Search

Abstract Background/Objective Observational real‐world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease‐modifying therapy (DMT) usage in multiple sclerosis (MS). Methods Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6‐month confirmed progression independent of relapse activity (PIRA; ≥ 0.5‐point Expanded Disability Status Scale (EDSS) score increase), 6‐month confirmed disability improvement (CDI; ≥ 0.5‐point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re‐baselined at 30 days from ALEM start (BL EDSS). Results Eighty‐seven ALEM‐treated patients (median age: 32 years, 72% female, 14% treatment‐naïve) were followed for a median of 55 (interquartile range 31–68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1–9 (p

Abstract Lumbar puncture (LP) is recommended in patients with thunderclap headache and negative computed tomography to rule out spontaneous subarachnoid haemorrhage (SAH). Blood contamination of cerebrospinal fluid (CSF) due to traumatic LP poses a diagnostic dilemma. Therefore, routine CSF parameters were investigated to distinguish between SAH and a traumatic LP. CSF red blood cell (RBC), white blood cell (WBC) count, total protein, CSF colour and supernatant were used for group comparisons of patients with SAH and ‘symptomatic controls’. Due to variable time intervals between bleeding onset and LP in SAH patients in contrast to patients with traumatic LP, where blood contamination of CSF occurs at the time of LP, CSF variables were adjusted for decay in time to allow comparability. Logistic regression analysis identified bloody CSF [odds ratio (OR) 32.6], xanthochromic supernatant [OR 15.5] and WBCadjusted [OR 4.5 (per increase of 100/µl)] as predictors of SAH, while age, sex and CSF total proteinadjusted were no predictors. Optimal cut-point of RBCadjusted (determined at day 1 after bleeding) was > 3667/µl to identify SAH patients with a 97% sensitivity and 94% specificity. Combination of low RBC and clear CSF supernatant was found in none of SAH patients. Combined CSF RBC count and CSF supernatant reliably distinguished traumatic LP from SAH.

Anti-CD20 therapies decrease the humoral response to SARS-CoV-2 immunization. We aimed to determine the extent of the humoral response to SARS-CoV-2 antigens in correlation with peripheral B-cell dynamics among patients with central nervous system inflammatory disorders treated with anti-CD20 medications. We retrospectively included patients receiving anti-CD20 therapy after antigen contact who were divided into responders (>7 binding antibody units (BAU)/mL) and non-responders (n = 34, non-responders n = 37, recall cohort n = 9). The B-cell counts among responders were significantly higher compared to non-responders (mean 1012 cells/µL ± SD 105 vs. mean 17 cells/µL ± SD 47; p < 0.001). Despite very low B-cell counts (mean 9 cells/µL ± SD 20), humoral response was preserved among the recall cohort (mean 1653 BAU/mL ± SD 2250.1) and did not differ significantly from responders (mean 735 BAU/mL ± SD 1529.9; p = 0.14). Our data suggest that peripheral B cells are required to generate antibodies to neo-antigens but not for a recall response during anti-CD20 therapy. Evaluation of B-cell counts and pre-existing SARS-CoV-2 antibodies might serve as biomarkers for estimating the immune competence to mount a humoral response to SARS-CoV-2 antigens.

IntroductionThe understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset.MethodsMultiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing–remitting disease course and four a primary progressive MS.ResultsThere were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression.DiscussionIn conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS.

Summary: Background: Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity. Methods: Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated. Findings: A total of 86 patients at a mean age of 33 ± 10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3). Interpretation: κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors. Funding: This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society.

Abstract Natalizumab (NTZ) has been used for treatment of highly active relapsing–remitting multiple sclerosis (MS). When stopping NTZ the risk of severe rebound phenomenon has to be considered. We aimed to investigate the use of NTZ in clinical routine and focused on identification of potential risk factors for disease reactivation after treatment discontinuation. At the Medical University of Innsbruck, Austria, we identified all MS patients who were treated with NTZ and performed a retrospective analysis on therapeutic decision making, disease course before, during and after treatment with NTZ and on risk factors for disease reactivation after NTZ discontinuation. 235 NTZ treated MS patients were included, of whom 105 had discontinued treatment. At NTZ start disease duration was 5.09 (IQR 2.09–10.57) years, average number of total relapses was 4 (IQR 3–6) and median EDSS 2.0 (range 0–6.5), whereby these values significantly decreased over time. Reduction of annualized relapse rate (ARR) on treatment was 93% and EDSS remained stable in 64%. In multivariate regression models only conversion to secondary progressive MS (SPMS) on treatment was significantly associated with lower risk of disease reactivation after NTZ, while ARR before treatment was associated with earlier disease reactivation. We could confirm the high therapeutic efficacy of NTZ which trends to be used earlier in the disease course nowadays. Discontinuation of NTZ seems safe only in patients who convert to SPMS during treatment, while higher ARR before NTZ increases the risk of disease reactivation after treatment discontinuation.

BackgroundSpontaneous subarachnoid hemorrhage (SAH) is a severe neurological disease that frequently requires placement of external ventricular drainage (EVD). Cerebrospinal fluid (CSF) obtained via the drain is used to detect potential complications of SAH.ObjectiveThis study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications.MethodsA total of thirty-three patients with spontaneous SAH who required an EVD and had at least three consecutive CSF samples collected over a period of more than 7 days were included in this study.ResultsA median of 6 longitudinally collected CSF samples per patient were available within 1–22 days after SAH onset. Overall, red blood cells (RBC) steadily decreased over time, whereas white blood cells (WBC) and total protein (TP) increased until days 6 and 13, respectively, and decreased thereafter. The estimated decay rates of RBC, WBC, and TP were 28, 22, and 6% per day. Distinct CSF patterns over time were linked to known complications after SAH. Patients with rebleeding showed increased RBC, TP, and phagocytosing cells compared to patients without re-bleeding. For ventriculitis, an elevated cell index with a higher proportion of granulocytes was characteristic. CSF of patients with delayed cerebral ischemia showed increased RBC and WBC compared to patients without DCI. Early CSF WBC and cell index were predictive for the occurrence of DCI and ventriculitis later during the disease course. The amount of daily CSF drainage via EVD had no impact on routine CSF parameters.ConclusionLongitudinal CSF characteristics are associated with SAH-related complications.

