Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism.

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.

Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

"Not me!" a qualitative, vignette-based study of nurses' and physicians' reactions to spiritual distress on neuro-oncological units.

PURPOSE: People with primary malignant brain tumors experience serious health-related suffering caused by limited prognosis and high symptom burden. Consequently, neuro-oncological healthcare workers can be affected emotionally in a negative way. The aim of this study was to analyze the attitudes and behavior of nurses and physicians when confronted with spiritual distress in these patients. METHODS: Neurospirit-DE is a qualitative vignette-based, multicenter, cross-sectional online survey that was conducted in Bavaria, Germany. Reflexive thematic analysis was used for data analysis. RESULTS: A total of 143 nurses and physicians working in neurological and neurosurgical wards in 46 hospitals participated in the survey. The participants questioned if the ability to provide spiritual care can be learned or is a natural skill. Spiritual care as a responsibility of the whole team was highlighted, and the staff reflected on the appropriate way of involving spiritual care experts. The main limitations to spiritual care were a lack of time and not viewing spiritual engagement as part of the professional role. Some were able to personally benefit from spiritual conversations with patients, but many participants criticized the perceived emotional burden while expressing the imminent need for specific training and team reflection. CONCLUSIONS: Most neuro-oncological nurses and physicians perceive spiritual care as part of their duty and know how to alleviate the patient's spiritual distress. Nonetheless, validation of spiritual assessment tools for neuro-oncology and standardized documentation of patients' distress, shared interprofessional training, and reflection on the professional and personal challenges faced when confronted with spiritual care in neuro-oncology require further improvement and training.

Skin sodium is increased in male patients with multiple sclerosis and related animal models.

Novel MRI techniques allow a noninvasive quantification of tissue sodium and reveal the skin as a prominent compartment of sodium storage in health and disease. Since multiple sclerosis (MS) immunopathology is initiated in the periphery and increased sodium concentrations induce proinflammatory immune cells, the skin represents a promising compartment linking high sodium concentrations and MS immunopathology. We used a 7-T sodium MRI (23Na-MRI) and inductively coupled plasma mass spectrometry to investigate the skin sodium content in two mouse models of MS. We additionally performed 3-T 23Na-MRI of calf skin and muscles in 29 male relapsing-remitting MS (RRMS) patients and 29 matched healthy controls. Demographic and clinical information was collected from interviews, and disease activity was assessed by expanded disability status scale scoring. 23Na-MRI and chemical analysis demonstrated a significantly increased sodium content in the skin during experimental autoimmune encephalomyelitis independent of active immunization. In male patients with RRMS, 23Na-MRI demonstrated a higher sodium signal in the area of the skin compared to age- and biological sex-matched healthy controls with higher sodium, predicting future disease activity in cranial MRI. In both studies, the sodium enrichment was specific to the skin, as we found no alterations of sodium signals in the muscle or other tissues. Our data add to the recently identified importance of the skin as a storage compartment of sodium and may further represent an important organ for future investigations on salt as a proinflammatory agent driving autoimmune neuroinflammation such as that in MS.

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 (nNationMS = 946, nBIONAT = 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-ß-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.

Outcome of glioblastoma patients after intensive care unit admission with invasive mechanical ventilation: a multicenter analysis.

PURPOSE: Patients with glioblastoma are exposed to severe symptoms and organs failures (e.g., coma or acute respiratory failure), that may require intensive care unit (ICU) admission and invasive mechanical ventilation (IMV). However, only limited data are available concerning the prognosis of patients with glioblastoma receiving IMV. We sought to describe the reasons for ICU admission, and outcomes of patients with glioblastoma requiring IMV for unplanned critical complications. METHODS: In this retrospective analysis, four certified interdisciplinary brain tumor centers performed a retrospective review of their electronic data systems. All patients with glioblastoma admitted to an in-house ICU and receiving IMV between January 2015 and December 2019 were included. Clinical and prognostic factors as well as relevant outcome parameters were evaluated by group comparisons and Kaplan Meier survival curves. RESULTS: We identified 33 glioblastoma patients with a duration of IMV of 9.2 ± 9.4 days. Main reasons for ICU admission were infection (n = 12; 34.3%) including 3 cases of Pneumocystis jirovecii pneumonia, status epilepticus (31.4%) and elevated intracranial pressure (22.9%). In-hospital mortality reached 60.6%. Younger age, low number of IMV days, better Karnofsky Performance Status Scale before admission and elevated intracranial pressure as cause of ICU admission were associated with positive prognostic outcome. CONCLUSION: We conclude that less than 50% of patients with glioblastoma have a favorable short-term outcome when unplanned ICU treatment with IMV is required. Our data mandate a careful therapy guidance and frequent reassessment of goals during ICU stay.

