N, Bourre B, Laplaud D, Ayrignac X, Durand-Dubief F, Ruet A, Vukusic S, Marignier R, Dauchet L, Zephir H.
A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica
Ann Clin Transl Neurol 2021 Oct;8(10):2025-2037
Giovannelli J, Ciron J, Cohen M, Kim H, Kim S, Stellmann J, Kleiter I, McCreay M, Greenberg B, Deschamps R, Audoin B, Maillart E, Papeix C, Collongues N, Bourre B, Laplaud D, Ayrignac X, Durand-Dubief F, Ruet A, Vukusic S, Marignier R, Dauchet L, Zephir H.
A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica
Objective: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used.Methods: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors.Results: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA.Interpretation: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX.
Ann Clin Transl Neurol 2021 Oct;8(10):2025-2037
Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen FF, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, Sühs KW.
Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis
Neurol Neuroimmunol Neuroinflamm 2021 Aug 24;8(6):e1062.
Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen FF, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, Sühs KW.
Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis
| Background and objectives: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE.Methods: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched.Results: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected.Discussion: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS. |
Neurol Neuroimmunol Neuroinflamm 2021 Aug 24;8(6):e1062.
Haker M, Heesen C, Wenzel L, Köpke S, Rahn AC, Jasper J.
Decision-making about corticosteroids in relapses of multiple sclerosis – development of a questionnaire based on the theory of planned behaviour
Mult Scler Relat Disord. 2021 Oct;55:103182.
Haker M, Heesen C, Wenzel L, Köpke S, Rahn AC, Jasper J.
Decision-making about corticosteroids in relapses of multiple sclerosis – development of a questionnaire based on the theory of planned behaviour
| Background: Walking disability is one of the most frequent and burdening symptoms of progressive multiple sclerosis (MS). Most of the exercise intervention studies that showed an improvement in mobility performance were conducted in low to moderately disabled relapsing-remitting MS patients with interventions using the legs. However, MS patients with substantial walking disability hardly can perform these tasks. Earlier work has indicated that aerobic arm training might also improve walking performance and could therefore be a therapeutic option in already moderately disabled progressive MS patients. Methods: Patients with progressive MS and EDSS 4-6.5 were randomized using a computer-generated algorithm list to either a waitlist control group (CG) or an intervention group (IG). The IG performed a 12-week home-based, individualized arm ergometry exercise training program. Maximum walking distance as measured by the 6-min walking test (6MWT) was the primary endpoint. Secondary endpoints included aerobic fitness, other mobility tests, cognitive functioning, as well as fatigue and depression. Results: Of n = 86 screened patients, 53 with moderate disability (mean EDSS 5.5, SD 0.9) were included and data of 39 patients were analyzed. Patients in the IG showed strong adherence to the program with a mean of 67 (SD 26.4) training sessions. Maximum work load (P max) increased in the training group while other fitness indicators did not. Walking distance in the 6MWT improved in both training and waitlist group but not significantly more in trained patients. Similarly, other mobility measures showed no differential group effect. Cognitive functioning remained unchanged. No serious events attributable to the intervention occurred. Conclusion: Although maximum work load improved, 3 months of high-frequency arm ergometry training of low to moderate intensity could not show improved walking ability or cognitive functioning in progressive MS compared to a waitlist CG. The study was registered at www.clinicaltrials.gov (NCT03147105) and funded by the local MS self-help organization.Keywords: aerobic exercise; arm ergometry; cognition; multiple sclerosis; progressive multiple sclerosis. |
Mult Scler Relat Disord. 2021 Oct;55:103182.
Heinrich l, Rosenthal F, Patra S, Schulz KH, Welsch GH, Vettorazzi E, Rosenkranz SC, Stellmann JP, Ramien C, Pöttgen J, Gold SM, Heesen C.
Arm Ergometry to Improve Mobility in Progressive Multiple Sclerosis (AMBOS)-Results of a Pilot Randomized Controlled Trial
Front Neurol. 2021 Jul 19;12:644533.
Heinrich l, Rosenthal F, Patra S, Schulz KH, Welsch GH, Vettorazzi E, Rosenkranz SC, Stellmann JP, Ramien C, Pöttgen J, Gold SM, Heesen C.
Arm Ergometry to Improve Mobility in Progressive Multiple Sclerosis (AMBOS)-Results of a Pilot Randomized Controlled Trial
Background: Walking disability is one of the most frequent and burdening symptoms of progressive multiple sclerosis (MS). Most of the exercise intervention studies that showed an improvement in mobility performance were conducted in low to moderately disabled relapsing-remitting MS patients with interventions using the legs. However, MS patients with substantial walking disability hardly can perform these tasks. Earlier work has indicated that aerobic arm training might also improve walking performance and could therefore be a therapeutic option in already moderately disabled progressive MS patients. Methods: Patients with progressive MS and EDSS 4-6.5 were randomized using a computer-generated algorithm list to either a waitlist control group (CG) or an intervention group (IG). The IG performed a 12-week home-based, individualized arm ergometry exercise training program. Maximum walking distance as measured by the 6-min walking test (6MWT) was the primary endpoint. Secondary endpoints included aerobic fitness, other mobility tests, cognitive functioning, as well as fatigue and depression. Results: Of n = 86 screened patients, 53 with moderate disability (mean EDSS 5.5, SD 0.9) were included and data of 39 patients were analyzed. Patients in the IG showed strong adherence to the program with a mean of 67 (SD 26.4) training sessions. Maximum work load (P max) increased in the training group while other fitness indicators did not. Walking distance in the 6MWT improved in both training and waitlist group but not significantly more in trained patients. Similarly, other mobility measures showed no differential group effect. Cognitive functioning remained unchanged. No serious events attributable to the intervention occurred. Conclusion: Although maximum work load improved, 3 months of high-frequency arm ergometry training of low to moderate intensity could not show improved walking ability or cognitive functioning in progressive MS compared to a waitlist CG. The study was registered at www.clinicaltrials.gov (NCT03147105) and funded by the local MS self-help organization.Keywords: aerobic exercise; arm ergometry; cognition; multiple sclerosis; progressive multiple sclerosis.
Front Neurol. 2021 Jul 19;12:644533.
Melief J, Huitinga I, Gold SM.
The stress-axis in multiple sclerosis: Clinical, cellular, and molecular aspects.
Handb Clin Neurol. 2021;181:119-126
Melief J, Huitinga I, Gold SM.
The stress-axis in multiple sclerosis: Clinical, cellular, and molecular aspects.
| Altered activity of the hypothalamus-pituitary-adrenal (HPA) stress-axis has been implicated in the pathogenesis and progression of multiple sclerosis (MS) and linked to the development of specific symptoms and comorbidities such as mood disorders, fatigue, or cognitive dysfunction. Overall the HPA-axis is activated or hyperresponsive in MS, though a hyporesponsive HPA-axis has been observed in a subgroup of MS patients that has a more severe course of the disease. Here we provide an overview of the possible causes of HPA-axis activation, sex- and subtype dependent differences, pathological, cellular, and molecular effects, and the clinical correlates of HPA-axis activity in MS. |
Handb Clin Neurol. 2021;181:119-126
Woo MS, Haag F, Nierhaus A, Jarczak D, Roedl K, Mayer C, Brehm TT, van der Meirschen M, Hennigs A, Christopeit M, Fiedler W, Karagiannis P, Burdelski C, Schultze A, Huber S, Addo MM, Schmiedel S, Friese MA, Kluge S, Schulze Zur Wiesch J
Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19
iScience. 2021 Jul 23;24(7):102752
Woo MS, Haag F, Nierhaus A, Jarczak D, Roedl K, Mayer C, Brehm TT, van der Meirschen M, Hennigs A, Christopeit M, Fiedler W, Karagiannis P, Burdelski C, Schultze A, Huber S, Addo MM, Schmiedel S, Friese MA, Kluge S, Schulze Zur Wiesch J
Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19
| COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical COVID-19 SeveriTy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients. Keywords: COVID-19; Immunology; Intensive Care Medicine; Liver damage; Severity prediction; Systems biology. |
iScience. 2021 Jul 23;24(7):102752
Ramaglia V, Dubey M, Malpede MA, Petersen N, de Vries SI, Ahmed SM, Lee DSW, Schenk GJ, Gold SM, Huitinga I, Gommerman JL, Geurts JJG, Kole MHP
Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
Acta Neuropathol. 2021 Oct;142(4):643-667.
Ramaglia V, Dubey M, Malpede MA, Petersen N, de Vries SI, Ahmed SM, Lee DSW, Schenk GJ, Gold SM, Huitinga I, Gommerman JL, Geurts JJG, Kole MHP
Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
| The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by intrinsic changes and a reduced spike output. Finally, consistent with excitability deficits, we show that cuprizone-treated mice exhibit impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS. Keywords: Complement; Demyelination; Hippocampus; Microglia; Multiple sclerosis; Synapses. |
Acta Neuropathol. 2021 Oct;142(4):643-667.
Ayzenberg I, Richter D, Henke E, Asseyer S, Paul F, Trebst C, Hümmert MW, Havla J, Kümpfel T, Ringelstein M, Aktas O, Wildemann B, Jarius S, Häußler V, Stellmann JP, Senel M, Klotz L, Pellkofer HL, Weber MS, Pawlitzki M, Rommer PS, Berthele A, Wernecke KD, Hellwig K, Gold R, Kleiter I, NEMOS (Neuromyelitis Optica Study Group)
Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder: A Cross-Sectional Study of 166 AQP4 Antibody-Seropositive Patients
Neurol Neuroimmunol Neuroinflamm. 2021 Apr 20;8(3):e985
Ayzenberg I, Richter D, Henke E, Asseyer S, Paul F, Trebst C, Hümmert MW, Havla J, Kümpfel T, Ringelstein M, Aktas O, Wildemann B, Jarius S, Häußler V, Stellmann JP, Senel M, Klotz L, Pellkofer HL, Weber MS, Pawlitzki M, Rommer PS, Berthele A, Wernecke KD, Hellwig K, Gold R, Kleiter I, NEMOS (Neuromyelitis Optica Study Group)
Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder: A Cross-Sectional Study of 166 AQP4 Antibody-Seropositive Patients
| Objectives: To evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort. Methods: We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory-II, and Short Form 36 Health Survey. Results: One hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, p = 0.018) and involved upper thoracic segments (OR = 1.31, p = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, p = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, p < 0.001) and especially neuropathic character (OR = 3.44, p < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain. Conclusions: Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD. |
Neurol Neuroimmunol Neuroinflamm. 2021 Apr 20;8(3):e985
Zhang HW, Huck K, Jähne K, Cichon F, Sonner JK, Ufer F, Bauer S, Woo MS, Green E, Lu K, Kilian M, Friese MA, Platten M, Sahm K.
Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma
Oncoimmunology. 2021 May 14;10(1):1920739
Zhang HW, Huck K, Jähne K, Cichon F, Sonner JK, Ufer F, Bauer S, Woo MS, Green E, Lu K, Kilian M, Friese MA, Platten M, Sahm K.
Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma
| Dendritic cell (DC) vaccination has proven to be an effective and safe adjuvant for cancer immunotherapies. As the presence of DCs within the tumor microenvironment promotes adaptive antitumor immunity, enhancement of DC migration toward the tumor microenvironment following DC vaccination might represent one possible approach to increase its therapeutic efficacy. While recent findings suggest the activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) as critical regulator of DC migration in the context of autoimmune diseases, we aimed to investigate the impact of Arc/Arg3.1 expression for DC-based cancer vaccines. To this end, DC migration capacity as well as the induction of T cell-mediated antitumor immunity was assessed in an experimental B16 melanoma model with Arc/Arg3.1-/- and Arc/Arg3.1-expressing BMDCs applied as a subcutaneous vaccine. While antigen presentation on DCs was critical for unleashing effective T cell mediated antitumor immune responses, Arc/Arg3.1 expression enhanced DC migration toward the tumor and secondary lymphoid organs. Moreover, Arc/Arg3.1-expressing BMDCs shape the tumor immune microenvironment by facilitating tumor recruitment of antigen-specific effector T cells. Thus, Arc/Arg3.1 may represent a novel therapeutic target in DCs in order to increase the therapeutic efficacy of DC vaccination. |
Oncoimmunology. 2021 May 14;10(1):1920739
Kneussel M, Friese MA
SnapShot: Neuronal dysfunction in inflammation
Neuron. 2021 May 19;109(10):1754-1754
Kneussel M, Friese MA
SnapShot: Neuronal dysfunction in inflammation
| Neuronal function relies on tightly controlled cytoskeleton transport with adaptive cargo trafficking as prerequisite for synaptic transmission. During inflammation in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), axonal transport efficiency declines, followed by neurodegeneration. Furthermore, neuroinflammation causes an imbalance between excitatory and inhibitory transmission, triggering synaptic dysfunction and loss. Recent data suggest that neuronal transport and synaptic deficits during neuroinflammation are functionally interconnected. |
Neuron. 2021 May 19;109(10):1754-1754
Häußler V, Ufer F, Pöttgen J, Wolschke C, Friese MA, Kröger N, Heesen C, Stellmann JP
aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis
Ann Clin Transl Neurol 2021 Jun;8(6):1269-1278
Häußler V, Ufer F, Pöttgen J, Wolschke C, Friese MA, Kröger N, Heesen C, Stellmann JP
aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis
| Objective: Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab. Methods: We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance. Results: Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients. Interpretation: aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS. |
Ann Clin Transl Neurol 2021 Jun;8(6):1269-1278
Pust GEA, Randerath J, Goetzmann L, Weierstall R, Korzinski M, Gold SM, Dettmers C, Ruettner B, Schmidt R.
Association of Fatigue Severity With Maladaptive Coping in Multiple Sclerosis: A Data-Driven Psychodynamic Perspective
Front Neurol. 2021 Apr 7;12:652177.
Pust GEA, Randerath J, Goetzmann L, Weierstall R, Korzinski M, Gold SM, Dettmers C, Ruettner B, Schmidt R.
Association of Fatigue Severity With Maladaptive Coping in Multiple Sclerosis: A Data-Driven Psychodynamic Perspective
| Fatigue in persons with multiple sclerosis (PwMS) is severely disabling. However, the underlying mechanisms remain incompletely understood. Recent research suggests a link to early childhood adversities and psychological trait variables. In line with these studies, this paper took a psychodynamic perspective on MS-fatigue. It was hypothesized that fatigue could represent a manifestation of maladaptive coping with intense emotions. The schema therapeutic mode model served as a theoretical and empirically validated framework, linking psychodynamic theory and empirical research methods. The study was based on a data set of N = 571 PwMS that has also served as the basis for another publication. Data was collected online. The Schema Mode Inventory was used to quantify regulatory strategies to cope with emotionally stressful experiences. In addition, depressive symptoms (Beck’s Depression Inventory – FastScreen), physical disability (Patient Determined Disease Steps), alexithymia (Toronto Alexithymia Scale-26), adverse childhood experiences (Childhood Trauma Questionnaire), and self-reported fatigue (Fatigue Scale for Motor and Cognitive Functions) were assessed. Latent profile analysis revealed three distinct groups of PwMS, based on their coping mode profiles: (1) PwMS with low maladaptive coping, (2) PwMS with avoidant/submissive coping styles, and (3) PwMS with avoidant/overcompensatory coping styles. Multivariate comparisons showed no significant difference in physical disability across the three groups. However, heightened levels of self-reported fatigue and depression symptoms occurred in PwMS with maladaptive coping styles. A path model uncovered that self-reported fatigue was robustly related to physical disability (β = 0.33) and detached/avoidant coping (Detached Protector; β = 0.34). There was no specific relation between any of the maladaptive coping modes and depression symptoms. Detached/avoidant coping was in turn predicted by childhood emotional abuse and neglect. The results indicate that childhood adversity and detached/avoidant coping styles may be associated with variability in MS-fatigue severity: PwMS that resort to detached/avoidant coping in response to negative emotions also tend to report heightened levels of fatigue, although they do not differ in their perceived disability from PwMS with low levels of fatigue and maladaptive coping. A link between MS-fatigue and the psychodynamic traumatic conversion model is discussed. The implications of these findings for therapeutic interventions require further study. |
Front Neurol. 2021 Apr 7;12:652177.
Zangemeister WH, Heesen C, Röhr D, Gold SM.
Oculomotor Fatigue and Neuropsychological Assessments mirror Multiple Sclerosis Fatigue
J Eye Mov Res. 2020 Sep 13;13(4):10.16910
Zangemeister WH, Heesen C, Röhr D, Gold SM.
Oculomotor Fatigue and Neuropsychological Assessments mirror Multiple Sclerosis Fatigue
| Fatigue is a major complaint in MS. Up to now no objective assessment tools have been established which hampers any treatment approach. Previous work has indicated an association of fatigue with cognitive measures of attention. Oculomotor tests have been established in healthy individuals as a read-out of fatigue, and to some extent in MS patients. Based on these observations we compared two groups of MS patients, one with fatigue (n=28) and one without fatigue (n=21) and a group of healthy subjects (n=15) with a standardised computerised measure of alertness and an oculomotor stress test. Patients with fatigue showed highly significant changes of their saccade dynamics as defined by the Main Sequence and Phase Plane plots: They showed slowing of saccades, the characteristical fatigue double peak, and an asymmetrical phase plane. Oculomotor tests differentiated significantly between fatigue and fatigabiliy in our MS patients. They also showed significantly worse performance in the alertness test as well as in the oculomotor task. Significantly slower reaction times were observed for tonic alertness in 2 series without a cue (p=.025 and p=.037) but not in phasic alertness with a cue (p=.24 and p=.34). Performance was influenced by disability as well as by affective state. We conclude, when controlling for disability and depression, saccadic stress tests and alertness tests could be used as an objective read-out for fatigability and fatigue in MS patients. |
J Eye Mov Res. 2020 Sep 13;13(4):10.16910
Has Silemek AC, Ranjeva JP, Bertrand Audoin, Heesen C, Gold SM, Kühn S, Weygandt M, Stellmann JP.
Delayed access to conscious processing in multiple sclerosis: Reduced cortical activation and impaired structural connectivity
Hum Brain Mapp. 2021 Apr 7.
Has Silemek AC, Ranjeva JP, Bertrand Audoin, Heesen C, Gold SM, Kühn S, Weygandt M, Stellmann JP.
Delayed access to conscious processing in multiple sclerosis: Reduced cortical activation and impaired structural connectivity
| Although multiple sclerosis (MS) is frequently accompanied by visuo-cognitive impairment, especially functional brain mechanisms underlying this impairment are still not well understood. Consequently, we used a functional MRI (fMRI) backward masking task to study visual information processing stratifying unconscious and conscious in MS. Specifically, 30 persons with MS (pwMS) and 34 healthy controls (HC) were shown target stimuli followed by a mask presented 8-150 ms later and had to compare the target to a reference stimulus. Retinal integrity (via optical coherence tomography), optic tract integrity (visual evoked potential; VEP) and whole brain structural connectivity (probabilistic tractography) were assessed as complementary structural brain integrity markers. On a psychophysical level, pwMS reached conscious access later than HC (50 vs. 16 ms, p < .001). The delay increased with disease duration (p < .001, β = .37) and disability (p < .001, β = .24), but did not correlate with conscious information processing speed (Symbol digit modality test, β = .07, p = .817). No association was found for VEP and retinal integrity markers. Moreover, pwMS were characterized by decreased brain activation during unconscious processing compared with HC. No group differences were found during conscious processing. Finally, a complementary structural brain integrity analysis showed that a reduced fractional anisotropy in corpus callosum and an impaired connection between right insula and primary visual areas was related to delayed conscious access in pwMS. Our study revealed slowed conscious access to visual stimulus material in MS and a complex pattern of functional and structural alterations coupled to unconscious processing of/delayed conscious access to visual stimulus material in MS. |
Hum Brain Mapp. 2021 Apr 7.
Poch T, Krause J, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E, Gagliani N, Schramm C.
Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis
J Hepatol. 2021 Aug;75(2):414-423
Poch T, Krause J, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E, Gagliani N, Schramm C.
Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis
| Background and aims: Little is known on the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). We here aimed to create an atlas of intrahepatic T cells and thereby in detail characterize T cells in human inflamed liver. Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n=11) and healthy donors (HD, n=4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on patients with PSC (n=24) and controls (HCV, n=5; NASH, n=3; ALD, n=16; LRM, n=10; HD, n=10). Results: We here present the landscape of intrahepatic T cells in PSC and reveal a population of intrahepatic naive-like CD4+ T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested a developmental propensity of these cells to acquire a TH17 polarization-state. Functional and chromatin accessibility experiments revealed a predisposition of circulating naive T cells from patients with PSC to polarize towards TH17 cells. Conclusion: We report on the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4+ T cells in PSC harbour the propensity to develop into TH17 cells. Lay summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We here generated a single-cell atlas of intrahepatic T cells in PSC, a type of immune cells that has previously been involved in the pathogenesis of PSC. This atlas provides a valuable data source to the field. Using that atlas, we identified a population of liver-resident naive-like CD4+ T cells which are expanded in livers of patients with PSC compared to healthy liver tissue and other liver diseases. Trajectory inference suggest that these cells have a propensity to acquire TH17-associated effector functions. Since TH17-polarized cells are considered to contribute to the development of PSC, our findings point towards a so far underestimated role of naive T cells in PSC. Keywords: Atlas; Immune-mediated liver disease; Naive T cells; Primary Sclerosing Cholangitis; Single-cell sequencing; T cells; T(H)17 cells; Tissue residency. |
J Hepatol. 2021 Aug;75(2):414-423
Bellmann-Strobl J, Paul F, Wuerfel J, Dörr J, Infante-Duarte C, Heidrich E, Körtgen B, Brandt A, Pfüller C, Radbruch H, Rust R, Siffrin V, Aktas O, Heesen C, Faiss J, Hoffmann F, Lorenz M, Zimmermann B, Groppa S, Wernecke KD, Zipp F.
Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial
Neurol Neuroimmunol Neuroinflamm. 2021 Mar 24;8(3):e981
Bellmann-Strobl J, Paul F, Wuerfel J, Dörr J, Infante-Duarte C, Heidrich E, Körtgen B, Brandt A, Pfüller C, Radbruch H, Rust R, Siffrin V, Aktas O, Heesen C, Faiss J, Hoffmann F, Lorenz M, Zimmermann B, Groppa S, Wernecke KD, Zipp F.
Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial
| Objective: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. Results: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. Conclusion: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. Classification of evidence: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. Trial registration information: Clinical trial registration number: NCT00525668. |
Neurol Neuroimmunol Neuroinflamm. 2021 Mar 24;8(3):e981
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis
Med (N Y). 2021 Mar 12;2(3):296-312
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis
| MS is a chronic autoimmune disease of the CNS associated with serious physical and cognitive disability. MS manifests most commonly in young adults with a relapsingremitting disease course (RRMS), in which recurrent episodes (relapses) of neurological symptoms are followed by clinical remission. The majority of MS patients develop a progressive form of the disease, in which an irreversible buildup of disability occurs, regardless of relapses, either from its clinical onset (primary progressive MS [PPMS]) or after approximately 10–20 years of RRMS (secondary progressive MS [SPMS]).1 Mechanistically, the relapses observed in RRMS have been linked to episodic bouts of CNS invasion by peripheral immune cells that cause demyelinating lesions in the white matter.1 therefore, targeting of the peripheral immune system can suppress RRMS disease activity as exemplified by the anti-integrin alpha 4 (ITGA4, CD49d) antibody natalizumab.2 Natalizumab blocks the extravasation of immune cells in the CNS, preventing their migration beyond the BBB and strongly suppressing relapses. Notably, in contrast to RRMS, the same treatment strategies, including natalizumab, are not effective in progressive MS, pointing to a subsequent uncoupling of disease activity from the peripheral immune system.3 Thus, there is a major unmet clinical need to understand the sequence of events that eventually leads to continuous neurodegeneration and disability progression. The best starting point would be to explore the basis for the uncoupling of the peripheral immune response and disability progression. Although it remains largely unknown and might partly be attributed to primary neurodegeneration, it could be explained by chronic organization of peripheral immune cells behind the BBB, beyond the reach of many common therapeutic strategies. This is suggested by the observation that the onset of progressive MS is best correlated with cortical lesions that are pathologically characterized by lymphocyte collections adjacent to the graymatter. 4–6 However, it is enigmatic whether such colonization of the CNS begins during the RRMS phase and therefore could be prevented at an early stage of disease. Here, we interrogated the basis of progressive MS by designing a study to (1) systematically identify immune cells homing to the CNS in RRMS, (2) test whether these cells become resident in the CNS of progressive MS patients, and (3) investigate them as a potential therapeutic target. For this purpose, we determined the signature of CNShoming cells trapped in the blood of natalizumab-treated RRMS patients using a high-dimensional readout of combined single-cell RNA sequencing (scRNA-seq) and protein surface marker profiling. We then tracked these cells in independent cohorts of both untreated RRMS and untreated progressive MS patients and investigated their localization directly in the CNS of progressive patients using spatial RNA sequencing of MS brains. Finally, we describe their detailed characteristics and suggest a strategy for specific targetingwith a view to delay or prevent the progressive phase ofMS that drives irreversible disability and is untreatable to this day. |
Med (N Y). 2021 Mar 12;2(3):296-312
Stellmann JP, Wanke N, Maarouf A, Gellißen S, Heesen C, Audoin B, Gold SM, Zaaraoui W, Poettgen J.
Cognitive performance shows domain specific associations with regional cortical thickness in multiple sclerosis
Neuroimage Clin. 2021 Feb 24; 30:102606
Stellmann JP, Wanke N, Maarouf A, Gellißen S, Heesen C, Audoin B, Gold SM, Zaaraoui W, Poettgen J.
Cognitive performance shows domain specific associations with regional cortical thickness in multiple sclerosis
| Multiple Sclerosis (MS) patients often suffer from significant cognitive impairment. Earlier research has shown relationships between regional cortical atrophy and cognitive deterioration. However, due to a large number of neuropsychological assessments and a heterogenous pattern of cognitive deficits in MS patients, reported associations patterns are also heterogenous. Using an extensive neuropsychological battery of 23 different tasks, we explored domain (attention/information processing, memory, spatial processing, executive functioning) and task-specific associations with regional cortical thickness in a representative sample of MS patients (N = 97). Cortical regions associated with multiple cognitive tasks in the left hemisphere were predominantly located in the inferior insula (attention p < 0.001, memory p = 0.047, spatial processing p = 0.004, executive functioning p = 0.037), the gyrus frontalis superior (attention p = 0.015, memory p = 0.037, spatial processing p = 0.033, executive functioning p = 0.017) and temporal medial (attention p < 0.001, memory two clusters p = 0.016 and p < 0.001, executive functioning p = 0.016). In the right hemisphere, we detected the strongest association in the sulcus interparietalis with five cluster (attention SDMT p = 0.003 and TAP_DA p < 0.001; memory Rey recall p = 0.013 and VLMT verbal learning p = 0.016; spatial processing Rey copy p < 0.001). We replicated parts of our results in an independent sample of 30 mildly disabled MS patients. Moreover, comparisons to 29 healthy controls showed that the regional associations seemed to represent rather pathophysiological dependency than a physiological one. We believe that our results may prove useful in diagnosis and rehabilitation of cognitive impairments and may serve as guidance in future magnetic resonance imaging (MRI) studies. |
Neuroimage Clin. 2021 Feb 24; 30:102606
Blome C, Carlton J, Heesen C, Janssen MF, Lloyd A, Otten M, Brazier J.
How to measure fluctuating impairments in people with MS: development of an ambulatory assessment version of the EQ-5D-5L in an exploratory study.
Qual Life Res. 2021 Jul;30(7):2081-2096
Blome C, Carlton J, Heesen C, Janssen MF, Lloyd A, Otten M, Brazier J.
How to measure fluctuating impairments in people with MS: development of an ambulatory assessment version of the EQ-5D-5L in an exploratory study.
| Background: Health fluctuations even within a single day are typical in multiple sclerosis (MS), but are not captured by widely used questionnaires like the EQ-5D-5L. This exploratory study aimed to develop an ambulatory assessment (AA) version of the EQ-5D-5L (EQ-5D-AA) where patients rate their health on mobile phones multiple times per day over several days, and to assess its feasibility and face validity. Methods: An initial EQ-5D-AA version was based on two patient focus groups. It was then tested and continuously developed in an iterative process: patients completed it over several days, followed by debriefing interviews. Findings were used to refine the EQ-5D-AA, with the resulting version being tested by the subsequent wave of patients until participants declared no need for changes anymore. Before and after the AA period, participants completed the standard paper-based EQ-5D-5L asking about ‚today‘. Results: Focus group participants reported that their impairments often fluctuated between and within days. They regarded an AA with three assessments per day over seven days most appropriate; assessment should be retrospective to the previous assessment, but not all items should be assessed at each time point. Four waves of AA testing were conducted. Thirteen out of the 17 participants preferred the AA over standard assessment as they regarded it more informative, but not too burdensome. Conclusion: The newly developed one-week AA of the EQ-5D-5L captures within-day and day-to-day health fluctuations in people with MS. From the patients‘ perspective, it is a feasible and face valid way to provide important information beyond what is captured by the standard EQ-5D-5L. |
Qual Life Res. 2021 Jul;30(7):2081-2096
Rosenkranz SC, Kaulen B, Zimmermann HG, Bittner AK, Dorr M, Stellmann JP
Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients
Front Neurosci. 2021 Feb 23;15:591302
Rosenkranz SC, Kaulen B, Zimmermann HG, Bittner AK, Dorr M, Stellmann JP
Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients
| Background: Impairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS). Objective: To study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls. Methods: We recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set. Results: We identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129-373 s). The AULCSF had better test-retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01). |
Front Neurosci. 2021 Feb 23;15:591302
Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Nornig S, Bauer S, Wagner I,Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA.
Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.
J Exp Med. 2021 May 3;218(5).e20201290
Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Nornig S, Bauer S, Wagner I,Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA.
Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.
| Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk-associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications. |
J Exp Med. 2021 May 3;218(5).e20201290
Graf LM, Rosenkranz SC, Hölzemer A, Hagel C, Goebell E, Jordan S, Friese MA, Addo MM, Schulze Zur Wiesch J, Beisel C.
Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study.
Front Neurol. 2021 Feb 4;12:632535.
Graf LM, Rosenkranz SC, Hölzemer A, Hagel C, Goebell E, Jordan S, Friese MA, Addo MM, Schulze Zur Wiesch J, Beisel C.
Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study.
| Background: Progressive multifocal leukoencephalopathy (PML) caused by JCV is a rare but frequently fatal disease of the central nervous system, usually affecting immunocompromised individuals. Our study aims to expand the data on patient characteristics, diagnosis, clinical course, possible PML-directed treatment, and outcome of patients with PML at a German tertiary-care hospital. Methods:In this single-center observational cohort study, 37 consecutive patients with a confirmed diagnosis of PML seen at the University Medical Center Hamburg-Eppendorf from 2013 until 2019 were retrospectively analyzed by chart review with a special focus on demographics, risk factors, and clinical aspects as well as PML-directed treatment and survival. Results:We identified 37 patients with definite, probable, and possible PML diagnosis. 36 patients (97%) had underlying immunosuppressive disorders such as HIV/AIDS (n = 17; 46%), previous treatment with monoclonal antibodies (n = 6; 16%), hematological or oncological malignancies (n = 6; 16%), sarcoidosis (n = 5; 14%), solid organ transplantation (n = 1; 3%), and diagnosis of mixed connective tissue disease (n = 1; 3%). In only one patient no evident immunocompromised condition was detected (n = 1; 3%). Treatment attempts to improve the outcome of PML were reported in 13 patients (n = 13; 35%). Twenty seven percent of patients were lost to follow-up (n = 10). Twenty four-month survival rate after diagnosis of PML was 56% (n = 15). Conclusion: This interdisciplinary retrospective study describes epidemiology, risk factors, clinical course, and treatment trials in patients with PML at a German tertiary-care hospital. Acquired immunosuppression due to HIV-1 constituted the leading cause of PML in this monocenter cohort. |
Front Neurol. 2021 Feb 4;12:632535.
Krause N, Riemann-Lorenz K, Steffen T, Rahn AC, Pöttgen J, Stellmann JP, Köpke S, Friede T, Icks A, Vomhof M, Temmes H, van de Loo M, Gold SM, Heesen C.
Study protocol for a randomised controlled trial of a web-based behavioural lifestyle programme for emPOWERment in early Mulitiple Sclerosis (POWER@MS1).
BMJ Open. 2021 Feb 16;11(2):e041720
Krause N, Riemann-Lorenz K, Steffen T, Rahn AC, Pöttgen J, Stellmann JP, Köpke S, Friede T, Icks A, Vomhof M, Temmes H, van de Loo M, Gold SM, Heesen C.
Study protocol for a randomised controlled trial of a web-based behavioural lifestyle programme for emPOWERment in early Mulitiple Sclerosis (POWER@MS1).
Introduction: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that mainly affects young adults. Uncertainty is a major psychological burden of the disease from diagnosis to prognosis, enhanced by the pressure to make early decisions on a diverse set of immunotherapies. Watchful waiting for 1-2 years while adapting goals and lifestyle habits to life with a chronic disease represents another reasonable option for persons with MS (PwMS). A behaviour change programme based on evidence-based patient information (EBPI) is not available in standard care. This randomised controlled trial (RCT) with an embedded process evaluation investigates the efficacy and cost-effectiveness of a web-based behavioural lifestyle programme to change lifestyle behaviour and reduce inflammatory disease activity in PwMS. Methods and analysis: A web-based behavioural intervention will be evaluated in an RCT aiming to recruit 328 persons with clinically isolated syndrome, suspected MS or confirmed MS for less than 1 year, who have not yet started immunotherapy. Moreover, a mixed-methods process evaluation and a health economic evaluation will be carried out. Participants will be recruited in at least 16 MS centres across Germany and randomised to an intervention group with 12 months of access to EBPI about lifestyle factors in MS, combined with a complex behaviour change programme or to a control group (optimised standard care). The combined primary endpoint is the incidence of new T2 lesions on MRI or confirmed relapses. Ethics and dissemination: The study has been approved by the Ethics Committee of the Hamburg Chamber of Physicians (PV6015). Trial results will be communicated at scientific conferences and meetings and presented on relevant patient websites and in patient education seminars.
BMJ Open. 2021 Feb 16;11(2):e041720
Rahn AC, Wenzel L, Icks A, Stahmann A, Scheiderbauer J, Grentzenberg K, Vomhof M, Montalbo J, Friede T, Heesen C, Köpke S.
Development and evaluation of an interactive web-based decision-making programme on relapse management for people with multiple sclerosis (POWER@MS2)-study protocol for a randomised controlled trial.
Trials. 2021 Feb 14;22(1):139.
Rahn AC, Wenzel L, Icks A, Stahmann A, Scheiderbauer J, Grentzenberg K, Vomhof M, Montalbo J, Friede T, Heesen C, Köpke S.
Development and evaluation of an interactive web-based decision-making programme on relapse management for people with multiple sclerosis (POWER@MS2)-study protocol for a randomised controlled trial.
| Introduction: Multiple sclerosis is a chronic inflammatory, degenerative disease of the central nervous system manifesting at first with relapses in about 85% of cases. In Germany, intravenous therapy with high-dose corticosteroids is the treatment standard of acute relapses. The treatment leads to a faster reduction of symptoms in about 25 of 100 treated patients but has no proven long-term benefits over placebo treatment. Intravenous treatment is not superior to oral treatment. Therefore, informed decisions on relapse management are required. An earlier randomised controlled trial showed that evidence-based patient information and education on relapse management leads to more informed decisions and more relapses not treated or treated with oral corticosteroids. This study aims to evaluate whether a web-based relapse management programme will positively change relapse management and strengthen autonomy in people with multiple sclerosis. Methods: The pragmatic double-blind randomised controlled trial is accompanied by a mixed-methods process evaluation and a health economic evaluation and follows the UK Medical Research Council guidance on developing and evaluating complex interventions. A total of 188 people with possible or relapsing-remitting multiple sclerosis with ≥ 1 relapse within the last year and/or ≥ 2 relapses within the last 2 years will be recruited and randomised using blocks. The intervention group receives a web- and dialogue-based decision aid on relapse management, a nurse-led webinar and access to a monitored chat forum. The control group receives standard information, which will be made available via the same online platform as the intervention. The primary endpoint is the proportion of relapses not treated or treated with oral corticosteroids. Key secondary endpoints are the annualised relapse rate, decision-making, empowerment, quality of life and cost-effectiveness. Facilitators and barriers will be assessed by mixed-methods process evaluation measures. The study ends when 81 relapses have been documented or after 24 months of observation per individual patient. Analyses will follow the intention-to-treat principle. Discussion: We hypothesise that the intervention will enhance patient empowerment and have a positive impact on patients‘ relapse management. |
Trials. 2021 Feb 14;22(1):139.
Rosenkranz SC, Shaposhnykov AA, Träger S, Engler JB, Witte ME, Roth V, Vieira V, Paauw N, Bauer S, Schwencke-Westphal C, Schubert C, Bal LC, Schattling B, Pless O, van Horssen J, Freichel M, Friese MA
Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
Elife.2021 Feb 10;10:e61798.
Rosenkranz SC, Shaposhnykov AA, Träger S, Engler JB, Witte ME, Roth V, Vieira V, Paauw N, Bauer S, Schwencke-Westphal C, Schubert C, Bal LC, Schattling B, Pless O, van Horssen J, Freichel M, Friese MA
Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
| While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator PGC-1α. In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity and maximum respiratory capacity. Moreover, Ppargc1a overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a aggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy. |
Elife.2021 Feb 10;10:e61798.
Thaler C, Kyselyova AA, Faizy TD, Nawka MT, Jespersen S, Hansen B, Stellmann JP, Heesen C, Stürner KH, Stark M, Fiehler J, Bester M, Gellißen S
Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging
PLoS One 2021 Feb 4;16(2):e0245844.
Thaler C, Kyselyova AA, Faizy TD, Nawka MT, Jespersen S, Hansen B, Stellmann JP, Heesen C, Stürner KH, Stark M, Fiehler J, Bester M, Gellißen S
Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging
| Background: Mean kurtosis (MK), one of the parameters derived from diffusion kurtosis imaging (DKI), has shown increased sensitivity to tissue microstructure damage in several neurological disorders. Methods: Thirty-seven patients with relapsing-remitting MS and eleven healthy controls (HC) received brain imaging on a 3T MR scanner, including a fast DKI sequence. MK and mean diffusivity (MD) were measured in the white matter of HC, normal-appearing white matter (NAWM) of MS patients, contrast-enhancing lesions (CE-L), FLAIR lesions (FLAIR-L) and black holes (BH). Results: Overall 1529 lesions were analyzed, including 30 CE-L, 832 FLAIR-L and 667 BH. Highest MK values were obtained in the white matter of HC (0.814 ± 0.129), followed by NAWM (0.724 ± 0.137), CE-L (0.619 ± 0.096), FLAIR-L (0.565 ± 0.123) and BH (0.549 ± 0.12). Lowest MD values were obtained in the white matter of HC (0.747 ± 0.068 10-3mm2/sec), followed by NAWM (0.808 ± 0.163 10-3mm2/sec), CE-L (0.853 ± 0.211 10-3mm2/sec), BH (0.957 ± 0.304 10-3mm2/sec) and FLAIR-L (0.976 ± 0.35 10-3mm2/sec). While MK differed significantly between CE-L and non-enhancing lesions, MD did not. Conclusion: MK adds predictive value to differentiate between MS lesions and might provide further information about diffuse white matter injury and lesion microstructure. |
PLoS One 2021 Feb 4;16(2):e0245844.
Silveira SL, Riemann-Lorenz K, Heesen C, Motl RW.
Current and Long-Term Physical Activity Among Adults with Multiple Sclerosis in the United States: COM-B Variables as Explanatory Factors
Int J Behav Med. 2021 Oct;28(5):561-574
Silveira SL, Riemann-Lorenz K, Heesen C, Motl RW.
Current and Long-Term Physical Activity Among Adults with Multiple Sclerosis in the United States: COM-B Variables as Explanatory Factors
| Background: Physical activity is an evidence-based, safe second-line approach for improved multiple sclerosis (MS) symptoms and disease progression. This study examined the contributions of Capability-Opportunity-Motivation-Behavior (COM-B) factors for understanding engagement in current and long-term physical activity among persons with MS in the United States (U.S.). Method: Adults with MS in the U.S. (N = 854) completed an online survey that included questions regarding demographic and clinical characteristics, COM-B constructs, Godin Leisure Time Exercise Questionnaire (GLTEQ), and Physical Activity Staging Questionnaire (PASQ). Participants were classified into groups based on the GLTEQ regarding current physical activity behavior and PASQ for long-term physical activity behavior. MANOVA and discriminant function analysis (DFA) identified COM-B constructs that differentiated physical activity groups. Results: MANOVA analyses indicated that all COM-B constructs were significantly different for both GLTEQ current physical activity groups (Wilks’s λ = .5, F(44, 1432) = 14.8) and PASQ long-term physical activity groups (Wilks’s λ = .4, F(44, 1464) = 16.9) status except Information Provision. DFA analysis regarding GLTEQ identified a function including exclusively Capability and Motivation sources of behavior that differentiated current physical activity groups such as intention and self-efficacy. DFA for PASQ identified a different function of the Capability and Motivation sources of behavior that differentiated long-term physical activity groups; the primary differentiating variables were action control and intention. Conclusion: Our results identify internal factors as the primary COM-B predictors of current and long-term physical activity among adults with MS in the U.S., and health promotion interventions may focus on assessing individual competencies and behavioral regulation for changing physical activity in MS. |
Int J Behav Med. 2021 Oct;28(5):561-574
Barabasch A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Eklund D, Kleiter I, Kasper J, Köpke S, Lezius S, Zapf A, Rahn AC, Heesen C.
Impact of a multimedia website with patient experiences of multiple sclerosis (PExMS) on immunotherapy decision making: study protocol for a pilot randomised controlled trial in a mixed-methods design.
Pilot Feasibility Stud. 2021 Jan 7;7(1):16.
Barabasch A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Eklund D, Kleiter I, Kasper J, Köpke S, Lezius S, Zapf A, Rahn AC, Heesen C.
Impact of a multimedia website with patient experiences of multiple sclerosis (PExMS) on immunotherapy decision making: study protocol for a pilot randomised controlled trial in a mixed-methods design.
| Background: A variety of management options (e.g. immunotherapies, lifestyle interventions, and rehabilitation) are available for people with relapsing-remitting multiple sclerosis (RRMS). Besides coping with the diagnosis, people with MS (pwMS) have to make complex decisions such as deciding about immunotherapies. In addition to factual information, reports of patient experiences (PEx) may support patients in decision-making. The added value of PEx in decision-making is not clear, and controlled studies are rare. Therefore, systematic methods are necessary to develop and analyse PEx. As there are no evaluated PEx for MS in Germany, we are currently creating a website presenting PEx structured according to topics and illustrated by video, audio, and text files. We aim to determine the feasibility of an intervention using PEx and evaluate whether PEx may help pwMS in their immunotherapy decision-making processes as a supplement to evidence-based information. Methods: This project will follow the Medical Research Council framework for development and evaluation of complex interventions. After the development of a website with PEx, a randomised controlled pilot trial (pilot RCT) will be conducted in 2-3 MS centres, clinics, or rehabilitation centres including 55 pwMS and accompanied by a process evaluation. Patients with a RRMS diagnosis considering immunotherapy are eligible. The primary outcome is decision self-efficacy. Secondary outcomes include preparation for decision-making, decisional conflict, risk knowledge, confidence in active participation, affective forecasting, social support, and self-reported impact of eHealth on its users. Participants will be randomly assigned either to (i) an intervention group with 4 weeks access to an evidence-based patient information resource and the PExMS-website as an adjunct or to (ii) the control group with access to evidence-based information alone. A 6-member advisory panel involving representatives of pwMS, researchers, and neurologists, who accompany the whole project, will mentor this pilot RCT. The intervention was developed with systematic methods, created with active patient involvement and in critical appraisal by an expert advisory panel. The study is innovative as it contributes to the controversial evidence on the use of PEx in the context of evidence-based patient information |
Pilot Feasibility Stud. 2021 Jan 7;7(1):16.
Stiglbauer V, Gamradt S, Scherzer M, Brasanac J, Otte C, Rose M, Hofmann T, Hinkelmann K, Gold SM
Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study
Cell Biochem Funct. 2021 Apr;39(3):423-431
Stiglbauer V, Gamradt S, Scherzer M, Brasanac J, Otte C, Rose M, Hofmann T, Hinkelmann K, Gold SM
Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study
| In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders. |
Cell Biochem Funct. 2021 Apr;39(3):423-431
Heine J, Prüß H, Scheel M, Brandt AU, Gold SM, Bartsch T, Paul F, Finke C.
Transdiagnostic hippocampal damage patterns in neuroimmunological disorders
Neuroimage Clin. 2020;28:102515
Heine J, Prüß H, Scheel M, Brandt AU, Gold SM, Bartsch T, Paul F, Finke C.
Transdiagnostic hippocampal damage patterns in neuroimmunological disorders
| Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity. |
Neuroimage Clin. 2020;28:102515
Woo MS, Malsy J, Pöttgen J, Seddiq Zai S, Ufer F, Hadjilaou A, Schmiedel S, Addo MM, Gerloff C, Heesen C, Schulze Zur Wiesch J, Friese MA
Frequent neurocognitive deficits after recovery from mild COVID-19
Brain Commun. 2020 Nov 23;2(2)
Woo MS, Malsy J, Pöttgen J, Seddiq Zai S, Ufer F, Hadjilaou A, Schmiedel S, Addo MM, Gerloff C, Heesen C, Schulze Zur Wiesch J, Friese MA
Frequent neurocognitive deficits after recovery from mild COVID-19
| Neuropsychiatric complications associated with coronavirus disease 2019 caused by the Coronavirus SARS-CoV-2 (COVID-19) are increasingly appreciated. While most studies have focussed on severely affected individuals during acute infection, it remains unclear whether mild COVID-19 results in neurocognitive deficits in young patients. Here, we established a screening approach to detect cognitive deficiencies in post-COVID-19 patients. In this cross-sectional study, we recruited 18 mostly young patients 20-105 days (median, 85 days) after recovery from mild to moderate disease who visited our outpatient clinic for post-COVID-19 care. Notably, 14 (78%) patients reported sustained mild cognitive deficits and performed worse in the Modified Telephone Interview for Cognitive Status screening test for mild cognitive impairment compared to 10 age-matched healthy controls. While short-term memory, attention and concentration were particularly affected by COVID-19, screening results did not correlate with hospitalization, treatment, viremia or acute inflammation. Additionally, Modified Telephone Interview for Cognitive Status scores did not correlate with depressed mood or fatigue. In two severely affected patients, we excluded structural or other inflammatory causes by magnetic resonance imaging, serum and cerebrospinal fluid analyses. Together, our results demonstrate that sustained sub-clinical cognitive impairments might be a common complication after recovery from COVID-19 in young adults, regardless of clinical course that were unmasked by our diagnostic approach. |
Brain Commun. 2020 Nov 23;2(2)
Patrick Ostkamp, Anke Salmen, Béatrice Pignolet, Dennis Görlich, Till F M Andlauer, Andreas Schulte-Mecklenbeck , Gabriel Gonzalez-Escamilla, Florence Bucciarelli, Isabelle Gennero, Johanna Breuer, Gisela Antony, Tilman Schneider-Hohendorf, Nadine Mykicki, Antonios Bayas, Florian Then Bergh, Stefan Bittner, Hans-Peter Hartung, Manuel A Friese, Ralf A Linker, Felix Luessi, Klaus Lehmann-Horn, Mark Mühlau, Friedemann Paul, Martin Stangel, Björn Tackenberg, Hayrettin Tumani, Clemens Warnke, Frank Weber, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Bertram Müller-Myhsok, Tania Kümpfel, Luisa Klotz, Sven G Meuth, Frauke Zipp, Bernhard Hemmer, Reinhard Hohlfeld, David Brassat, Ralf Gold, Catharina C Gross , Carsten Lukas , Sergiu Groppa , Karin Loser , Heinz Wiendl , Nicholas Schwab , German Competence Network Multiple Sclerosis (KKNMS) and the BIONAT Network
Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity
Proc Natl Acad Sci USA 2021 Jan 5;118(1):e2018457118
Patrick Ostkamp, Anke Salmen, Béatrice Pignolet, Dennis Görlich, Till F M Andlauer, Andreas Schulte-Mecklenbeck , Gabriel Gonzalez-Escamilla, Florence Bucciarelli, Isabelle Gennero, Johanna Breuer, Gisela Antony, Tilman Schneider-Hohendorf, Nadine Mykicki, Antonios Bayas, Florian Then Bergh, Stefan Bittner, Hans-Peter Hartung, Manuel A Friese, Ralf A Linker, Felix Luessi, Klaus Lehmann-Horn, Mark Mühlau, Friedemann Paul, Martin Stangel, Björn Tackenberg, Hayrettin Tumani, Clemens Warnke, Frank Weber, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Bertram Müller-Myhsok, Tania Kümpfel, Luisa Klotz, Sven G Meuth, Frauke Zipp, Bernhard Hemmer, Reinhard Hohlfeld, David Brassat, Ralf Gold, Catharina C Gross , Carsten Lukas , Sergiu Groppa , Karin Loser , Heinz Wiendl , Nicholas Schwab , German Competence Network Multiple Sclerosis (KKNMS) and the BIONAT Network
Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity
| Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (n NationMS = 946, n BIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS. |
Proc Natl Acad Sci USA 2021 Jan 5;118(1):e2018457118
Anna C Alegiani, Anne C Rahn, Anke Steckelberg, Götz Thomalla, Christoph Heesen, Sascha Köpke
Quality of Stroke Patient Information Applied in Randomized Controlled Trials-Literature Review
Front. Neurol. 2020 Dec 7;11:526515.
Anna C Alegiani, Anne C Rahn, Anke Steckelberg, Götz Thomalla, Christoph Heesen, Sascha Köpke
Quality of Stroke Patient Information Applied in Randomized Controlled Trials-Literature Review
| Background: Strokes have a huge impact on patients‘ quality of life. Although there are potentially effective secondary preventions and treatment options for stroke patients, adherence is mostly low. Low disease and treatment-related knowledge and, consequently, a lack of informed decision-making in stroke patients may contribute to this problem. However, stroke patient information did not seem to have relevant effects on patients‘ knowledge in randomized controlled trials. One contributing factor may be the lack of thoroughly developed patient information materials. Methods: We aimed to evaluate the quality of patient information materials for stroke patients by using randomized controlled trials, applying quality criteria for evidence-based patient information (EBPI). We conducted a literature search (MEDLINE, Embase, CINAHL, PsycINFO, and CENTRAL). To be included in the review, research had to be randomized controlled trials that provided stroke patient information, were published in English, and had knowledge assessed as the primary endpoint. Authors of primary studies were contacted and asked for information materials applied. Results: We screened 15,507 hits and identified 30 eligible studies. Information materials were available for only eight studies. Analyses revealed that all available materials had important shortcomings concerning EBPI quality criteria [concerning, for example, structural information (e.g., reporting conflicts of interest), content information (e.g., reporting sources of information), or comprehensive descriptions of treatment effects and side effects]. Frequently, treatment effects were reported only narratively without providing absolute numbers, values, or frequencies. Conclusion: Quality of materials differed, but none sufficiently fulfilled EBPI quality criteria. Unsatisfactory trial results concerning patient knowledge and patient involvement in decision-making may at least partially be explained by limitations of the provided materials. Future patient information should consider EBPI quality criteria. |
Front. Neurol. 2020 Dec 7;11:526515.
Meyer-Arndt L, Hetzer S. Asseyer S, Bellmann-Strobl J, Scheel M, Stellmann JP, Heesen C, Engel AK, Brandt AU, Haynes JD, Paul F, Gold SM, Weygandt M.
Blunted neural and psychological stress processing predicts future grey matter atrophy in multiple sclerosis.
Neurobiol Stress. 2020 Jul 27;13:100244
Meyer-Arndt L, Hetzer S. Asseyer S, Bellmann-Strobl J, Scheel M, Stellmann JP, Heesen C, Engel AK, Brandt AU, Haynes JD, Paul F, Gold SM, Weygandt M.
Blunted neural and psychological stress processing predicts future grey matter atrophy in multiple sclerosis.
| Background: Multiple sclerosis (MS) is characterized by two neuropathological key aspects: inflammation and neurodegeneration. Clinical studies support a prospective link between psychological stress and subsequent inflammatory disease activity. However, it is unknown if a similar link exists for grey matter (GM) degeneration as the key driver of irreversible disability. Methods: We tested whether neural network activity triggered in a psychological fMRI stress paradigm (a mental arithmetic task including social evaluation) conducted at a baseline time point predicts future GM atrophy in 25 persons with MS (14 females). Atrophy was determined between the baseline and a follow-up time point with a median delay of 1012 (Rg: 717-1439) days. Additionally, atrophy was assessed in 22 healthy subjects (13 females; median delay 771 [Rg: 740-908] days between baseline and follow-up) for comparison. Results: An analysis of longitudinal atrophy in patients revealed GM loss in frontal, parietal, and cerebellar areas. Cerebellar atrophy was more pronounced in patients than controls. Future parietal and cerebellar atrophy could be predicted based on activity of two networks. Perceived psychological stress was negatively related to future parietal atrophy in patients and activity of the network predictive of parietal atrophy was positively linked to perceived stress. Conclusions: We have shown that blunted neural and psychological stress processing have a detrimental effect on the course of MS and are interrelated. Together with research showing that psychological and neural stress processing can be altered through interventions, our findings suggest that stress processing might constitute an important modifiable disease factor. |
Neurobiol Stress. 2020 Jul 27;13:100244
Er-Lukowiak M, Duan Y, Rassendren F, Ulmann L, Nicke A, Ufer F, Friese MA, Koch-Nolte F, Magnus T, Rissiek B.
A P2rx7 Passenger Mutation Affects the Vitality and Function of T cells in Congenic Mice
iScience. 2020 Nov 27;23(12)
Er-Lukowiak M, Duan Y, Rassendren F, Ulmann L, Nicke A, Ufer F, Friese MA, Koch-Nolte F, Magnus T, Rissiek B.
A P2rx7 Passenger Mutation Affects the Vitality and Function of T cells in Congenic Mice
| Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several transgenic mice carry a P2rx7 passenger mutation that affects the function of T cells. By the example of P2rx4tm1Rass we demonstrate that P2X4ko T cells express higher levels of P2X7 and are more sensitive toward the P2X7 activators ATP and NAD+, rendering these cells more vulnerable toward NAD-induced cell death (NICD) compared with wild type (WT). The enhanced NICD sensitivity confounded functional assays e.g. cytokine production and cell migration. Our results need to be considered when working with P2rx4tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes. |
iScience. 2020 Nov 27;23(12)
Schiffmann I, Freund M, Vettorazzi E, Stellmann JP, Heyer-Borchelt S, D'Hooghe M, Häußler V, Rahn AC, Heesen C.
Assessing the effect of an evidence-based patient online educational tool for people with multiple sclerosis called UMIMS-understanding magnetic resonance imaging in multiple sclerosis: study protocol for a double-blind, randomized controlled trial
Trials. 2020 Dec 9;21(1):1008.
Schiffmann I, Freund M, Vettorazzi E, Stellmann JP, Heyer-Borchelt S, D'Hooghe M, Häußler V, Rahn AC, Heesen C.
Assessing the effect of an evidence-based patient online educational tool for people with multiple sclerosis called UMIMS-understanding magnetic resonance imaging in multiple sclerosis: study protocol for a double-blind, randomized controlled trial
| Background: While magnetic resonance imaging (MRI) plays a major role in the lives of people with multiple sclerosis (pwMS), studies have shown that MRI-specific knowledge in pwMS is limited. Moreover, poor knowledge was associated with negative feelings towards MRI (e.g. anxiety concerning MRI scan). Because information sources about MRI in MS for pwMS are not available, we designed and evaluated an evidence-based online educational platform about MRI in MS called „Understanding MRI in MS“ (UMIMS). Based on a pilot study in n= 79 subjects, an educational intervention was found to be feasible and effective. We hypothesize that MRI-specific knowledge can be increased by using UMIMS and that, subsequently, negative feelings towards MRI will be reduced and shared decision-making competences increased. Methods: This randomized, controlled, double-blinded trial (RCT) will recruit n = 120 pwMS. The intervention group will receive access to UMIMS. The control group will get access to a specifically developed control website, which visually imitates UMIMS and contains the standard information available by several MS self-help organizations. The change in MRI-specific knowledge assessed via the MRI-risk knowledge questionnaire (MRI-RIKNO) after the intervention is the primary endpoint at 2 weeks. Several secondary endpoints will be assessed at different timepoints throughout the study, e.g. emotions towards MRI, autonomy preferences, threat by MS and shared decision-making competences. The study includes a process evaluation. Discussion: The aim of this RCT is to prove that access to an education tool on MRI in MS will increase pwMS‘ MRI-specific knowledge and enhance shared decision-making when discussing decisions involving MRI results during patient-physician encounters. |
Trials. 2020 Dec 9;21(1):1008.
Benecke M, Kasper J, Heesen C, Schäffler N, Reissmann DR.
Patient autonomy in dentistry: demonstrating the role for shared decision making
BMC Med. Informations 2020 Dec 2;20(1):318.
Benecke M, Kasper J, Heesen C, Schäffler N, Reissmann DR.
Patient autonomy in dentistry: demonstrating the role for shared decision making
Background: Evidence-based practice, decision aids, patient preferences and autonomy preferences (AP) play an important role in making decisions with the patient. They are crucial in the process of a shared decision making (SDM) and can be incorporated into quality criteria for patient involvement in health care. However, there are few studies on SDM and AP in the field of dentistry. This study explored patients‘ autonomy preferences in dentistry in comparison to other medical domains, comparing them with patient preferences in two other cohorts of patients with different conditions and in different health care settings.
Methods: A sample of 100 dental patients attending 16 dentists was consecutively recruited in a university-based prosthodontic clinic. Patients‘ and dentists‘ preferences regarding their roles in dental decision making for commonly performed diagnostic and treatment decisions were compared using the Control Preference Scale (CPS). This was followed by cross sectional surveys to study autonomy preferences in three additional cohorts recruited from general practices (n = 100), a multiple sclerosis clinic (n = 109), and a university-based prosthodontic clinic (n = 100). A questionnaire with combined items from the Autonomy Preference Index (API) to assess general and the CPS to assess specific preferences was used in the additional cohorts.
Results: Dentists were less willing to give patients control than patients were willing to enact autonomy. However, decisions about management of tooth loss were considered relevant for a shared decision making by both parties. When comparing cohorts from different samples, the highest AP was expressed by people with multiple sclerosis and the lowest by patients in dentistry (means: dentistry 2.5, multiple sclerosis 2.1, general practice 2.4, p = .035). There were considerable intra-individual differences in autonomy preferences referring to different decision types (p < .001). In general, more autonomy was desired for treatment decisions in comparison to diagnostic decisions, for trivial compared to severe conditions, and for dental care compared to general practice (all: p < .001).
Conclusion: There is an important role of patient participation in decision making in dentistry. Furthermore, PA should be considered with respect to specific medical decisions instead of assessing autonomy preferences in general implying a need for communication skills training of health care professionals.
BMC Med. Informations 2020 Dec 2;20(1):318.
Otte C, Chae WR, Nowacki J, Kaczmarczyk M, Piber D, Roepke S, Märschenz S, Lischewski S, Schmidt S, Ettrich B, Grabe HJ, Hegerl U, Hinkelmann K, Hofmann T, Janowitz D, Junghanns K, Kahl KG, Klein JP, Krueger THC, Leicht G, Prvulovic D, Reif A, Schoettle D, Strauss M, Westermair A, Friede T, Gold SM.
Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial
BMJ Open. 2020 Dec 1;10(12):e040119.
Otte C, Chae WR, Nowacki J, Kaczmarczyk M, Piber D, Roepke S, Märschenz S, Lischewski S, Schmidt S, Ettrich B, Grabe HJ, Hegerl U, Hinkelmann K, Hofmann T, Janowitz D, Junghanns K, Kahl KG, Klein JP, Krueger THC, Leicht G, Prvulovic D, Reif A, Schoettle D, Strauss M, Westermair A, Friede T, Gold SM.
Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial
Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity.
Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients‘ self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12.
Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences.
BMJ Open. 2020 Dec 1;10(12):e040119.
Pust GEA, Untiedt B, Randerath J, Barabasch A, Köpke S, Rahn AC, Hansen H, Heesen C.
Exploring Adherence to First-Line and Second-Line Immunotherapies in Multiple Sclerosis: An Interview Study
Int J MS Care. Sep-Oct 2020;22(5):219-225.
Pust GEA, Untiedt B, Randerath J, Barabasch A, Köpke S, Rahn AC, Hansen H, Heesen C.
Exploring Adherence to First-Line and Second-Line Immunotherapies in Multiple Sclerosis: An Interview Study
| Background: Treatment adherence is fundamental in multiple sclerosis (MS) management. Adherence rates vary significantly between studies, ranging from 30% to almost 90%, depending on assessment method and medication type. This study aimed to identify patient-related categories associated with treatment modification or discontinuation in people with MS receiving either first- or second-line treatment. Methods: Semistructured interviews were performed with 23 people with MS: 11 receiving first-line treatment and 12 receiving second-line treatment. Medication history, experiences with previous medications, decision-making processes regarding immunotherapy, adherence behavior, and reasons for adherence/nonadherence were explored using open-ended questions. Qualitative content analysis was performed using a combined deductive-inductive approach in building a coding frame. Differences in coding frequencies were compared between the two groups and analyzed quantitatively. Cohen’s kappas of 0.76 for people with MS receiving first-line treatment and 0.64 for the second-line sample were achieved between the two coders. Results: One key reason for nonadherence reported by first-line-treated people with MS was burdensome side effects, and for adherence was belief in medication effectiveness. In people with MS receiving second-line treatment, lack of perceived medication effectiveness was a key category related to changes in or discontinuation of immunotherapy. Reasons for adherence were positive illness beliefs/perceptions and belief in highly active disease. Intentional nonadherence was a major issue for first-line treatment and less relevant for second-line treatment. Conclusions: These results indicate specific differences in factors mitigating adherence in people with MS receiving first- and second-line treatment. Keywords: Adherence; First-line treatment; Immunotherapy; Multiple sclerosis (MS); Second-line treatment. |
Int J MS Care. Sep-Oct 2020;22(5):219-225.
Montes-Cobos E, Huscher B, Engler JB, Woo MS, Binkle L, Bauer S, Kursawe N, Moles M, Friese MA, Ufer F.
Voltage-Gated Proton Channel Hv1 Controls TLR9 Activation in Plasmacytoid Dendritic Cells
J Immunol. 2020 Dec 1;205(11):3001-3010
Montes-Cobos E, Huscher B, Engler JB, Woo MS, Binkle L, Bauer S, Kursawe N, Moles M, Friese MA, Ufer F.
Voltage-Gated Proton Channel Hv1 Controls TLR9 Activation in Plasmacytoid Dendritic Cells
| The voltage-gated proton channel Hv1 regulates proton fluxes across membranes, thereby influencing pH-dependent processes. Plasmacytoid dendritic cells (pDCs) require a particularly tight regulation of endosomal pH to ensure strong type I IFN secretion exclusively during infection, avoiding autoimmunity. However, whether Hv1 is important for pH control in pDCs is presently unknown. In this study, we show that mouse pDCs require Hv1 to achieve potent type I IFN responses after the recognition of foreign DNA by endosomal TLR9. Genetic disruption of Hvcn1, which encodes Hv1, impaired mouse pDC activation by CpG oligonucleotides in vitro and in vivo, reducing IFN-α secretion and the induction of IFN-stimulated genes. Mechanistically, Hvcn1 deficiency delayed endosomal acidification and enhanced intracellular reactive oxygen species production, consequently limiting protease activity and TLR9 signaling. Our study reveals a critical role of Hv1 during innate immune responses and places this channel as a key modulator of type I IFN production, the hallmark function of pDCs, commending Hv1 as an attractive target for modulating type I IFN-driven autoimmunity. |
J Immunol. 2020 Dec 1;205(11):3001-3010
Wakonig K, Eitel F, Ritter K, Hetzer S, Schmitz-Hübsch T, Bellmann-Strobl J, Haynes JD, Brandt AU, Gold SM, Paul F, Weygandt M.
Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis
Front Neurol. 2020 Oct 6;11:568850.
Wakonig K, Eitel F, Ritter K, Hetzer S, Schmitz-Hübsch T, Bellmann-Strobl J, Haynes JD, Brandt AU, Gold SM, Paul F, Weygandt M.
Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis
| Background: Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. Objective: To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). Methods: 36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Results: Relaxation was differentially linked to heart rate in both groups (t = 2.20, p = 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants (t = 1.99, p = 0.045) although this link differed weakly between groups (t = 1.62, p = 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS (t = -5.55, pfamily-wise-error(FWE)corrected = 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) (t = -4.89, pFWE = 0.039). Conclusion: PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS. Keywords: autoimmunity; brain reward system; gray matter; multiple sclerosis; neuroinflammation; psychological relaxation; psychophysiological stress responses; ventromedial prefrontal cortex (vmPFC). |
Front Neurol. 2020 Oct 6;11:568850.
Kosch R, Schiffmann I, Daumer M, Lederer C, Scalfari A, Galea I, Scheiderbauer J, Rahn A, Heesen C.
Long-term prognostic counselling in people with multiple sclerosis using an online analytical processing tool.
Mult Scler. 2020 Oct 26
Kosch R, Schiffmann I, Daumer M, Lederer C, Scalfari A, Galea I, Scheiderbauer J, Rahn A, Heesen C.
Long-term prognostic counselling in people with multiple sclerosis using an online analytical processing tool.
| Background: Prognostic counselling is a sensitive issue in medicine and especially so in MS due to the highly heterogeneous disease course. However, people with MS (pwMS) seek prognostic information. The web-based ‚Evidence-Based Decision Support Tool in Multiple Sclerosis‘ (EBDiMS) uses data of 717 patients from the London/Ontario cohort to calculate personalized long-term prognostic information. Objective: The aim of this study was to investigate the feasibility and effect of long-term prognostic counselling in pwMS using EBDiMS. Methods: Ninety consecutive pwMS were provided with personalized estimations of expected time to reach Expanded Disability Status Scale (EDSS) scores of 6 and 8 and time to conversion to secondary-progressive MS. Participants gave estimates on their own putative prognosis and rated the tool’s acceptability on six-step Likert-type scales. Results: Participants rated EBDiMS as highly understandable, interesting and relevant for patient-physician encounters, coping and therapy decisions. Although it provoked a certain degree of worry in some participants, 95% would recommend using the tool. Participants‘ own prognosis estimates did not change significantly following EBDiMS. Conclusion: Long-term prognostic counselling using an online tool has been shown to be feasible in a clinical setting. EBDiMS provides pwMS with relevant, easy-to-understand, long-term prognostic information without causing relevant anxiety. |
Mult Scler. 2020 Oct 26
Rahn AC, Riemann-Lorenz K, Alegiani A, Pust GEA, van de Roemer A, Schmitz L, Vettorazzi E, Köpke S, Heesen C.
Comprehension of confidence intervals in audio-visual patient information materials for people with multiple sclerosis (COCO-MS): A web-based randomised controlled, parallel group trial
Patient Educ and Couns. 2021 May;104(5):1132-1139
Rahn AC, Riemann-Lorenz K, Alegiani A, Pust GEA, van de Roemer A, Schmitz L, Vettorazzi E, Köpke S, Heesen C.
Comprehension of confidence intervals in audio-visual patient information materials for people with multiple sclerosis (COCO-MS): A web-based randomised controlled, parallel group trial
| Objectives: To evaluate patient information materials on confidence intervals (CIs) in multiple sclerosis to be used with patient decision aids. Methods: Web-based randomised controlled parallel group trial with four study arms. Participants were equally allocated to one of three versions of audio-visual patient information or to a standard written information (arm IV). In the short version (arm III), CIs were explained without using an example, in the other two versions examples were used (arm I and arm II). The examples are based on an apple farmer who wants to estimate the average weight of his apples (arm I) and to test a treatment against worms (arm II). Primary endpoint was comprehension of CIs, assessed with a six-item multiple-choice questionnaire. Results: 855 of 1068 (80 %) randomised participants completed the survey (71 % arm I, 73 % arm II, 87 % arm III, 90 % arm IV). The median of correctly answered questions on CIs was 4 out of 6 questions in arms I and II and 5 out of 6 questions in arm III. Compared to the standard information (arm IV), all the other arms scored better on the comprehension questionnaire (ANOVA, p ≤0.003). Conclusions: Information about CIs can be presented comprehensibly. High scores and a high rate of completers indicate that the short version is the favourable one. Practice implications: Information materials on CIs should be used alongside absolute risk reductions in patient decision aids to enhance the interpretation of study results. |
Patient Educ and Couns. 2021 May;104(5):1132-1139
Giovanetti AM, Barabasch A, Giordano A, Quintas R, Barello S, Graffigna G, Alifieri S, Schiffmann I, Muche-Borowski C, Borreani C, Heesen C, Solari A; ManTra project
Construction of a User-Led Resource for People Transitioning to Secondary Progressive Multiple Sclerosis: Results of an Internation Nominal Group Study
Front. Neurol. 2020 Aug 18;11:798
Giovanetti AM, Barabasch A, Giordano A, Quintas R, Barello S, Graffigna G, Alifieri S, Schiffmann I, Muche-Borowski C, Borreani C, Heesen C, Solari A; ManTra project
Construction of a User-Led Resource for People Transitioning to Secondary Progressive Multiple Sclerosis: Results of an Internation Nominal Group Study
| Background: ManTra is a mixed-methods, co-production research project for developing an intervention (resource) for people with newly diagnosed secondary progressive multiple sclerosis (pwSPMS) in Italy and Germany. In previous project actions, six resources were outlined, meeting the needs prioritized by pwSPMS. Aims: This study aims to achieve multiple-stakeholder consensus on the most suitable resource and to refine the consensus resource. Methods: Two nominal group technique (NGT) meetings were held, one in Milan and one in Hamburg. Participants were pwSPMS (five in Italy/six in Germany), pwSPMS significant others (SOs, four/five), healthcare professionals (HPs, seven/four), and health service researchers/patient and citizen organizations representatives (HPCORs, five/five). Two of the four resources discussed in each meeting were the same in Italy and Germany: „Promoting the engagement of pwSPMS: a program for the patients and the HPs“ and „Enriched physiotherapy program for pwSPMS.“ The other two were „A personalized care plan for pwSPMS“ and „Roadmap for social and economic benefits“ in Italy and „Metacognitive and everyday life training for pwSPMS“ and „Psychological support for pwSPMS“ in Germany. Each meeting consisted of two plenary sessions and a parallel group session (four stakeholder groups: pwSPMS, SOs, HPs, and HPCORs) in between. Meetings‘ narratives were analyzed thematically. Results: The two meetings were rich in participation and discussion. In Italy, the consensus resource was „A personalized care plan for pwSPMS.“ Refinements included enrichment with pwSPMS engagement, inclusion of additional HPs, improved definition of the MS nurse’s role within the interdisciplinary panel, and community care integration. In Germany, the consensus resource was „Psychological support for pwSPMS.“ Refinements included reshaping this resource into a more comprehensive and adaptive rehabilitation intervention and training the psychologist in recognizing client’s rehabilitative needs and enhancing his/her autonomy. Conclusions: The NGT eased multiple-stakeholder deliberation and resource fine-tuning in both countries. |
Front. Neurol. 2020 Aug 18;11:798
Pust GEA, Dettmers C, Randerath J, Rahn AC, Heesen C, Schmidt R, Gold SM
Fatigue in Multiple Sclerosis Is Associated With Childhood Adversities
Front Psychiatry 2020 Aug 28;11:811.
Pust GEA, Dettmers C, Randerath J, Rahn AC, Heesen C, Schmidt R, Gold SM
Fatigue in Multiple Sclerosis Is Associated With Childhood Adversities
| Fatigue is a common and disabling symptom in patients with Multiple Sclerosis (PwMS). Its pathogenesis, however, is still not fully understood. Potential psychological roots, in particular, have received little attention to date. The present study examined the association of childhood adversities, specific trait characteristics, and MS disease characteristics with fatigue symptoms utilizing path analysis. Five hundred and seventy-one PwMS participated in an online survey. Standardized psychometric tools were applied. The Childhood Trauma Questionnaire (CTQ) served to assess childhood adversities. Trait variables were alexithymia (Toronto Alexithymia Scale; TAS-26) and early maladaptive schemas (Young Schema Questionnaire; YSQ). Current pathology comprised depression (Beck’s Depression Inventory FastScreen; BDI-FS) and anxiety symptoms (State-Trait Anxiety Inventory; STAI-state), as well as physical disability (Patient determined Disease Steps; PDDS). The Fatigue Scale for Motor and Cognitive Functions (FSMC) was the primary outcome variable measuring fatigue. PwMS displayed high levels of fatigue and depression (mean FSMC score: 72; mean BDI-II score: 18). The final path model revealed that CTQ emotional neglect and emotional abuse remained as the only significant childhood adversity variables associated with fatigue. There were differential associations for the trait variables and current pathology: TAS-26, the YSQ domain impaired autonomy and performance, as well as all current pathology measures had direct effects on fatigue symptoms, accounting for 28.2% of the FSMC variance. Bayesian estimation also revealed indirect effects from the two CTQ subscales on FSMC. The final model fitted the data well, also after a cross-validation check and after replacing the FSMC with the Chalder Fatigue Questionnaire (CFQ). This study suggests an association psychological factors on fatigue in Multiple Sclerosis. Childhood adversities, as well as specific trait characteristics, seem to be associated with current pathology and fatigue symptoms. The article discusses potential implications and limitations. |
Front Psychiatry 2020 Aug 28;11:811.
Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber M, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner S, Hartung HP, Aktas O, Albrecht P.
Author response: Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders
Neurology. 2020 Sep 29;95(13):610.
Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber M, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner S, Hartung HP, Aktas O, Albrecht P.
Author response: Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders
| No abstract available |
Neurology. 2020 Sep 29;95(13):610.
Rosenkranz SC, Shaposhnykov A, Schnappauff O, Epping L, Vieira V, Heidermann K, Schattling B, Tsvilovskyy V, Liedtke W, Meuth SG, Freichel M, Gelderblom M, Friese MA
TRPV4-mediated regulation of the blood brain barrier is abolished during inflammation
Front Cell Dev Biol. 2020 Aug 27;8:849
Rosenkranz SC, Shaposhnykov A, Schnappauff O, Epping L, Vieira V, Heidermann K, Schattling B, Tsvilovskyy V, Liedtke W, Meuth SG, Freichel M, Gelderblom M, Friese MA
TRPV4-mediated regulation of the blood brain barrier is abolished during inflammation
Blood-brain barrier (BBB) dysfunction is critically involved in determining the extent of several central nervous systems (CNS) pathologies and here in particular neuroinflammatory conditions. Inhibiting BBB breakdown could reduce the level of vasogenic edema and the number of immune cells invading the CNS, thereby counteracting neuronal injury. Transient receptor potential (TRP) channels have an important role as environmental sensors and constitute attractive therapeutic targets that are involved in calcium homeostasis during pathologies of the CNS. Transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable, nonselective cation channel highly expressed in endothelial cells. As it is involved in the regulation of the blood brain barrier permeability and consequently cerebral edema formation, we anticipated a regulatory role of TRPV4 in CNS inflammation and subsequent neuronal damage. Here, we detected an increase in transendothelial resistance in mouse brain microvascular endothelial cells (MbMECs) after treatment with a selective TRPV4 inhibitor. However, this effect was abolished after the addition of IFNγ and TNFa indicating that inflammatory conditions override TRPV4-mediated permeability. Accordingly, we did not observe a protection of Trpv4-deficient mice when compared to wildtype controls in a preclinical model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and no differences in infarct sizes following transient middle cerebral artery occlusion (tMCAO), the experimental stroke model, which leads to an acute postischemic inflammatory response. Furthermore, Evans Blue injections did not show differences in alterations of the blood brain barrier (BBB) permeability between genotypes in both animal models. Together, TRPV4 does not regulate brain microvascular endothelial permeability under inflammation.
Front Cell Dev Biol. 2020 Aug 27;8:849
Zhai Y, Nasseri N, Pöttgen J, Gezhelbash E, Heesen C, Stellmann JP.
Smartphone Accelerometry: A Smart and Reliable Measurement of Real-Life Physical Activity in Multiple Sclerosis and Healthy Individuals
Front Neruol. 2020 Aug 14;11:688
Zhai Y, Nasseri N, Pöttgen J, Gezhelbash E, Heesen C, Stellmann JP.
Smartphone Accelerometry: A Smart and Reliable Measurement of Real-Life Physical Activity in Multiple Sclerosis and Healthy Individuals
Background: Mobility impairment is common in persons with multiple sclerosis (pwMS) and can be assessed with clinical tests and surveys that have restricted ecological validity. Commercial research-based accelerometers are considered to be more valuable as they measure real-life mobility. Smartphone accelerometry might be an easily accessible alternative. Objective: To explore smartphone accelerometry in comparison to clinical tests, surveys, and a wrist-worn ActiGraph in pwMS and controls. Methods: Sixty-seven pwMS and 70 matched controls underwent mobility tests and surveys. Real-life data were collected with a smartphone and an ActiGraph over 7 days. We explored different smartphone metrics in a technical validation course and computed afterward correlation between ActiGraph (steps per minute), smartphone accelerometry (variance of vector magnitude), clinical tests, and surveys. We also determined the ability to separate between patients and controls as well as between different disability groups. Results: Based on the technical validation, we found the variance of the vector magnitude as a reliable estimate to discriminate wear time and no wear-time of the smartphone. Due to a further association with different activity levels, it was selected for real-life analyses. In the cross-sectional study, ActiGraph correlated moderately (r = 0.43, p < 0.05) with the smartphone but less with clinical tests (rho between |0.211| and |0.337|). Smartphone data showed stronger correlations with age (rho = -0.487) and clinical tests (rho between |0.565| and |0.605|). ActiGraph only differed between pwMS and controls (p < 0.001) but not between disability groups. At the same time, the smartphone showed differences between pwMS and controls, between RRMS and PP-/SPMS, and between participants with/without ambulatory impairment (all p < 0.001). Conclusions: Smartphone accelerometry provides better estimates of mobility and disability than a wrist-worn standard accelerometer in a free-living context for both controls and pwMS. Given the fact that no additional device is needed, smartphone accelerometry might be a convenient outcome of real-life ambulation in healthy individuals and chronic diseases such as MS.
Front Neruol. 2020 Aug 14;11:688
Voskuhl RR, Patel K, Paul F, Gold SM, Scheel M, Kuchling J, Cooper G, Asseyer S, Chien C, Brandt AU, Meyer CE, MacKenzie-Graham A.
Sex differences in brain atrophy in multiple sclerosis.
Biol Sex Differ. 2020 Aug 28;11(1):49
Voskuhl RR, Patel K, Paul F, Gold SM, Scheel M, Kuchling J, Cooper G, Asseyer S, Chien C, Brandt AU, Meyer CE, MacKenzie-Graham A.