Early spinal cord pseudoatrophy in interferon-beta-treated multiple sclerosis.

BACKGROUND AND PURPOSE: Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain. METHODS: A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n = 84) and untreated patients (n = 45). RESULTS: Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year. CONCLUSIONS: These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment.

Salt-responsive gut commensal modulates TH17 axis and disease.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Oligodendrocytes regulate the adhesion molecule ICAM-1 in neuroinflammation.

Recently, oligodendrocytes (Ol) have been attributed potential immunomodulatory effects. Yet, the exact mode of interaction with pathogenic CNS infiltrating lymphocytes remains unclear. Here, we attempt to dissect mechanisms of Ol modulation during neuroinflammation and characterize the interaction of Ol with pathogenic T cells. RNA expression analysis revealed an upregulation of immune-modulatory genes and adhesion molecules (AMs), ICAM-1 and VCAM-1, in Ol when isolated from mice undergoing experimental autoimmune encephalomyelitis (EAE). To explore whether AMs are involved in the interaction of Ol with infiltrating T cells, we performed co-culture studies on mature Ol and Th1 cells. Live cell imaging analysis showed direct interaction between both cell types. Eighty percentage of Th1 cells created contacts with Ol that lasted longer than 15 min, which may be regarded as physiologically relevant. Exposure of Ol to Th1 cells or their supernatant resulted in a significant extension of Ol processes, and upregulation of AMs as well as other immunomodulatory genes. Our observations indicate that blocking of oligodendroglial ICAM-1 can reduce the number of Th1 cells initially contacting the Ol. These results suggest that AMs may play a role in the interaction between Ol and Th1 cells. We identified Ol interacting with CD4+ cells in vivo in spinal cord tissue of EAE diseased mice indicating that our in vitro findings are of interest to further scientific research in this field. Further characterization and understanding of Ol interaction with infiltrating cells may lead to new therapeutic strategies enhancing Ol protection and remyelination potential. Oligodendrocytes regulate immune modulatory genes and adhesion molecules during autoimmune neuroinflammation Oligodendrocytes interact with Th1 cells in vitro in a physiologically relevant manner Adhesion molecules may be involved in Ol-Th1 cell interaction.

Early remission in multiple sclerosis is linked to altered coherence of the Cerebellar Network.

BACKGROUND: The development of permanent disability in multiple sclerosis (MS) is highly variable among patients, and the exact mechanisms that contribute to this disability remain unknown. METHODS: Following the idea that the brain has intrinsic network organization, we investigated changes of functional networks in MS patients to identify possible links between network reorganization and remission from clinical episodes in MS. Eighteen relapsing-remitting MS patients (RRMS) in their first clinical manifestation underwent resting-state functional MRI and again during remission. We used ten template networks, identified from independent component analysis, to compare changes in network coherence for each patient compared to those of 44 healthy controls from the Human Connectome Project test-retest dataset (two-sample t-test of pre-post differences). Combining a binomial test with Monte Carlo procedures, we tested four models of how functional coherence might change between the first clinical episode and remission: a network can change its coherence (a) with itself ("one-with-self"), (b) with another network ("one-with-other"), or (c) with a set of other networks ("one-with-many"), or (d) multiple networks can change their coherence with respect to one common network ("many-with-one"). RESULTS: We found evidence supporting two of these hypotheses: coherence decreased between the Executive Control Network and several other networks ("one-with-many" hypothesis), and a set of networks altered their coherence with the Cerebellar Network ("many-with-one" hypothesis). CONCLUSION: Given the unexpected commonality of the Cerebellar Network's altered coherence with other networks (a finding present in more than 70% of the patients, despite their clinical heterogeneity), we conclude that remission in MS may result from learning processes mediated by the Cerebellar Network.

Longitudinal Sodium MRI of Multiple Sclerosis Lesions: Is there Added Value of Sodium Inversion Recovery MRI.