Sex differences in brain atrophy in multiple sclerosis.
| Background: Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls. Methods: Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. Results: VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. Conclusion: More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression. |
Biol Sex Differ. 2020 Aug 28;11(1):49
Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger M, Steptoe A, Whooley MA, Otte C
Comorbid depression in medical diseases
Nat Rev Dis Primers. 2020 Aug 20;6(1):69
Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger M, Steptoe A, Whooley MA, Otte C
Comorbid depression in medical diseases
Depression is one of the most common comorbidities of many chronic medical diseases including cancer and cardiovascular, metabolic, inflammatory and neurological disorders. Indeed, the prevalence of depression in these patient groups is often substantially higher than in the general population, and depression accounts for a substantial part of the psychosocial burden of these disorders. Many factors can contribute to the occurrence of comorbid depression, such as shared genetic factors, converging biological pathways, social factors, health behaviours and psychological factors. Diagnosis of depression in patients with a medical disorder can be particularly challenging owing to symptomatic overlap. Although pharmacological and psychological treatments can be effective, adjustments may need to be made for patients with a comorbid medical disorder. In addition, symptoms or treatments of medical disorders may interfere with the treatment of depression. Conversely, symptoms of depression may decrease adherence to treatment of both disorders. Thus, comprehensive treatment plans are necessary to optimize care.
Nat Rev Dis Primers. 2020 Aug 20;6(1):69
Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE
Aerobic Exercise Induces Functional and Structural Reorganization of CNS Networks in Multiple Sclerosis: A Randomized Controlled Trial
Front Hum Neurosci. 2020 Jun 30;15:255
Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE
Aerobic Exercise Induces Functional and Structural Reorganization of CNS Networks in Multiple Sclerosis: A Randomized Controlled Trial
| Objectives: Evidence from animal studies suggests that aerobic exercise may promote neuroplasticity and could, therefore, provide therapeutic benefits for neurological diseases such as multiple sclerosis (MS). However, the effects of exercise in human CNS disorders on the topology of brain networks, which might serve as an outcome at the interface between biology and clinical performance, remain poorly understood. Methods: We investigated functional and structural networks in patients with relapsing-remitting MS in a clinical trial of standardized aerobic exercise. Fifty-seven patients were randomly assigned to moderate-intensity exercise for 3 months or a non-exercise control group. We reconstructed functional networks based on resting-state functional magnetic resonance imaging (MRI) and used probabilistic tractography on diffusion-weighted imaging data for structural networks. Results: At baseline, compared to 30 healthy controls, patients exhibited decreased structural connectivity that was most pronounced in hub regions of the brain. Vice versa, functional connectivity was increased in hubs. After 3 months, we observed hub independent increased functional connectivity in the exercise group while the control group presented a loss of functional hub connectivity. On a structural level, the control group remained unchanged, while the exercise group had also increased connectivity. Increased clustering of hubs indicates a better structural integration and internal connectivity at the top of the network hierarchy. Conclusion: Increased functional connectivity of hubs contrasts a loss of structural connectivity in relapsing-remitting MS. Under an exercise condition, a further hub independent increase of functional connectivity seems to translate in higher structural connectivity of the whole brain. |
Front Hum Neurosci. 2020 Jun 30;15:255
Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE
Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis mutants
Hum Mol Genet. 2020 Sep 29;29(16):2647-2661
Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE
Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis mutants
| Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS and TDP-43 mislocalization in MNs is a key pathological feature of > 95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined Translating Ribosome Affinity Purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43-driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease. |
Hum Mol Genet. 2020 Sep 29;29(16):2647-2661
Hermann J, Bender M, Schumacher D, Woo MS, Shaposhnykov A, Rosenkranz SC, Kuryshev V, Meier C, Guse AH, Friese MA, Freichel M, Tsvilovskyy V
Contribution of NAADP to Glutamate-Evoked Changes in CA2+ Homeostasis in Mouse Hippocampal Neurons
Front Cell Dev. Biol 2020 Jun 25;8:496
Hermann J, Bender M, Schumacher D, Woo MS, Shaposhnykov A, Rosenkranz SC, Kuryshev V, Meier C, Guse AH, Friese MA, Freichel M, Tsvilovskyy V
Contribution of NAADP to Glutamate-Evoked Changes in CA2+ Homeostasis in Mouse Hippocampal Neurons
| Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that evokes calcium release from intracellular organelles by the engagement of calcium release channels, including members of the Transient Receptor Potential (TRP) family, such as TRPML1, the (structurally) related Two Pore Channel type 1 (TPC1) and TPC2 channels as well as Ryanodine Receptors type 1 (RYR1; Guse, 2012). NAADP evokes calcium release from acidic calcium stores of many cell types (Guse, 2012), and NAADP-sensitive Ca2+ stores have been described in hippocampal neurons of the rat (Bak et al., 1999; McGuinness et al., 2007). Glutamate triggers Ca2+-mediated neuronal excitotoxicity in inflammation-induced neurodegenerative pathologies such as Multiple Sclerosis (MS; Friese et al., 2014), and when applied extracellularly to neurons glutamate can elevate NAADP levels in these cells. Accordingly, glutamate-evoked Ca2+ signals from intracellular organelles were inhibited by preventing organelle acidification (Pandey et al., 2009). Analysis of reported RNA sequencing experiments of cultured hippocampal neurons revealed the abundance of Mcoln1 (encoding TRPML1), Tpcn1, and Tpcn2 (encoding TPC1 and TPC2, respectively) as potential NAADP target channels in these cells. Transcripts encoding Ryr1 were not found in contrast to Ryr2 and Ryr3. To study the contribution of NAADP signaling to glutamate-evoked calcium transients in murine hippocampal neurons we used the NAADP antagonists Ned-19 (Naylor et al., 2009) and BZ194 (Dammermann et al., 2009). Our results show that both NAADP antagonists significantly reduce glutamate-evoked calcium transients. In addition to extracellular glutamate application, we studied synchronized calcium oscillations in the cells of the neuronal cultures evoked by addition of the GABAA receptor antagonist bicuculline. Pretreatment with Ned-19 (50 μM) or BZ194 (100 μM) led to an increase in the frequency of bicuculline-induced calcium oscillations at the cost of calcium transient amplitudes. Interestingly, Ned-19 triggered a rise in intracellular calcium concentrations 25 min after bicuculline stimulation, leading to the question whether NAADP acts as a neuroprotective messenger in hippocampal neurons. Taken together, our results are in agreement with the concept that NAADP signaling significantly contributes to glutamate evoked Ca2+ rise in hippocampal neurons and to the amplitude and frequency of synchronized Ca2+ oscillations triggered by spontaneous glutamate release events. |
Front Cell Dev. Biol 2020 Jun 25;8:496
Gasperi C, Andlauer TFM, Keatin A, Knier B, Klein A, Pernpeintner V, Lichtner P, Gold R, Zipp F, Then Bergh F, Stangel M, Tumani H, Wildemann B, Wiendl H, Bayas A, Kümpfel T, Zettl UK, Linkner RA, Ziemann U, Knop M, Warnke C, Friese MA, Paul F, Tackenberg B, Berhele A, Hemmer B.
Genetic determinants of the humoral immune response in MS
Neurol Neuroimmunol Neuroinflamm. 2020 Jul 16;7(5)
Gasperi C, Andlauer TFM, Keatin A, Knier B, Klein A, Pernpeintner V, Lichtner P, Gold R, Zipp F, Then Bergh F, Stangel M, Tumani H, Wildemann B, Wiendl H, Bayas A, Kümpfel T, Zettl UK, Linkner RA, Ziemann U, Knop M, Warnke C, Friese MA, Paul F, Tackenberg B, Berhele A, Hemmer B.
Genetic determinants of the humoral immune response in MS
| Objective: In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS). Methods: Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively. Results: The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 × 10-23), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], p = 2.06 × 10-24) and A (β = -0.42 [-0.54 to -0.31], p = 7.48 × 10-11) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest p = 2.14 × 10-7) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], p = 1.38 × 10-2) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], p = 1.01 × 10-5) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], p = 4.46 × 10-3). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts. Conclusion: Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms. |
Neurol Neuroimmunol Neuroinflamm. 2020 Jul 16;7(5)
Golde S, Heine J, Pöttgen J, Mantwill M, Lau S, Wingenfeld K, Otte C, Penner IK, Engel AK, Heesen C, Stellmann JP, Dziobek I, Finke C, Gold SM
Distinct Functional Connectivity Signartures of Impaired Social Cognition in Multiple Sclerosis
Front Neurol. 2020 Jun 25;11:507
Golde S, Heine J, Pöttgen J, Mantwill M, Lau S, Wingenfeld K, Otte C, Penner IK, Engel AK, Heesen C, Stellmann JP, Dziobek I, Finke C, Gold SM
Distinct Functional Connectivity Signartures of Impaired Social Cognition in Multiple Sclerosis
| Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions. |
Front Neurol. 2020 Jun 25;11:507
Woo MS, Steins D, Häußler V, Kohsar M, Haag F, Elias-Hamp B, Heesen C, Lütgehetmann M, Schulze zur Wiesch J, Friese MA.
Control of SARS-CoV-2 infection in rituximab-treated neuroimmunological patients.
J Neurol. 2021 Jan;268(1):5-7
Woo MS, Steins D, Häußler V, Kohsar M, Haag F, Elias-Hamp B, Heesen C, Lütgehetmann M, Schulze zur Wiesch J, Friese MA.
Control of SARS-CoV-2 infection in rituximab-treated neuroimmunological patients.
Individuals with autoimmune diseases, such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), that require long-term immunosuppression are regarded as particularly vulnerable in the current COVID-19 pandemic. However, few details about the effect of individual immunotherapies have been reported, which could instruct us about the immunological control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specific antibodies are detectable within 2–19 days and have been extensively analyzed for diagnostic purposes and vaccine development. It is unclear whether a durable antibody response is required for recovery of COVID-19 or whether it might even contribute to the pathogenesis by perpetuating hyperinflammation as has been shown for the closely related middle-east-respiratory-syndrome (MERS) coronavirus.
J Neurol. 2021 Jan;268(1):5-7
Nasseri NN, Ghezelbash E, Zhai Y, Patra S, Riemann-Lorenz K, Heesen C, Rahn AC, Stellmann JP
Feasibility of a smartphone app to enhance physical activity in progressive MS: a pilot randomized controlled pilot trial over three months.
PeerJ. 2020 Jun 23;8:e9303
Nasseri NN, Ghezelbash E, Zhai Y, Patra S, Riemann-Lorenz K, Heesen C, Rahn AC, Stellmann JP
Feasibility of a smartphone app to enhance physical activity in progressive MS: a pilot randomized controlled pilot trial over three months.
| Background: People with chronic progressive multiple sclerosis (CPMS) have limited options in medical treatment. Enhancing physical activity (PA) might promote neuroregeneration in multiple sclerosis (MS) and positively influence disability, thus providing an alternative to medical treatment. Previous studies indicate that evidence-based patient information (EBPI) is essential for inducing behavioral change, e.g. enhancing PA. Objective: To investigate feasibility of a smartphone app providing EBPI about the benefit of PA and a simple activity feedback to enhance PA in people with CPMS in a pilot randomized controlled trial over 3 months. Methods: Thirty-eight people with CPMS (mean age 51 years, median Expanded Disability Status Scale 4.0) were 1:1 randomized into either a control group (n = 20) or an intervention group (n = 18). The intervention group received access to a multimedia EBPI app including activity feedback, texts, figures and videos. In the control group, participants received a leaflet with unspecific information about exercising in general. The EPBI itself was designed based on a systematic review. At baseline and after 3 months, all participants underwent clinical performance tests, filled in questionnaires and received an activity monitor (Actigraph®) for 7 days. The primary endpoint was the rate of responders defined as participants with a 20% increase of physical acitivity (time of moderate or vigiorous PA-MVPA) or 20% increase of the number of steps, both assessed with the activity monitor. As secondary endpoints, we compared accelerometry, performance and questionnaires adjusted for baseline measurments between the groups (ANCOVA). Moreover, we used questionnaires to compare knowledge about exercise (activity requiring physical effort, carried out to improve or improve health and fitness) in MS, usability of the app in general and motivation towards a more active lifestyle after 3 months in both groups. Results: The groups showed significant differences in disease duration and PA according to the Godin-Leisure Time Exercise Questionnaire at baseline. After 3 months, we detected no difference in the rate of responders, which was an overall 22%. However, MVPA significantly increased in both groups (p < 0.001) and the intervention group tended to have a higher motivation towards a more active lifestyle (Cohens D = 0.7, p = 0.09) as measured by the questionnaire. Reponses also showed, that participants appreciated the app but claimed a lack of interactivity as a short-coming. Conclusion: Just providing information in a multimedia smartphone app did not enhance physical activitiy more than a simple leaflet in this small pilot trial in CPMS. However, the group of app users tended to have a higher motivation towards a more active lifestyle. Overall, the concept of a smartphone app to support an active lifestyle in MS is highly appreciated by participants. |
PeerJ. 2020 Jun 23;8:e9303
Witt G, Keminer O, Leu J, Tandon R, Meiser I, Willing A, Winschel I, Abt JC, Brändl B, Sébastien I, Friese MA, Müller FJ, Neubauer JC, Claussen C, Zimmermann H, Gribbon P, Pless O
An Automated and High-Throughput-Screening Compatible Pluripotent Stem Cell-Based Test Platform for Developmental and Reproductive Toxicity Assessment of Small Molecule Compounds
Cell Biol Toxicol. 2021 Apr;37(2):229-243.
Witt G, Keminer O, Leu J, Tandon R, Meiser I, Willing A, Winschel I, Abt JC, Brändl B, Sébastien I, Friese MA, Müller FJ, Neubauer JC, Claussen C, Zimmermann H, Gribbon P, Pless O
An Automated and High-Throughput-Screening Compatible Pluripotent Stem Cell-Based Test Platform for Developmental and Reproductive Toxicity Assessment of Small Molecule Compounds
| The embryonic stem cell test (EST) represents the only validated and accepted in vitro system for the detection and classification of compounds according to their developmental and reproductive teratogenic potency. The widespread implementation of the EST, however, in particular for routine application in pharmaceutical development, has not been achieved so far. Several drawbacks still limit the high-throughput screening of potential drug candidates in this format: The long assay period, the use of non-homogeneous viability assays, the low throughput analysis of marker protein expression and the compatibility of the assay procedures to automation. We have therefore introduced several advancements into the EST workflow: A reduction of the assay period, an introduction of homogeneous viability assays, and a straightforward analysis of marker proteins by flow cytometry and high content imaging to assess the impact of small molecules on differentiation capacity. Most importantly, essential parts of the assay procedure have been adapted to lab automation in 96-well format, thus enabling the interrogation of several compounds in parallel. In addition, extensive investigations were performed to explore the predictive capacity of this next-generation EST, by testing a set of well-known embryotoxicants that encompasses the full range of chemical-inherent embryotoxic potencies possible. Due to these significant improvements, the augmented workflow provides a basis for a sensitive, more rapid, and reproducible high throughput screening compatible platform to predict in vivo developmental toxicity from in vitro data which paves the road towards application in an industrial setting. Graphical abstract •The embryonic stem cell test to predict teratogenicity was made automation-compatible. •Several key improvements to the assay procedure have been introduced to increase performance. •The workflow was adapted to human iPS cells and isogenic fibroblast donor cells. |
Cell Biol Toxicol. 2021 Apr;37(2):229-243.
Gunbey H, Has A, Aslan K, Saglam D, Avci U, Sayit A, Incesu L.
Microstructural white matter abnormalities in hypothyroidism evaluation with diffusion tensor imaging tract-based spatial statistical analysis
Radiol Med 2021 Feb;126(2):283-290.
Gunbey H, Has A, Aslan K, Saglam D, Avci U, Sayit A, Incesu L.
Microstructural white matter abnormalities in hypothyroidism evaluation with diffusion tensor imaging tract-based spatial statistical analysis
Purpose: Hypothyroidism is presented in a wide range from neuropsychiatric problems including depression, memory and cognitive disorders to poor motor coordination. Against the background of morphologic, functional and molecular changes on the white and grey matter of the brain, we aimed to investigate the effects of hypothyroidism on white matter (WM) integrity using tract-based spatial statistics (TBSS).Methods: Eighteen patients with hyperthyroidism and 14 age-sex-matched healthy control subjects were included in this study. TBSS was used in the diffusion tensor imaging study for whole-brain voxel wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) of WM.Results: When compared to the control group, the whole brain TBSS revealed extensive reductions of FA in the supratentorial WM including corticospinal tract, posterior limb of the internal capsule (PLIC), uncinate fasciculus, inferior longitudinal fasciculus (p < 0.005). The ROI analyses showed RD increment of superior longitudinal fasciculus, AD decrement of cingulum (CIN), external capsule, PLIC and corpus callosum (CC) in patients with hypothyroidism (p < 0.005). Autoimmune and non-autoimmune hypothyroidism patient subgroups showed a significant difference in terms of hippocampus FA, CIN MD, CC MD, CC AD, CIN RD, SLF RD, CC RD (p < 0.005). CIN FA values showed a negative correlation with the Beck Depression Inventory (p = 0.007, r = – 852).Conclusions: These preliminary results of TBSS analyses represented FA and AD decrement, and RD increment in several WM tracts and indicates the demyelination process underlying pathophysiology of clinical aspects of hypothyroidism.
Radiol Med 2021 Feb;126(2):283-290.
Stürner KH, Werz O, Koeberle A, Otto M, Pless O, Leypoldt F, Paul F, Heesen C.
Lipid Mediator Profiles Predict Response to Therapy With an Oral Frankincense Extract in Relapsing-Remitting Multiple Sclerosis
Sci Rep. 2020 May 29;10(1):8776
Stürner KH, Werz O, Koeberle A, Otto M, Pless O, Leypoldt F, Paul F, Heesen C.
Lipid Mediator Profiles Predict Response to Therapy With an Oral Frankincense Extract in Relapsing-Remitting Multiple Sclerosis
| Lipid mediators (LMs) are a unique class of immunoregulatory signalling molecules and known to be affected by frankincense extracts. We performed LM profiling by metabololipidomics in plasma samples from 28 relapsing-remitting multiple sclerosis (RR-MS) patients who took a standardised frankincense extract (SFE) daily for eight months in a clinical phase IIa trial (NCT01450124) and in 28 age- and gender-matched healthy controls. Magnetic resonance imaging, immunological outcomes and serum neurofilament light chain levels were correlated to changes in the LM profiles of the RR-MS cohort. Eight out of 44 analysed LMs were significantly reduced during an eight-month treatment period by the SFE and seven of these eight significant LM derive from the 5-lipoxygenase (5-LO) pathway. Baseline levels of 12- and 15-LO products were elevated in patients who exhibited disease activity (EDA) during SFE treatment compared to no-evidence-of-disease-activity (NEDA) patients and could predict treatment response to the SFE in a prediction model at baseline. Oral treatment with an SFE significantly reduces 5-LO-derived LMs in RR-MS patients during an eight-month treatment period. Treatment response to an SFE, however, seems to be related to 12-,15-LO and cyclooxygenase product levels before SFE exposure. Further studies should confirm their biomarker potential in RR-MS and SFE treatment. |
Sci Rep. 2020 May 29;10(1):8776
Bittner S, Steffen F, Uphaus T, Muthuraman M, Fleischer V, Salmen A, Luessi F, Berthele A, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Linker R, Heesen C, Stangel M, Wildemann B, Then Bergh F, Tackenberg B, Kuempfel T, Weber F, Zettl UK, Ziemann U, Tumani H, Groppa S, Mühlau M, Hemmer B, Wiendl H, Gold R, Zipp F; KKNMS consortium
Clinical Implications of Serum Neurofilament in Newly Diagnosed MS Patients: A Longitudinal Multicentre Cohort Study
EBioMedicine. 2020 Jun;56:102807
Bittner S, Steffen F, Uphaus T, Muthuraman M, Fleischer V, Salmen A, Luessi F, Berthele A, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Linker R, Heesen C, Stangel M, Wildemann B, Then Bergh F, Tackenberg B, Kuempfel T, Weber F, Zettl UK, Ziemann U, Tumani H, Groppa S, Mühlau M, Hemmer B, Wiendl H, Gold R, Zipp F; KKNMS consortium
Clinical Implications of Serum Neurofilament in Newly Diagnosed MS Patients: A Longitudinal Multicentre Cohort Study
| Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels. Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions |
EBioMedicine. 2020 Jun;56:102807
Pust GEA, Untiedt B, Weierstall-Pust R, Randerath J, Barabasch A, Rahn AC, Heesen C.
Medication beliefs in first-line and second-line treated multiple sclerosis patients
Mult Scler Relat Disord. 2020 May 4;42:102144
Pust GEA, Untiedt B, Weierstall-Pust R, Randerath J, Barabasch A, Rahn AC, Heesen C.
Medication beliefs in first-line and second-line treated multiple sclerosis patients
| Background: Immune treatments of multiple sclerosis (MS) can be classified in first-line and second-line approaches. While in both treatment efficacy is often not easy to assess in the short-term, treatment and illness beliefs may differ in first-line and second-line treated patients. The current study aimed to assess differential beliefs about medicine and illness perception between these groups based on the hypothesis that they are closely connected to adherence behaviour. Methods: An online survey through the website of the German MS Society was performed investigating beliefs about immune treatments as well as the patients‘ illness perceptions with validated questionnaires. Demographic factors, disability and self-reported adherence rates were studied as moderator variables. Results: In total, 630 patients participated. Data of 433 first-line treated and 192 second-line treated patients with MS (PwMS) were analysed. Necessity beliefs and also concerns beliefs were significantly higher in second-line treated PwMS (MANCOVA p =.001 and p =.006) and generally in patients with higher disability, while illness perception did not differ between groups. Self-assessed adherence rates were around 70% for oral treatments and injectables irrespective of first-line or second-line. Nonadherence was below 5% for infusion treatments. However, most patients reported only single omissions. Conclusion: The current study reveals differential behavioural attitudes between first-line versus second-line-treated PwMS. However, follow-up studies are needed to further unravel the relationship between behavioural attitudes and treatment adherence. |
Mult Scler Relat Disord. 2020 May 4;42:102144
Gharakhanlou R, Wesselmann L, Rademacher A, Lampit A, Negaresh R, Kaviani M, Oberste M, Motl RW, Sandroff BM, Bansi J, Baker JS, Heesen C, Zimmer P, Javelle F.
Exercise training and cognitive performance in persons with multiple sclerosis: A systematic review and multilevel meta-analysis of clinical trials.
Mult Scler. 2021 Nov;27(13):1977-1993.
Gharakhanlou R, Wesselmann L, Rademacher A, Lampit A, Negaresh R, Kaviani M, Oberste M, Motl RW, Sandroff BM, Bansi J, Baker JS, Heesen C, Zimmer P, Javelle F.
Exercise training and cognitive performance in persons with multiple sclerosis: A systematic review and multilevel meta-analysis of clinical trials.
| BACKGROUND: Cognitive impairment is common, debilitating, and poorly managed in persons with multiple sclerosis (pwMS). Exercise training might have positive effects on cognitive performance in pwMS, yet the overall magnitude, heterogeneity, and potential moderators remain unclear. OBJECTIVE: This three-level meta-analysis aims to identify the effects of exercise training and those of exercise modalities on global and domain-specific cognitive performance in pwMS. METHODS: MEDLINE, PsycInfo, SportDiscus, CENTRAL, and EMBASE were screened for randomized and non-randomized clinical trials from inception to 27 January 2020, yielding 3091 articles. Based on titles and abstracts, 75 articles remained in the selection process. After full-text evaluation, 13 studies were inally selected (PROSPERO pre-registered). RESULTS: The pooled effect of exercise training on the global cognitive performance was null (g = 0.04, 95% confidence interval (CI): -0.11 to 0.18) and no significant differences were displayed among domains. Heterogeneity within studies was null (I2(2)= 0.0%) and between studies was low (I2(3)= 25.1%). None of the moderators (exercise modalities, age, Expanded Disability Status Scale (EDSS), supervision, cognitive domains) reached significance. However, the exercise volume explained most of the overall heterogeneity (slope = 4.651 × 10-5, R2(2) = 100%, R2(3) = 52.34%). CONCLUSION: These results do not support the efficacy of exercise training on global or domain-specific cognitive performance in pwMS. Future studies are needed to determine whether higher training dose are beneficial. |
Mult Scler. 2021 Nov;27(13):1977-1993.
Abrahamyan S, Eberspächer B, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Schroeder C, Grüter T, Tackenberg B, Paul F, Then-Bergh F, Kümpfel T, Weber F, Stangel M, Bayas A, Wildemann B, Heesen C, Zettl U, Warnke C, Antony G, Hessler N, Wiendl H, Bittner S, Hemmer B, Gold R, Salmen A, Ruprecht K; German Competence Network Multiple Sclerosis (KKNMS); Other members of the KKNMS that acted as collaborators in this study.
Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.
J Neurol Neurosurg Psychiatry. 2020 Jul;91(7):681-686
Abrahamyan S, Eberspächer B, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Schroeder C, Grüter T, Tackenberg B, Paul F, Then-Bergh F, Kümpfel T, Weber F, Stangel M, Bayas A, Wildemann B, Heesen C, Zettl U, Warnke C, Antony G, Hessler N, Wiendl H, Bittner S, Hemmer B, Gold R, Salmen A, Ruprecht K; German Competence Network Multiple Sclerosis (KKNMS); Other members of the KKNMS that acted as collaborators in this study.
Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.
| OBJECTIVE: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS). METHODS: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany. RESULTS: EBNA1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts. CONCLUSION: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS. |
J Neurol Neurosurg Psychiatry. 2020 Jul;91(7):681-686
Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L.
A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.
Cell Death Dis. 2020 May 1;11(5):303
Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L.
A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.
| Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects. |
Cell Death Dis. 2020 May 1;11(5):303
Engel S, Graetz C, Salmen A, Muthuraman M, Toenges G, Ambrosius B, Bayas A, Berthele A, Heesen C, Klotz L, Kümpfel T, Linker RA, Meuth SG, Paul F, Stangel M, Tackenberg B, Then Bergh F, Tumani H, Weber F, Wildemann B, Zettl UK, Antony G, Bittner S, Groppa S, Hemmer B, Wiendl H, Gold R, Zipp F, Lill CM, Luessi F; German Competence Network of Multiple Sclerosis.
Is APOE ε4 associated with cognitive performance in early MS?
Neurol Neuroimmunol Neuroinflamm. 2020 May 1;7(4):e728.
Engel S, Graetz C, Salmen A, Muthuraman M, Toenges G, Ambrosius B, Bayas A, Berthele A, Heesen C, Klotz L, Kümpfel T, Linker RA, Meuth SG, Paul F, Stangel M, Tackenberg B, Then Bergh F, Tumani H, Weber F, Wildemann B, Zettl UK, Antony G, Bittner S, Groppa S, Hemmer B, Wiendl H, Gold R, Zipp F, Lill CM, Luessi F; German Competence Network of Multiple Sclerosis.
Is APOE ε4 associated with cognitive performance in early MS?
| Objective: To assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS). Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the APOE carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors. Results: APOE ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for APOE ε4 heterozygosity or APOE ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for APOE carrier status. Conclusion: Along with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS. |
Neurol Neuroimmunol Neuroinflamm. 2020 May 1;7(4):e728.
Topp J, Heesen C, Augustin M, Andrees V,Blome C
Challenges and lessons learned from using anchoring vignettes to explore quality of liefe response behavior
Qual Life Res. 2020 Aug;29(8):2149-2159
Topp J, Heesen C, Augustin M, Andrees V,Blome C
Challenges and lessons learned from using anchoring vignettes to explore quality of liefe response behavior
| PURPOSE: Asking patients to rate health-related quality of life (HRQoL) of hypothetical individuals described in anchoring vignettes has been proposed to enhance knowledge on how patients understand and respond to HRQoL questionnaires. In this article, we describe the development of anchoring vignettes and explore their utility for measuring response shift in patients‘ self-reports of HRQoL. METHODS: We conducted an explorative mixed-methods study. One hundred patients with multiple sclerosis or psoriasis participated in two interviews at intervals of 3-6 months. During both interviews, patients assessed HRQoL of 16 hypothetical individuals on the SF-12 questionnaire (two vignettes for each of the eight domains of the SF-12). In addition to these quantitative ratings, we used the think-aloud method to explore changes in patients‘ verbalization of their decision processes during vignette ratings. RESULTS: Agreement of vignette ratings at baseline and follow-up was low (ICCs < 0.55). In addition, paired sample t-tests revealed no significant directional mean changes in vignette ratings. Thus, ratings changed non-directionally, neither confirming retest reliability nor a systematic change of assessment. Furthermore, patients‘ verbalization of their decision processes did not indicate whether or not the assessment strategy of individual patients had changed. CONCLUSIONS: Patients‘ ratings of anchoring vignettes fluctuate non-directionally over time. The think-aloud method appears not to be informative in exploring whether these fluctuations are due to changes in the individual decision process. Overall, vignettes might not be an appropriate approach to explore response shift, at least with regard to the specific target population and the use of the SF-12. |
Qual Life Res. 2020 Aug;29(8):2149-2159
Heitmann H, Haller B, Tiemann L, Mühlau M, Berthele A, Tölle TR, Salmen A, Ambrosius B, Bayas A, Asseyer S, Hartung HP, Heesen C, Stangel M, Wildemann B, Haars S, Groppa S, Luessi F, Kümpfel T, Nischwitz S, Meuth SG, Klotz L, Linker RA, Zettl UK, Ziemann U, Tumani H, Tackenberg B, Zipp F, Wiendl H, Gold R, Hemmer B, Ploner M.
Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.
Pain. 2020 Apr;161(4):787-796
Heitmann H, Haller B, Tiemann L, Mühlau M, Berthele A, Tölle TR, Salmen A, Ambrosius B, Bayas A, Asseyer S, Hartung HP, Heesen C, Stangel M, Wildemann B, Haars S, Groppa S, Luessi F, Kümpfel T, Nischwitz S, Meuth SG, Klotz L, Linker RA, Zettl UK, Ziemann U, Tumani H, Tackenberg B, Zipp F, Wiendl H, Gold R, Hemmer B, Ploner M.
Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.
| Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology. |
Pain. 2020 Apr;161(4):787-796
Dalgas U, Hvid LG, Kwakkel G, Motl RW, de Groot V, Feys P, Op't Eijnde B, Coote S, Beckerman H, Pfeifer K, Streber R, Peters S, Riemann-Lorenz K, Rosenkranz SC, Centonze D, Van Asch P, Bansi J, Sandroff BM, Pilutti LA, Ploughman M, Freeman J, Paul L, Dawes H, Romberg A, Kalron A, Stellmann JP, Friese MA, Heesen C.
Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.
Mult Scler. 2020 Oct;26(11):1303-1308
Dalgas U, Hvid LG, Kwakkel G, Motl RW, de Groot V, Feys P, Op't Eijnde B, Coote S, Beckerman H, Pfeifer K, Streber R, Peters S, Riemann-Lorenz K, Rosenkranz SC, Centonze D, Van Asch P, Bansi J, Sandroff BM, Pilutti LA, Ploughman M, Freeman J, Paul L, Dawes H, Romberg A, Kalron A, Stellmann JP, Friese MA, Heesen C.
Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.
| Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely „Definitions and terminology,“ „Study methodology,“ „Reporting and outcomes,“ „Adherence to exercise,“ and „Mechanisms of action.“ Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS. |
Mult Scler. 2020 Oct;26(11):1303-1308
Faizy TD, Thaler C, Broocks G, Flottmann F, Leischner H, Kniep H, Nawabi J, Schön G, Stellmann JP, Kemmling A, Reddy R, Heit JJ, Fiehler J, Kumar D, Hanning U.
The Myelin Water Fraction Serves as a Marker for Age-Related Myelin Alterations in the Cerebral White Matter – A Multiparametric MRI Aging Study.
Front Neurosci. 2020 Feb 24;14:136
Faizy TD, Thaler C, Broocks G, Flottmann F, Leischner H, Kniep H, Nawabi J, Schön G, Stellmann JP, Kemmling A, Reddy R, Heit JJ, Fiehler J, Kumar D, Hanning U.
The Myelin Water Fraction Serves as a Marker for Age-Related Myelin Alterations in the Cerebral White Matter – A Multiparametric MRI Aging Study.
| Quantitative MRI modalities, such as diffusion tensor imaging (DTI) or magnetization transfer imaging (MTI) are sensitive to the neuronal effects of aging of the cerebral white matter (WM), but lack the specificity for myelin content. Myelin water imaging (MWI) is highly specific for myelin and may be more sensitive for the detection of changes in myelin content inside the cerebral WM microstructure. In this multiparametric imaging study, we evaluated the performance of myelin water fraction (MWF) estimates as a marker for myelin alterations during normal-aging. Multiparametric MRI data derived from DTI, MTI and a novel, recently-proposed MWF-map processing and reconstruction algorithm were acquired from 54 healthy subjects (aged 18-79 years) and region-based multivariate regression analysis was performed. MWFs significantly decreased with age in most WM regions (except corticospinal tract) and changes of MWFs were associated with changes of radial diffusivity, indicating either substantial alterations or preservation of myelin content in these regions. Decreases of fractional anisotropy and magnetization transfer ratio were associated with lower MWFs in commissural fiber tracts only. Mean diffusivity had no regional effects on MWF. We conclude that MWF estimates are sensitive for the assessment of age-related myelin alterations in the cerebral WM of normal-aging brains. |
Front Neurosci. 2020 Feb 24;14:136
Riemann-Lorenz K, Motl RW, Casey B, Coote S, Daubmann A, Heesen C.
Possible determinants of long-term adherence to physical activity in multiple sclerosis-theory-based development of a comprehensive questionnaire and results from a German survey study.
Disabil Rehabil. 2021 Nov;43(22):3175-3188
Riemann-Lorenz K, Motl RW, Casey B, Coote S, Daubmann A, Heesen C.
Possible determinants of long-term adherence to physical activity in multiple sclerosis-theory-based development of a comprehensive questionnaire and results from a German survey study.
| Purpose: To examine the possible contributions of capability, opportunity, and motivation for explaining long-term physical activity among people with multiple sclerosis and to report the results of a German survey study.Methods: The questionnaire, which was based on an expert interview study and behavior change theory, was structured and detailed applying the Theoretical Domains Framework. A total of 1027 people with multiple sclerosis provided data on sociodemographics, disease-related characteristics, and a set of constructs possibly related to long-term adherence. Participants were assigned to three groups: not regularly active, currently regularly active, and long-term regularly active. Eta squared was calculated to assess the magnitude of differences between groups using ANOVA.Results: Moderate or large differences between groups were identified for many domains within capability, opportunity, and motivation. For the following theoretical domains, large differences (η2 ≥0.140) were observed: Intention, Behavioural Regulation, Beliefs about Capabilities and Goals.Conclusions: Our results suggest that capability, opportunity, and motivation should be targeted simultaneously when designing future interventions. Inactive people with multiple sclerosis might benefit most from interventions increasing action self-efficacy and intention. Boosting autonomous motivation, goal setting, action planning as well as maintenance and recovery self-efficacy could have a positive effect on long-term adherence.IMPLICATIONS FOR REHABILITATIONThis study applied the COM-B model and Theoretical Domains Framework to identify a set of constructs for explaining long-term physical activity among people with MS.Behaviour change and maintenance interventions for people with MS should include techniques that foster intention, perceived self-efficacy and self-regulatory skills, and promote goal setting and autonomy of motivation for regular physical activity.Although barriers of the physical and social environmental context did not seem to be that important in our sample, scientists should consider addressing them in interventions for inactive and more disabled people with MS.Information about the benefits of physical activity should be regularly provided in MS rehabilitation, while further research should explore the relevance of information provision and knowledge for behaviour change in different groups of people with MS. |
Disabil Rehabil. 2021 Nov;43(22):3175-3188
Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Nunez NG, De Feo D, Kickingereder P, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L, Sahm F, Schriompf D., Meyer J, Allen A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M, Wick W, Becher B, Platten M
Heterogeneity of Response to Immune Checkpoint Blockade in Hypermutated Expermimental Gliomas
Nat Commun 2020 Feb 178;11(1):931
Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Nunez NG, De Feo D, Kickingereder P, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L, Sahm F, Schriompf D., Meyer J, Allen A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M, Wick W, Becher B, Platten M
Heterogeneity of Response to Immune Checkpoint Blockade in Hypermutated Expermimental Gliomas
| Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB. |
Nat Commun 2020 Feb 178;11(1):931
Conversion to secondary progressive multiple sclerosis: Multistakeholder experiences and needs in Italy
PloS One 2020 Feb 13;15(2):e0228587
Conversion to secondary progressive multiple sclerosis: Multistakeholder experiences and needs in Italy
| Background: Conversion to secondary progressive multiple sclerosis (SPMS) is associated with a relatively poor prognosis, and SPMS is responsible for the majority of the social and economic costs associated with MS. Managing the Transition to SPMS (ManTra) is a mixed methods project conducted in Italy and Germany aimed to set up a user-led resource to empower and improve the quality of life of newly diagnosed SPMS patients. Aims: To assess the experiences and the needs of Italian people who recently converted to SPMS, patient significant others (SOs), neurologists and other health professionals (HPs). Methods: We conducted 15 personal semistructured interviews (PSIs) with SPMS patients who transitioned up to five years, and three focus group meetings (FGMs), one of SPMS SOs, one of neurologists, and one of other HPs. Participants were purposely selected from the three geographic areas of Italy, and varied in terms of gender, education and (for patients) disease severity. PSIs and FGMs were audiorecorded, transcribed and analyzed by two researchers using the framework analysis. Results: One hundred sub-categories were identified, grouped into 13 categories and four themes: ‚awareness of the transition‘, ‚communication of the transition‘, ‚dealing with symptoms worsening‘, and ’needs‘. The major unmet needs were collected in four dimensions ‚organization and management; ‚empowerment training‘; ‚information‘; and ‚policies‘. Conclusions: Two are the main findings: first, the widespread lack of awareness around the transition; second, the need to improve the quality of the care pathway in the Italian context. It was particularly stressed the need for a holistic and multidisciplinary approach (with patients and SOs as members of the team), the development of an ad hoc plan of follow up visits with easy access to MS specialists‘ consultation/treatment; specialized training for each stakeholders; more information on SPMS, daily management and changes at policy level. |
PloS One 2020 Feb 13;15(2):e0228587
Has Silemek AC, Fischer L, Pöttgen J, Penner IK, Engel AK, Heesen C, Gold SM, Stellmann JP.
Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability.
Neuroimage Clin. 2020 Jan 12;25:102177
Has Silemek AC, Fischer L, Pöttgen J, Penner IK, Engel AK, Heesen C, Gold SM, Stellmann JP.
Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability.
| Multiple Sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), which can lead to severe cognitive impairment over time. Magnetic resonance imaging (MRI) is currently the best available biomarker to track MS pathophysiology in vivo and examine the link to clinical disability. However, conventional MRI metrics have limited sensitivity and specificity to detect direct associations between symptoms and their underlying CNS substrates. In this study, we aimed to investigate structural and resting state functional connectomes and subnetworks associated with neuropsychological (NP) performance using a graph theoretical approach. A comprehensive NP test battery was administered in a sample of patients with relapsing remitting MS (RRMS) and mild disability [n = 33, F/M = 20/13, age = 40.9 ± 9.7, median [Expanded Disability Status Scale] (EDSS) = 2, range =0-4] and compared to healthy controls (HC) [n = 29, F/M = 19/10, age = 41.0 ± 8.5] closely matched for age, sex, and level of education. The NP battery comprised the most relevant domains of cognitive dysfunction in MS including attention, processing speed, verbal and spatial learning and memory, and executive function. While standard MRI metrics showed good correlations with TAP Alertness test, disease duration and neurological exams, structural networks showed closer associations with 9-hole peg test and cognitive performances. Decreased graph strength was associated with two out of the 5 NP tests in the spatial learning and memory domain specified by BVMT [Sum 1-3] and BVMT [Recall], and with also SDMT which is one out of the 9 NP tests in the attention/processing speed domain, while no correlation was found between these scores and functional connectivity. Nodal strength was decreased in all subnetworks based on Yeo atlas in patients compared to HC; however, no difference was observed in nodal level of functional connectivity between the groups. The difference in structural and functional nodal connectivity between the groups was also observed in the relationship between structural and functional connectivity within the groups; the relationship between nodal degree and nodal strength was reversed in patients but positive in controls. On a nodal level, structural and functional networks (mainly the default mode network) were correlated with more than one cognitive domain rather than one specific network for each domain within patients. Interestingly, poorer cognitive performance was mostly correlated with increased functional connectivity but decreased structural connectivity in patients. Increased functional connectivity in the default mode network had both positive as well as negative associations with verbal and spatial learning and memory, possibly indicating adaptive and maladaptive mechanisms. In conclusion, our results suggest that cognitive performance, even in patients with RRMS and very mild disability, may reflect a loss of structural connectivity. In contrast, widespread increases in functional connectivity may be the result of maladaptive processes. |
Neuroimage Clin. 2020 Jan 12;25:102177
van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N, Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.
Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
Acta Neuropathol 2020 May;139(5):959-962.
van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N, Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.
Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
| The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once. |
Acta Neuropathol 2020 May;139(5):959-962.
Stürner KH, Siembab I, Schön G, Stellmann JP, Heidari N, Fehse B, Heesen C, Eiermann TH, Martin R, Binder TM.
Is multiple sclerosis progression associated with the HLA-DR15 haplotype?
Mult Scler J Exp Transl Clin. 2019 Dec 9;5(4)
Stürner KH, Siembab I, Schön G, Stellmann JP, Heidari N, Fehse B, Heesen C, Eiermann TH, Martin R, Binder TM.
Is multiple sclerosis progression associated with the HLA-DR15 haplotype?
| Background: The prevalence of multiple sclerosis is associated with the major histocompatibility complex class II DR15 haplotype HLA-DRB1*15:01∼HLA-DRB5*01:01. Objective: To assess whether multiple sclerosis progression is associated with the main susceptibility haplotype HLA-DRB1*15:01∼HLA-DRB5*01:01. Methods: Patients (n = 1230) and healthy controls (n = 2110) were genotyped for HLA-DRB1 and HLA-DRB5. The baseline Expanded Disability Status Scale (EDSS) score was determined and patients were followed for at least 3 years. Results: After follow-up of the consecutive cohort 349 patients were classified as having clinical isolated syndrome and 881 patients as having multiple sclerosis. The susceptibility allele HLA-DRB1*15:01 was more frequent in clinical isolated syndrome (odds ratio 1.56) and multiple sclerosis (odds ratio 3.17) compared to controls. HLA- DRB1*15:01 was the only enriched HLA-DRB1 allele in multiple sclerosis patients. Comparison of clinical characteristics between HLA-DRB1*15:01∼HLA-DRB5*01:01 negative and positive patients with multiple sclerosis showed that baseline EDSS score, disease duration and frequency of the category secondary progressive multiple sclerosis with relapse were increased in the HLA-DRB1*15:01∼HLA-DRB5*01:01 positive group. Conclusion: The study confirmed HLA-DRB1*15:01 and HLA-DRB5*01:01 as the main susceptibility alleles and showed weak indirect evidence for a role in progression of the disease. |
Mult Scler J Exp Transl Clin. 2019 Dec 9;5(4)
Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber MS, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner A, Hartung HP, Aktas O, Albrecht P; Neuromyelitis Optica Study Group (NEMOS).
Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.
Neurology. 2020 Jan 28;94(4):e407-e418
Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber MS, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner A, Hartung HP, Aktas O, Albrecht P; Neuromyelitis Optica Study Group (NEMOS).
Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.
| OBJECTIVE: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks. METHODS: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models. RESULTS: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively. CONCLUSION: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance. |
Neurology. 2020 Jan 28;94(4):e407-e418
Gold SM, Otte C.
Differential impact of affective and cognitive symptoms on remission of major depression.
Lancet Psychiatry. 2019 Dec;6(12):980.
Gold SM, Otte C.
Differential impact of affective and cognitive symptoms on remission of major depression.
Lancet Psychiatry. 2019 Dec;6(12):980.
Topp J, Andrees V, Heesen C, Augustin M, Blome C
Recall of health-related quality of life: how does memory affect the SF-6D in patients with psoriasis or multiple sclerosis? A prospective observational study in Germany.
BMJ Open. 2019 Nov 21;9(11):e032859
Topp J, Andrees V, Heesen C, Augustin M, Blome C
Recall of health-related quality of life: how does memory affect the SF-6D in patients with psoriasis or multiple sclerosis? A prospective observational study in Germany.
| OBJECTIVE: This study aimed to quantify recall bias in the measurement of health-related quality of life (HRQoL), that is, the extent to which recollection is impaired and leads to distorted judgements. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: One hundred patients with two paradigmatic chronic diseases (50 with multiple sclerosis and 50 with psoriasis) were recruited at two outpatient clinics. METHODS AND OUTCOME MEASURES: Patients completed the online version of the 12-Item Short Form Survey (SF-12) repeatedly for 28 consecutive days: (1) daily, considering the past 24 hours; (2) weekly, considering the past 7 days; and (3) on the last day of data collection, considering the past 4 weeks. SF-12 scores for all three measurement approaches were subsequently converted into preference-based utility indices (Short-Form Six-Dimension). Agreement of the three indices was analysed on group and individual patient levels. RESULTS: The mean age of participants was 40.3 years (±12.0), and 63% were female. The utility index based on daily recall (0.74±0.13) was more positive than indices based on a weekly (0.70±0.13, p<0.001) or a monthly (0.70±0.14, p<0.001) recall. While agreement of measurement approaches was high on group level (intraclass correlation coefficient>0.85), it was lower for the subgroup of patients experiencing high variability of HRQoL over time. Bland-Altman plots revealed considerable differences on individual patient level. CONCLUSIONS: On the group level, retrospective overestimation and underestimation of HRQoL almost cancelled out one another and recall bias was relatively small. Therefore, a 4-week recall period could be appropriate when group-level data are used for research or economic evaluations. In contrast, recall bias can be considerable on the individual patient level and may thus impact decision-making in clinical practice. |
BMJ Open. 2019 Nov 21;9(11):e032859
Sonner, J. K., Keil, M., Falk-Paulsen, M., Mishra, N., Rehman, A., Kramer, M., Deumelandt, K., Röwe, J., Sanghvi, K., Wolf, L., von Landenberg, A., Wolff, H., Bharti, R., Oezen, I., Lanz, T. V., Wanke, F., Tang, Y., Brandao, I., Mohapatra, S. R., Epping, L., Grill, A., Röth, R., Niesler, B., Meuth, S. G., Opitz, C. A., Okun, J. G., Reinhardt, C., Kurschus, F. C., Wick, W., Bode, H. B., Rosenstiel, P., Platten, M.
Dietary Tryptophan Links Encephalogenicity of Autoreactive T Cells With Gut Microbial Ecology
Nat Commun 2019 Oct 25;10(1):4877
Sonner, J. K., Keil, M., Falk-Paulsen, M., Mishra, N., Rehman, A., Kramer, M., Deumelandt, K., Röwe, J., Sanghvi, K., Wolf, L., von Landenberg, A., Wolff, H., Bharti, R., Oezen, I., Lanz, T. V., Wanke, F., Tang, Y., Brandao, I., Mohapatra, S. R., Epping, L., Grill, A., Röth, R., Niesler, B., Meuth, S. G., Opitz, C. A., Okun, J. G., Reinhardt, C., Kurschus, F. C., Wick, W., Bode, H. B., Rosenstiel, P., Platten, M.
Dietary Tryptophan Links Encephalogenicity of Autoreactive T Cells With Gut Microbial Ecology
| The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid – tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation. |
Nat Commun 2019 Oct 25;10(1):4877
Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM.
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.
Cell Rep. 2019 Oct 22;29(4):810-815
Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM.
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.
| Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track „private“ T cell clones associated with disease activity in autoimmunity. |
Cell Rep. 2019 Oct 22;29(4):810-815
Palotai M, Nazeri A, Cavallari M, Healy BC, Glanz B, Gold SM, Weiner HL, Chitnis T, Guttmann CRG
History of fatigue in multiple sclerosis is associated with grey matter atrophy.
Sci Rep. 2019 Oct 14;9(1):14781.
Palotai M, Nazeri A, Cavallari M, Healy BC, Glanz B, Gold SM, Weiner HL, Chitnis T, Guttmann CRG
History of fatigue in multiple sclerosis is associated with grey matter atrophy.
Fatigue in multiple sclerosis (MS) has been associated with brain damage with low replicability. Temporal fatigue fluctuations have not been considered. We assessed whether sustained fatigue (SF) associates more strongly with grey matter (GM) changes than reversible fatigue (RF). Patients were stratified into three groups according to historical fatigue levels: SF (n = 30, i.e. patients who reported fatigue at the latest ≥2 assessments), RF (n = 31, i.e. patients not fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 37). Groups were compared for brain GM volume using cross-sectional voxel-based and volumetric analyses of 3T T1-weighted MRI. Confounding effects of depression and related medications were also investigated. SF and RF patients showed similar anatomical distribution of GM atrophy. While we robustly replicated the anatomical patterns of GM atrophy described in previous work, we also found an association between hippocampal atrophy and fatigue. Depression showed confounding effects in frontal, parietal, occipital, accumbal and thalamic regions. Assessed treatments showed confounding effects in frontal, parietal and striatal areas. Our results suggest that history of clinically-relevant fatigue in currently non-fatigued patients is associated with GM atrophy, potentially explaining inconsistent findings of previous studies that stratified patients using a single fatigue assessment.
Sci Rep. 2019 Oct 14;9(1):14781.
Largey F, Jelcic I, Sospedra M, Heesen C, Martin R, Jelcic I.
Effects of natalizumab therapy on intrathecal antiviral antibody responses in MS
Neurol Neuroimmunol Neuroinflamm. 2019 Sep 25;6(6)
Largey F, Jelcic I, Sospedra M, Heesen C, Martin R, Jelcic I.
Effects of natalizumab therapy on intrathecal antiviral antibody responses in MS
| OBJECTIVE: To investigate the effects of natalizumab (NAT) treatment on intrathecally produced antiviral antibodies in MS. METHODS: We performed a longitudinal, observational study analyzing both serum and CSF samples collected before and during NAT treatment for antibodies against measles, rubella, mumps, influenza, entero, herpes, and polyoma viruses, including JC polyomavirus (JCV) and its nearest homologue BK polyomavirus (BKV), and bacterial control antigens by ELISA to determine the antigen-specific CSF antibody index (CAI). CAI ≥1.5 indicated intrathecal synthesis of antigen-specific antibodies. Oligoclonal bands (OCBs) by isoelectric focusing and total IgG, IgM, and IgA by immunonephelometry were analyzed additionally. RESULTS: Intrathecal synthesis of JCV- and BKV-specific IgG was detected in 20% of patients with MS at baseline and was lost significantly more frequently during NAT treatment compared with other intrathecal antiviral and antibacterial antibody reactivities. Peripheral JCV- and BKV-specific antibody responses persisted, and no cross-reactivity between JCV- and BKV-specific CSF antibodies was found. Intrathecal production of antibodies against measles, rubella, and zoster antigens (MRZ reaction) was most prevalent and persisted (73.3% before vs 66.7% after 1 year of NAT therapy). CSF OCBs also persisted (93.3% vs 80.0%), but total CSF IgG and IgM levels declined significantly. CONCLUSIONS: These data indicate that JCV-specific antibodies are produced intrathecally in a minority of patients with MS, and NAT treatment affects the intrathecal humoral immune response against JCV relatively specifically compared with other neurotropic viruses. Further studies are needed to determine whether this effect translates to higher risk of progressive multifocal leukoencephalopathy development. |
Neurol Neuroimmunol Neuroinflamm. 2019 Sep 25;6(6)
Solari A, Giovannetti AM, Giordano A, Tortorella C, Torri Clerici V, Brichetto G, Granella F, Lugaresi A, Patti F, Salvetti M, Pesci I, Pucci E, Centonze D, Danni MC, Bonavita S, Ferraro D, Gallo A, Gajofatto A, Nociti V, Grimaldi L, Grobberio M, Lanzillo R, Di Giovanni R, Gregori S, Manni A, Pietrolongo E, Bertagnoli S, Ronzoni M, Compagnucci L, Fantozzi R, Allegri B, Arena S, Buscarinu MC, Sabattini L, Quartuccio ME, Tsantes E, Confaloneri P, Tacchino A, Schiffmann I, Rahn AC, Kleiter I, Messmer Uccelli M, Barabasch A, Heesen C, The ManTra Project
Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.
Front Neurol. 2019 Aug 22;10:916.
Solari A, Giovannetti AM, Giordano A, Tortorella C, Torri Clerici V, Brichetto G, Granella F, Lugaresi A, Patti F, Salvetti M, Pesci I, Pucci E, Centonze D, Danni MC, Bonavita S, Ferraro D, Gallo A, Gajofatto A, Nociti V, Grimaldi L, Grobberio M, Lanzillo R, Di Giovanni R, Gregori S, Manni A, Pietrolongo E, Bertagnoli S, Ronzoni M, Compagnucci L, Fantozzi R, Allegri B, Arena S, Buscarinu MC, Sabattini L, Quartuccio ME, Tsantes E, Confaloneri P, Tacchino A, Schiffmann I, Rahn AC, Kleiter I, Messmer Uccelli M, Barabasch A, Heesen C, The ManTra Project
Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.
| Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders. Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified. Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs. Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001). Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients). All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: „physiotherapy“ and „active patient care involvement.“ The other two differed across countries: „an individualized health care plan“ and „information on social rights and policies“ in Italy, and „psychological support“ and „cognitive rehabilitation“ in Germany. Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries. |
Front Neurol. 2019 Aug 22;10:916.
Golde S., Wingenfeld K, Riepenhausen A, Schröter N, Fleischer J, Prüssner J, Grimm S, Fan Y, Hellmann-Regen J, Beck A, Gold SM, Otte C.
Healthy women with severe early life trauma show altered neural facilitation of emotion inhibition under acute stress.
Psychol Med. 2020; 50(12):2075-2084
Golde S., Wingenfeld K, Riepenhausen A, Schröter N, Fleischer J, Prüssner J, Grimm S, Fan Y, Hellmann-Regen J, Beck A, Gold SM, Otte C.
Healthy women with severe early life trauma show altered neural facilitation of emotion inhibition under acute stress.
| Across psychopathologies, trauma-exposed individuals suffer from difficulties in inhibiting emotions and regulating attention. In trauma-exposed individuals without psychopathology, only subtle alterations of neural activity involved in regulating emotions have been reported. It remains unclear how these neural systems react to demanding environments, when acute (non-traumatic but ordinary) stress serves to perturbate the system. Moreover, associations with subthreshold clinical symptoms are poorly understood. The present fMRI study investigated response inhibition of emotional faces before and after psychosocial stress situations. Specifically, it compared 25 women (mean age 31.5 ± 9.7 years) who had suffered severe early life trauma but who did not have a history of or current psychiatric disorder, with 25 age- and education-matched trauma-naïve women. Under stress, response inhibition related to fearful faces was reduced in both groups. Compared to controls, trauma-exposed women showed decreased left inferior frontal gyrus (IFG) activation under stress when inhibiting responses to fearful faces, while activation of the right anterior insula was slightly increased. Also, groups differed in brain-behaviour correlations. Whereas stress-induced false alarm rates on fearful stimuli negatively correlated with stress-induced IFG signal in controls, in trauma-exposed participants, they positively correlated with stress-induced insula activation. Neural facilitation of emotion inhibition during stress appears to be altered in trauma-exposed women, even without a history of or current psychopathology. Decreased activation of the IFG in concert with heightened bottom-up salience of fear related cues may increase vulnerability to stress-related diseases. |
Psychol Med. 2020; 50(12):2075-2084
Engler JB, Heckmann NF, Jäger J, Gold SM, Friese MA.
Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis.
J Immunol. 2019 Oct 1;203(7):1743-1752.
Engler JB, Heckmann NF, Jäger J, Gold SM, Friese MA.
Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis.
| Disease activity of autoimmune disorders such as multiple sclerosis and its mouse model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to nonspecific immunomodulation or mediated by Ag-specific regulation of disease-causing conventional T cells (Tcon) and immunosuppressive regulatory T cells (Tregs) remains elusive. In the current study, we systematically analyzed changes of the TCRβ repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV13-2 chain and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE-associated Ags. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity. |
J Immunol. 2019 Oct 1;203(7):1743-1752.
Kesgin F, Suddick K, Heesen c, Wright J.
Developing a fall prevention program: what are the views and opinions of people with multiple sclerosis?
Dishabil. Rehabil. 2021 Apr;43(8):1065-1073
Kesgin F, Suddick K, Heesen c, Wright J.
Developing a fall prevention program: what are the views and opinions of people with multiple sclerosis?
| Purpose: Falls are common in people with multiple sclerosis (MS), yet there are a few targeted fall prevention programs. Existing programs report a high dropout rate and a low adherence, which may be due to a mismatch between program characteristics and participants preferences. To clarify a possible discrepancy, this study investigates the views and opinions of persons with MS on fall prevention programs. Methods: Two focus groups (n = 11) were conducted with people with MS who have a history of falls, near falls or who are concerned about their balance/falling risk. The data were analyzed using a qualitative content analysis with an inductive approach. Results: Participants preferred short-term programs taking place in rehabilitation clinics, or physiotherapy or occupational therapy practices. They believed that the awareness for fall prevention needs to be raised among healthcare professionals. Participants expected better consultation from physio and occupational therapists regarding mobility aids and home modification. The participants wanted the programs to be practical, in-person and in groups. Online interventions were strongly rejected. Further, participants wanted balance/strength exercises and the inclusion of falling techniques in programs. The competence of knowing and accepting capacity may be an important factor in preventing falls. Conclusions: Investigating the views and opinions of persons with MS on fall prevention programs gave important information which can be used to inform the development of such programs. IMPLICATIONS FOR REHABILITATION People with multiple sclerosis (MS) prefer short-term fall prevention programs that are practical, in-person and in groups. Online interventions were strongly rejected. People with MS want balance/strength exercises and falling techniques included within fall prevention programs. People with MS believe that awareness regarding falls prevention needs to be raised among healthcare professionals. Also, services regarding mobility aids and home modification from physio and occupational therapists are currently unsatisfactory. People with MS believe that competence in knowing and accepting their capacity to engage in activities may be a decisive factor in preventing falls. |
Dishabil. Rehabil. 2021 Apr;43(8):1065-1073
Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DH.
Neuronal vulnerability and multilineage diversity in multiple sclerosis.
Nature. 2019 Sep;573(7772):75-82.
Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DH.
Neuronal vulnerability and multilineage diversity in multiple sclerosis.
| Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions. |
Nature. 2019 Sep;573(7772):75-82.
Bittner S, Engel S, Lange C, Weber MS, Haghikia A, Luessi F, Korn T, Klotz L, Bayas A, Paul F, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Trebst C, Warnke C, Linker R, Kerschensteiner M, Zettl U, Tumani H, Brück W, Meuth SG1 Kümpfel T, Hemmer B, Wiendl H, Gold R, Zipp F.
Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany.
Nervenarzt. 2019 Dec;90(12):1245-1253
Bittner S, Engel S, Lange C, Weber MS, Haghikia A, Luessi F, Korn T, Klotz L, Bayas A, Paul F, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Trebst C, Warnke C, Linker R, Kerschensteiner M, Zettl U, Tumani H, Brück W, Meuth SG1 Kümpfel T, Hemmer B, Wiendl H, Gold R, Zipp F.
Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany.
| After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence. |
Nervenarzt. 2019 Dec;90(12):1245-1253
Andrees V, Westenhöfer J, Blome C, Heesen C, Augustin M, Topp J.
Towards patients‘ understanding of health-related quality of life-a mixed-method study in psoriasis and multiple sclerosis.
Qual Life Res. 2019 Oct;28(10):2717-2729.
Andrees V, Westenhöfer J, Blome C, Heesen C, Augustin M, Topp J.
Towards patients‘ understanding of health-related quality of life-a mixed-method study in psoriasis and multiple sclerosis.
| PURPOSE: Patients‘ individual understanding of health-related quality of life (HRQoL) varies widely, making the measurement of this complex and subjective construct challenging. Anchoring vignettes, i.e., descriptions of fictive patients may provide insights into patients‘ individual questionnaire reference frames, assessment processes, and understanding of HRQoL. This study analyzes how patients assess HRQoL of vignettes. METHODS: This exploratory mixed-method study included 100 patients with a chronic disease (50 multiple sclerosis (MS); 50 psoriasis). Sixteen vignettes, two for each domain of the SF-12v2, were developed based on literature recommendations and pretested in a convenience sample of seven healthy individuals. Patients assessed their own HRQoL and HRQoL of the vignettes on the SF-12v2. In semi-structured interviews, they justified their assessments. We quantitatively analyzed associations of vignette assessments with individual characteristics using linear regression models and qualitatively analyzed assessment justifications. RESULTS: Patients‘ age and disease were significant (p < 0.05) predictors for ten and seven vignette assessments, respectively. Older patients assessed vignettes being less extreme; patients diagnosed with MS rated them more positively. Overall, adjusted R2 values ranged from 0.033 to 0.172. Qualitatively, most of the ratings were based on the evaluation of symptoms or impairments in daily life. Fewer participants ranked different dimensions of HRQoL in a personal hierarchy or assumed impairments beyond the vignette description. CONCLUSIONS: The understanding of HRQoL may vary substantially and is associated with individual characteristics, individual assessment strategies, and probably other intrinsic factors as explained variance was quite low. Therefore, usage of generic instruments only allows for limited comparison across groups. |
Qual Life Res. 2019 Oct;28(10):2717-2729.
Weygandt M, Behrens J, Brasanac J, Söder E, Meyer-Arndt L, Wakonig K, Ritter K, Brandt AU, Bellmann-Strobl J, Gold SM, Haynes JD, Paul F.
Neural mechanisms of perceptual decision-making and their link to neuropsychiatric symptoms in multiple sclerosis.
Mult Scler Relat Disord. 2019 May 30;33:139-145
Weygandt M, Behrens J, Brasanac J, Söder E, Meyer-Arndt L, Wakonig K, Ritter K, Brandt AU, Bellmann-Strobl J, Gold SM, Haynes JD, Paul F.
Neural mechanisms of perceptual decision-making and their link to neuropsychiatric symptoms in multiple sclerosis.
| BACKGROUND: Decision-making (DM) capabilities are impaired in multiple sclerosis (MS). A variety of researchers hypothesized that this impairment is associated with reduced quality of life (QoL) and neuropsychiatric symptoms. Studies explicitly testing this hypothesis, however, are rare, provided inconclusive results, or evaluated only a limited selection of DM domains. Consequently, we conducted the first MS study on perceptual DM (e.g. deciding whether a car will fit into a parking lot based on a visual percept) to test this assumption. METHODS: Specifically, we used an fMRI task that measured brain activity in 30 MS patients and 19 healthy controls (HCs) while the participants repeatedly decided whether objects referenced indirectly via their written object names would fit into a shoebox to investigate neural mechanisms of perceptual DM. The objects varied in size and thus decision difficulty. From these data, we determined voxel-wise brain activity parameters reflecting (i) decision difficulty and (ii) decision speed and related them to behavioral DM performance, QoL, mild to moderate depressive symptoms, and fatigue. RESULTS: Patients showed reduced DM performance. Activity reflecting decision difficulty in the middle temporal gyrus was negatively related to DM performance across MS patients and HCs; activity reflecting decision speed in MS patients was associated with depressive symptoms and fatigue in areas of the dorsal visual stream. CONCLUSION: The study shows that the perceptual DM capacity is reduced in MS. Moreover, the link between neural mechanisms of perceptual DM and neuropsychiatric symptoms suggests that an impairment in this domain is clinically relevant. |
Mult Scler Relat Disord. 2019 May 30;33:139-145
Alegiani AC, Albrecht S, Rahn AC, Köpke S, Thomalla G, Heesen C.
Reasons for delayed admission after stroke: results of a qualitative and quantitative survey.
Patient Prefer Adherence. 2019 May 8;13:739-747
Alegiani AC, Albrecht S, Rahn AC, Köpke S, Thomalla G, Heesen C.
Reasons for delayed admission after stroke: results of a qualitative and quantitative survey.
| Background: Acute stroke treatment shows time-dependent benefit to prevent disability. Public information campaigns and streamlining of emergency management have been performed, but still, only one-third of acute stroke patients are admitted >4.5 hrs after symptom onset. Patients and methods: We interviewed 15 patients, presenting >4.5 hrs after symptom onset, regarding symptom recognition, emotions and their first action after symptom onset. Recorded interviews were analyzed by standardized descriptive analysis. Based on the results, a quantitative survey was developed. One hundred consecutive stroke unit patients surveyed to compare patients presenting within 4.5 hrs and more than 4.5 hrs of symptom onset. Results: Patients predominantly noticed symptoms by themselves. The most commonly expressed feelings were uncertainty and shame. The most frequent action was waiting. Patients described moderate knowledge about stroke in general, but felt less informed regarding their stroke risk. Magazines (51%) were the most frequently indicated source of information, while general practitioners only accounted for 26%. Significantly better knowledge was shown in the answers on closed questions compared to open questions, although the same items were named. Conclusion: Shame, uncertainty and insufficient individual risk knowledge about stroke were the most important factors delaying admission after stroke. Individual risk counseling could be investigated to close the gap between general stroke knowledge and recognition of own stroke risk. |
Patient Prefer Adherence. 2019 May 8;13:739-747
van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W6,, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T5, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.
A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
Acta Neuropathol. 2019 Aug;138(2):237-250
van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W6,, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T5, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.
A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
| The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. |
Acta Neuropathol. 2019 Aug;138(2):237-250
Faizy TD, Broocks G, Frischmuth I, Westermann C, Flottmann F, Schönfeld MH2, Nawabi J, Leischner H, Kutzner D2, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U.
Spectrally fat-suppressed coronal 2D TSE sequences may be more sensitive than 2D STIR for the detection of hyperintense optic nerve lesions.
Eur Radiol. 2019 Nov;29(11):6266-6274
Faizy TD, Broocks G, Frischmuth I, Westermann C, Flottmann F, Schönfeld MH2, Nawabi J, Leischner H, Kutzner D2, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U.
Spectrally fat-suppressed coronal 2D TSE sequences may be more sensitive than 2D STIR for the detection of hyperintense optic nerve lesions.
| OBJECTIVES: The aim of the study is to compare coronal spectrally fat-suppressed 2D turbo spin-echo (TSE) with 2D short-tau inversion-recovery (STIR) sequences for the detection of optic nerve hyperintensities in patients with acute optic nerve neuritis (ON). METHODS: A retrospective review of patients with suspected unilateral ON and pathological visual evoked potentials, who received coronal TSE and STIR sequences with similar fast and clinically feasible acquisition times in addition to our standard imaging protocol. All images were evaluated and compared concerning the presence of optic nerve lesions, lesion lengths, and signal intensities in different anatomical parts of the optic nerves and CNR measures. A summary confidence score (CS) was calculated based on each reader’s subjective confidence regarding the scoring items. RESULTS: Interobserver agreements regarding the detection of optic nerve lesions were excellent for both sequences (TSE, κ = 0.89 and STIR, κ = 0.80). Greater extensions (17.4 ± 6.3 mm vs. 14.1 ± 5.8 mm), as well as higher numbers of optic nerve lesions in symptomatic nerves, were detected on TSE (49/52) compared with STIR (45/52) sequences (both p < 0.001). Overall CS were significantly (p < 0.001) higher for TSE (2.8) compared with STIR (2.1) sequences regarding the presence or absence of optic nerve lesions. CNR ratios of lesions‘ mean signal intensities vs. ipsilateral surrounding orbital fat and vs. signal intensity measurements from contralateral optic nerves were significantly higher on TSE compared with STIR (p < 0.001 for both comparisons). CONCLUSION: Spectrally fat-suppressed coronal 2D TSE sequences appear to be more sensitive for the detection of hyperintense optic lesions compared with 2D STIR sequences. KEY POINTS: • Spectrally fat-suppressed TSE sequences showed higher detection rates of hyperintense optic nerve lesions, as well as a higher reader confidence scores compared with STIR. • Optic nerve signal abnormalities on TSE sequences were brighter and showed a greater expansion along the optic nerve course. • CNR measures were significantly higher on TSE compared with STIR, when comparing the ratios of mean signal intensities of optic nerve lesions to ipsilateral orbital fat and to contralateral healthy optic nerves of both sequences. |
Eur Radiol. 2019 Nov;29(11):6266-6274
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Nat Neurosci. 2019 Jun;22(6):887-896
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.Nat Neurosci. 2019 Jun;22(6):887-896
Pust GEA, Pöttgen J, Randerath J, Lau S, Heesen C, Gold SM, Penner IK
In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients.
J Neurol. 2019 Jul;266(7):1663-1673
Pust GEA, Pöttgen J, Randerath J, Lau S, Heesen C, Gold SM, Penner IK
In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients.
Fatigue is among the most disabling symptoms in patients with multiple sclerosis (PwMS). The common distinction between cognitive and motor fatigue is typically incorporated in self-rating instruments, such as the Chalder Fatigue Questionnaire (CFQ), the Fatigue Scale for Motor and Cognitive Functions (FSMC) or the Modified Fatigue Impact Scale (MFIS). The present study investigated the factor structure of the CFQ, the FSMC and the MFIS utilizing exploratory (EFA) and confirmatory factor analysis (CFA) as well as exploratory structural equation modeling (ESEM). Data of 1.403 PwMS were analyzed, utilizing four samples. The first sample (N = 605) was assessed online and split into two stratified halves to perform EFA, CFA, and ESEM on the CFQ and FSMC. The second sample (N = 293) was another online sample. It served to calculate CFA and ESEM on the CFQ and FSMC. The third sample was gathered in a clinical setting (N = 196) and analyzed by applying CFA and ESEM to the FSMC. The fourth sample (N = 309) was assessed in a clinical setting and allowed to run a CFA and ESEM on the MFIS. Proposed factor structures of all questionnaires were largely confirmed in EFA. However, none of the calculated CFAs and ESEMs could verify the proposed factor structures of the three measures, even with oblique rotation techniques. The findings might have implications for future research into the pathophysiological basis of MS-related fatigue and could affect the suitability of such measures as outcomes for treatment trials, presumably targeting specific sub-components of fatigue.J Neurol. 2019 Jul;266(7):1663-1673
Chae WR, Nagel JM, Kuehl LK, Gold SM, Wingenfeld K, Otte C.
Predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression.
J Affect Disord. 2019 Jun 1;252:99-106
Chae WR, Nagel JM, Kuehl LK, Gold SM, Wingenfeld K, Otte C.
Predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression.
| BACKGROUND: Many depressed patients do not achieve response or remission despite adequate treatment. Identifying predictors of outcome can contribute to developing therapeutic algorithms for difficult-to-treat depression. Therefore, we examined clinical predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression. METHODS: Three hundred and fifty-one consecutive inpatients admitted to a tertiary care university hospital (specialized psychiatry unit for treatment of unipolar and bipolar depression) between January 2014 and December 2016 were characterized by a set of sociodemographic and clinical variables. The predictive value of these variables for response (≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score) and remission (MADRS score at discharge < 10) were explored using bivariate analysis and logistic regression. RESULTS: Greater symptom severity and fewer psychotropic medications at the time of admission predicted response. Remission rates were higher for patients with non-chronic depression, higher number of previous depressive episodes, fewer psychotropic medications and less severe depression at admission. LIMITATIONS: This was a retrospective study without a control group. The sample was drawn from a single inpatient ward specialized for difficult-to-treat depression. CONCLUSIONS: Greater baseline depression severity might be a proxy for a less chronic course of depression thereby explaining its association with greater response rates. Fewer episodes in the past and polypharmacy could indicate treatment-resistance and chronicity, contributing to lower remission rates. Therefore, preventing chronicity should be a central aim of depression treatment. |
J Affect Disord. 2019 Jun 1;252:99-106
Riemann-Lorenz K, Wienert J, Streber R, Motl RW, Coote S, Heesen C
Long-term physical activity in people with multiple sclerosis: exploring expert views on facilitators and barriers.
Disabil Rehabil. 2019 Mar 23:1-13
Riemann-Lorenz K, Wienert J, Streber R, Motl RW, Coote S, Heesen C
Long-term physical activity in people with multiple sclerosis: exploring expert views on facilitators and barriers.
| PURPOSE: To explore the views of experts on facilitators and barriers of long-term physical activity among people with multiple sclerosis living in different European countries. METHODS: We conducted semi-structured telephone or face to face interviews with twelve multiple sclerosis and physical activity experts (scientists, practitioners, patient representatives) from five European countries. Interviews were audio-recorded, transcribed verbatim and analyzed using thematic analysis. RESULTS: We identified 20 themes and categorized them into environmental and personal factors. The most frequently mentioned and intensively discussed themes were environmental factors. The themes were structured according to possible intervention level: organizational, interpersonal and intrapersonal level themes. Themes at the organizational level comprised availability, access and quality of exercise/physical activity options; health system characteristics like services and organization, health professionals and information provision. The interpersonal level comprised social support and peer support. Disease related factors were the most frequently mentioned intrapersonal level theme. In our study, more codes were obtained for environmental factors than for personal factors. CONCLUSIONS: The results suggested that environmental factors may need to be addressed in particular to increase long-term physical activity adherence. This study will inform the design of a survey questionnaire assessing possible barriers and facilitators among people with multiple sclerosis. Implications for rehabilitation Long-term physical activity among people with multiple sclerosis is subject to a number of modifiable determinants: personal and environmental factors. Multiple sclerosis exercise experts emphasized the importance of environmental factors on the organizational and interpersonal level. Future physical activity interventions should be guided by a social-ecological perspective. Addressing environmental and personal factors simultaneously to reach optimal long-term outcomes should be considered in future interventions. |
Disabil Rehabil. 2019 Mar 23:1-13
Schuster S, Ozga AK, Stellmann JP, Deb-Chatterji M, Häußler V, Matschke J, Gerloff C, Thomalla G, Magnus T.
Relapse rates and long-term outcome in primary angiitis of the central nervous system.
J Neurol. 2019 Jun;266(6):1481-1489
Schuster S, Ozga AK, Stellmann JP, Deb-Chatterji M, Häußler V, Matschke J, Gerloff C, Thomalla G, Magnus T.
Relapse rates and long-term outcome in primary angiitis of the central nervous system.
OBJECTIVE: To analyze the treatment response in patients with primary angiitis of the central nervous system (PACNS). METHODS: In a single-center retrospective observational study, we assessed relapses, remission, and long-term outcome by use of the modified Rankin Scale (mRS) under different immunotherapies. Eligible patients had CNS biopsy in favor of PACNS or neuroimaging compatible with PACNS after exclusion of an alternative diagnosis. Regression models, recurrent event, and linear mixed-effects models were used to estimate the annual relapse rate, relapse and outcome predictors. Favorable outcome was defined as mRS < 3. RESULTS: Of 44 patients, 26 (59%) were female, median age at diagnosis was 43.5 (range 14-83) years, and 25 (57%) had biopsy-proven diagnosis. Median follow-up was 5.1 years. Glucocorticoids were administered in 30 patients at diagnosis (68%), 33 patients (75%) received cyclophosphamide, and 86% of patients had maintenance therapy > 24 months. Overall, 201 treatment episodes with 104 relapses and 4 (9%) deaths occurred. 26 patients had relapses (59.1%). The annual relapse rate was 1.4 (CI 1.1-1.8). Male sex was the only significant predictor of relapse (HR = 3.27, 95% CI 1.57-6.82). Remission occurred in 30 patients (68%). Favorable outcome was evident in 80% of patients after 2 years and 66% of patients at last follow-up. CONCLUSIONS: PACNS is a relapsing-remitting disease with a heterogeneous disease course and mostly favorable outcome under immunotherapy. Male patients have a higher relapse risk; no other relapse or outcome predictor could be identified. PACNS subtype stratification is needed to further evaluate predictors of response.J Neurol. 2019 Jun;266(6):1481-1489
Schaefer LM, Poettgen J, Fischer A, Gold S, Stellmann JP, Heesen C
Impairment and restrictions in possibly benign multiple sclerosis.
Brain Behav. 2019 April;9(4):e01259
Schaefer LM, Poettgen J, Fischer A, Gold S, Stellmann JP, Heesen C
Impairment and restrictions in possibly benign multiple sclerosis.
OBJECTIVE: The aim was to describe a broad range of health dimensions in possibly benign multiple sclerosis (MS) hypothesizing that despite some limitations there is a high adaptation to the disease. METHODS: All patients from an outpatient university clinic data registry with an Expanded Disability Status Scale (EDSS) ≤3.5 and disease duration ≥15 years were addressed in a cross-sectional study. Physical impairment, neuropsychological functioning but also influence on activities and patient reported outcome measures including coping were studied. RESULTS: One hundred and twenty-five patients could be included (mean EDSS: 2.8; mean disease duration: 24 years). Cognitive impairment was minor (8%) but fatigue (73%) and depression (46%) were prevalent. Nevertheless, QOL and daily activities seemed to be less affected. Patients showed high social support, coping abilities, and sense of coherence, which was predictive for their perceived benignity of the disease. Based on the EDSS alone, we estimated the rate of benign MS after 15 years of MS as high as 23% decreasing to 16% if cognition was included in the definition. However, cognitive performance was not relevantly associated with other outcomes. CONCLUSION: Common benign MS definitions seem to simplify a complex disease picture where different impairments and personal resources lead to more or less impact on people’s lives.Brain Behav. 2019 April;9(4):e01259
Faizy TD, Broocks G, Thaler C, Rauch G, Gebert P, Stürner KH, Flottmann F, Leischner H, Kniep HC, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U
Development of Cortical Lesion Volumes on Double Inversion Recovery MRI in Patients With Relapse-Onset Multiple Sclerosis.
Front Neurol. 2019 Feb 22;10:133
Faizy TD, Broocks G, Thaler C, Rauch G, Gebert P, Stürner KH, Flottmann F, Leischner H, Kniep HC, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U
Development of Cortical Lesion Volumes on Double Inversion Recovery MRI in Patients With Relapse-Onset Multiple Sclerosis.