BACKGROUND: Sodium enhancement has been demonstrated in multiple sclerosis (MS) lesions. PURPOSE: To investigate sodium MRI with and without an inversion recovery pulse in acute MS lesions in an MS relapse and during recovery. STUDY TYPE: Prospective. SUBJECTS: Twenty-nine relapsing-remitting MS patients with an acute relapse were included. FIELD STRENGTH/SEQUENCE: A 3D density-adapted radial sodium sequence at 3 T using a dual-tuned (23 Na/1 H) head coil. ASSESSMENT: Full-brain images of the tissue sodium concentration (TSC1, n = 29) and a sodium inversion recovery sequence (SIR1, n = 20) at the beginning of the anti-inflammatory therapy and on medium-term follow-up visits (days 27-99, n = 12 [TSC], n = 5 [SIR]) were measured. Regions of interest (RoIs) with contrast enhancement (T1 CE+) and without change in T1-weighted imaging (FL + T1n) were normalized (nTSC and nSIR). To gain insight on the origin of the TSC enhancement at time point 1, it is investigated whether the nTSC enhancement of the lesions is accompanied by a change of the respective nSIR. Potential prognostic value of nSIR1 is examined referring to the nTSC progression. STATISTICAL TESTS: nTSC and nSIR were compared regarding the type of lesion and the time point using a one-way ANOVA. Pearson's correlation coefficient was calculated for nTSC over nSIR and for nTSC1-nTSC2 over nSIR1. A P-value <0.05 was considered statistically significant. RESULTS: At the first measurement, all lesion types showed increased nTSC, while nSIR was decreased in the FL + T1 n and the T1 CE+ lesions in comparison to the normal-appearing white matter. For acute lesions, the difference between nTSC at baseline and nTSC at time point 2 showed a significant correlation with the baseline nSIR. DATA CONCLUSION: At time point 1, nTSC is increased, while nSIR is unchanged or decreased in the lesions. The mean sodium IR signal at baseline correlates with recovery or progression of an acute lesion. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 4.

Association Between Use of a Flying Intervention Team vs Patient Interhospital Transfer and Time to Endovascular Thrombectomy Among Patients With Acute Ischemic Stroke in Nonurban Germany.

Importance: The benefit of endovascular thrombectomy (EVT) for acute ischemic stroke is highly time-dependent, and it is challenging to expedite treatment for patients in remote areas. Objective: To determine whether deployment of a flying intervention team, compared with patient interhospital transfer, is associated with a shorter time to endovascular thrombectomy and improved clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This was a nonrandomized controlled intervention study comparing 2 systems of care in alternating weeks. The study was conducted in a nonurban region in Germany including 13 primary telemedicine-assisted stroke centers within a telestroke network. A total of 157 patients with acute ischemic stroke for whom decision to pursue thrombectomy had been made and deployment of flying intervention team or patient interhospital transfer was initiated were enrolled between February 1, 2018, and October 24, 2019. The date of final follow-up was January 31, 2020. Exposures: Deployment of a flying intervention team for EVT in a primary stroke center vs patient interhospital transfer for EVT to a referral center. Main Outcomes and Measures: The primary outcome was time delay from decision to pursue thrombectomy to start of the procedure in minutes. Secondary outcomes included functional outcome after 3 months, determined by the distribution of the modified Rankin Scale score (a disability score ranging from 0 [no deficit] to 6 [death]). Results: Among the 157 patients included (median [IQR] age, 75 [66-80] y; 80 [51%] women), 72 received flying team care and 85 were transferred. EVT was performed in 60 patients (83%) in the flying team group vs 57 (67%) in the transfer group. Median (IQR) time from decision to pursue EVT to start of the procedure was 58 (51-71) minutes in the flying team group and 148 (124-177) minutes in the transfer group (difference, 90 minutes [95% CI, 75-103]; P < .001). There was no significant difference in modified Rankin Scale score after 3 months between patients in the flying team (n = 59) and transfer (n = 57) groups who received EVT (median [IQR] score, 3 [2-6] vs 3 [2-5]; adjusted common odds ratio for less disability, 1.91 [95% CI, 0.96-3.88]; P = .07). Conclusions and Relevance: In a nonurban stroke network in Germany, deployment of a flying intervention team to local stroke centers, compared with patient interhospital transfer to referral centers, was significantly associated with shorter time to EVT for patients with acute ischemic stroke. The findings may support consideration of a flying intervention team for some stroke systems of care, although further research is needed to confirm long-term clinical outcomes and to understand applicability to other geographic settings.

The role of the gut microbiota and microbial metabolites in neuroinflammation.

Recent literature indicates a potential importance of the gut microbiota for immune-mediated diseases. For instance, decreased diversity of commensals or an outgrowth of some bacterial strains, referred to as gut dysbiosis, was recently linked to hypertension, colitis, lupus, rheumatoid arthritis, and multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) as pivotal animal model of MS revealed a potential importance of microbial metabolites, including short-chain fatty acids or tryptophan metabolites. Both metabolites may influence the disease by modulation of the immune system, mainly by inducing Treg. These studies prompted researchers to investigate the contribution of the gut microbiota and microbial metabolites in the pathogenesis of MS. This review summarizes recent findings on the gut microbiota in MS patients and discusses the potential mechanisms how microbial metabolites may affect neuroinflammation. Many of these studies have been performed in the EAE model and were later reversely translated to humans. We also give a short summary on dietary high-salt effects on microbiota components and discuss the potential relevance of high-salt as a risk factor in MS.