Background and Objective: In multiple sclerosis (MS) patients, Double Inversion Recovery (DIR) magnetic resonance imaging (MRI) can be used to detect cortical lesions (CL). While the quantity and distribution of CLs seems to be associated with patients‘ disease course, literature lacks frequent assessments of CL volumes (CL-V) in this context. We investigated the reliability of DIR for the longitudinal assessment of CL-V development with frequent follow-up MRIs and examined the course of CL-V progressions in relation to white-matter lesions (WML), contrast enhancing lesions (CEL) and clinical parameters in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Methods: In this post-hoc analysis, image- and clinical data of a subset of 24 subjects that were part of a phase IIa clinical trial on the „Safety, Tolerability and Mechanisms of Action of Boswellic Acids in Multiple Sclerosis (SABA)“ (ClinicalTrials.gov, NCT01450124) were included. The study was divided in three phases (screening, treatment, study-end). All patients received 12 MRI follow-up-examinations (including DIR) during a 16-months period. CL-Vs were assessed for each patient on each follow-up MRI separately by two experienced neuroradiologists. Results of neurological screening tests, as well as other MRI parameters (WML number and volume and CELs) were included from the SABA investigation data. Results: Inter-rater agreement regarding CL-V assessment over time was good-to-excellent (κ = 0.89). Mean intraobserver variability was 1.1%. In all patients, a total number of 218 CLs was found. Total CL-Vs of all patients increased during the 4 months of baseline screening followed by a continuous and significant decrease from month 5 until study-end (p < 0.001, Kendall'W = 0.413). A positive association between WML volumes and CL-Vs was observed during baseline screening. Decreased CL-V were associated with lower EDSS and also with improvements of SDMT- and SCRIPPS scores. Conclusion: DIR MRI seems to be a reliable tool for the frequent assessment of CL-Vs. Overall CL-Vs decreased during the follow-up period and were associated with improvements of cognitive and disability status scores. Our results suggest the presence of short-term CL-V dynamics in RRMS patients and we presume that the laborious evaluation of lesion volumes may be worthwhile for future investigations. Clinical Trial Numbers: www.ClinicalTrials.gov, "The SABA trial"; number: NCT01450124.Front Neurol. 2019 Feb 22;10:133
Engels K, Schiffmann I, Weierstall R, Rahn AC, Daubmann A, Pust G, Chard D, Lukas C, Scheiderbauer J, Stellmann JP, Heesen C
Emotions towards magnetic resonance imaging in people with multiple sclerosis.
Acta Neurol Scand. 2019 Jun;139(6):497-504.
Engels K, Schiffmann I, Weierstall R, Rahn AC, Daubmann A, Pust G, Chard D, Lukas C, Scheiderbauer J, Stellmann JP, Heesen C
Emotions towards magnetic resonance imaging in people with multiple sclerosis.
OBJECTIVES: People with multiple sclerosis (pwMS) often have magnetic resonance imaging (MRI) examinations. While MRI can help guide MS management, it may be a source of anxiety for pwMS. We aimed to develop and validate a questionnaire on the „EMotions and Attitudes towards MRI“ (MRI-EMA). MATERIAL & METHODS: The questionnaire was developed, tested in 2 samples of pwMS and validated in a sample of n=457 pwMS using exploratory (EFA) and confirmatory factor analysis (CFA). RESULTS: EFA revealed 4 factors underlying the questionnaire: fear of MRI scan, fear of MRI results, feeling of control over the disease and feeling of competence in the patient-physician encounter. CFA confirmed the model fit. Receiving the MRI results, but not undergoing the procedure was associated with anxiety. Seeing MRI results gave participants a feeling of control over the disease. Only 50% felt competent to discuss MRI findings with their physician. Fear of MRI results was especially high and feeling of competence low in participants with a short disease duration and little MRI experience. CONCLUSION: PwMS don’t feel competent when discussing the role, MRI plays in their care. Receiving MRI results caused anxiety and provides some pwMS with a – perhaps false – feeling of control over the disease. The MRI-EMA constitutes a new tool for the assessments of pwMS‘ feelings towards MRI, that can be applied in future research and clinical settings.Acta Neurol Scand. 2019 Jun;139(6):497-504.
Tintelnot J, Ufer F, Engler JB, Winkler H, Lücke K, Mittrücker HW, Friese MA
Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice
Eur J Immunol. 2019 May;49(5):724-736
Tintelnot J, Ufer F, Engler JB, Winkler H, Lücke K, Mittrücker HW, Friese MA
Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice
The key function of migratory dendritic cells (migDCs) is to take up antigens in peripheral tissues and migrate to draining lymph nodes (dLN) to initiate immune responses. Recently, we discovered that in the mouse immune system activity-regulated cytoskeleton associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) is exclusively expressed by migDCs and is a central driver of fast inflammatory migration. However, the frequency of Arc/Arg3.1-expressing cells in different migDC subsets and Langerhans cells (LCs), their phylogenetic origin, transcription factor dependency and functional role remain unclear. Here we found that Arc/Arg3.1+ migDCs derived from common DC precursors and radio-resistant LCs. We found Arc/Arg3.1+ migDCs in varying frequencies within each migDC subset and LCs. Consistently, they showed superiority in inflammatory migration. Arc/Arg3.1 expression was independent of the transcription factors Irf4 or Batf3 in vivo. In intradermal Staphylococcus aureus infection that relies on inflammatory antigen transport, Arc/Arg3.1 deletion reduced T cell responses. By contrast, Arc/Arg3.1 deficiency did not hamper the immune response to systemic Listeria monocytogenes infection, which does not require antigen transport. Thus, Arc/Arg3.1 expression is independent of ontogeny and phenotype and although it is restricted to a small fraction within each migDC subset and LCs, Arc/Arg3.1+ migDCs are important to facilitate infectious migration.Eur J Immunol. 2019 May;49(5):724-736
Schreurs RRCE, Baumdick ME, Sagebiel AF, Kaufmann M, Mokry M, Klarenbeek PL, Schaltenberg N, Steinert FL, van Rijn JM, Drewniak A, The SML, Bakx R, Derikx JPM, de Vries N, Corpeleijn WE, Pals ST, Gagliani N, Friese MA, Middendorp S, Nieuwenhuis EES, Reinshagen K, Geijtenbeek TBH, van Goudoever JB, Bunders MJ.
Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life.
Immunity. 2019 Feb 19;50(2):462-476
Schreurs RRCE, Baumdick ME, Sagebiel AF, Kaufmann M, Mokry M, Klarenbeek PL, Schaltenberg N, Steinert FL, van Rijn JM, Drewniak A, The SML, Bakx R, Derikx JPM, de Vries N, Corpeleijn WE, Pals ST, Gagliani N, Friese MA, Middendorp S, Nieuwenhuis EES, Reinshagen K, Geijtenbeek TBH, van Goudoever JB, Bunders MJ.
Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life.
Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.Immunity. 2019 Feb 19;50(2):462-476
Stork L, Brück W, von Gottberg P, Pulkowski U, Kirsten F, Glatzel M, Rauer S, Scheibe F, Radbruch H, Hammer E, Stürner KH, Kaulen B, Heesen C, Hoffmann F, Brock S, Pawlitzki M, Bopp T, Metz I.
Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.
Mult Scler. 2019 Oct;25(12):1618-1632
Stork L, Brück W, von Gottberg P, Pulkowski U, Kirsten F, Glatzel M, Rauer S, Scheibe F, Radbruch H, Hammer E, Stürner KH, Kaulen B, Heesen C, Hoffmann F, Brock S, Pawlitzki M, Bopp T, Metz I.
Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.
BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018.OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.Mult Scler. 2019 Oct;25(12):1618-1632
Beckmann H, Augustin M, Heesen C, Poettgen J, Blome C.
Benefit evaluation in multiple sclerosis relapse treatment from the patients‘ perspective – Development and validation of a new questionnaire
Mult Scler Relat Disord. 2018 Dec 17;28:256-261
Beckmann H, Augustin M, Heesen C, Poettgen J, Blome C.
Benefit evaluation in multiple sclerosis relapse treatment from the patients‘ perspective – Development and validation of a new questionnaire
BACKGROUND: Little is known on how to measure patient-relevant benefit of relapse treatment in relapsing-remitting multiple sclerosis (MS). The objective of this study was to develop and validate a new method for monitoring recovery from MS relapses and patient-relevant treatment benefits. METHODS: A 27-item questionnaire was developed using a multi-step approach comprising open item collection, multidisciplinary expert panel and cognitive debriefing. It was evaluated regarding psychometric properties and feasibility in a longitudinal validation study with 100 patients with MS undergoing relapse treatment. Construct validity was tested by correlations with patient and physician global impressions of change as well as disease-specific and generic health-related quality of life (HRQoL) measures. RESULTS: Results of the feasibility survey indicated high patient acceptance. Reliability was high (Cronbach’s α = 0.90). While the Expanded Disability Status Scale (EDSS) was not sensitive to change, Patient Benefit Index for Multiple Sclerosis (PBI-MS) showed a high correlation cross-sectionally with patient global impression of change (PaGIC) (r = 0.60, p < 0.001). Significant moderate to high correlations were found with change in generic HRQoL (r = 0.55-0.61, p < 0.001) and lower correlations with change in disease-specific HRQoL (r = -0.36, p < 0.01). CONCLUSION: The PBI-MS is a reliable and valid instrument for ascertaining patient-relevant benefits of acute relapse treatment; it appears suited for use in routine care and in clinical or health care studies.Mult Scler Relat Disord. 2018 Dec 17;28:256-261
Hierweger AM, Engler JB, Friese MA, Reichardt HM, Lydon J, DeMayo F, Mittrücker HW, Arck PC.
Progesterone modulates the T cell response via glucocorticoid receptor-dependent pathways.
Am J Reprod Immunol. 2019 Feb.;81(2):e13084
Hierweger AM, Engler JB, Friese MA, Reichardt HM, Lydon J, DeMayo F, Mittrücker HW, Arck PC.
Progesterone modulates the T cell response via glucocorticoid receptor-dependent pathways.
PROBLEM: Steroid hormones such as progesterone and glucocorticoids rise during pregnancy and are accountable for the adaptation of the maternal immune system to pregnancy. How steroid hormones induce fetal tolerance is not fully understood. We hypothesized that steroid hormones selectively regulate the T cell response by promoting T cell death. METHOD OF STUDY: We incubated murine spleen cells isolated from non-pregnant and pregnant mice with physiological concentrations of steroid hormones in vitro and analyzed T cell subsets after 48 h of incubation. RESULTS: We found that progesterone and the synthetic glucocorticoid dexamethasone induce T cell death. CD4+ regulatory T cells (Treg ) were refractory towards progesterone-induced cell death, in contrast to conventional CD4+ T cells, which resulted in a preferential enrichment of CD4+ Treg cells in culture. T cells isolated from pregnant mice at early and late gestation showed comparable sensitivity to steroid-induced cell death. The target receptor for progesterone in immune cells is controversially discussed. We provide here support of progesterone binding to the glucocorticoid receptor as only T cells lacking the glucocorticoid but not the progesterone receptor showed resistance against progesterone-induced death. CONCLUSIONS: Our results indicate that high levels of progesterone during pregnancy can induce selective T cell death by binding the glucocorticoid receptor. Although physiological hormone concentrations were used, due to different bioavailability of steroid hormones in vivo these results have to be validated in an in vivo model. This mechanism might ensure immunological tolerance at the feto-maternal interface at gestation.Am J Reprod Immunol. 2019 Feb.;81(2):e13084
Baquet L, Hasselmann H, Patra S, Stellmann JP, Vettorazzi E, Engel AK, Rosenkranz SC, Poettgen J, Gold SM, Schulz KH, Heesen C.
Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
PeerJ. 2018 Dec 12;6:e6037
Baquet L, Hasselmann H, Patra S, Stellmann JP, Vettorazzi E, Engel AK, Rosenkranz SC, Poettgen J, Gold SM, Schulz KH, Heesen C.
Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
Background: Only few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in multiple sclerosis. Objective and Methods: This randomized controlled trial with 34 patients in the intervention group (IG) (mean: 38.2 years (±9.6)) and 34 patients in the control group (CG) (mean: 39.6 years (±9.7)) aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting multiple sclerosis (RRMS). The primary outcome was verbal learning assessed by the verbal learning and memory test (VLMT). Patients were randomized to an IG or a waitlist CG. Patients in the IG exercised according to an individually tailored training schedule (with two to three sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores. Results: A total of 77 patients with RRMS were screened and 68 participants randomized (CG n = 34; IG n = 34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean expanded disability status scale of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms. Conclusion: This study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS. The trial was prospectively registered at clinicaltrials.PeerJ. 2018 Dec 12;6:e6037
Heesen C., Rahn AC.
Guest Editorial: Shared Decision Making in Managing Multiple Sclerosis: Revisiting the Research Agenda.
Int J MS Care. 2018 Nov-Dec;20(6)
Heesen C., Rahn AC.
Guest Editorial: Shared Decision Making in Managing Multiple Sclerosis: Revisiting the Research Agenda.
Keywords: Disease-modifying therapy; Multiple sclerosis; Patient perspective; Patient preference; Shared decision makingInt J MS Care. 2018 Nov-Dec;20(6)
Hasselmann H, Gamradt S, Taenzer A, Nowacki J, Zain R, Patas K, Ramien C, Paul F, Wingenfeld K, Piber D, Gold SM, Otte C.
Pro-inflammatory Monocyte Phenotype and Cell-Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder.
Front Immunol. 2018 Nov 23;9:2693
Hasselmann H, Gamradt S, Taenzer A, Nowacki J, Zain R, Patas K, Ramien C, Paul F, Wingenfeld K, Piber D, Gold SM, Otte C.
Pro-inflammatory Monocyte Phenotype and Cell-Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder.
Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11β-hydroxysteroid dehydrogenase type 1; 11β -HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1β, or TNF-α. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes.Front Immunol. 2018 Nov 23;9:2693
Johnen A, Bürkner PC, Landmeyer NC, Ambrosius B, Calabrese P, Motte J, Hessler N, Antony G, König IR, Klotz L, Hoshi MM, Aly L, Groppa S, Luessi F, Paul F, Tackenberg B, Bergh FT, Kümpfel T, Tumani H, Stangel M, Weber F, Bayas A, Wildemann B, Heesen C, Zettl UK, Zipp F, Hemmer B, Meuth SG, Gold R, Wiendl H, Salmen A; German Competence Network Multiple Sclerosis (KKNMS).
Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).
J Neurol. 2019 Feb;266(2):386-397
Johnen A, Bürkner PC, Landmeyer NC, Ambrosius B, Calabrese P, Motte J, Hessler N, Antony G, König IR, Klotz L, Hoshi MM, Aly L, Groppa S, Luessi F, Paul F, Tackenberg B, Bergh FT, Kümpfel T, Tumani H, Stangel M, Weber F, Bayas A, Wildemann B, Heesen C, Zettl UK, Zipp F, Hemmer B, Meuth SG, Gold R, Wiendl H, Salmen A; German Competence Network Multiple Sclerosis (KKNMS).
Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).
BACKGROUND: Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis. METHODS: Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes. RESULTS: At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year. CONCLUSIONS: Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.J Neurol. 2019 Feb;266(2):386-397
Giordano A, Liethmann K, Köpke S, Poettgen J, Rahn AC, Drulovic J, Beckmann Y, Sastre-Garriga J, Galea I, Heerings M, Jongen PJ, Vettorazzi E, Solari A, Heesen C; AutoMS group
Risk knowledge of people with relapsing-remitting multiple sclerosis – Results of an international survey
PLoS One. 2018 Nov 29;13(11):e0208004.
Giordano A, Liethmann K, Köpke S, Poettgen J, Rahn AC, Drulovic J, Beckmann Y, Sastre-Garriga J, Galea I, Heerings M, Jongen PJ, Vettorazzi E, Solari A, Heesen C; AutoMS group
Risk knowledge of people with relapsing-remitting multiple sclerosis – Results of an international survey
BACKGROUND: Adequate disease and treatment-related risk knowledge of people with Multiple Sclerosis (pwMS) is a prerequisite for informed choices in medical encounters. Previous work showed that MS risk knowledge is low among pwMS and role preferences are different in Italy and Germany. OBJECTIVE: We investigated the level of risk knowledge and role preferences in 8 countries and assessed putative variables associated with risk knowledge. METHODS: An online-survey was performed based on the Risk knowledge questionnaire for people with relapsing-remitting MS (RIKNO 2.0), the electronic Control Preference Scale (eCPS), and other patient questionnaires. Inclusion criteria of participants were: (1) age ≥18 years, (2) a diagnosis of relapsing-remitting MS (RRMS), (3) being in a decision making process for a disease modifying drug. RESULTS: Of 1939 participants from Germany, Italy, the Netherlands, Serbia, Spain and Turkey, 986 (51%) (mean age 38.6 years [range 18-67], 77% women, 7.8 years of disease duration) completed the RIKNO 2.0, with a mean of 41% correct answers. There were less than 50 participants in the UK and Estonia and data were not analysed. Risk knowledge differed across countries (p < 0.001). Variables significantly associated with higher risk knowledge were higher education (p < 0.001), previous experience with disease modifying drugs (p = 0.001), correct answer to a medical data interpretation question (p < 0.001), while higher fear for wheelchair dependency was negatively associated to risk knowledge (p = 0.001). CONCLUSION: MS risk knowledge was overall low and differed across participating countries. These data indicate that information is an unmet need of most pwMS.PLoS One. 2018 Nov 29;13(11):e0208004.
Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Hellwig K, Pache F, Ruprecht K, Havla J, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Krumbholz M, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Zettl UK, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C; NEMOS (Neuromyelitis Optica Study Group).
Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.
Neurol Neuroimmunol Neuroinflamm. 2018 Sep 26;5(6):e504
Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Hellwig K, Pache F, Ruprecht K, Havla J, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Krumbholz M, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Zettl UK, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C; NEMOS (Neuromyelitis Optica Study Group).
Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, p = 0.046). Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.Neurol Neuroimmunol Neuroinflamm. 2018 Sep 26;5(6):e504
International Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu; International Multiple Sclerosis Genetics Consortium. Mitrovič M, Patsopoulos NA, Beecham AH, Dankowski T, Goris A, Dubois B, D'hooghe MB, Lemmens R, Van Damme P, Søndergaard HB, Sellebjerg F, Sorensen PS, Ullum H, Thørner LW, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud PA, Andlauer TFM, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh FT, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill CM, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone MA, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen CE, Bos SD, Myhr KM, Celius EG, Lie BA, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier SJ, Calabresi PA, Cree BAC, Cross A, Davis MF, Haines JL, de Bakker PIW, Delgado S, Dembele M, Edwards K, Fitzgerald KC, Hakonarson H, Konidari I, Lathi E, Manrique CP, Pericak-Vance MA, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth DR, Harbo HF, Ivinson AJ, Hauser SL, Compston A, Stewart G, Zipp F, Barcellos LF, Baranzini SE, Martinelli-Boneschi F, D'Alfonso S, Ziegler A, Oturai A, McCauley JL, Sawcer SJ, Oksenberg JR, De Jager PL, Kockum I, Hafler DA, Cotsapas C.
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.
Cell. 2018 Nov 29;175(6):1679-1687
International Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu; International Multiple Sclerosis Genetics Consortium. Mitrovič M, Patsopoulos NA, Beecham AH, Dankowski T, Goris A, Dubois B, D'hooghe MB, Lemmens R, Van Damme P, Søndergaard HB, Sellebjerg F, Sorensen PS, Ullum H, Thørner LW, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud PA, Andlauer TFM, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh FT, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill CM, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone MA, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen CE, Bos SD, Myhr KM, Celius EG, Lie BA, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier SJ, Calabresi PA, Cree BAC, Cross A, Davis MF, Haines JL, de Bakker PIW, Delgado S, Dembele M, Edwards K, Fitzgerald KC, Hakonarson H, Konidari I, Lathi E, Manrique CP, Pericak-Vance MA, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth DR, Harbo HF, Ivinson AJ, Hauser SL, Compston A, Stewart G, Zipp F, Barcellos LF, Baranzini SE, Martinelli-Boneschi F, D'Alfonso S, Ziegler A, Oturai A, McCauley JL, Sawcer SJ, Oksenberg JR, De Jager PL, Kockum I, Hafler DA, Cotsapas C.
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.
| Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. |
Cell. 2018 Nov 29;175(6):1679-1687
Heesen C, Scalfari A, Galea I.
Prognostic information for people with MS: Impossible or inevitable?
Mult Scler. 2020 Jun;26(7):771-773.
Heesen C, Scalfari A, Galea I.
Prognostic information for people with MS: Impossible or inevitable?
Delivering prognostic information is a challenging issue in medicine and has been largely neglected in the past. A major reason has been a suspected nocebo effect of pessimistic estimates, although this is largely unproven. Among people with multiple sclerosis (MS), there is a strong unmet need to receive long-term prognostic information. This viewpoint discusses reasons for this blind spot in physicians‘ attitude, foremost among which is the uncertainty of prognostic estimates. Possible strategies to move forward include tools to identify matching patients from large well-defined databases, to deliver an evidence-based individualized estimate of long-term prognosis, and its confidence interval, in a clinical setting.Mult Scler. 2020 Jun;26(7):771-773.
Tezer FI, Erdal A, Gumusyayla S, Has AC, Gocmen R, Oguz KK
Differences in diffusion tensor imaging changes between narcolepsy with and without cataplexy.
Sleep Med. 2018 Sep 18;52:128-133
Tezer FI, Erdal A, Gumusyayla S, Has AC, Gocmen R, Oguz KK
Differences in diffusion tensor imaging changes between narcolepsy with and without cataplexy.
OBJECTIVE: The distinctive clinical finding of Type 1 narcolepsy compared to Type 2 is the presence of cataplexy. Several neuroimaging studies have also reported abnormalities in narcolepsy patients with or without cataplexy. However, there are conflicting results to differentiate them. In this study, we aimed to clarify the white matter changes in narcolepsy patients both with and without cataplexy and compared them with healthy adults to evaluate microstructural differences in the brain. METHODS: Eleven narcolepsy patients with cataplexy (NC), 12 narcolepsy patients without cataplexy (NOC) and healthy age- and gender-matched controls (N = 16) were studied. Whole-brain diffusion tensor imaging (DTI) was obtained and tract-based spatial statistics were used to localize white matter abnormalities. RESULTS: Compared with the healthy controls, both NC and NOC patients exhibited significant fractional anisotropy (FA) decreases in the bilateral cerebellar hemispheres, bilateral thalami, the corpus callosum and left anterior-medial temporal white matter. Compared with the controls, the NC patients‘ FA values were also decreased in the midbrain. No significant correlations were found between FA values and clinical-polysomnographic variables. CONCLUSION: This DTI study has demonstrated white matter abnormalities in the midbrain-brainstem regions as a distinctive finding of narcolepsy patients with cataplexy. Involvement of bilateral temporal lobes with greater changes on the left lobe is also a supporting finding of patients with cataplexy. DTI changes in the midbrain-brainstem and bilateral temporal lobes can be signs of different pathological mechanisms in these patients.Sleep Med. 2018 Sep 18;52:128-133
Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP,, Reddy R, Fiehler J, Sedlacik J, Gellißen S.
Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.
Sci Rep. 2018 Oct 9;8(1):14991
Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP,, Reddy R, Fiehler J, Sedlacik J, Gellißen S.
Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.
Myelin Water Fraction (MWF) measurements derived from quantitative Myelin Water Imaging (MWI) may detect demyelinating changes of the cerebral white matter (WM) microstructure. Here, we investigated age-related alterations of the MWF in normal aging brains of healthy volunteers utilizing two fast and clinically feasible 3D gradient and spin echo (GRASE) MWI sequences with 3 mm and 5 mm isotropic voxel size. In 45 healthy subjects (age range: 18-79 years), distinct regions of interest (ROI) were defined in the cerebral WM including corticospinal tracts. For the 3 mm sequence, significant correlations of the mean MWF with age were found for most ROIs (r < -0.8 for WM ROIs; r = -0.55 for splenium of corpus callosum; r = -0.75 for genu of corpus callosum; p < 0.001 for all ROIs). Similar correlations with age were found for the ROIs of the 5 mm sequence. No significant correlations were found for the corticospinal tract and the occipital WM (p > 0.05). Mean MWF values obtained from the 3 mm and 5 mm sequences were strongly comparable. The applied 3D GRASE MWI sequences were found to be sensitive for age-dependent myelin changes of the cerebral WM microstructure. The reported MWF values might be of substantial use as reference for further investigations in patient studies.Sci Rep. 2018 Oct 9;8(1):14991
Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP, Reddy R, Fiehler J, Sedlacik J, Gellißen S.
Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.
Sci Rep. 2018 Oct 9;8(1):14991.
Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP, Reddy R, Fiehler J, Sedlacik J, Gellißen S.
Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.
| Myelin Water Fraction (MWF) measurements derived from quantitative Myelin Water Imaging (MWI) may detect demyelinating changes of the cerebral white matter (WM) microstructure. Here, we investigated age-related alterations of the MWF in normal aging brains of healthy volunteers utilizing two fast and clinically feasible 3D gradient and spin echo (GRASE) MWI sequences with 3 mm and 5 mm isotropic voxel size. In 45 healthy subjects (age range: 18-79 years), distinct regions of interest (ROI) were defined in the cerebral WM including corticospinal tracts. For the 3 mm sequence, significant correlations of the mean MWF with age were found for most ROIs (r < -0.8 for WM ROIs; r = -0.55 for splenium of corpus callosum; r = -0.75 for genu of corpus callosum; p < 0.001 for all ROIs). Similar correlations with age were found for the ROIs of the 5 mm sequence. No significant correlations were found for the corticospinal tract and the occipital WM (p > 0.05). Mean MWF values obtained from the 3 mm and 5 mm sequences were strongly comparable. The applied 3D GRASE MWI sequences were found to be sensitive for age-dependent myelin changes of the cerebral WM microstructure. The reported MWF values might be of substantial use as reference for further investigations in patient studies. |
Sci Rep. 2018 Oct 9;8(1):14991.
Stanelle-Bertram S, Walendy-Gnirß K, Speiseder T, Thiele S, Asante IA, Dreier C, Kouassi NM, Preuß A, Pilnitz-Stolze G, Müller U, Thanisch S, Richter M, Scharrenberg R, Kraus V, Dörk R, Schau L, Herder V, Gerhauser I, Pfankuche VM, Käufer C, Walt I , Moraes T, Sellau J, Hoenow S, Schmidt-Chanasit J, Jansen S, Schattling B, Ittrich H, Bartsch U, Renné T, Bartenschlager R, Arck P, Cadar D, Friese MA, Vapalahti O, Lotter H, Benites S, Rolling L, Gabriel M, Baumgärtner W, Morellini F, Hölter SM, Amarie O, Fuchs H, Hrabe de Angelis M, Löscher W, Calderon de Anda F, Gabriel G
Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.
Nat Microbiol. 2018 Oct;3(10):1161-1174.
Stanelle-Bertram S, Walendy-Gnirß K, Speiseder T, Thiele S, Asante IA, Dreier C, Kouassi NM, Preuß A, Pilnitz-Stolze G, Müller U, Thanisch S, Richter M, Scharrenberg R, Kraus V, Dörk R, Schau L, Herder V, Gerhauser I, Pfankuche VM, Käufer C, Walt I , Moraes T, Sellau J, Hoenow S, Schmidt-Chanasit J, Jansen S, Schattling B, Ittrich H, Bartsch U, Renné T, Bartenschlager R, Arck P, Cadar D, Friese MA, Vapalahti O, Lotter H, Benites S, Rolling L, Gabriel M, Baumgärtner W, Morellini F, Hölter SM, Amarie O, Fuchs H, Hrabe de Angelis M, Löscher W, Calderon de Anda F, Gabriel G
Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.
Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth.Nat Microbiol. 2018 Oct;3(10):1161-1174.
Filser M, Schreiber H, Pöttgen J, Ullrich S, Lang M, Penner IK.
The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study.
J Neurol. 2018 Nov;265(11):2587-2593
Filser M, Schreiber H, Pöttgen J, Ullrich S, Lang M, Penner IK.
The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study.
BACKGROUND: Recent research has convincingly shown that the ability to work mainly depends on the cognitive status in multiple sclerosis (MS). An international committee of experts recommended a brief neuropsychological battery to evaluate cognitive performance in MS. BICAMS comprises three tests, the Symbol Digit Modalities Test (SDMT), the learning trials of the California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). OBJECTIVE: To validate BICAMS on a sample of German MS patients and healthy controls (HCs). METHODS: According to the international guidelines for validation, examiner’s instructions were standardized and translated into German. Due to the availability of better normative data for future applications in routine clinical care and classification of individual performance degree, the Rey Auditory Verbal Learning Test (RAVLT) (German version: Verbaler Lern- und Merkfähigkeits-Test, VLMT) was chosen instead of CVLT-II. 172 MS patients and 100 HCs entered the study. BICAMS was administered at baseline and retest (after 3-4 weeks). RESULTS: The groups did not differ in age, gender or education. Mean age of MS patients was 43.33 years (SD 11.64); 68% were female and 86.9% had relapsing-remitting MS. Patients performed significantly worse than HCs on the SDMT (p < 0.01) and on BVMT-R (p < 0.05) but not on VLMT. In addition, BICAMS was shown to be reliable over time: r = 0.71 for BVMT-R, r = 0.72 for VLMT and r = 0.85 for SDMT. SDMT z-score proved to be a good predictor for the ability to work in a full-time (p < 0.001) as well as in a part-time job (p < 0.001). VLMT z-score turned out to be a significant predictor only for the ability to work in a part-time job, while BVMT-R z-score showed no significant predictive value. CONCLUSION: In this German validation study with the VLMT, the modified BICAMS (BICAMS-M) turned out to reliably detect cognitive problems in MS patients and to monitor cognitive performance over time. SDMT revealed the best predictive value for working ability. Moreover, only the SDMT was able to predict the ability to work in a part-time or full-time job. Following these results, application of the SDMT is recommended for medical statements on working ability of MS patients.J Neurol. 2018 Nov;265(11):2587-2593
Köpke S, Giordano A, Veronese S, Rahn AC, Kleiter I, Basedow-Rajwich B, Fornari A, Battaglia MA, Drulovic J, Kooij L, Koops J, Mens J, Meza Murillo ER, Milanov I, Milo R, Patti F, Pekmezovic T, Sastre-Garriga J, Vosburgh J, Voltz R, Bay J, Oliver DJ, Solari A.
Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis.
Eur J Neurol. 2019 Jan;26(1):41-50
Köpke S, Giordano A, Veronese S, Rahn AC, Kleiter I, Basedow-Rajwich B, Fornari A, Battaglia MA, Drulovic J, Kooij L, Koops J, Mens J, Meza Murillo ER, Milanov I, Milo R, Patti F, Pekmezovic T, Sastre-Garriga J, Vosburgh J, Voltz R, Bay J, Oliver DJ, Solari A.
Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis.
BACKGROUND AND PURPOSE: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. METHODS: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. RESULTS: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for ‚advance care planning‘ to 98% for ‚multidisciplinary rehabilitation‘), and <5% replied 'I prefer not to answer' to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. CONCLUSIONS: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes.Eur J Neurol. 2019 Jan;26(1):41-50
Stoessel D, Stellmann JP, Willing A, Behrens B, Rosenkranz SC, Hodecker SC, Stürner KH, Reinhardt S, Fleischer S, Deuschle C, Maetzler W, Berg D, Heesen C, Walther D, Schauer N, Friese MA, Pless O
Metabolomic Profiles for Primary Progressive Multiple Sclerosis Stratification and Disease Course Monitoring.
Front Hum Neurosci. 2018 Jun 4;12:226
Stoessel D, Stellmann JP, Willing A, Behrens B, Rosenkranz SC, Hodecker SC, Stürner KH, Reinhardt S, Fleischer S, Deuschle C, Maetzler W, Berg D, Heesen C, Walther D, Schauer N, Friese MA, Pless O
Metabolomic Profiles for Primary Progressive Multiple Sclerosis Stratification and Disease Course Monitoring.
Primary progressive multiple sclerosis (PPMS) shows a highly variable disease progression with poor prognosis and a characteristic accumulation of disabilities in patients. These hallmarks of PPMS make it difficult to diagnose and currently impossible to efficiently treat. This study aimed to identify plasma metabolite profiles that allow diagnosis of PPMS and its differentiation from the relapsing-remitting subtype (RRMS), primary neurodegenerative disease (Parkinson’s disease, PD), and healthy controls (HCs) and that significantly change during the disease course and could serve as surrogate markers of multiple sclerosis (MS)-associated neurodegeneration over time. We applied untargeted high-resolution metabolomics to plasma samples to identify PPMS-specific signatures, validated our findings in independent sex- and age-matched PPMS and HC cohorts and built discriminatory models by partial least square discriminant analysis (PLS-DA). This signature was compared to sex- and age-matched RRMS patients, to patients with PD and HC. Finally, we investigated these metabolites in a longitudinal cohort of PPMS patients over a 24-month period. PLS-DA yielded predictive models for classification along with a set of 20 PPMS-specific informative metabolite markers. These metabolites suggest disease-specific alterations in glycerophospholipid and linoleic acid pathways. Notably, the glycerophospholipid LysoPC(20:0) significantly decreased during the observation period. These findings show potential for diagnosis and disease course monitoring, and might serve as biomarkers to assess treatment efficacy in future clinical trials for neuroprotective MS therapies.Front Hum Neurosci. 2018 Jun 4;12:226
Buhse S, Rahn AC, Bock M, Mühlhauser I
Causal interpretation of correlational studies – Analysis of medical news on the website of the official journal for German physicians
Plos One. 2018 Max 3;13(5):e0196833
Buhse S, Rahn AC, Bock M, Mühlhauser I
Causal interpretation of correlational studies – Analysis of medical news on the website of the official journal for German physicians
BACKGROUND: Media frequently draws inappropriate causal statements from observational studies. We analyzed the reporting of study results in the Medical News section of the German medical journal Deutsches Ärzteblatt (DÄ). METHODS: Study design: Retrospective quantitative content analysis of randomly selected news reports and related original journal articles and press releases. A medical news report was selected if headlines comprised at least two linked variables. Two raters independently categorized the headline and text of each news report, conclusions of the abstract and full text of the related journal article, and the press release. The assessment instrument comprised five categories from ’neutral‘ to ‚unconditionally causal‘. Outcome measures: degree of matching between 1) news headlines and conclusions of the journal article, 2) headlines and text of news reports, 3) text and conclusions, and 4) headlines and press releases. We analyzed whether news headlines rated as unconditionally causal based on randomized controlled trials (RCTs). RESULTS: One-thousand eighty-seven medical news reports were published between April 2015 and May 2016. The final random sample comprised 176 news reports and 100 related press releases. Degree of matching: 1) 45% (79/176) for news headlines and journal article conclusions, 2) 55% (97/176) for headlines and text, 3) 53% (93/176) for text and conclusions, and 4) 41% (41/100) for headlines and press releases. Exaggerations were found in 45% (80/176) of the headlines compared to the conclusions of the related journal article. Sixty-five of 137 unconditionally causal statements of the news headlines were phrased more weakly in the subsequent news text body. Only 52 of 137 headlines (38%) categorized as unconditionally causal reported RCTs. CONCLUSION: Reporting of medical news in the DÄ medical journal is misleading. Most headlines that imply causal associations were not based on RCTs. Medical journalists should follow standards of reporting scientific study results.Plos One. 2018 Max 3;13(5):e0196833
Mueller SH, Färber A, Prüss H, Melzer N, Golombeck KS, Kümpfel T, Thaler F, Elisak M, Lewerenz J, Kaufmann M, Sühs KW, Ringelstein M, Kellinghaus C, Bien CG, Kraft A, Zettl UK, Ehrlich S, Handreka R, Rostásy K, Then Bergh F, Faiss JH, Lieb W, Franke A, Kuhlenbäumer G, Wandinger KP, Leypoldt F; German Network for Research on Autoimmune Encephalitis (GENERATE).
Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.
Ann Neurol. 2018 Apr;83(4):863-869
Mueller SH, Färber A, Prüss H, Melzer N, Golombeck KS, Kümpfel T, Thaler F, Elisak M, Lewerenz J, Kaufmann M, Sühs KW, Ringelstein M, Kellinghaus C, Bien CG, Kraft A, Zettl UK, Ehrlich S, Handreka R, Rostásy K, Then Bergh F, Faiss JH, Lieb W, Franke A, Kuhlenbäumer G, Wandinger KP, Leypoldt F; German Network for Research on Autoimmune Encephalitis (GENERATE).
Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.
We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified.Ann Neurol. 2018 Apr;83(4):863-869
Jarius S, Ruprecht K, Stellmann JP, Huss A, Ayzenberg I, Willing A, Trebst C, Pawlitzki M, Abdelhak A, Grüter T, Leypoldt F, Haas J, Kleiter I, Tumani H, Fechner K, Reindl M, Paul F, Wildemann B.
MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature.
J Neuroinflammation. 2018 Mar 19;15(1):88
Jarius S, Ruprecht K, Stellmann JP, Huss A, Ayzenberg I, Willing A, Trebst C, Pawlitzki M, Abdelhak A, Grüter T, Leypoldt F, Haas J, Kleiter I, Tumani H, Fechner K, Reindl M, Paul F, Wildemann B.
MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature.
BACKGROUND: Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG. OBJECTIVE: To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria. METHODS: For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017. RESULTS: None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests. CONCLUSION: Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified.J Neuroinflammation. 2018 Mar 19;15(1):88
Pöttgen J, Moss-Morris R, Wendebourg J, Feddersen L, Lau S, Köpke S, Meyer B, Friede T, Penner I, Heesen C, Gold SM
Randomised controlled trial of a self-guided online fatigue intervention in multiple sclerosis
J Neurol Neurosurg Psychiatry. 2018 Sep;89(9):970-976
Pöttgen J, Moss-Morris R, Wendebourg J, Feddersen L, Lau S, Köpke S, Meyer B, Friede T, Penner I, Heesen C, Gold SM
Randomised controlled trial of a self-guided online fatigue intervention in multiple sclerosis
Fatigue is a major disabling symptom in many chronic diseases including multiple sclerosis (MS), but treatment options are limited.Here, we tested the effectiveness of a self-guided , interactive, online fatigue management programme (ELEVIDA) based on principles of cognitive behavioural therapy (CBT) and related psychotherapeutic approaches (eg, mindfulness) for reducing fatigue in MS. METHODS: Patients with MS and self-reported fatigue were recruited via the website of the German MS Society and assigned via an automated randomisation generator (1:1, no blocking or stratification) to a 12-week online intervention (ELEVIDA, n=139, 82% female, mean age 40.8, median patient determined disease steps (PDDS) 3.0) or a waitlist control group (n=136, 79% female, mean age 41.9, median PDDS 3.0). The primary outcome was the Chalder Fatigue Scale. Outcomes were assessed at baseline, at week 12 (postintervention) and at follow-up (week 24). RESULTS: Compared with the control group, significantly greater reductions in Chalder Fatigue Scale scores were seen in the ELEVIDA group at week 12 (primary endpoint, intention-to-treat analysis: between-group mean difference 2.74 points; 95% CI 1.16 to 4.32; p=0.0007; effect size d=0.53), with effects sustained at week 24 (intention-to-treat analysis: between-group mean difference 2.19 points; 95% CI 0.57 to 3.82; p=0.0080). CONCLUSIONS: Our trial provides evidence for the effectiveness of a self-guided , internet-based intervention to reduce fatigue in MS. Interventions such as ELEVIDA may be a suitable low barrier, cost-effective treatment option for MS fatigue.J Neurol Neurosurg Psychiatry. 2018 Sep;89(9):970-976
Ridley B, Nagel AM, Bydder M, Maarouf A, Stellmann JP, Gherib S, Verneuil J, Viout P, Guye M, Ranjeva JP, Zaaraoui W.
Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study.
Sci Rep. 2018 Mar 12;8(1):4357
Ridley B, Nagel AM, Bydder M, Maarouf A, Stellmann JP, Gherib S, Verneuil J, Viout P, Guye M, Ranjeva JP, Zaaraoui W.
Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study.
Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo 23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*short and T2*long and in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo 23Na-MRI signal, 23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo 23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo 23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.Sci Rep. 2018 Mar 12;8(1):4357
Patas K, Willing A, Demiralay C, Engler JB, Lupu A, Ramien C, Schäfer T, Gach C, Stumm L, Chan K, Vignali M, Arck PC, Friese MA, Pless O, Wiedemann K, Agorastos A, Gold SM.
T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder.