Decline and Recurrence of Stroke Consultations during the COVID-19 Pandemic Lockdown Parallels Population Activity Levels.

BACKGROUND: The COVID-19 pandemic lockdown (CPL) lead to a significant decrease in emergency admissions worldwide. We performed a timely analysis of ischemic stroke (IS) and related consultations using the telestroke TEMPiS "working diagnosis" database prior (PL), within (WL), and after easing (EL) of CPL. METHODS: Twelve hospitals were selected and data analyzed regarding IS (including intravenous thrombolysis [intravenous recombinant tissue plasminogen; IV rtPA] and endovascular thrombectomy [EVT]) and related events from February 1 to June 15 during 2017-2020. In addition, we aimed to correlate events to various mobile phone mobility data. RESULTS: Following the significant reduction of IS, IV rtPA, and EVT cases during WL compared to PL in 2020 longitudinally (p values <0.048), we observed increasing numbers of consultations, IS, recommendations for EVT, and IV rtPA with the network in EL over WL not reaching PL levels yet. Absolute numbers of all consultations paralleled best to mobility data of public transportation over walking and driving mobility. CONCLUSIONS: While the decrease in emergency admissions including stroke during CPL can only be in part attributed by patients not seeking medical attention, stroke awareness in the pandemic, and direct COVID-19 triggered stroke remains of high importance. The number of consultations in TEMPiS during the lockdown parallels best with mobility of public transportation. As a consequence, exposure to common viruses, well-known triggers for acute cerebrovascular events and other diseases, are reduced and may add to the decline in stroke consultations. Further studies comparing national responses toward the course of the COVID-19 pandemic and stroke incidences are needed.

Cardiovascular fingolimod effects on rapid baroreceptor unloading are counterbalanced by baroreflex resetting.

BACKGROUND AND PURPOSE: Initial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation. PATIENTS AND METHODS: Twenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p < 0.05). RESULTS: RRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation. CONCLUSIONS: VR-decreases 3-6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.

[Immunotherapy and personalized treatment of multiple sclerosis]. / Immuntherapie und personalisierte Behandlung bei Multipler Sklerose.

Personalized medicine requires a patient-oriented approach with the exact classification of the disease being determined by the underlying pathophysiological processes. In particular, the optimal treatment of multiple sclerosis (MS) requires personalized treatment that goes beyond the pure concept of precision medicine; however, due to the lack of robust biomarkers beyond cranial magnetic resonance imaging and a lacking detailed understanding of some aspects of MS pathogenesis, this approach is not yet fully implemented. Important questions for a better therapeutic stratification of MS patients are: (1) when does MS start? (2) Does the spectrum of MS really span multiple diseases? (3) When does the progressive phase of the disease begin? (4) In which phase of the disease is there a therapeutic window for immunotherapy? Recent findings indicate that MS represents a spectrum of diseases and that there is a therapeutic delay of several years, on which the optimal treatment effect of a disease-modifying treatment depends. For a personalized treatment of MS it is important to determine the exact disease stage of the patient and to react to the development or increase of focal inflammatory activity in a timely manner.

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)]. / Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper).

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).

Voxel-wise lesion mapping of self-reported urinary incontinence in multiple sclerosis.

AIMS: Besides spinal lesions, urinary incontinence may be attributed to particular cerebral lesion sites in multiple sclerosis (MS) patients. We intended to determine the contribution of suprapontine lesions to urinary incontinence in MS using a voxel-wise lesion analysis. METHODS: In this retrospective study, we sought MS patients with documented urinary incontinence in a local database. We established a control group of MS-patients without documented urinary incontinence matched for gender, age, and disease severity. Patients with urinary incontinence due to local diseases of the urinary tract were excluded. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3T). After manual delineation and transformation into stereotaxic space, we determined the lesion overlap and compared the presence or absence of urinary incontinence voxel-wise between patients with and without lesions in a given voxel performing the Liebermeister test with 4000 permutations. RESULTS: A total of 56 patients with urinary incontinence and MS fulfilled the criteria and were included. The analysis yielded associations between urinary incontinence and MS in the frontal white matter, temporo-occipital, and parahippocampal regions. CONCLUSIONS: Our voxel-wise analysis indicated associations between self-reported urinary incontinence and lesions in the left frontal white matter and right parahippocampal region. Thus, our data suggest that dysfunction of supraspinal bladder control due to cerebral lesions may contribute to the pathophysiology of urinary incontinence in MS.

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis.

Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2+APC+ oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.