Front Immunol. 2018 Feb 20;9:291
Patas K, Willing A, Demiralay C, Engler JB, Lupu A, Ramien C, Schäfer T, Gach C, Stumm L, Chan K, Vignali M, Arck PC, Friese MA, Pless O, Wiedemann K, Agorastos A, Gold SM.
T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder.
While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case-control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/- cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.Front Immunol. 2018 Feb 20;9:291
von Bismarck O, Dankowski T, Ambrosius B, Hessler N, Antony G, Ziegler A, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Tackenberg B, Stoppe M, Then Bergh F, Tumani H, Kümpfel T, Stangel M, Heesen C, Wildemann B, Paul F, Bayas A, Warnke C, Weber F, Linker RA, Ziemann U, Zettl UK, Zipp F, Wiendl H, Hemmer B, Gold R, Salmen A.
Treatment choices and neuropsychological symptoms of a large cohort of early MS.
Neurol Neuroimmunol Neuroinflamm. 2018 Mar 1;5(3)
von Bismarck O, Dankowski T, Ambrosius B, Hessler N, Antony G, Ziegler A, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Tackenberg B, Stoppe M, Then Bergh F, Tumani H, Kümpfel T, Stangel M, Heesen C, Wildemann B, Paul F, Bayas A, Warnke C, Weber F, Linker RA, Ziemann U, Zettl UK, Zipp F, Wiendl H, Hemmer B, Gold R, Salmen A.
Treatment choices and neuropsychological symptoms of a large cohort of early MS.
Objective: To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods: The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results: Of 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion: Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients.Neurol Neuroimmunol Neuroinflamm. 2018 Mar 1;5(3)
Pöttgen J, Rose A, van de Vis W4, Engelbrecht J5, Pirard M6, Lau S1,2, Heesen C1,2, Köpke S7; RiMS Special Interest Group Psychology and Neuropsychology.
Sexual dysfunctions in MS in relation to neuropsychiatric aspects and its psychological treatment: A scoping review.
PLoS One. 2018 Feb 27;13(2)
Pöttgen J, Rose A, van de Vis W4, Engelbrecht J5, Pirard M6, Lau S1,2, Heesen C1,2, Köpke S7; RiMS Special Interest Group Psychology and Neuropsychology.
Sexual dysfunctions in MS in relation to neuropsychiatric aspects and its psychological treatment: A scoping review.
OBJECTIVE: Sexual dysfunction in multiple sclerosis (MS) is a significant, but often underestimated and overlooked suffering. Interventions to treat sexual dysfunction in MS are rare. The relation between sexual dysfunction in MS and psychological as well as neuropsychological aspects is evident. However, this field of research remains markedly underdeveloped in this severe chronic illness. The aim of this scoping review is to describe the relevant knowledge in this area and to identify psychological interventions to treat sexual dysfunctions in MS. METHODS: A scoping review was conducted to answer the following questions: (1) Which psychological and neuropsychological factors impact on sexual dysfunction in MS and vice versa? (2) What kind of psychological interventions aiming to improve sexual dysfunctions in MS are available? A comprehensive search and review of MEDLINE, PsycINFO, and CINAHL was completed by using a recent methodological framework for scoping reviews. RESULTS: 23 publications covering a total of 13,259 people with MS and 532 healthy controls were identified. Sexual dysfunction was found to be very common in MS and there is an obvious relation to psychological disorders as e.g. depression and anxiety and also to psychological aspects as partner relationship and quality of life. The relation between sexual dysfunction in MS and neuropsychological impairment has only rarely been studied and no clear results were found. Only two studies were identified, assessing the effectiveness of psychological intervention studies on sexual dysfunction in people with MS, and a third study presenting a secondary analysis of a study targeting depression. All three studies reported significant improvements in sexual dysfunction as well as partly in psychological variables. CONCLUSIONS: There is a pressing need for the development and adequate evaluation of psychological interventions for sexual dysfunctions in MS. In addition, sexual dysfunction and its impact on psychological wellbeing should be more focussed in clinical care.PLoS One. 2018 Feb 27;13(2)
Willing A, Jäger J, Reinhardt S, Kursawe N, Friese MA.
Production of IL-17 by MAIT Cells Is Increased in Multiple Sclerosis and Is Associated with IL-7 Receptor Expression.
J Immunol. 2018 Feb 1;200(3):974-982
Willing A, Jäger J, Reinhardt S, Kursawe N, Friese MA.
Production of IL-17 by MAIT Cells Is Increased in Multiple Sclerosis and Is Associated with IL-7 Receptor Expression.
Multiple sclerosis (MS) is a T cell-driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4+ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17+ MAIT cells as well as an increased expression of retinoic acid-related orphan receptor (ROR)γt and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.J Immunol. 2018 Feb 1;200(3):974-982
Stürner KH, Stellmann JP, Dörr J, Paul F, Friede T, Schammler S, Reinhardt S, Gellissen S, Weissflog G, Faizy TD, Werz O, Fleischer S, Vaas LAI, Herrmann F, Pless O, Martin R, Heesen C
A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).
J Neurol Neurosurg Psychiatry. 2018 Apr.;89(4):330-338
Stürner KH, Stellmann JP, Dörr J, Paul F, Friede T, Schammler S, Reinhardt S, Gellissen S, Weissflog G, Faizy TD, Werz O, Fleischer S, Vaas LAI, Herrmann F, Pless O, Martin R, Heesen C
A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).
OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial.J Neurol Neurosurg Psychiatry. 2018 Apr.;89(4):330-338
Heesen C, Haase R, Melzig S, Poettgen J, Berghoff M, Friedemann P, Zettl U, Marziniak M, Angstwurm K, Kern R, Ziemssen T, Stellmann JP
Perceptions on the value of bodily functions in multiple sclerosis.
Acta Neurol Scand. 2018 Mar;137(3):356-362
Heesen C, Haase R, Melzig S, Poettgen J, Berghoff M, Friedemann P, Zettl U, Marziniak M, Angstwurm K, Kern R, Ziemssen T, Stellmann JP
Perceptions on the value of bodily functions in multiple sclerosis.
BACKGROUND: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians‘ perceptions. METHODS: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed. RESULTS: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients‘ and physicians‘ ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016). CONCLUSION: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians.Acta Neurol Scand. 2018 Mar;137(3):356-362
Gieras A, Gehbauer C, Perna-Barrull D, Engler JB, Diepenbruck I, Glau L, Joosse SA, Kersten N, Klinge S, Mittrücker HW, Friese MA, Vives-Pi M, Tolosa E
Prenatal Administration of Betamethasone Causes Changes in the T Cell Receptor Repertoire Influencing Development of Autoimmunity.
Front Immunol. 2017 Nov 13;8:1505
Gieras A, Gehbauer C, Perna-Barrull D, Engler JB, Diepenbruck I, Glau L, Joosse SA, Kersten N, Klinge S, Mittrücker HW, Friese MA, Vives-Pi M, Tolosa E
Prenatal Administration of Betamethasone Causes Changes in the T Cell Receptor Repertoire Influencing Development of Autoimmunity.
Prenatal glucocorticoids are routinely administered to pregnant women at risk of preterm delivery in order to improve survival of the newborn. However, in half of the cases, birth occurs outside the beneficial period for lung development. Glucocorticoids are potent immune modulators and cause apoptotic death of immature T cells, and we have previously shown that prenatal betamethasone treatment at doses eliciting lung maturation induce profound thymocyte apoptosis in the offspring. Here, we asked if there are long-term consequences on the offspring’s immunity after this treatment. In the non-obese diabetic mouse model, prenatal betamethasone clearly decreased the frequency of pathogenic T cells and the incidence of type 1 diabetes (T1D). In contrast, in the lupus-prone MRL/lpr strain, prenatal glucocorticoids induced changes in the T cell repertoire that resulted in more autoreactive cells. Even though glucocorticoids transiently enhanced regulatory T cell (Treg) development, these cells did not have a protective effect in a model for multiple sclerosis which relies on a limited repertoire of pathogenic T cells for disease induction that were not affected by prenatal betamethasone. We conclude that prenatal steroid treatment, by inducing changes in the T cell receptor repertoire, has unforeseeable consequences on development of autoimmune disease. Our data should encourage further research to fully understand the consequences of this widely used treatment.Front Immunol. 2017 Nov 13;8:1505
Thaler C, Faizy TD, Sedlacik J, Bester M, Stellmann JP, Heesen C, Fiehler J, Siemonsen S.
The use of multiparametric quantitative magnetic resonance imaging for evaluating visually assigned lesion groups in patients with multiple sclerosis.
J Neurol. 2018 Jan;265(1):127-133
Thaler C, Faizy TD, Sedlacik J, Bester M, Stellmann JP, Heesen C, Fiehler J, Siemonsen S.
The use of multiparametric quantitative magnetic resonance imaging for evaluating visually assigned lesion groups in patients with multiple sclerosis.
In multiple sclerosis (MS), inflammatory lesions present a broad spectrum of histopathologic processes. For a better discrimination, lesions are visually defined into different lesion groups according to their appearance on conventional magnetic resonance imaging (MRI). The aim of this study was to investigate the properties of different MS lesion groups using multiparametric quantitative MRI. 35 patients diagnosed with relapsing-remitting MS received 3 Tesla MRI including magnetization-prepared 2 rapid acquisition gradient echo, diffusion tensor imaging and magnetization transfer imaging. Lesion segmentation was performed for T2 lesions, black holes and contrast-enhancing lesions. A subtraction mask was created including only T2 lesions that did not correspond to a black hole or contrast-enhancing lesion. T1 relaxation time (T1-RT), magnetization transfer ratio (MTR), mean diffusivity (MD) and fractional anisotropy (FA) were determined for every lesion and in normal-appearing white matter. Only MD differed significantly between all lesion groups and NAWM (p < 0.05), while FA differed between all lesion groups but not NAWM. T1-RT and MTR were not useful imaging biomarkers to distinguish between lesion groups. A lack of sensitivity and specificity and unproportional alterations of quantitative MRI measures, due to heterogenous histopathologic processes within lesions, may be a possible explanation for missing discrimination. Thus, not only interpretation of visually defined MS lesion but also interpretation of quantitative MRI measures remains challenging and should be conducted carefully.J Neurol. 2018 Jan;265(1):127-133
Heesen C, Pöttgen J, Rahn AC, Liethmann K, Kasper J, Vahter L, Drulovic J, Van Nunen A, Wilkie D, Beckmann Y, Paul F, Köpke S, Giordano A, Solari A; AutoMS-group.
What should a person with relapsing-remitting multiple sclerosis know? – Focus group and survey data of a risk knowledge questionnaire (RIKNO 2.0).
Mult Scler Relat Disord. 2017 Nov;18:186-195
Heesen C, Pöttgen J, Rahn AC, Liethmann K, Kasper J, Vahter L, Drulovic J, Van Nunen A, Wilkie D, Beckmann Y, Paul F, Köpke S, Giordano A, Solari A; AutoMS-group.
What should a person with relapsing-remitting multiple sclerosis know? – Focus group and survey data of a risk knowledge questionnaire (RIKNO 2.0).
BACKGROUND: Risk knowledge is relevant to make informed decisions in multiple sclerosis (MS). The risk knowledge questionnaire for relapsing-remitting MS (RIKNO 1.0) was developed and piloted in Germany. OBJECTIVE: To produce a revised RIKNO 2.0 questionnaire using mixed methodology in a European setting. METHODS: The questionnaire was translated in seven languages. MS patient and health professional (HP) expert feedback was obtained from Germany, Italy, Estonia, Serbia, and the UK. A German web-based survey of RIKNO 2.0 compared the tool with the MS Knowledge Questionnaire (MSKQ), each one used with two versions (with/without a „don’t know“ DN option). RESULTS: While RIKNO 2.0 was considered difficult, it was rated as highly educational. One item was reframed, and two new items were added. The web-based German survey (n = 708 completers) showed that the DN version did not increase participation rate and did not produce significantly higher scores. Internal consistency (Cronbach alpha) without SN response was 0.73. RIKNO 2.0 scores showed normality distribution irrespective of the answering format. Item difficulty was high ranging from 0.07 to 0.79. Less than 50% of questions were answered correctly (mean 8.9) compared to 80.4% in the MSKQ (mean 20.1). Higher numeracy competency and education were significantly, albeit weakly, associated to higher scores for both RIKNO 2.0 and MSKQ. CONCLUSION: Including „don’t know“ options in knowledge questionnaires does not increase percentage of correct replies. RIKNO 2.0 is a complex questionnaire to be used in an educational context and studies on patient information. The tool is now available in seven languages.Mult Scler Relat Disord. 2017 Nov;18:186-195
Akbulak RÖ, Rosenkranz SC, Schaeffer BN, Pinnschmidt HO, Willems S, Heesen C, Hoffmann BA
Acute and long-term effects of fingolimod on heart rhythm and heart rate variability in patients with multiple sclerosis.
Mult Scler Relat Disord. 2018 Jan;19:44-49
Akbulak RÖ, Rosenkranz SC, Schaeffer BN, Pinnschmidt HO, Willems S, Heesen C, Hoffmann BA
Acute and long-term effects of fingolimod on heart rhythm and heart rate variability in patients with multiple sclerosis.
BACKGROUND: Fingolimod can lead to increased risk of cardiac events such as bradycardia or atrioventricular (AV) block. OBJECTIVE: Evaluate acute and long-term effects of fingolimod on heart rhythm (HR), heart rate variability (HRV) and development of AV-blocks. METHODS: In 64 patients with relapsing-remitting multiple sclerosis Holter ECG monitoring (HEM) and HRV analysis were performed 24h before, six h during and 72h after initiation of fingolimod. We additionally analyzed a 24h HEM after a follow up of ≥ three months. RESULTS: Heart rate (HR) decreased significantly (p < 0.001) under fingolimod treatment with nadir at five hours after starting and maintained decreased for 72h. Five (7.8%) patients suffered from new-onset AV-block requiring cessation of treatment. In four of five patients (80%), the AV-block could only be documented in the 72h-HEM with a median time of occurrence at 14h. The mean heart rate was still significant lower after a mean follow up time of 14.1 ± 9.6 months (85.0 ± 9.8 vs. 75.3 ± 16.2 bpm; p = 0.002) in comparison to baseline. CONCLUSION: The treatment with fingolimod leads to an increase of vagal activation which persists even after 14 months of treatment. These changes did not return to baseline levels on treatment with fingolimod. Based on our data an additional at least 24h hour-HEM after the initiation of fingolimod therapy should be considered.Mult Scler Relat Disord. 2018 Jan;19:44-49
Schlüter K, Maier J, Patra S, Gold SM, Heesen C, Schulz KH1.
Aberrant peak lactate response in MS.
NeuroRehabilitation. 2017;41(4):811-822
Schlüter K, Maier J, Patra S, Gold SM, Heesen C, Schulz KH1.
Aberrant peak lactate response in MS.
BACKGROUND: The peak blood lactate response to an exhaustive exercise test in a number of chronic conditions has been shown to differ from that seen in healthy, untrained individuals. However, this has not been investigated for patients with multiple sclerosis (MS). OBJECTIVE: The main objective was to determine and compare the peak blood lactate response to exercise and the maximal workload between two groups of MS patients with different illness severity. METHODS: Twenty-five patients with a relapsing-remitting disease course (Group RR) and 41 patients with a secondary- or primary chronic progressive disease course (group CP) performed an exhaustive incremental bicycle ergometry. Peak blood lactate, maximal workload, peak oxygen consumption and maximal heart rate were measured. RESULTS: The peak blood lactate levels and maximal workload differed significantly between the groups (group CP < group RR; p < 0.001). Furthermore spiroergometric peak performance markers in both groups were significantly lower than predicted for healthy age and sex matched untrained groups. CONCLUSION: A reduced peak blood lactate response to exercise is a novel finding for MS patients. This calls into doubt if the lactate performance tests and lactate thresholds used for healthy individuals can be transferred to MS patients.NeuroRehabilitation. 2017;41(4):811-822
Rosenkranz SC, Kaulen B, Neuhaus A, Siemonsen S, Köpke S, Daumer M, Stellmann JP, Heesen C
Low clinical conversion rate in clinically isolated syndrome (CIS) patients – diagnostic benefit of McDonald 2010 criteria?
Eur J Neurol. 2018 Feb;25(2):247-e9
Rosenkranz SC, Kaulen B, Neuhaus A, Siemonsen S, Köpke S, Daumer M, Stellmann JP, Heesen C
Low clinical conversion rate in clinically isolated syndrome (CIS) patients – diagnostic benefit of McDonald 2010 criteria?
BACKGROUND: New diagnostic criteria of Multiple Sclerosis (MS) increase the number of patients being diagnosed with MS while a substantial part might not convert to clinically definite MS (CDMS). OBJECTIVE: Diagnostic accuracy of the McDonald 2005 and 2010 criteria for conversion to CDMS was evaluated in an unselected cohort of patients in whom a MS diagnostic workup was decided. METHODS: We analyzed clinical, MRI and CSF data in all patients who presented with symptoms suspicious for MS at the University based MS outpatient clinic between 2006 and 2010 (n=165). RESULTS: Follow-up was available for 131 patients. During the mean follow-up period of 2 years, 19% of patients developed clinically definite multiple sclerosis (CDMS) whereas 64% of the patients fulfilling McDonald2010 criteria did not convert to CDMS.Eur J Neurol. 2018 Feb;25(2):247-e9
Rahn AC, Köpke S, Backhus I, Kasper J, Anger K, Untiedt B, Alegiani A, Kleiter I, Mühlhauser I, Heesen C.
Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) – Feasibility testing, pilot randomised controlled trial and mixed methods process evaluation.
Int J Nurs Stud. 2018 Feb.;78:26-36
Rahn AC, Köpke S, Backhus I, Kasper J, Anger K, Untiedt B, Alegiani A, Kleiter I, Mühlhauser I, Heesen C.
Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) – Feasibility testing, pilot randomised controlled trial and mixed methods process evaluation.
BACKGROUND: Treatment decision-making is complex for people with multiple sclerosis. Profound information on available options is virtually not possible in regular neurologist encounters. The „nurse decision coach model“ was developed to redistribute health professionals‘ tasks in supporting immunotreatment decision-making following the principles of informed shared decision-making. OBJECTIVES: To test the feasibility of a decision coaching programme and recruitment strategies to inform the main trial. DESIGN: Feasibility testing and parallel pilot randomised controlled trial, accompanied by a mixed methods process evaluation. SETTING: Two German multiple sclerosis university centres. PARTICIPANTS PILOT TRIAL: People with suspected or relapsing-remitting multiple sclerosis facing immunotreatment decisions on first line drugs were recruited. Randomisation to the intervention (n=38) or control group (n=35) was performed on a daily basis. Quantitative and qualitative process data were collected from people with multiple sclerosis, nurses and physicians. METHODS: We report on the development and piloting of the decision coaching programme. It comprises a training course for multiple sclerosis nurses and the coaching intervention. The intervention consists of up to three structured nurse-led decision coaching sessions, access to an evidence-based online information platform (DECIMS-Wiki) and a final physician consultation. After feasibility testing, a pilot randomised controlled trial was performed. People with multiple sclerosis were randomised to the intervention or control group. The latter had also access to the DECIMS-Wiki, but received otherwise care as usual. Nurses were not blinded to group assignment, while people with multiple sclerosis and physicians were. The primary outcome was ‚informed choice‘ after six months including the sub-dimensions‘ risk knowledge (after 14days), attitude concerning immunotreatment (after physician consultation), and treatment uptake (after six months). Quantitative process evaluation data were collected via questionnaires. Qualitative interviews were performed with all nurses and a convenience sample of nine people with multiple sclerosis. RESULTS: 116 people with multiple sclerosis fulfilled the inclusion criteria and 73 (63%) were included. Groups were comparable at baseline. Data of 51 people with multiple sclerosis (70%) were available for the primary endpoint. In the intervention group 15 of 31 (48%) people with multiple sclerosis achieved an informed choice after six months and 6 of 20 (30%) in the control group. Process evaluation data illustrated a positive response towards the coaching programme as well as good acceptance. CONCLUSIONS: The pilot-phase showed promising results concerning acceptability and feasibility of the intervention, which was well perceived by people with multiple sclerosis, most nurses and physicians. Delegating parts of the immunotreatment decision-making process to trained nurses has the potential to increase informed choice and participation as well as effectiveness of patient-physician consultations.Int J Nurs Stud. 2018 Feb.;78:26-36
Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, Feys P, Thompson AJ
Exercise in patients with multiple sclerosis.
Lancet Neurol. 2017 Oct;16(10):848-856
Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, Feys P, Thompson AJ
Exercise in patients with multiple sclerosis.
Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient-clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis.Lancet Neurol. 2017 Oct;16(10):848-856
Giovannetti AM, Giordano A, Pietrolongo E, Confalonieri P, De Luca G, Tortorella C, Trojano M, Messmer Uccelli M, Torri Clerici V, Gitto L, Köpke S, Borreani C, Heesen C, Solari A2 ManTra project.
Managing the transition (ManTra): a resource for persons with secondary progressive multiple sclerosis and their health professionals: protocol for a mixed-methods study in Italy.
BMJ Open. 2017 Aug 23;7(8):e017254
Giovannetti AM, Giordano A, Pietrolongo E, Confalonieri P, De Luca G, Tortorella C, Trojano M, Messmer Uccelli M, Torri Clerici V, Gitto L, Köpke S, Borreani C, Heesen C, Solari A2 ManTra project.
Managing the transition (ManTra): a resource for persons with secondary progressive multiple sclerosis and their health professionals: protocol for a mixed-methods study in Italy.
INTRODUCTION: 15 years after clinical onset, about 50% of patients with relapsing-remitting multiple sclerosis convert to secondary progressive multiple sclerosis (SPMS). Notwithstanding the importance of this transition, knowledge of the experiences and needs of patients and carers is fragmentary, and targeted interventions are not available. Managing the Transition to SPMS (ManTra) is a mixed methodology project to develop and test a user-led resource for newly diagnosed patients with SPMS. Here, we describe the developmental phase, consisting of a literature review and a new research study involving key stakeholders, in which we construct the resource. METHODS AND ANALYSIS: Round 1: The literature review and study will be conducted in parallel. The latter will identify patient needs using a qualitative approach consisting of: personal semistructured interviews with >15 recently diagnosed patients with SPMS; three focus group meetings (one with significant others of patients, one with neurologists and one with other health professionals caring for patients with SPMS). An online survey (>200 recently diagnosed Italian patients with SPMS) will follow to verify needs in a larger independent sample. An expert panel will outline a set of candidate resources/interventions that aim to satisfy the needs thus identified. Round 2: Consensus on the final resource will be obtained in a 1-day meeting of recently diagnosed patients with SPMS, significant others, health professionals and other stakeholders, using the nominal group technique. The expert panel will refine the resource, identify the outcome measures to assess its efficacy and ascertain the most suitable comparator (ManTra Phase 2, not part of this protocol). ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of each of the involved centres: Foundation IRCCS Neurological Institute C Besta, Milan ; G D’Annunzio University of Chieti-Pescara and the Aldo Moro University of Bari. The results will be published in peer-reviewed journals, presented at conferences and a lay summary sent to participants.BMJ Open. 2017 Aug 23;7(8):e017254
Stellmann JP, Hodecker S, Cheng B, Wanke N, Young KL, Hilgetag C, Gerloff C, Heesen C, Thomalla G, Siemonsen S.
Reduced rich-club connectivity is related to disability in primary progressive MS.
Neurol Neuroimmunol Neuroinflamm. 2017 Jul 27;4(5):e375
Stellmann JP, Hodecker S, Cheng B, Wanke N, Young KL, Hilgetag C, Gerloff C, Heesen C, Thomalla G, Siemonsen S.
Reduced rich-club connectivity is related to disability in primary progressive MS.
OBJECTIVE: To investigate whether the structural connectivity of the brain’s rich-club organization is altered in patients with primary progressive MS and whether such changes to this fundamental network feature are associated with disability measures. METHODS: We recruited 37 patients with primary progressive MS and 21 healthy controls for an observational cohort study. Structural connectomes were reconstructed based on diffusion-weighted imaging data using probabilistic tractography and analyzed with graph theory. RESULTS: We observed the same topological organization of brain networks in patients and controls. Consistent with the originally defined rich-club regions, we identified superior frontal, precuneus, superior parietal, and insular cortex in both hemispheres as rich-club nodes. Connectivity within the rich club was significantly reduced in patients with MS (p = 0.039). The extent of reduced rich-club connectivity correlated with clinical measurements of mobility (Kendall rank correlation coefficient τ = -0.20, p = 0.047), hand function (τ = -0.26, p = 0.014), and information processing speed (τ = -0.20, p = 0.049). CONCLUSIONS: In patients with primary progressive MS, the fundamental organization of the structural connectome in rich-club and peripheral nodes was preserved and did not differ from healthy controls. The proportion of rich-club connections was altered and correlated with disability measures. Thus, the rich-club organization of the brain may be a promising network phenotype for understanding the patterns and mechanisms of neurodegeneration in MS.Neurol Neuroimmunol Neuroinflamm. 2017 Jul 27;4(5):e375
Thaler C, Schneider T, Sedlacik J, Kutzner D, Stellmann JP, Heesen C, Fiehler J, Siemonsen S.
T1w dark blood imaging improves detection of contrast enhancing lesions in multiple sclerosis.
PLoS One. 2017 Aug 10;12(8):e0183099.
Thaler C, Schneider T, Sedlacik J, Kutzner D, Stellmann JP, Heesen C, Fiehler J, Siemonsen S.
T1w dark blood imaging improves detection of contrast enhancing lesions in multiple sclerosis.
PURPOSE: In multiple sclerosis (MS) the sensitivity for detection of contrast enhancing lesions (CEL) in T1-weighted scans is essential for diagnostics and therapy decisions. The purpose of our study was to evaluate the sensitivity of T1w MPRAGE scans in comparison to T1w dark blood technique (T1-DB) for CEL in MS. MATERIALS AND METHODS: 3T MR imaging was performed in 37 MS patients, including T2-weighted imaging, T1w MPRAGE before and after gadolinium injection (unenhanced-T1 and T1-CE) and T1-DB imaging. After gadolinium application, the T1-DB scan was performed prior to T1-CE. From unenhanced-T1 and T1-CE scans, subtraction images (T1-SUB) were calculated. The number of CEL was determined separately on T1-CE and T1-DB by two raters independently. Lesions only detected on T1-DB scans then were verified on T1-SUB. Only lesions detected by both raters were included in further analysis. RESULTS: In 16 patients, at least one CEL was detected by both rater, either on T1-CE or T1-DB. All lesions that were detected on T1-CE were also detected on T1-DB images. The total number of contrast enhancing lesions detected on T1-DB images (n = 54) by both raters was significantly higher than the corresponding number of lesions identified on T1-CE (n = 27) (p = 0.01); all of these lesions could be verified on SUB images. In 21 patients, no CEL was detected in any of the sequences. CONCLUSIONS: The application of T1-DB technique increases the sensitivity for CEL in MS, especially for those lesions that show only subtle increase in intensity after Gadolinium application but remain hypo- or iso-intense to surrounding tissue.PLoS One. 2017 Aug 10;12(8):e0183099.
Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, Friese MA.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Sci. Immunol. 2016 Sep 23;1(3):eaaf86665
Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, Friese MA.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activityregulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 asa universal switch in migDCs that may be exploited to selectively modify immune responses.Sci. Immunol. 2016 Sep 23;1(3):eaaf86665
Gaissmaier W, Giese H, Galesic M, Garcia-Retamero R, Kasper J, Kleiter I, Meuth SG, Köpke S, Heesen C
Numeracy of multiple sclerosis patients: A comparison of patients from the PERCEPT study to a German probabilistic sample.
Patient Educ Couns. 2018 Jan;101(1):74-78
Gaissmaier W, Giese H, Galesic M, Garcia-Retamero R, Kasper J, Kleiter I, Meuth SG, Köpke S, Heesen C
Numeracy of multiple sclerosis patients: A comparison of patients from the PERCEPT study to a German probabilistic sample.
OBJECTIVE: A shared decision-making approach is suggested for multiple sclerosis (MS) patients. To properly evaluate benefits and risks of different treatment options accordingly, MS patients require sufficient numeracy – the ability to understand quantitative information. It is unknown whether MS affects numeracy. Therefore, we investigated whether patients‘ numeracy was impaired compared to a probabilistic national sample. METHODS: As part of the larger prospective, observational, multicenter study PERCEPT, we assessed numeracy for a clinical study sample of German MS patients (N=725) with a standard test and compared them to a German probabilistic sample (N=1001), controlling for age, sex, and education. Within patients, we assessed whether disease variables (disease duration, disability, annual relapse rate, cognitive impairment) predicted numeracy beyond these demographics. RESULTS: MS patients showed a comparable level of numeracy as the probabilistic national sample (68.9% vs. 68.5% correct answers, P=0.831). In both samples, numeracy was higher for men and the highly educated. Disease variables did not predict numeracy beyond demographics within patients, and predictability was generally low. CONCLUSION: This sample of MS patients understood quantitative information on the same level as the general population. PRACTICE IMPLICATIONS: There is no reason to withhold quantitative information from MS patients.Patient Educ Couns. 2018 Jan;101(1):74-78
Kjolhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG, Stenager E, Petersen T, Vissing K, Heesen C, Dalgas U
Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?
Mult Scler. 2018 Sep;24(10):1356-1365
Kjolhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG, Stenager E, Petersen T, Vissing K, Heesen C, Dalgas U
Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?
BACKGROUND: Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can counteract brain atrophy in other populations. OBJECTIVE: To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS. METHODS: This study was a 24-week randomised controlled cross-over trial, including a Training ( n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group ( n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness). RESULTS: While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus. CONCLUSION: PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.Mult Scler. 2018 Sep;24(10):1356-1365
Weygandt M, Wakonig K, Behrens J, Meyer-Arndt L, Söder E, Brandt AU, Bellmann-Strobl J, Ruprecht K, Gold SM, Haynes JD, Paul F
Brain activity, regional gray matter loss, and decision-making in multiple sclerosis.
Mult Scler. 2018 Aug;24(9):1163-1173.
Weygandt M, Wakonig K, Behrens J, Meyer-Arndt L, Söder E, Brandt AU, Bellmann-Strobl J, Ruprecht K, Gold SM, Haynes JD, Paul F
Brain activity, regional gray matter loss, and decision-making in multiple sclerosis.
BACKGROUND: Decision-making (DM) abilities deteriorate with multiple sclerosis (MS) disease progression which impairs everyday life and is thus clinically important. OBJECTIVE: To investigate the underlying neurocognitive processes and their relation to regional gray matter (GM) loss induced by MS. METHODS: We used a functional magnetic resonance imaging (fMRI) Iowa Gambling Task to measure DM-related brain activity in 36 MS patients and 21 healthy controls (HC). From this activity, we determined neural parameters of two cognitive stages, a deliberation („choice“) period preceding a choice and a post-choice („feedback“) stage reporting decision outcomes. These measures were related to DM separately in intact and damaged GM areas as determined by a voxel-based morphometry analysis. RESULTS: Severely affected patients (with high lesion burden) showed worse DM-learning than HC ( t = -1.75, p = 0.045), moderately affected (low lesion burden) did not. Activity in the choice stage in intact insular ( t = 4.60, pFamily-Wise Error [FWE] corrected = 0.034), anterior cingulate ( t = 4.50, pFWE = 0.044), and dorsolateral prefrontal areas ( t = 4.43, pFWE = 0.049) and in insular areas with GM loss ( t = 3.78, pFWE = 0.011) was positively linked to DM performance across patients with severe tissue damage and HC. Furthermore, activity in intact orbitofrontal areas was positively linked to DM-learning during the feedback stage across these participants ( t = 4.49, pFWE = 0.032). During none of the stages, moderately affected patients showed higher activity than HC, which might have indicated preserved DM due to compensatory activity. CONCLUSION: We identified dysregulated activity linked to impairment in specific cognitive stages of reward-related DM. The link of brain activity and impaired DM in areas with MS-induced GM loss suggests that this deficit might be tightly coupled to MS neuropathology.Mult Scler. 2018 Aug;24(9):1163-1173.
Heesen C, Berger T, Riemann-Lorenz K, Krause N, Friede T, Pöttgen J, Meyer B, Lühmann D.
Mobile health interventions in multiple sclerosis: A systematic review.
Mult Scler 2023 Oct 28
Heesen C, Berger T, Riemann-Lorenz K, Krause N, Friede T, Pöttgen J, Meyer B, Lühmann D.
Mobile health interventions in multiple sclerosis: A systematic review.
Background: Persons with multiple sclerosis (pwMS) might be particularly well suited to benefit from digital health applications because they are, on average, younger and less severely disabled than patients with many other chronic diseases. Many digital health applications for pwMS have been developed. Objectives: Analysis of the evidence of digital health applications to improve health outcomes from a patient perspective. Methods: A systematic review was performed on all randomized controlled trials (RCTs) that have studied mobile health interventions for pwMS, that is, which can be applied with a smartphone, tablet, or laptop to improve patient-reported outcomes. Results: Of the 1127 articles identified in the literature search, 13 RCTs fit the inclusion criteria. Two trials studied messaging systems, two depression interventions, one addressed MS fatigue, five cognition, and three mobility issues, of which two focused on spasticity management. One trial aimed to enhance physical activity. Most were pilot studies that cannot yield definitive conclusions regarding efficacy. One depression intervention and one fatigue intervention showed significant results across several outcomes. Conclusion: Several mobile self-guided digital health applications for pwMS have been tested in RCTs, and two interventions targeting depression and fatigue have demonstrated significant effects. Challenges remain regarding implementation into routine care.Mult Scler 2023 Oct 28
Hadjilaou A, Brandi J, Riehn M, Friese MA, Jacobs T.
Pathogeneric mechanisms and treatment targets in cerebral malaria.
Nat Rev Neurol. 2023 Nov;19(11):688-709
Hadjilaou A, Brandi J, Riehn M, Friese MA, Jacobs T.
Pathogeneric mechanisms and treatment targets in cerebral malaria.
Malaria, the most prevalent mosquito-borne infectious disease worldwide, has accompanied humanity for millennia and remains an important public health issue despite advances in its prevention and treatment. Most infections are asymptomatic, but a small percentage of individuals with a heavy parasite burden develop severe malaria, a group of clinical syndromes attributable to organ dysfunction. Cerebral malaria is an infrequent but life-threatening complication of severe malaria that presents as an acute cerebrovascular encephalopathy characterized by unarousable coma. Despite effective antiparasite drug treatment, 20% of patients with cerebral malaria die from this disease, and many survivors of cerebral malaria have neurocognitive impairment. Thus, an important unmet clinical need is to rapidly identify people with malaria who are at risk of developing cerebral malaria and to develop preventive, adjunctive and neuroprotective treatments for cerebral malaria. This Review describes important advances in the understanding of cerebral malaria over the past two decades and discusses how these mechanistic insights could be translated into new therapies.Nat Rev Neurol. 2023 Nov;19(11):688-709
Kümpfel T, Giglhuber K, Aktas O, Ayzenberg I, Bellmann-Strobl J, Häußler V, Havla J, Hellwig K, Hümmert MW, Jarius S, Kleiter I, Klotz L, Krumbholz M, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Trebst C, Tumani H, Warnke C, Wildemann B, Berthele A; Neuromyelitis Optica Study Group (NEMOS).
Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack Therapy and long-term management.
J Neurol. 2024 Jan;271(1):141-176
Kümpfel T, Giglhuber K, Aktas O, Ayzenberg I, Bellmann-Strobl J, Häußler V, Havla J, Hellwig K, Hümmert MW, Jarius S, Kleiter I, Klotz L, Krumbholz M, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Trebst C, Tumani H, Warnke C, Wildemann B, Berthele A; Neuromyelitis Optica Study Group (NEMOS).
Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack Therapy and long-term management.
This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab – most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings.J Neurol. 2024 Jan;271(1):141-176
Jarius S, Aktas O, Ayzenberg I, Bellmann-Strobl J, Berthele A, Giglhuber K, Häußler V, Havla J, Hellwig K, Hümmert MW, Kleiter I, Klotz L, Krumbholz M, Kümpfel T, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Tumani H, Wildemann B, Trebst C; Neuromyelitis Optica Study Group (NEMOS).
Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis
J. Neurol. 2023 Jul;270(7):3341-3368
Jarius S, Aktas O, Ayzenberg I, Bellmann-Strobl J, Berthele A, Giglhuber K, Häußler V, Havla J, Hellwig K, Hümmert MW, Kleiter I, Klotz L, Krumbholz M, Kümpfel T, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Tumani H, Wildemann B, Trebst C; Neuromyelitis Optica Study Group (NEMOS).
Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis
The term ’neuromyelitis optica spectrum disorders‘ (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options.J. Neurol. 2023 Jul;270(7):3341-3368
Konen FF, Möhn N, Witte T, Schefzyk M, Wiestler M, Lovric S, Hufendiek K, Schwenkenbecher P, Sühs KW, Friese MA, Klotz L, Pul R, Pawlitzki M, Hagin D, Kleinschnitz C, Meuth S, Skripuletz T.
Treatment of autoimmunity: The impact of disease-modifying therapies in multiple sclerosis and comorbid autoimmune disorders.
Autoimmun Rev. 2023 May;22(5):103312
Konen FF, Möhn N, Witte T, Schefzyk M, Wiestler M, Lovric S, Hufendiek K, Schwenkenbecher P, Sühs KW, Friese MA, Klotz L, Pul R, Pawlitzki M, Hagin D, Kleinschnitz C, Meuth S, Skripuletz T.
Treatment of autoimmunity: The impact of disease-modifying therapies in multiple sclerosis and comorbid autoimmune disorders.
More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient’s current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient’s treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.Autoimmun Rev. 2023 May;22(5):103312
Haker M, Peper J, Haagen M, Heesen C, Rahn AC.
The Psychological Impact of Parental Multiple Sclerosis on Childred and Adolescents: A Systematic Review.
Int J MS Care. 2023 Mar-Apr;25(2):63-70
Haker M, Peper J, Haagen M, Heesen C, Rahn AC.
The Psychological Impact of Parental Multiple Sclerosis on Childred and Adolescents: A Systematic Review.
Background: Multiple sclerosis (MS) is a common debilitating neurologic disease that affects mostly young women. This review provides an overview of research on the psychosocial impact of parental MS on children to inform clinicians and support people with MS considering parenthood. Methods: A systematic review of the literature was performed by searching the MEDLINE, PsycINFO, and PSYNDEX databases. We included quantitative and mixed-method studies assessing psychosocial outcomes of children with a parent with MS. Studies were screened for eligibility and evaluated for risk of bias. Results: We screened 608 references, assessed 72 studies in full-text, and included 28 studies in this review. Most of the studies reported on psychosocial adjustment processes, with most results suggesting negative consequences, including difficulties with mood, behavior, or social interaction. Several studies also described associations between children with a parent with MS and increased incidences of psychiatric disorders. Nevertheless, some studies claimed that children with a parent with MS were not more likely to have psychosocial problems compared with children without a parent with MS. A few studies indicated probable positive effects of parental MS, eg potentially increased social competence. Other investigated outcomes were children’s coping skills, early childhood development, body image, and effects on education, and these were unaffected or only slightly affected by having a parent with MS. Conclusions: Having a parent with MS has a relevant effect on children. However, the heterogeneous nature and varying quality of the included studies limit the interpretability of these findings. Further research is needed to provide robust evidence.Int J MS Care. 2023 Mar-Apr;25(2):63-70
Schubert C, Steinberg L, Peper J, Ramien C, Hellwig K, Köpke S, Solari A, Giordano A, Gold SM, Friede T, Heesen C, Rahn AC.
Postpartum relapse risk in multiple sclerosis: a systematic review and meta-anlysis.
Neurol Neurosurg Psychiatry. 2023 Sep;94(9):718-725.
Schubert C, Steinberg L, Peper J, Ramien C, Hellwig K, Köpke S, Solari A, Giordano A, Gold SM, Friede T, Heesen C, Rahn AC.
Postpartum relapse risk in multiple sclerosis: a systematic review and meta-anlysis.
The influence of pregnancy on the course of multiple sclerosis (MS) has long been controversial. While historical evidence suggests a substantial decline in relapse rates during pregnancy followed by a rebound in the postpartum period, more recent work yielded equivocal results. We performed a systematic review and meta-analysis on data from cohort studies to determine whether women with MS experience increased relapse rates after delivery. A systematic literature search was conducted in the databases MEDLINE and Epistemonikos on the topic ‚motherhood choice in MS‘ in March 2022. We included cohort studies assessing the association between pregnancy and MS relapse activity defined by the annualised relapse rate after 3, 6, 9 and 12 months post partum. Furthermore, information about disease-modifying therapies (DMT) and breast feeding was considered, if available. 5369 publications were identified. Of these, 93 full-text articles on MS relapse activity during the postpartum period were screened. 11 studies including 2739 pregnancies were eligible. Women with MS showed a significantly increased relapse rate in the first 6 months post partum, compared with preconception with the incidence rate ratio (IRR) almost doubled in the first 3 months post partum (1.87, 95% CI 1.40 to 2.50). However, at 10-12 months post partum, the IRR decreased significantly (0.81, 95% CI 0.67 to 0.98). Subanalysis on influencing parameters suggested that preconceptional DMTs (IRR for highly-effective DMTs 2.76, 95% CI 1.34 to 5.69) and exclusive breast feeding (risk ratio 0.39, 95% CI 0.18 to 0.86) significantly influenced postpartum relapse risk. Increased postpartum annualised relapse rate and possible modifiers should be considered in counselling women with MS who are considering pregnancy.
Neurol Neurosurg Psychiatry. 2023 Sep;94(9):718-725.
Seddiq Zai S, Heesen C, Buhmann C, das Nair R, Pöttgen J.
Driving ability and predictors for driving performance in Multiple Sclerosis: A systematic review.
Front Neurol. 2022 Nov 30;13:1056411
Seddiq Zai S, Heesen C, Buhmann C, das Nair R, Pöttgen J.
Driving ability and predictors for driving performance in Multiple Sclerosis: A systematic review.
Objective: To provide an overview of the evidence on driving ability in persons with multiple sclerosis (PwMS), specifically to (i) study the impact of MS impairment on driving ability and (ii) evaluate predictors for driving performance in MS. Methods: To identify relevant studies, different electronic databases were screened in accordance with PRISMA guidelines; this includes reference lists of review articles, primary studies, and trial registers for protocols. Furthermore, experts in the field were contacted. Two reviewers independently screened titles, abstracts, and full-texts to identify relevant articles targeting driving in people with MS that investigated driving-related issues with a formal driving assessment (defined as either an on-road driving assessment; or naturalistic driving in a car equipped with video cameras to record the driving; or a driving simulator with a steering wheel, a brake pedal, and an accelerator). Results: Twenty-four publications, with 15 unique samples (n = 806 PwMS), were identified. To assess driving ability, on-road tests (14 papers) and driving simulators (10 papers) were used. All studies showed moderate to high study quality in the CASP assessment. About 6 to 38% of PwMS failed the on-road tests, showing difficulties in different areas of driving. Similarly, PwMS showed several problems in driving simulations. Cognitive and visual impairment appeared to most impact driving ability, but the evidence was insufficient and inconsistent. Conclusion: There is an urgent need for more research and standardized guidelines for clinicians as one in five PwMS might not be able to drive safely. On-road tests may be the gold standard in assessing driving ability, but on-road protocols are heterogeneous and not infallible. Driving simulators assess driving ability in a standardized way, but without standardized routes and driving outcomes, comparability between studies is difficult. Different aspects, such as cognitive impairment or vision problems, impact driving ability negatively and should be taken into consideration when making decisions about recommending driving cessation.
Front Neurol. 2022 Nov 30;13:1056411
Filser M, Buchner A, Fink GR, Gold SM, Penner IK.
The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools.
J Neurol 2023 Jan;270(1):171-207.
Filser M, Buchner A, Fink GR, Gold SM, Penner IK.
The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools.
Introduction: In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems. Methods: This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review. Results: Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified. Discussion: In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients.
J Neurol 2023 Jan;270(1):171-207.
Holz A, Riefflin M, Heesen C, Riemann-Lorenz K, Obi N, Becher H.
Brestfeeding and risk of multiple sclerosis: a systematic review and meta-analysis of observational studies.
Neuroepidemiology. 2022;56(6):391-401
Holz A, Riefflin M, Heesen C, Riemann-Lorenz K, Obi N, Becher H.
Brestfeeding and risk of multiple sclerosis: a systematic review and meta-analysis of observational studies.
Introduction: The causes of multiple sclerosis (MS) are not fully understood, yet. Genetic predisposition, environmental and lifestyle factors as well as an interplay thereof constitute relevant factors in the development of MS. Especially early-life risk factors such as having been breastfed may also be of relevance. Breast milk provides the new-born not only with essential nutrients and vitamins but also with numerous immune-active molecules, metabolites, oligosaccharides and microbial components that are important for the development of the immune system. We present a systematic review and meta-analysis on the influence of having been breastfed during infancy on the risk of developing MS. Methods: The databases MEDLINE, Cochrane Library and Web of Science were systematically searched for studies on breastfeeding and MS published between database inception and May 18, 2022. Observational studies comparing persons with MS (pwMS) to healthy controls with regard to having been breastfed during the first two years of life were eligible for inclusion. A random effects meta-analysis was calculated to estimate pooled effect sizes using the Mantel-Haenszel method for dichotomous outcomes. The Newcastle-Ottawa Scale (NOS) was used for quality analysis. Results: 15 studies (13 case-control, 2 cohort) were included of which 12 were rated as high quality. The meta-analysis of crude odds ratios (OR) yielded a risk estimate of ORcrude = 0.82 (95% CI 0.70-0.96) for MS in breastfed vs. non-breastfed individuals with substantial heterogeneity (I² = 68.2%). Using adjusted OR, when available, reduced heterogeneity (I² = 48.9%) and resulted in an ORadjusted = 0.86 (95% CI 0.75-0.99). Restricting the analysis to studies with high quality scores (i.e. ≥6/9 points) resulted in a combined ORcrude of 0.79 (95% CI 0.66-0.94) and an ORadjusted = 0.83 (95% CI 0.71-0.98), respectively.
Discussion/conclusion: The meta-analysis showed a small protective effect of having been breastfed on MS risk. This adds to the knowledge that breastfeeding is beneficial for the immunological health of a child. Future studies on the influence of having been breastfed on MS risk should apply a uniform definition of breastfeeding and investigate possible sex-specific aspects
Neuroepidemiology. 2022;56(6):391-401
Oqueka T, Galow S, Simon M, Weidmann A, Stübiger N, Zengin-Sahm E, Sinning C, Krusche M, Ruffer N, Steurer S, Schick-Bengardt X, Sebode M, Horst LJ, Steinmetz OM, Melderis S, Rosenkranz SC, Möller K, Jantke H, Klose H
Sarcoidosis as prime example of a granulomatous disease.
Z Rheumatol. 2022 Sep;81(7):535-548
Oqueka T, Galow S, Simon M, Weidmann A, Stübiger N, Zengin-Sahm E, Sinning C, Krusche M, Ruffer N, Steurer S, Schick-Bengardt X, Sebode M, Horst LJ, Steinmetz OM, Melderis S, Rosenkranz SC, Möller K, Jantke H, Klose H
Sarcoidosis as prime example of a granulomatous disease.
Sarcoidosis is the most frequent immunologically related granulomatous disease and can serve as a model for understanding diseases within this category. The evidence on the diagnostics and treatment is so far limited. It is therefore all the more important that two new and significant guidelines on diagnosis and treatment of sarcoidosis were published during the last 2 years. Additionally, there were more new publications, which were considered for this review article. In this context, this review article provides a current update and overview of sarcoidosis. Pathophysiologically, there is an increasing understanding of the complex processes and interactions involved in the inflammatory processes and granuloma formation. The probability of a diagnosis of sarcoidosis is determined by compatible histology, the exclusion of differential diagnoses and if possible evidence of a multiorgan manifestation. The clinical course is variable and ranges from an asymptomatic manifestation to severe life-threatening organ failure. The most frequently affected organ are the lungs. Pulmonary fibrosis is the most severe form and is also decisive for mortality. An increasing focus is on the extrapulmonary organ manifestations, in particular, cardiac, hepatosplenic, gastrointestinal, renal, ocular and neurological involvement. Treatment, which consists primarily of immunosuppression, should be initiated in cases of organ-threatening or quality of life-impairing activity of the disease. Additional organ-specific management must also be evaluated. In cases of organ failure transplantation should be considered. Due to the limited evidence especially for the treatment of multiorgan sarcoidosis, when possible, patients with this disease should be included in clinical trials.
Z Rheumatol. 2022 Sep;81(7):535-548
Lehnert T, Röver C, Köpke S, Rio J, Chard D, Fittpaldo AV, Friede T, Heesen C, Rahn AC
Immunotherapy for people with clinically isolated syndrome or relapsing-remitting multiple sclerosis: treatment response by demographic, clinical, and biomarker subgroups (PROMISE) – a systematic review protocol.
Syst Rev. 2022 Jul 1;11(1):134
Lehnert T, Röver C, Köpke S, Rio J, Chard D, Fittpaldo AV, Friede T, Heesen C, Rahn AC
Immunotherapy for people with clinically isolated syndrome or relapsing-remitting multiple sclerosis: treatment response by demographic, clinical, and biomarker subgroups (PROMISE) – a systematic review protocol.
Background: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect. The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity. Methods: We will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes. MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane „Risk of Bias 2“ tool, and the certainty of evidence will be assessed using GRADE. Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models. Discussion: Given that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases.
Syst Rev. 2022 Jul 1;11(1):134
Heesen C, Magyari M, Stellmann JP, Lederer C, Giovannoni G, Scalfari A, Daumer M.
The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) –Critical Review facing the 20 anniversary
Mult Scler Relat Disord. 2022 Jul;63:103885
Heesen C, Magyari M, Stellmann JP, Lederer C, Giovannoni G, Scalfari A, Daumer M.
The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) –Critical Review facing the 20 anniversary
The SLCMSR was formed as an international Multiple Sclerosis Trials, Research and Resource Center to identify clinical MRI and other predictors of the course of multiple sclerosis (MS) based on a large database of natural history and clinical trial data. Using an elaborate validation concept several key findings were published, challenging established outcome parameters and their assessment in MS such as disability ratings with Expanded Disability Status Scale (EDSS), relapses and MRI endpoints. Sustained increase of EDSS appeared to be an invalid outcome for 2-3 year clinical trials at least in patients with relapsing-remitting MS. The number of gadolinium-enhancing lesions and T2-lesion load on MRI were shown not to have a meaningful additional predictive value for the disease course. These issues risen some 15 years ago had triggered controversial discussions which have also been noticed by regulatory authorities and they all have not been resolved. In addition the SLCMSR contributed to the development of new outcomes such as real-world walking speed as an attractive, ecologically valid tool based on a wearable device. A so-called evidence-based-decision-support tool was constructed to provide individual prognostic estimates based on a matching algorithm to a given database. This paper condensates the findings of 20 years of critical MS research.
Mult Scler Relat Disord. 2022 Jul;63:103885
Attfield KE, Jensen LT, Kaufmann M, Friese MA, Fugger L.
The immunology of multiple sclerosis.
Nat Rev Immunol. 2022 Dec;22(12):734-750
Attfield KE, Jensen LT, Kaufmann M, Friese MA, Fugger L.
The immunology of multiple sclerosis.
Our incomplete understanding of the causes and pathways involved in the onset and progression of multiple sclerosis (MS) limits our ability to effectively treat this complex neurological disease. Recent studies explore the role of immune cells at different stages of MS and how they interact with cells of the central nervous system (CNS). The findings presented here begin to question the exclusivity of an antigen-specific cause and highlight how seemingly distinct immune cell types can share common functions that drive disease. Innovative techniques further expose new disease-associated immune cell populations and reinforce how environmental context is critical to their phenotype and subsequent role in disease. Importantly, the differentiation of immune cells into a pathogenic state is potentially reversible through therapeutic manipulation. As such, understanding the mechanisms that provide plasticity to causal cell types is likely key to uncoupling these disease processes and may identify novel therapeutic targets that replace the need for cell ablation.
Nat Rev Immunol. 2022 Dec;22(12):734-750
Mokry C, Warnke C, Gehring K, Hegen H, Salmen A, Kraemer M, Kleiter I, Fasshauer E, Scheiderbauer J, Lühmann D, Köpke S, Berthele A, Heesen C
Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis
Mult Scler Relat Disord. 2022 Jan;57:103434
Mokry C, Warnke C, Gehring K, Hegen H, Salmen A, Kraemer M, Kleiter I, Fasshauer E, Scheiderbauer J, Lühmann D, Köpke S, Berthele A, Heesen C
Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis
| Background: In May 2021, a new guideline on the diagnosis and treatment of multiple sclerosis and related disorders was released in Germany. Since the success of a guideline depends on how it integrates into everyday clinical practice, the German Society for Neurology (DGN) has launched a multimethod implementation project. Here we report on the results based on the consultation version of the guideline. Methods: We used qualitative and quantitative data analyses to capture the nature and extent of barriers and facilitating factors to the implementation. We centered on the guideline’s chapter A on diagnosis, relapse therapy, and immunotherapy of multiple sclerosis. We performed nine online focus group discussions and a web-based survey and analyzed emails and letters with comments from stakeholders and independent parties that were sent spontaneously or by invitation. Results: 94 neurologists answered the survey, and ≥70% agreed with the recommendations of the guideline on each major content topic. Barriers to implementation were detected in group discussions and written input. The most controversial issues of the guideline were „early treatment“, „criteria for starting or switching therapy“, „stepwise escalation versus early aggressive treatment“, „classification of drugs into three categories of efficacy“ and the scenarios on „treatment cessation“. Some appreciated the highly structured recommendations, but others felt that the guideline restricts the free choice of therapy, or they were afraid of recourse claims. Some considered the guideline as too cautious regarding treatment initiation, possibly delaying necessary therapies. Others appreciated that conflicts of interests of the guideline’s authoring group were minimized and thought that the new guideline is clearer, more extensive and practical. Conclusion: In contrast to the survey, feedback in the focus group discussions and from individuals was diverse and sometimes more critical. Based on the overall feedback rate of about 250 people in relation to the number of 6500 board-certified neurologists in Germany, the overall appreciation of the guideline can only be considered as an indicator and not proof of acceptance. Results of this analysis were incorporated into several adjustments to the final guideline of 2021. Since the guideline is to be updated regularly under the auspices of a „living guideline“, active interaction with users will continue to matter and help to improve it. |
Mult Scler Relat Disord. 2022 Jan;57:103434
Sforzini L, Worrell C, Kose M, Anderson IM, Aouizerate B, Arolt V, Bauer M, Baune BT, Blier P, Cleare AJ, Cowen PJ, Dinan TG, Fagiolini A, Ferrier IN, Hegerl U, Krystal AD, Leboyer M, McAllister-Williams RH, McIntyre RS, Meyer-Lindenberg A, Miller AH, Nemeroff CB, Normann C, Nutt D, Pallanti S, Pani L, Penninx BWJH, Schatzberg AF, Shelton RC, Yatham LN, Young AH, Zahn R, Aislaitner G, Butlen-Ducuing F, Fletcher C, Haberkamp M, Laughren T, Mäntylä FL, Schruers K, Thomson A, Arteaga-Henríquez G, Benedetti F, Cash-Gibson L, Chae WR, De Smedt H, Gold SM, Hoogendijk WJG, Mondragón VJ, Maron E, Martynowicz J, Melloni E, Otte C, Perez-Fuentes G, Poletti S, Schmidt ME, van de Ketterij E, Woo K, Flossbach Y, Ramos-Quiroga JA, Savitz AJ, Pariante CM.
A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.
Mol Psychiatry. 2022 Mar;27(3):1286-1299
Sforzini L, Worrell C, Kose M, Anderson IM, Aouizerate B, Arolt V, Bauer M, Baune BT, Blier P, Cleare AJ, Cowen PJ, Dinan TG, Fagiolini A, Ferrier IN, Hegerl U, Krystal AD, Leboyer M, McAllister-Williams RH, McIntyre RS, Meyer-Lindenberg A, Miller AH, Nemeroff CB, Normann C, Nutt D, Pallanti S, Pani L, Penninx BWJH, Schatzberg AF, Shelton RC, Yatham LN, Young AH, Zahn R, Aislaitner G, Butlen-Ducuing F, Fletcher C, Haberkamp M, Laughren T, Mäntylä FL, Schruers K, Thomson A, Arteaga-Henríquez G, Benedetti F, Cash-Gibson L, Chae WR, De Smedt H, Gold SM, Hoogendijk WJG, Mondragón VJ, Maron E, Martynowicz J, Melloni E, Otte C, Perez-Fuentes G, Poletti S, Schmidt ME, van de Ketterij E, Woo K, Flossbach Y, Ramos-Quiroga JA, Savitz AJ, Pariante CM.
A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.
| Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD. |
Mol Psychiatry. 2022 Mar;27(3):1286-1299
Rahn AC, Solari A, Beckermann H, Nicholas R, Wilkie D, Heesen C, Giordano A;Rehabilitation in Multiple Sclerosis (RIMS) Special Interest Group on Patient Autonomy
„I will respect the Autonomy of My Patient“: A Scoping Review of Shared Decision Making in Multiple Sclerosis
Int J MS Care. Nov-Dec 2020;22(6):276-284
Rahn AC, Solari A, Beckermann H, Nicholas R, Wilkie D, Heesen C, Giordano A;Rehabilitation in Multiple Sclerosis (RIMS) Special Interest Group on Patient Autonomy
„I will respect the Autonomy of My Patient“: A Scoping Review of Shared Decision Making in Multiple Sclerosis
| Background: Patient autonomy is a bioethical principle that was strengthened in the revised Declaration of Geneva. Shared decision making (SDM) is particularly relevant in the management of multiple sclerosis (MS) because many preference-sensitive decisions have to be made during the disease course. We aimed to summarize the available evidence on SDM in the MS field and to inform future research and practice. Methods: We performed a scoping review by searching MEDLINE (past 5 years). Studies were included if they reported primary/secondary research and focused on SDM related to people with MS. Data were grouped into topics, with results presented in narrative form. Results: From 865 references, we included 55 studies conducted mostly in Europe. Half of the studies were observational, followed by qualitative (20%), mixed-methods (17%), randomized controlled trials (RCTs, 5%), quasi-experimental (5%), and reviews (4%). Most studies addressed people with relapsing-remitting MS (85%); the remaining addressed health care professionals, patients‘ significant others, or a combination. We identified five main topics: decisions on disease-modifying drugs, decisions on chronic cerebrospinal venous insufficiency treatment, information provision and patient education, health literacy, and risk knowledge. Conclusions: The high proportion of included studies on SDM in MS in Europe suggests an earlier adoption of these concepts in this area. Decisions on disease-modifying drugs was the prevalent topic. Only 5% of studies were RCTs, indicating that more research is needed to study the effectiveness of SDM interventions. Studies addressing people with primary and secondary progressive MS are also needed. |
Int J MS Care. Nov-Dec 2020;22(6):276-284
Pöttgen J, van de Vis W, van Nunen A, Rose A, Engelbrecht J, Pirard M, Lau S, Heesen C, Köpke S;Rehabilitation in Multiple Sclerosis (RIMS) Sepcial Interest Group on Psychology and Neuropsychologie
Psychobehavioral Treatment Options for Sexual Dysfunction in Multiple Sclerosis: A Systematic Review
Int J MS Care. Nov-Dec 2020;22(6):285-293.
Pöttgen J, van de Vis W, van Nunen A, Rose A, Engelbrecht J, Pirard M, Lau S, Heesen C, Köpke S;Rehabilitation in Multiple Sclerosis (RIMS) Sepcial Interest Group on Psychology and Neuropsychologie
Psychobehavioral Treatment Options for Sexual Dysfunction in Multiple Sclerosis: A Systematic Review
| Background: Sexual dysfunction in multiple sclerosis (MS) is a significant but overlooked impairment, and treatment options are rare. The aims of this systematic review were to identify psychological interventions used to treat sexual dysfunction in MS, to estimate their benefit, and to note appropriate treatment approaches for research projects and clinical use. Methods: A systematic review update was conducted to find psychological interventions aiming to improve sexual dysfunction in MS. A comprehensive search and review of MEDLINE, PsycINFO, CINAHL, and PubMed were completed, and the effects and quality of selected studies were reported. Results: Six publications with 295 participants were identified. All selected studies assessed the effectiveness of psychological interventions on sexual dysfunction or sexual satisfaction in people with MS; four studies directly targeted sexual dysfunction in MS, one was a mindfulness yoga program to improve fatigue and quality of life, and one other presented a secondary analysis of a study targeting depression in MS. All six studies reported significant improvements in sexual dysfunction or sexual satisfaction and somewhat in psychological variables. Conclusions: A pressing need for development and adequate evaluation of psychological interventions for sexual dysfunction in MS remains. In addition, assessment of sexual dysfunction in MS and its treatment should be more focused in clinical care. |
Int J MS Care. Nov-Dec 2020;22(6):285-293.
Köhler-Forsberg O, Otte C, Gold SM, Ostergaard SD
Statins in the treatment of depression: Hype or Hope?
Pharmacol Ther. 2020 Jul 8
Köhler-Forsberg O, Otte C, Gold SM, Ostergaard SD
Statins in the treatment of depression: Hype or Hope?
| Many patients with depression do not respond sufficiently to antidepressant treatment, necessitating other treatment approaches. HMG-CoA reductase inhibitors (i.e. statins), which are frequently used for their cardioprotective properties, have also been studied regarding potential antidepressant effects. Possible mechanisms underlying an antidepressant effect of statins may include the anti-inflammatory, antioxidant and lipid lowering properties of this class of drugs. This review provides an overview of this field by reviewing the following aspects: 1) Candidate mechanisms that could mediate putative antidepressant effects of statins; 2) The evidence for and against antidepressant effects of statins in patients with major depressive disorder and among individuals with a medical disease and depressive symptoms; and 3) The safety of statin treatment. Three small placebo-controlled trials conducted in Iran (total N=172) have found that statins as add-on to selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in patients with major depressive disorder (MDD). Statin treatment in individuals without MDD do not seem to affect mood or protect against development of depression. Treatment with statins – including the combination with SSRIs – is generally considered to be safe. While the initial evidence for the antidepressant effect of the combination of an SSRI and a statin is promising, larger clinical trials, appropriately powered, and with depression as a pre-defined primary endpoint are needed. |
Pharmacol Ther. 2020 Jul 8
Alexander T, Badoglio M, Henes J, Heesen C, Arnold R, Radbruch A, Snowden JA, Hiepe F.
[Autologous hematopoietic stem cell transplantation for autoimmune diseases : Current indications and mode of action, a review on behalf of the EBMT Autoimmune Diseases Working Party (ADWP)].
Z Rheumatol 2020 Jun;79(5):419-428.
Alexander T, Badoglio M, Henes J, Heesen C, Arnold R, Radbruch A, Snowden JA, Hiepe F.
[Autologous hematopoietic stem cell transplantation for autoimmune diseases : Current indications and mode of action, a review on behalf of the EBMT Autoimmune Diseases Working Party (ADWP)].
| The recent introduction of biologic and targeted synthetic disease-modifying drugs has led to more specificity in the treatment of autoimmune diseases; however, they require continuous or intermittent administration, are associated with cumulative risks for side effects, result in high costs and provide no cure. In contrast, high-dose chemotherapy followed by transplantation of autologous hematopoietic stem cells (AHSCT) has been demonstrated to induce clinical remission in various autoimmune diseases that can persist over many years without continued maintenance therapy. The principle behind AHSCT is an elimination of important components of the autoreactive immunological memory with subsequent regeneration of the complete immune system. Several studies have indicated that such an immune reset is associated with fundamental changes in the immune repertoire leading to an induction of tolerance against self-antigens. This article presents the current indications of AHSCT for autoimmune diseases based on the registry data of the European Society of Blood and Marrow Transplantation (EBMT) and discusses the results from mechanistic studies, which provide detailed insights into the mode of action of this treatment. |
Z Rheumatol 2020 Jun;79(5):419-428.
Gold SM, Willing A, Leypoldt F, Paul F, Friese MA.
Sex differences in autoimmune disorders of the central nervous system.
Semin Immunopathol. 2019 Mar;41(2):177-188
Gold SM, Willing A, Leypoldt F, Paul F, Friese MA.
Sex differences in autoimmune disorders of the central nervous system.
Stronger adaptive immune responses in females can be observed in different mammals, resulting in better control of infections compared to males. However, this presumably evolutionary difference likely also drives higher incidence of autoimmune diseases observed in humans. Here, we summarize sex differences in the most common autoimmune diseases of the central nervous system (CNS) and discuss recent advances in the understanding of possible underlying immunological and CNS intrinsic mechanisms. In multiple sclerosis (MS), the most common inflammatory disease of the CNS, but also in rarer conditions, such as neuromyelitis optica spectrum disorders (NMOSD) or neuronal autoantibody-mediated autoimmune encephalitis (AE), sex is one of the top risk factors, with women being more often affected than men. Immunological mechanisms driving the sex bias in autoimmune CNS diseases are complex and include hormonal as well as genetic and epigenetic effects, which could also be exerted indirectly via modulation of the microbiome. Furthermore, CNS intrinsic differences could underlie the sex bias in autoimmunity by differential responses to injury. The strong effects of sex on incidence and possibly also activity and progression of autoimmune CNS disorders suggest that treatments need to be tailored to each sex to optimize efficacy. To date, however, due to a lack of systematic studies on treatment responses in males versus females, evidence in this area is still sparse. We argue that studies taking sex differences into account could pave the way for sex-specific and therefore personalized treatment.Semin Immunopathol. 2019 Mar;41(2):177-188
Köpke S, Solari A, Khan F, Heesen C, Giordano A.
Information provision for people with multiple sclerosis.
Cochrane Database Syst Rev 2018 Oct 14;10:CD008757.
Köpke S, Solari A, Khan F, Heesen C, Giordano A.
Information provision for people with multiple sclerosis.
BACKGROUND: People with multiple sclerosis (MS) are confronted with a number of important uncertainties concerning many aspects of the disease. Among others, these include diagnosis, prognosis, disease course, disease-modifying therapies, symptomatic therapies and non-pharmacological interventions. It has been shown that people with MS demand adequate information to be able to actively participate in medical decision making and to self-manage their disease. On the other hand, it has been found that patients‘ disease-related knowledge is poor. Therefore, guidelines have recommended clear and concise high-quality information at all stages of the disease. Several studies have outlined communication and information deficits in the care of people with MS and, accordingly, a number of information and decision support programmes have been published. OBJECTIVES: To evaluate the effectiveness of information provision interventions for people with MS that aim to promote informed choice and improve patient-relevant outcomes. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register which contains trials from CENTRAL (The Cochrane Library 2013, Issue 6), MEDLINE, EMBASE, CINAHL, LILACS, PEDro and clinical trials registries (12 June 2013) as well as other sources. In addition, we searched PsycINFO, trial registries, and reference lists of identified articles. We also contacted trialists. SELECTION CRITERIA: Randomised controlled trials, cluster randomised controlled trials and quasi-randomised trials comparing information provision for people with MS or suspected MS (intervention groups) with usual care or other types of information provision (control groups) were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the retrieved articles for relevance and methodological quality, and extracted data. Critical appraisal of studies addressed the risk of selection bias, performance bias, attrition bias and detection bias. We contacted authors of relevant studies for additional information. MAIN RESULTS: Ten randomised controlled trials involving a total of 1314 participants met the inclusion criteria and were analysed. The interventions addressed a variety of topics using different approaches for information provision in different settings. Topics included disease-modifying therapy, relapse management, self-care strategies, fatigue management, family planning and general health promotion. The interventions contained decision aids, educational programmes, self-care interventions and personal interviews with physicians. All interventions were complex interventions using more than one active component, but the number and extent of the intervention components differed markedly between studies. The studies had a variable risk of bias. We did not perform meta-analyses due to marked clinical heterogeneity. All four studies assessing MS-related knowledge (524 participants; moderate-quality evidence) detected significant differences between groups as a result of the interventions indicating that information provision may successfully increase participants‘ knowledge. There were mixed results from four studies reporting effects on decision making (836 participants; low-quality evidence) and from five studies assessing quality of life (605 participants; low-quality evidence). There were no adverse events in the six studies reporting on adverse events. AUTHORS‘ CONCLUSIONS: Information provision for people with MS seems to increase disease-related knowledge, with less clear results on decision making and quality of life. There seem to be no negative side effects from informing patients about their disease. Interpretation of study results remains challenging due to the marked heterogeneity of the interventions and outcome measures.Cochrane Database Syst Rev 2018 Oct 14;10:CD008757.
Rahn AC, Köpke S, Stellmann JP, Schiffmann I, Lukas C, Chard D, Heesen C
Magnetic resonance imaging as a prognostic disability marker in clinically isolated syndrome: A systematic review.
Acta Neurol Scand. 2019 Jan;139(1):18-32
Rahn AC, Köpke S, Stellmann JP, Schiffmann I, Lukas C, Chard D, Heesen C
Magnetic resonance imaging as a prognostic disability marker in clinically isolated syndrome: A systematic review.
Magnetic resonance imaging (MRI) is the key prognostic tool in people with a clinically isolated syndrome (CIS). There is increasing interest in treating people following a CIS in the hope that conversion to multiple sclerosis (MS) will be prevented and future disability reduced. So far, the prognostic value of MRI for disability following a CIS has not been evaluated systematically. We systematically searched MEDLINE and EMBASE. Cohort studies were selected if they reported associations of MRI and disability following a CIS, included at least 50 people with a CIS at baseline, had at least 5 years of follow-up and obtained at least one structural MRI measurement (T1 lesions, T2 lesions, T1 contrast-enhancing lesions or brain atrophy). We assessed the studies for quality and rated the completeness of MRI reporting. In total, 13 studies were identified reporting on the following: T2 lesion number and volume, T2 infratentorial lesion number and volume, T1 contrast-enhancing lesions and grey matter fraction. T2 brain lesion number determined soon after the occurrence of a CIS was associated with disability progression after 5-7 years, with an increased risk when 10 or more lesions were present. Infratentorial lesions were also associated with a higher risk of subsequent disability. The number and distribution of MRI-visible lesions soon after a CIS are associated with disability later on, and may offer additional useful information when making treatment decisions in people with early MS. Further work is required to determine whether other measures have a higher predictive potential.Acta Neurol Scand. 2019 Jan;139(1):18-32
Schiffmann I, Scheiderbauer J,Riemann-Lorenz K, Heesen C.
Does cladribine have an impact on brain atrophy in people with relapsing remitting multiple sclerosis?
Mult Scler. 2018 Sep;24(10):1387-1388
Schiffmann I, Scheiderbauer J,Riemann-Lorenz K, Heesen C.
Does cladribine have an impact on brain atrophy in people with relapsing remitting multiple sclerosis?
In their paper, De Stefano et al. Describe the reduction of the percentage brain volume change (PBVC) in patients with relapsing remitting multiple sclerosis (RRMS treated with the purine analog cladribine over a period of 24 months. While we highly appreciate the aim of looking at atrophy rates in new MS treatments, we would like to point out that the calculations and figures used may be misleading.Mult Scler. 2018 Sep;24(10):1387-1388
Gold SM, Voskuhl RR
Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application.
Semin Immunopathol. 2016 Nov;38(6):709-718
Gold SM, Voskuhl RR
Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application.
Translational research generally refers to a „bench to bedside“ approach where basic science discoveries in models move to clinical trials in humans. However, a „bedside to bench to bedside“ approach may be more promising with respect to clinical relevance, since it starts with a clinical observation that can serve as a research paradigm to elucidate mechanisms and translate them back into novel therapeutic approaches. The effect of pregnancy on human autoimmune disorders in general, and multiple sclerosis (MS) in particular, serves as an intriguing example of how this can be used to understand disease pathobiology and discover new therapeutic targets. Disease activity in MS undergoes pronounced shifts in the time before, during, and after pregnancy. The most well-known and established example is a reduction in relapse rates in the last trimester by 70-80 %. However, disease activity reappears in the first few months after delivery, temporarily overshooting pre-pregnancy levels. This phenomenon has since its first description served as a model for investigating novel treatment options in animal models and has cumulated in successful phase 2a and 2b trials in female MS patients. However, recently, a number of other clinical observations have been made that might be similarly suitable to offer additional insights into pathobiological mechanisms of MS activity, progression, and possibly even incidence. Here, we outline the various changes in the clinical course of MS that have been described in relation to pregnancy, both short term and long term, and discuss how these may inform the development of novel treatments for autoimmune diseases.Semin Immunopathol. 2016 Nov;38(6):709-718
Ramien C, Taenzer A, Lupu A, Heckmann N, Engler JB, Patas K, Friese MA, Gold SM
Sex effects on inflammatory and neurodegenerative processes in multiple sclerosis.
Neurosci Biobehav Rev. 2016 Aug;67:137-46
Ramien C, Taenzer A, Lupu A, Heckmann N, Engler JB, Patas K, Friese MA, Gold SM
Sex effects on inflammatory and neurodegenerative processes in multiple sclerosis.
Clinical observations in human autoimmune diseases such as multiple sclerosis (MS) suggest a pivotal role of sex-related factors in the etiopathogenesis. These include a female preponderance in MS incidence and an increasing sex bias over time, a parent-of-origin effect in MS inheritance, and the protective effect of pregnancy on disease activity. The complex interplay of factors contributing to these clinical phenomena, however, is incompletely understood and may include sex hormones as well as genetic or epigenetic sex differences. While genetic and hormonal effects are impossible to study independently in humans, novel mouse models have started to unravel the cause-effect relationship between individual sex-related factors and autoimmunity. Here, we present the evidence for mechanisms underlying sex differences in the immune system and the central nervous system (CNS) and how these might help to explain some of the clinically observed sex differences in MS. A better understanding of the molecular underpinnings may ultimately help to devise sex-specific treatment strategies as well as highlight novel avenues for therapy in both sexes.Neurosci Biobehav Rev. 2016 Aug;67:137-46
Friese, MA
Widespread synaptic loss in multiple sclerosis.
Brain. 2016 Jan;139(Pt 1):2-4
Friese, MA
Widespread synaptic loss in multiple sclerosis.
This scientific commentary refers to ‘Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis’, by Jürgens et al. (doi:10.1093/brain/awv353).Brain. 2016 Jan;139(Pt 1):2-4
Dendrou CA, Fugger L, Friese MA.
Immunopathology of multiple sclerosis.
Nat. Rev. Immunol. 2015;15:545-58.
Dendrou CA, Fugger L, Friese MA.
Immunopathology of multiple sclerosis.
Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.Nat. Rev. Immunol. 2015;15:545-58.
van Buel EM, Patas K, Peters M, Bosker FJ, Eisel UL, Klein HC
Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all?
Transl Psychiatry. 2015;5:e609
van Buel EM, Patas K, Peters M, Bosker FJ, Eisel UL, Klein HC
Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all?
A low-grade inflammatory response is commonly seen in the peripheral blood of major depressive disorder (MDD) patients, especially those with refractory and chronic disease courses. However, electroconvulsive therapy (ECT), the most drastic intervention reserved for these patients, is closely associated with an enhanced haematogenous as well as neuroinflammatory immune response, as evidenced by both human and animal studies. A related line of experimental evidence further shows that inflammatory stimulation reinforces neurotrophin expression and may even mediate dramatic neurogenic and antidepressant-like effects following exposure to chronic stress. The current review therefore attempts a synthesis of our knowledge on the neurotrophic and immunological aspects of ECT and other electrically based treatments in psychiatry. Perhaps contrary to contemporary views, we conclude that targeted potentiation, rather than suppression, of inflammatory responses may be of therapeutic relevance to chronically depressed patients or a subgroup thereof.Transl Psychiatry. 2015;5:e609
Galea I, Ward-Abel N, Heesen C.
Relapse in multiple sclerosis.
BMJ 2015;350:h1765.
Galea I, Ward-Abel N, Heesen C.
Relapse in multiple sclerosis.
Relapse of multiple sclerosis is a patient reported, or objectively observed, event typical of an acute inflammatory demyelinating event in the central nervous system, current or historical, with a duration of at least 24 hours. The differential diagnosis of a relapse includes alternative neurological diagnoses, pseudo-relapses, short lived paroxysmal symptoms, day to day fluctuations, and functional symptoms. Clinically significant or severe relapses may benefit from treatment with corticosteroid for five days. Documentation and timely communication of the relapse to the patient’s multiple sclerosis specialist service, such as through the multiple sclerosis specialist nurse, is important, to enable timely decisions on immunotherapy initiation or escalation. Non-adherence with immunotherapy is under-recognised by both patients and doctors.BMJ 2015;350:h1765.
Heesen C, Bruce J, Feys P, Sastre-Garriga J, Solari A, Eliasson L, Matthews V, Hausmann B, Ross AP, Asano M, Imonen-Charalambous K, Köpke S, Clyne W, Bissell P.
Adherence in multiple sclerosis (ADAMS): classification, relevance, and research needs. A meeting report.
Mult. Scler. 2014;20:1795-8.
Heesen C, Bruce J, Feys P, Sastre-Garriga J, Solari A, Eliasson L, Matthews V, Hausmann B, Ross AP, Asano M, Imonen-Charalambous K, Köpke S, Clyne W, Bissell P.
Adherence in multiple sclerosis (ADAMS): classification, relevance, and research needs. A meeting report.
BACKGROUND: Adherence to medical interventions is a global problem. With an increasing amount of partially effective but expensive drug treatments adherence is increasingly relevant in multiple sclerosis (MS). Perceived lack of efficacy and side effects as well as neuropsychiatric factors such as forgetfulness, fatigue and depression are major determinants. However, research on adherence to behavioural interventions as part of rehabilitative interventions has only rarely been studied. METHODS: In a one-day meeting health researchers as well as patient representatives and other stakeholders discussed adherence issues in MS and developed a general draft research agenda within a focus group session. RESULTS: The focus group addressed four major areas: (1) focussing patients and their informal team; (2) studying health care professionals; (3) comparing practice across cultures; and (4) studying new adherence interventions. CONCLUSIONS: A focus on patient preferences as well as a non-judgmental discussion on adherence issues with patients should be at the core of adherence work.Mult. Scler. 2014;20:1795-8.
Köpke S, Solari A, Khan F, Heesen C, Giordano A.
Information provision for people with multiple sclerosis.
Cochrane Database Syst Rev 2014;4:CD008757.
Köpke S, Solari A, Khan F, Heesen C, Giordano A.
Information provision for people with multiple sclerosis.
BACKGROUND: People with multiple sclerosis (MS) are confronted with a number of important uncertainties concerning many aspects of the disease. Among others, these include diagnosis, prognosis, disease course, disease-modifying therapies, symptomatic therapies and non-pharmacological interventions. It has been shown that people with MS demand adequate information to be able to actively participate in medical decision making and to self-manage their disease. On the other hand, it has been found that patients‘ disease-related knowledge is poor. Therefore, guidelines have recommended clear and concise high-quality information at all stages of the disease. Several studies have outlined communication and information deficits in the care of people with MS and, accordingly, a number of information and decision support programmes have been published. OBJECTIVES: To evaluate the effectiveness of information provision interventions for people with MS that aim to promote informed choice and improve patient-relevant outcomes. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register which contains trials from CENTRAL (The Cochrane Library 2013, Issue 6), MEDLINE, EMBASE, CINAHL, LILACS, PEDro and clinical trials registries (12 June 2013) as well as other sources. In addition, we searched PsycINFO, trial registries, and reference lists of identified articles. We also contacted trialists. SELECTION CRITERIA: Randomised controlled trials, cluster randomised controlled trials and quasi-randomised trials comparing information provision for people with MS or suspected MS (intervention groups) with usual care or other types of information provision (control groups) were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the retrieved articles for relevance and methodological quality, and extracted data. Critical appraisal of studies addressed the risk of selection bias, performance bias, attrition bias and detection bias. We contacted authors of relevant studies for additional information. MAIN RESULTS: Ten randomised controlled trials involving a total of 1314 participants met the inclusion criteria and were analysed. The interventions addressed a variety of topics using different approaches for information provision in different settings. Topics included disease-modifying therapy, relapse management, self-care strategies, fatigue management, family planning and general health promotion. The interventions contained decision aids, educational programmes, self-care interventions and personal interviews with physicians. All interventions were complex interventions using more than one active component, but the number and extent of the intervention components differed markedly between studies. The studies had a variable risk of bias. We did not perform meta-analyses due to marked clinical heterogeneity. All four studies assessing MS-related knowledge (524 participants; moderate-quality evidence) detected significant differences between groups as a result of the interventions indicating that information provision may successfully increase participants‘ knowledge. There were mixed results from four studies reporting effects on decision making (836 participants; low-quality evidence) and from five studies assessing quality of life (605 participants; low-quality evidence). There were no adverse events in the six studies reporting on adverse events. AUTHORS‘ CONCLUSIONS: Information provision for people with MS seems to increase disease-related knowledge, with less clear results on decision making and quality of life. There seem to be no negative side effects from informing patients about their disease. Interpretation of study results remains challenging due to the marked heterogeneity of the interventions and outcome measures.Cochrane Database Syst Rev 2014;4:CD008757.
Schattling B, Eggert B, Friese MA.
Acquired channelopathies as contributors to development and progression of multiple sclerosis.
Exp. Neurol. 2014;262 Pt A:28-36.
Schattling B, Eggert B, Friese MA.
Acquired channelopathies as contributors to development and progression of multiple sclerosis.
Multiple sclerosis (MS), the most frequent inflammatory disease of the central nervous system (CNS), affects about two and a half million individuals worldwide and causes major burdens to the patients, which develop the disease usually at the age of 20 to 40. MS is likely referable to a breakdown of immune cell tolerance to CNS self-antigens resulting in focal immune cell infiltration, activation of microglia and astrocytes, demyelination and axonal and neuronal loss. Here we discuss how altered expression patterns and dysregulated functions of ion channels contribute on a molecular level to nearly all pathophysiological steps of the disease. In particular the detrimental redistribution of ion channels along axons, as well as neuronal excitotoxicity with regard to imbalanced glutamate homeostasis during chronic CNS inflammation will be discussed in detail. Together, we describe which ion channels in the immune and nervous system commend as attractive future drugable targets in MS treatment.Exp. Neurol. 2014;262 Pt A:28-36.
Friese MA, Schattling B, Fugger L.
Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis.
Nat Rev Neurol 2014;10:225-38.
Friese MA, Schattling B, Fugger L.
Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis.
Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration–which causes irreversible disability–are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.Nat Rev Neurol 2014;10:225-38.
Heesen C, Cohen JA.
Does the patient know best? Quality of life assessment in multiple sclerosis trials.
Mult. Scler. 2014;20:131-2.
Heesen C, Cohen JA.
Does the patient know best? Quality of life assessment in multiple sclerosis trials.
Mult. Scler. 2014;20:131-2.
Hellmann-Regen J, Piber D, Hinkelmann K, Gold SM, Heesen C, Spitzer C, Endres M, Otte C.
Depressive syndromes in neurological disorders.
Eur Arch Psychiatry Clin Neurosci 2013;263 Suppl 2:S123-36.
Hellmann-Regen J, Piber D, Hinkelmann K, Gold SM, Heesen C, Spitzer C, Endres M, Otte C.
Depressive syndromes in neurological disorders.
Depressive syndromes represent a common and often characteristic feature in a number of neurological disorders. One prominent example is the development of post-stroke depression, which can be observed in more than one-third of stroke survivors in the aftermath of an ischemic stroke. Thus, post-stroke depression represents one of the most prevalent, disabling, and potentially devastating psychiatric post-stroke complications. On the other hand, depressive syndromes may also be considered as a risk factor for certain neurological disorders, as recently revealed by a meta-analysis of prospective cohort studies, which demonstrated an increased risk for ischemic events in depressed patients. Moreover, depressive syndromes represent common comorbidities in a number of other neurological disorders such as Parkinson’s disease, multiple sclerosis, or epilepsy, in which depression has a strong impact on both quality of life and outcome of the primary neurological disorder.Eur Arch Psychiatry Clin Neurosci 2013;263 Suppl 2:S123-36.
Heesen C, Köpke S, Solari A, Geiger F, Kasper J.
Patient autonomy in multiple sclerosis–possible goals and assessment strategies.
J. Neurol. Sci. 2013;331:2-9.
Heesen C, Köpke S, Solari A, Geiger F, Kasper J.
Patient autonomy in multiple sclerosis–possible goals and assessment strategies.
Patient autonomy has been increasingly acknowledged as prerequisite for successful medical decision making in Western countries. In medical decisions with a need to involve a health professional, patient autonomy becomes apparent in the extent of patients‘ participation in the communication as described in the concept of shared decision making. Patient autonomy can be derived from different perspectives or goals and the focus of evaluation approaches may vary accordingly. Multiple sclerosis (MS) is a paradigmatic disease to study patient autonomy mainly because MS patients are highly disease competent and due to ambiguous evidence on many aspects of disease-related medical decision making. This review gives an overview on measurement issues in studying decision making in MS, categorized according to prerequisites, process measures and outcomes of patient autonomy. As relevant prerequisites role preferences, risk attribution, risk tolerance, and risk knowledge are discussed. Regarding processes, we distinguish intra-psychic and interpersonal aspects. Intra-psychic processes are elucidated using the theory of planned behavior, which guided development of a 30-item scale to capture decisions about immunotherapy. Moreover, a theory of uncertainty management has been created resulting in the development of a corresponding measurement concept. Interpersonal processes evolving between physician and patient can be thoroughly analyzed from different perspectives by use of the newly developed comprehensive MAPPIN’SDM inventory. Concerning outcomes, besides health related outcomes, we discuss match of preferred roles during the decision encounters (preference match), decisional conflict as well as an application of the multidimensional measure of informed choice to decisions of MS patients. These approaches provide an overview on patient-inherent and interpersonal factors and processes modulating medical decision making and health behavior in MS and beyond.J. Neurol. Sci. 2013;331:2-9.
Patas K, Engler JB, Friese MA, Gold SM.
Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity.
J. Reprod. Immunol. 2013;97:140-6.
Patas K, Engler JB, Friese MA, Gold SM.
Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system of presumed autoimmune origin. Intriguingly, pregnancy in female MS patients is associated with a substantial decrease in relapse rate. However, post-partum the relapse rate increases in a rebounding fashion above the rate seen before pregnancy. Wide gaps remain in our understanding of the biological mechanisms underlying these pregnancy-related effects in MS patients. To date, most attempts to explain MS disease amelioration during pregnancy have focused on levels of circulating hormones with immunomodulatory properties such as estrogens and global shifts in systemic maternal immune cell composition. However, recent advances in our understanding of feto-maternal tolerance have provided evidence that fetal antigens directly interact with the maternal immune system. This results in specific immunomodulation such as fetal-antigen-dependent induction of regulatory T cells. Thus, the „shaping“ of maternal immune responses by fetal antigens may represent an endogenous pathway by which antigen-specific immunomodulation might also contribute to reinstalling tolerance to autoantigens in MS. Reproductive immunology therefore has great potential to provide insights into MS immunopathogenesis and highlight novel avenues for treatment of MS and other autoimmune diseases.J. Reprod. Immunol. 2013;97:140-6.
Piber D, Hinkelmann K, Gold SM, Heesen C, Spitzer C, Endres M, Otte C.
Depression and neurological diseases.
Nervenarzt 2012;83:1423-33.
Piber D, Hinkelmann K, Gold SM, Heesen C, Spitzer C, Endres M, Otte C.
Depression and neurological diseases.
In many neurological diseases a depressive syndrome is a characteristic sign of the primary disease or is an important comorbidity. Post-stroke depression, for example, is a common and relevant complication following ischemic brain infarction. Approximately 4 out of every 10 stroke patients develop depressive disorders in the course of the disease which have a disadvantageous effect on the course and the prognosis. On the other hand depression is also a risk factor for certain neurological diseases as was recently demonstrated in a meta-analysis of prospective cohort studies which revealed a much higher stroke risk for depressive patients. Furthermore, depression plays an important role in other neurological diseases with respect to the course and quality of life, such as Parkinson’s disease, multiple sclerosis and epilepsy. This article gives a review of the most important epidemiological, pathophysiological and therapeutic aspects of depressive disorders as a comorbidity of neurological diseases and as a risk factor for neurological diseases.Nervenarzt 2012;83:1423-33.
Heesen C, Köpke S, Kasper J, Poettgen J, Tallner A, Mohr DC, Gold SM.
Behavioral interventions in multiple sclerosis: a biopsychosocial perspective.
Expert Rev Neurother 2012;12:1089-100.
Heesen C, Köpke S, Kasper J, Poettgen J, Tallner A, Mohr DC, Gold SM.
Behavioral interventions in multiple sclerosis: a biopsychosocial perspective.
Managing uncertainty is a major challenge associated with the diagnosis of multiple sclerosis (MS). In addition to physical symptoms, neuropsychiatric symptoms are highly prevalent in this disease. Depression in particular is more common in MS than in other chronic diseases. While substantial achievements have been made in the therapy of MS and an increasing number of immunomodulatory treatments are now available, the long-term benefits of these are still a matter of debate. Importantly, while the approved therapies show good efficacy on inflammatory lesions and relapse rate, and may slow certain aspects of disease progression, improvements in function have rarely been reported. On the other hand, behavioral interventions have recently been shown to significantly improve fatigue and depression as well as motor function. In addition, recent evidence suggests that group education or face-to-face behavioral interventions may decrease inflammatory disease activity (such as relapse rate or lesion formation measured by MRI). Therefore, behavioral interventions not only ameliorate symptoms but may have the potential to modify the disease process itself.Expert Rev Neurother 2012;12:1089-100.
Heesen C, Gold SM.
Don’t stress about it! Is stress management a disease-modifying therapy for multiple sclerosis?
Neurology 2012;79:398-9.
Heesen C, Gold SM.
Don’t stress about it! Is stress management a disease-modifying therapy for multiple sclerosis?
Neurology 2012;79:398-9.
Willing A, Friese MA.
CD8-mediated inflammatory central nervous system disorders.
Curr. Opin. Neurol. 2012;25:316-21.
Willing A, Friese MA.
CD8-mediated inflammatory central nervous system disorders.
PURPOSE OF REVIEW: In central nervous system (CNS) autoimmune disorders, CD8+ T cells have been reported to exert cytotoxic as well as regulatory functions. In virus-induced (meningo) encephalitis, they are essential for viral clearance, but can also cause severe immunopathology. This review aims to summarize the multifaceted roles CD8+ T cells can play in inflammatory CNS disorders. RECENT FINDINGS: Recent evidence for a role of CD8+ T cells in multiple sclerosis comes from genetic association studies confirming a protective effect of the HLA-A0201 allele. Besides their dominance in white matter lesions, CD8+ T cells contribute to immune infiltrates in cortical demyelinating lesions. Having infiltrated the CNS, CD8+ T cells migrate along an inflammation-induced fibrous network. Although CD8+ T cells are generally considered to be crucial for acute viral clearance, they can also induce autoimmune-like immunopathology by, for example, encountering a virus in adulthood while being at the same time latently infected by a related virus. Inadequate control of latent viruses under immunosuppressive treatments or immunodeficiencies is becoming increasingly important in neurology clinical work. SUMMARY: Future research should aim at identifying the specificity and functional phenotype of brain-infiltrating CD8+ T cells in autoimmune diseases and viral immunopathology in order to develop therapeutic strategies specifically targeting CNS-relevant immune reactions.Curr. Opin. Neurol. 2012;25:316-21.
Voskuhl RR, Gold SM.
Sex-related factors in multiple sclerosis susceptibility and progression.
Nat Rev Neurol 2012;8:255-63.
Voskuhl RR, Gold SM.
Sex-related factors in multiple sclerosis susceptibility and progression.
The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences might provide important insight into mechanisms of pathogenesis and progression of the disease in patients. MS occurs more frequently in women than in men, indicating that sex-related factors have an effect on an individual’s susceptibility to developing the condition. These factors include hormonal, genetic and environmental influences, as well as gene-environment interactions and epigenetic mechanisms. Interestingly, women do not have a poorer prognosis than men with MS despite a higher incidence of the disease and more-robust immune responses, which suggests a mechanism of resilience. Furthermore, the state of pregnancy has a substantial effect on disease activity, characterized by a reduction in relapse rates during the third trimester but an increased relapse rate in the postpartum period. However, pregnancy has little effect on long-term disability in women with MS. The unravelling of the mechanisms underlying these clinical observations in the laboratory and application of the results to the clinical setting is a unique and potentially fruitful strategy to develop novel therapeutic approaches for MS.Nat Rev Neurol 2012;8:255-63.
Fischer A, Heesen C, Gold SM.
Biological outcome measurements for behavioral interventions in multiple sclerosis.
Ther Adv Neurol Disord 2011;4:217-29.
Fischer A, Heesen C, Gold SM.
Biological outcome measurements for behavioral interventions in multiple sclerosis.
Behavioral interventions including exercise, stress management, patient education, psychotherapy and multidisciplinary neurorehabilitation in general are receiving increasing recognition in multiple sclerosis (MS) clinical practice and research. Most scientific evaluations of these approaches have focused on psychosocial outcome measures such as quality of life, fatigue or depression. However, it is becoming increasingly clear that neuropsychiatric symptoms of MS are at least partially mediated by biological processes such as inflammation, neuroendocrine dysfunction or regional brain damage. Thus, successful treatment of these symptoms with behavioral approaches could potentially also affect the underlying biology. Rigidly designed scientific studies are needed to explore the potential of such interventions to affect MS pathology and biological pathways linked to psychological and neuropsychiatric symptoms of MS. Such studies need to carefully select outcome measures on the behavioral level that are likely to be influenced by the specific intervention strategy and should include biomarkers with evidence for an association with the outcome parameter in question. In this overview, we illustrate how biological and psychological outcome parameters can be combined to evaluate behavioral interventions. We focus on two areas of interest as potential targets for behavioral interventions: depression and fatigue.Ther Adv Neurol Disord 2011;4:217-29.
Friese MA, Magnus T.
[Autoimmune synaptic encephalopathies].
Nervenarzt 2011;82:1239-49.
Friese MA, Magnus T.
[Autoimmune synaptic encephalopathies].
Antibody-associated limbic encephalitis was usually seen as a paraneoplastic syndrome where the antibodies would target intracellular proteins. However, recent reports challenged this idea and described antibodies that target synaptic proteins expressed on the cell surface. These antibodies are not necessarily linked to tumors and should be regarded as a distinct entity of different autoimmune diseases. They are of direct clinical relevance since their binding to their target antigen is likely the cause of the clinical symptoms and, therefore, immune treatment often results in a beneficial outcome. Tests which differentiate these antibodies are now available in specialized laboratories.Nervenarzt 2011;82:1239-49.
Heesen C.
Treating multiple sclerosis with information.
Mult. Scler. 2010;16:1302.
Heesen C.
Treating multiple sclerosis with information.
Mult. Scler. 2010;16:1302.
Heesen C, Solari A, Giordano A, Kasper J, Köpke S.
Decisions on multiple sclerosis immunotherapy: new treatment complexities urge patient engagement.
J. Neurol. Sci. 2011;306:192-7.
Heesen C, Solari A, Giordano A, Kasper J, Köpke S.
Decisions on multiple sclerosis immunotherapy: new treatment complexities urge patient engagement.
For patients with multiple sclerosis (MS) involvement in treatment decisions becomes ever more imperative. Recently new therapeutic options have become available for the treatment of MS and more will be licensed in the near future. Although more efficacious and easier to administer, the new drugs pose increased risks of severe side effects. Also, new diagnostic criteria lead to more and earlier MS diagnoses. Facing increasingly complex decisions, patients need up-to-date evidence-based information and decision support systems in order to make informed decision together with physicians based on their autonomy preferences. This article summarizes recently terminated and ongoing trials on MS patient education and decision aids conducted by the authors‘ study groups. Programs on relapse management, immunotherapy, and for patients with suspected and early MS have been developed and evaluated in randomized controlled clinical trials. It could be shown that the programs successfully increase knowledge and allow patients to make informed decisions based on their preferences. For the near future, we aim to develop a modular program for all relevant decisions in MS to increase patients‘ self-management and empower patients to develop their individual approach with the disease. Faced by a disease with many uncertainties, this should enhance patients‘ sense of control. Still, it remains a challenge to adequately assess decision quality. Therefore, a study in six European and one Australian centers will start soon aiming to establish adequate tools to assess decision-making quality.J. Neurol. Sci. 2011;306:192-7.
Friese MA.
[Multiple sclerosis].
Dtsch. Med. Wochenschr. 2010;135:527-31.
Friese MA.
[Multiple sclerosis].
Dtsch. Med. Wochenschr. 2010;135:527-31.
Gold SM, Voskuhl RR.
Estrogen and testosterone therapies in multiple sclerosis.
Prog. Brain Res. 2009;175:239-51.
Gold SM, Voskuhl RR.
Estrogen and testosterone therapies in multiple sclerosis.
It has been known for decades that females are more susceptible than men to inflammatory autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis, and psoriasis. In addition, female patients with these diseases experience clinical improvements during pregnancy with a temporary „rebound“ exacerbation postpartum. These clinical observations indicate an effect of sex hormones on disease and suggest the potential use of the male hormone testosterone and the pregnancy hormone estriol, respectively, for the treatment of MS. A growing number of studies using the MS animal model experimental autoimmune encephalomyelitis (EAE) support a therapeutic effect of these hormones. Both testosterone and estriol have been found to induce anti-inflammatory as well as neuroprotective effects. Findings from two recent pilot studies of transdermal testosterone in male MS patients and oral estriol in female MS patients are encouraging. In this paper, we review the preclinical and clinical evidence for sex hormone treatments in MS and discuss potential mechanisms of action.Prog. Brain Res. 2009;175:239-51.
Gold SM, Voskuhl RR.
Estrogen treatment in multiple sclerosis.
J. Neurol. Sci. 2009;286:99-103.
Gold SM, Voskuhl RR.
Estrogen treatment in multiple sclerosis.
Currently available treatments for multiple sclerosis (MS) reduce inflammatory lesions on MRI and decrease clinical relapses but have limited effects on disability. Novel treatment options that target both the inflammatory as well as the neurodegenerative component of the disease are therefore needed. A growing body of evidence from basic science and clinical studies supports the therapeutic potential of estrogens in MS. Mechanisms of action include both immunomodulatory and directly neuroprotective pathways. A first pilot trial of oral estriol treatment showed encouraging results. There are now several phase II trials underway to further determine the efficacy of estrogen treatment in MS.J. Neurol. Sci. 2009;286:99-103.
Fugger L, Friese MA, Bell JI.
From genes to function: the next challenge to understanding multiple sclerosis.
Nat. Rev. Immunol. 2009;9:408-17.
Fugger L, Friese MA, Bell JI.
From genes to function: the next challenge to understanding multiple sclerosis.
Susceptibility to multiple sclerosis is jointly determined by genetic and environmental factors, and progress has been made in defining some of these genetic associations, as well as their possible interactions with the environment. However, definitive proof for the involvement of specific genetic determinants in the disease will only come from studies that examine their functional roles in disease pathogenesis. New and combined approaches are needed to analyse the complexity of gene regulation and the functional contribution of each genetic determinant to disease susceptibility or pathophysiology. These studies should proceed in parallel with the use of genetically defined human populations to explore how both genetic and environmental factors affect the function of the pathways in individuals with and without disease, and how these determine the inherited risk of multiple sclerosis.Nat. Rev. Immunol. 2009;9:408-17.
Friese MA, Fugger L.
T cells and microglia as drivers of multiple sclerosis pathology.
Brain 2007;130:2755-7.
Friese MA, Fugger L.
T cells and microglia as drivers of multiple sclerosis pathology.
Brain 2007;130:2755-7.
Gold SM, Heesen C.
Stress and disease progression in multiple sclerosis and its animal models.
Neuroimmunomodulation 2006;13:318-26.
Gold SM, Heesen C.
Stress and disease progression in multiple sclerosis and its animal models.
Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems–the hypothalamic-pituitary-adrenal axis and the autonomic nervous system–and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS.Neuroimmunomodulation 2006;13:318-26.
Heesen C, Gold SM, Huitinga I, Reul JM.
Stress and hypothalamic-pituitary-adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis – a review.
Psychoneuroendocrinology 2007;32:604-18.
Heesen C, Gold SM, Huitinga I, Reul JM.
Stress and hypothalamic-pituitary-adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis – a review.
Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS with an assumed autoimmune-mediated pathogenesis. Stressful life events have been hypothesized as potential triggers of disease exacerbation. Animal studies using experimental autoimmune encephalomyelitis (EAE), as a model for MS, suggest that decreased hypothalamic-pituitary-adrenal (HPA) function may play a role in the increased susceptibility and severity of the disease. Histopathological studies of the hypothalamus point to disturbances in corticotropin-releasing hormone (CRH) regulation as a result of MS lesions in this area. Functional endocrine tests (e.g., the combined Dexamethasone-CRH test) showed a disturbed negative feedback after steroid application in MS patients. Hyper- and hypoactivity of the HPA axis, have been described to be associated with more severe courses. This paper presents an overview of the evidence for a role of HPA dysfunction in EAE and MS based on stress-experimental studies.Psychoneuroendocrinology 2007;32:604-18.
Heesen C, Mohr DC, Huitinga I, Bergh FT, Gaab J, Otte C, Gold SM.
Stress regulation in multiple sclerosis: current issues and concepts.
Mult. Scler. 2007;13:143-8.
Heesen C, Mohr DC, Huitinga I, Bergh FT, Gaab J, Otte C, Gold SM.
Stress regulation in multiple sclerosis: current issues and concepts.
Since its first description by Charcot, psychological stress has been considered a triggering factor for exacerbations in multiple sclerosis, but until recently the clinical evidence for a causal relation was weak. Over the past years, a growing number of studies have started to elucidate this association and highlight potential mechanisms, including brain-immune communication. On 5 June 2005, a panel of international researchers discussed the current evidence. This article summarizes the observational, animal experimental, as well as human experimental findings on stress regulation in MS, as well as studies on the functioning of the major stress response systems, ie, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomous nervous system (ANS) in MS. Consensus statements from the group to these aspects are given. Research objectives and strategies are delineated, as well as clinical implications.Mult. Scler. 2007;13:143-8.
Heesen C, Kasper J, Köpke S, Richter T, Segal J, Mühlhauser I.
Informed shared decision making in multiple sclerosis–inevitable or impossible?
J. Neurol. Sci. 2007;259:109-17.
Heesen C, Kasper J, Köpke S, Richter T, Segal J, Mühlhauser I.
Informed shared decision making in multiple sclerosis–inevitable or impossible?
Patients and health authorities increasingly claim active roles in health care decision making processes. As immune therapies in MS are partially effective MS is a prototypic condition for a shared decision making process. The treatment of acute relapses and the initiation, change or withdrawal of so called disease-modifying treatments are key decisions in MS management. We developed two decision aids following the phased approach of the framework of increasing evidence for complex interventions for these key decisions. In prestudies we found that 80% of MS patients demand autonomous roles in treatment decisions which contrasts with a poor knowledge of risks. On the other hand MS patients are not disturbed by evidence-based, balanced complex information. MS patients do understand this kind of information and are able to transfer new abilities to other situations. Currently we study the effects of a 4-hour education programme on relapse management versus an information leaflet in controls in 150 MS patients. In a second trial with n=298 MS patients we study the effects of an evidence-based patient information on immunotherapy on decisional role preference and performance in the patient physician encounter. Results in early 2007 will show to which extent patient education with a focus on evidence-based patient information influences participation in the decision making process.J. Neurol. Sci. 2007;259:109-17.
Friese MA, Jensen LT, Willcox N, Fugger L.
Humanized mouse models for organ-specific autoimmune diseases.
Curr. Opin. Immunol. 2006;18:704-9.
Friese MA, Jensen LT, Willcox N, Fugger L.
Humanized mouse models for organ-specific autoimmune diseases.
Murine models for human autoimmune diseases are an essential tool for studying pathogenesis and for identifying new therapeutic targets. Mice are not the natural disease host, and conventional models have proved to be poor predictors of efficacy and safety in recent trials aiming to translate drug and biologic treatments to humans. Evidently, further steps towards recapitulating human diseases are urgently needed, for example using transgenic predisposing human HLA allele(s) plus T-cell receptor(s) implicated in a representative patient’s autoimmune disease. The latest development – humanizing most of the immune system by transplanting human hematopoietic stem cells into severely immunodeficient mice – should lead to even better modeling.Curr. Opin. Immunol. 2006;18:704-9.
Gold SM, Irwin MR.
Depression and immunity: inflammation and depressive symptoms in multiple sclerosis.
Neurol Clin 2006;24:507-19.
Gold SM, Irwin MR.
Depression and immunity: inflammation and depressive symptoms in multiple sclerosis.
There is strong evidence that depression involves alterations in multiple aspects of immunity that may contribute to the development or exacerbation of a number of medical disorders and also may play a role in the pathophysiology of depressive symptoms. Accordingly, aggressive management of depressive disorders in medically ill populations or individuals at risk for disease may improve disease outcome or prevent disease development. On the other hand, in light of data suggesting that immune processes may interact with the pathophysiologic pathways known to contribute to depression, novel approaches to the treatment of depression may target relevant aspects of the immune response. Taken together, the data provide compelling evidence that a psychoimmunologic frame of reference may have profound implications regarding the consequences and treatment of depression. In addition, this approach may be used to investigate the possibility that peripheral and central production of cytokines may account for neuropsychiatric symptoms in inflammatory diseases. This article summarizes evidence for a cytokine-mediated pathogenesis of depression and fatigue in MS. The effects of central inflammatory processes may account for some of the behavioral symptoms seen in patients who have MS that cannot be explained by psychosocial factors or CNS damage. This immune-mediated hypothesis is supported by indirect evidence from experimental and clinical studies of the effect of cytokines on behavior, which have found that both peripheral and central cytokines may cause depressive symptoms. Emerging clinical data from patients who have MS support an association of central inflammation (as measured by MRI) and inflammatory markers with depressive symptoms and fatigue. Based on the literature reviewed in this article, subtypes of MS fatigue and depression may exist that are caused by different pathogenetic mechanisms, including inflammation and CNS damage as well as psychosocial factors or predisposition. The existence of these subtypes could have important clinical implications. For example, an inflammatory depression may require different therapeutic approaches than a reactive depression in MS. Future research should aim to characterize these subtypes better with the goal of optimizing treatment.Neurol Clin 2006;24:507-19.
Gold SM, Voskuhl RR.
Testosterone replacement therapy for the treatment of neurological and neuropsychiatric disorders.
Curr Opin Investig Drugs 2006;7:625-30.
Gold SM, Voskuhl RR.
Testosterone replacement therapy for the treatment of neurological and neuropsychiatric disorders.
There is an accumulating body of evidence in the literature suggesting that testosterone may be neuroprotective and therefore have therapeutic value in the treatment of neurodegenerative diseases. In this article, the potential mechanisms of action of testosterone on the central nervous system are discussed, as well as the current evidence supporting the effect of testosterone on neurological impairment. Lower endogenous testosterone levels appear to be associated with some neurological disabilities. Conversely, a therapeutic benefit of exogenous testosterone supplementation on some cognitive abilities has been shown in pilot trials involving healthy elderly men as well as patients with multiple sclerosis and Alzheimer’s disease. Further study of the therapeutic potential of testosterone is warranted in neurological and neuropsychiatric diseases.Curr Opin Investig Drugs 2006;7:625-30.
Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L.
The value of animal models for drug development in multiple sclerosis.
Brain 2006;129:1940-52.
Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L.
The value of animal models for drug development in multiple sclerosis.
The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.Brain 2006;129:1940-52.
Heesen C, Romberg A, Gold S, Schulz KH.
Physical exercise in multiple sclerosis: supportive care or a putative disease-modifying treatment.
Expert Rev Neurother 2006;6:347-55.
Heesen C, Romberg A, Gold S, Schulz KH.
Physical exercise in multiple sclerosis: supportive care or a putative disease-modifying treatment.
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease affecting young adults and leading to considerable disability. For many years, patients have been advised to avoid physical activity. Today, however, an increasing number of studies have shown beneficial effects of exercise training in MS. It has been reported that such programs not only improve fitness parameters but can also enhance quality of life and beneficially affect some suggestive disability measures. Pilot studies even indicate a neuroprotective potential. This review summarizes the findings of the major clinical trials on exercise in MS. Possible biological effect mediators, such as neurotrophic factors or anti-inflammatory cytokines, will be discussed. Exercise management guidelines will be proposed and possible further research strategies are presented.Expert Rev Neurother 2006;6:347-55.
Schulz KH, Heesen C, Gold SM.
The concept of allostasis and allostatic load: psychoneuroimmunological findings.
Psychother Psychosom Med Psychol 2005;55:452-61.
Schulz KH, Heesen C, Gold SM.
The concept of allostasis and allostatic load: psychoneuroimmunological findings.
Classical theories have conceptualized stress as a reaction to threat to the homeostasis within the organism requiring an adaptive response. However, postulating mechanisms that could link such responses to long-term detrimental health outcomes remains difficult. The allostatic load concept enables us to think about how mediators can be protective in the short run but may have damaging effects when overused and/or not shut off. It further facilitates the formulation of cause-effects cascades to explain the link of dysregulations in stress mediators such as glucocorticoids and catecholamines and increased susceptibility for certain diseases. In the first section, we briefly summarize the theoretical background. We then employ the concept to integrate findings from basic and clinical research on dysregulations of the stress response systems in multiple sclerosis and breast cancer. Based on this model, it seems likely that such dysregulations are implicated in progression and possibly pathogenesis of these diseases. When using allostatic load as a heuristic model, one needs to consider that stress mediators and outcomes are interconnected in a non-linear network.Psychother Psychosom Med Psychol 2005;55:452-61.
Gold SM, Mohr DC, Huitinga I, Flachenecker P, Sternberg EM, Heesen C.
The role of stress-response systems for the pathogenesis and progression of MS.
Trends Immunol. 2005;26:644-52.
Gold SM, Mohr DC, Huitinga I, Flachenecker P, Sternberg EM, Heesen C.
The role of stress-response systems for the pathogenesis and progression of MS.
Disease progression in multiple sclerosis (MS)–an inflammatory demyelinating and neurodegenerative disease with a presumed T-cell driven autoimmune origin–has long been hypothesized to be associated with stress. However, this notion has only recently been supported by prospective clinical studies. Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the immune system and the two major stress response systems, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous system. Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability. Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of stress response systems in MS pathogenesis and progression.Trends Immunol. 2005;26:644-52.
Friese MA, Jones EY, Fugger L.
MHC II molecules in inflammatory diseases: interplay of qualities and quantities.
Trends Immunol. 2005;26:559-61.
Friese MA, Jones EY, Fugger L.
MHC II molecules in inflammatory diseases: interplay of qualities and quantities.
It is generally accepted that MHC II molecules confer susceptibility to inflammatory diseases because of the different abilities they possess for binding and presenting peptides to T cells. A new study suggests that the level of MHC II gene expression is also a risk factor for such diseases. It shows that a polymorphism in the promoter of the MHC II transactivator (MHC2TA) gene (which encodes CIITA), leads to reduced MHC2TA expression, and hence reduced production of MHC II molecules. This predisposes to rheumatoid arthritis, multiple sclerosis and myocardial infarction.Trends Immunol. 2005;26:559-61.
Steckelberg A, Berger B, Köpke S, Heesen C, Mühlhauser I.
[Criteria for evidence-based patient information].
Z Arztl Fortbild Qualitatssich 2005;99:343-51.
Steckelberg A, Berger B, Köpke S, Heesen C, Mühlhauser I.
[Criteria for evidence-based patient information].
Evidence-based patient information (EBPI) is a prerequisite for informed patient choice. However, there is as yet no discussion as to what can be expected of EBPI. The present paper provides an overview of the criteria presently used or discussed for the development of EBPI. Ethics guidelines demand that EBPI are offered and made available to all patients. The presentation of information should be clear and consider risk communication as a source of framing of data. Patients should be involved in the process of development and evaluation.Z Arztl Fortbild Qualitatssich 2005;99:343-51.
Schulz KH, Heesen C.
[Effects of exercise in chronically ill patients. Examples from oncology and neurology].
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2005;48:906-13.
Schulz KH, Heesen C.
[Effects of exercise in chronically ill patients. Examples from oncology and neurology].
Epidemiologic studies increasingly have demonstrated a correlation between physical inactivity and certain chronic diseases. Already in the 1970s exercise programs for cardiovascular patients were established, whereas in other severe chronic illnesses such as breast cancer or multiple sclerosis exposure to physical stress seemed to be a contraindication. Today there is a grow ing body of evidence demonstrating positive physical as well as psychic effects of exercise training in patients with these diseases. These studies are summarized and complementary studies of our group are described in more detail. In patients with breast cancer we were able to demonstrate persistent psychosocial effects even 1 year after completion of the training program. In patients with multiple sclerosis we could confirm an induction of neurotrophic factors in trained individuals. Correspondingly, there is accumulating evidence showing positive effects of exercise on cognitive function, especially in the aged. Potential pathophysiological pathways regarding a progression to dementia are presented. Consequently exercise programs could play a pivotal role in the prevention and therapy of the cognitive decline in the aged in an aging society.Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2005;48:906-13.
Köpke S, Heesen C.
Corticosteroids treatment of multiple sclerosis.
J. Neurol. Sci. 2005;234:117-8; author reply 119-20.
Köpke S, Heesen C.
Corticosteroids treatment of multiple sclerosis.
J. Neurol. Sci. 2005;234:117-8; author reply 119-20.
Holmes S, Friese MA, Siebold C, Jones EY, Bell J, Fugger L.
Multiple sclerosis: MHC associations and therapeutic implications.
Expert Rev Mol Med 2005;7:1-17.
Holmes S, Friese MA, Siebold C, Jones EY, Bell J, Fugger L.
Multiple sclerosis: MHC associations and therapeutic implications.
Multiple sclerosis (MS) is an autoimmune disease with an important genetic component. The strongest genetic association is with the major histocompatibility complex (MHC) region. Several MHC alleles predispose to the disease, the most prominent of which are certain alleles in the HLA-DR2 haplotype. Functional and structural studies have helped to explain the molecular basis of these associations. Although there is currently no curative treatment for MS, an increased understanding of the disease has aided the design of immunotherapies that act on the immune system more specifically than the longstanding drugs. Many of these therapies work at the antigen-specific level, disrupting the interaction between T-cell receptors and MHC molecules that leads to disease.Expert Rev Mol Med 2005;7:1-17.
Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Götschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freimüller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Brück W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, Jügelt E, et. al.
Escalating immunotherapy of multiple sclerosis–new aspects and practical application.
J. Neurol. 2004;251:1329-39.
Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Götschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freimüller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Brück W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, Jügelt E, et. al.
Escalating immunotherapy of multiple sclerosis–new aspects and practical application.
Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.J. Neurol. 2004;251:1329-39.
Friese MA, Steinle A, Weller M.
The innate immune response in the central nervous system and its role in glioma immune surveillance.
Onkologie 2004;27:487-91.
Friese MA, Steinle A, Weller M.
The innate immune response in the central nervous system and its role in glioma immune surveillance.
The innate immune system encompasses natural killer (NK) cells, macrophages and granulocytes, the complement system and antimicrobial peptides. Recognition pathways of the innate immune system include microbial non-self recognition, missing-self recognition and induced- self recognition. The central nervous system (CNS) participates in responses of the innate immune system. However, immune inhibitory and anti-inflammatory mechanisms physiologically outbalance and counteract immune activity and thereby limit immune-mediated tissue damage in the brain. Human gliomas appear to take advantage of this immunosuppressive milieu. Moreover, glioma cells themselves interfere with anti-tumor immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta. Yet, although glioma cells exhibit all cellular features of malignancy, these tumors very rarely metastasize outside the brain, raising the possibility of immune-mediated control of these cells outside, but not inside, the brain. Accordingly, activating the innate immune system by forcing glioma cells to express danger signals such as NKG2D ligands is a promising strategy of immunotherapy for these tumors.Onkologie 2004;27:487-91.
Köpke S, Heesen C, Kasper J, Mühlhauser I.
Steroid treatment for relapses in multiple sclerosis – the evidence urges shared decision-making.
Acta Neurol. Scand. 2004;110:1-5.
Köpke S, Heesen C, Kasper J, Mühlhauser I.
Steroid treatment for relapses in multiple sclerosis – the evidence urges shared decision-making.
OBJECTIVES: Therapy of acute relapses in multiple sclerosis with corticosteroids (CC) remains uncertain with respect to route, dosage and effectiveness. This makes the treatment of relapses a clinical field where ’shared decision-making (SDM)‘ could be of advantage for the patients. A prerequisite for SDM is the provision of evidence-based information for the patients. The British General Medical Council (GMC) has published ethical guidelines on seeking patients‘ consent for medical interventions, formulating topics of information patients need in order to make an informed treatment decision. METHODS: Medical databases were searched for evidence on the treatment of acute relapses with CC. RESULTS: The available evidence on relapse treatment is ambiguous and weak. It does not provide enough evidence to sufficiently inform patients following the topics formulated by the GMC. CONCLUSION: Good evidence is lacking, supporting the concept of SDM in the therapy of relapses.Acta Neurol. Scand. 2004;110:1-5.
Zipfel PF, Hellwage J, Friese MA, Hegasy G, Jokiranta ST, Meri S.
Factor H and disease: a complement regulator affects vital body functions.
Mol. Immunol. 1999;36:241-8.
Zipfel PF, Hellwage J, Friese MA, Hegasy G, Jokiranta ST, Meri S.
Factor H and disease: a complement regulator affects vital body functions.
Factor H is a multidomain and multifunctional protein. As a complement regulator factor H determines the fate of newly formed C3b and controls formation and stability of C3 convertases both in the fluid phase and on cell surfaces. In addition, this plasma protein displays functions outside complement control as it has been suggested to act as an adhesion protein, to be a ligand for the cellular integrin receptor CR3 (CD11b/CD18) and to display chemotactic activity. Genetic and pathophysiological analyses describe a role for factor H in vital body functions. Depletion or the absence of factor H due to genetic reasons leads to unrestricted C3 consumption. A reduced amount of factor H in plasma or mutations within the factor H gene may lead to glomerulonephritis (type II MPGN) or hemolytic uremic syndrome (HUS). Certain pathogenic organisms have been shown to evade complement attack by binding factor H from the host. Such specific factor H binding components have been demonstrated on the surface of microbes, e.g., Streptococcus pyogenes and Neisseria gonorrhoeae. Here, we summarize the current knowledge how abnormalities in function of the central complement regulator factor H are associated with human diseases.Mol. Immunol. 1999;36:241-8.
Institute of Neuroimmunology
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Bärbel Reimers
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