The chimeric anti-CD20 antibody rituximab has demonstrated good efficacy as an off-label treatment in chronic inflammatory demyelinating polyneuropathy (CIDP), while the humanized anti-CD20 antibody ocrelizumab has been approved for treatment of multiple sclerosis (MS), whereas there is no evidence for its use in CIDP so far. We present a patient suffering from CIDP and MS, both refractory to standard treatment and both showing marked improvement on ocrelizumab. To the best of our knowledge, this is a unique report of CIDP with an almost full electrophysiological recovery on ocrelizumab which could be considered as a potential treatment option for refractory CIDP.

Abstract Introduction Intracranial neoplasms are an uncommon cause of symptomatic parkinsonism. We here report a patient with an extensive middle and posterior fossa arachnoid cyst presenting with parkinsonism that was treated by neurosurgical intervention. Methods Retrospective chart review and clinical examination of the patient. Case report This 55-year-old male patient with hemiparkinsonism and recurrent bouts of headaches was first diagnosed in 1988. CT scans revealed multiple cystic lesions compressing brainstem and basal ganglia, which were partially resected. Subsequently, the patient was free of complaints for 20 years. In 2009 the patient presented once more with severe unilateral tremor and thalamic pain affecting the right arm. Despite symptomatic treatment with L-Dopa and pramipexole symptoms worsened over time. In 2014 there was further progression with increasing hemiparkinsonism, hemidystonia, unilateral thalamic pain and pyramidal signs. Repeat CT scanning revealed a progression of the cysts as well as secondary hydrocephalus. Following repeat decompression of the brainstem and fenestration of all cystic membranes parkinsonism improved with a MDS- UPDRS III score reduction from 39 to 21. Histology revealed arachnoid cystic material. Conclusion We report on a rare case of recurrent symptomatic hemiparkinsonism resulting from arachnoid cysts.

Background:Evidence guiding personalized decision-making with respect to disease-modifying therapy (DMT) around pregnancy in relapsing multiple sclerosis (RMS) is lacking.Objective:To generate and validate a risk score for disease reactivation intrapartum and postpartum in RMS.Methods:From the Vienna Innsbruck MS database (VIMSD), we included 343 pregnancies in patients with RMS. Primary endpoint was disease reactivation. Patients were randomly assigned 2:1 in a generation and validation dataset. A predictive score was calculated using the Cox regression and validated.Results:In the generation dataset, occurrence of relapse and type of DMT in the year before conception, DMT washout duration, the Expanded Disability Status Scale (EDSS) at conception, and time until DMT restart postpartum were identified as independent predictors of disease reactivation (p < 0.001). The resulting 10-point risk score robustly predicted reactivation (explaining 75% of variance, p < 0.001) identifying patients at high [≥6 points; mean risk 65%; range 50–100%; hazard ratio (HR) 14.5], intermediate (3–5 points; mean risk 24%; range 15–35%; HR 4.3), and low risk (≤2 points; mean risk 6%; range 0–8%) of disease reactivation in pregnancy and up to 6 months postpartum.Conclusion:The composite Vienna Innsbruck Pregnancy Risk in Multiple Sclerosis (VIPRiMS) score is a valuable clinical tool to support patients and neurologists in anticipating risk and, thus, individualizing treatment decision-making around pregnancy.

To determine whether there is a correlation between myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases and varicella zoster virus (VZV) infection. We provide a case report and performed a study to determine the frequency of MOG antibodies (MOG-IgG) in neurological VZV infections. Patients admitted to the Medical University of Innsbruck from 2008–2020 with a diagnosis of a neurological manifestation of VZV infection (n=59) were included in this study; patients with neuroborreliosis (n=34) served as control group. MOG-IgG was detected using live cell-based assays. In addition, we performed a literature review focusing on MOG and aquaporin-4 (AQP4) antibodies and their association with VZV infection. Our case presented with VZV-associated longitudinally extensive transverse myelitis and had MOG-IgG at a titer of 1:1280. In the study, we did not detect MOG-IgG in any other patient neither in the VZV group (including 15 with VZV encephalitis/myelitis) nor in the neuroborreliosis group. In the review of the literature, 3 cases with MOG-IgG and additional 9 cases with AQP4 IgG associated disorders in association with a VZV infection were identified. MOG-IgG are rarely detected in patients with VZV infections associated with neurological diseases.

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, and Switzerland).

BackgroundReports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS).ObjectiveTo assess routine CSF parameters in MS patients and the frequency of pathologic findings by applying novel RL.MethodsCSF white blood cells (WBC), CSF total protein (CSF-TP), CSF/serum albumin quotient (Qalb), intrathecal synthesis of immunoglobulins (Ig) A, M and G, oligoclonal IgG bands (OCB) were determined in patients with clinically isolated syndrome (CIS) and MS.ResultsOf 541 patients 54% showed CSF pleocytosis with a WBC count up to 40/μl. CSF cytology revealed lymphocytes, monocytes and neutrophils in 99%, 41% and 9% of patients. CSF-TP and Qalb were increased in 19% and 7% applying age-corrected RL as opposed to 34% and 26% with conventional RL. Quantitative intrathecal IgG, IgA and IgM synthesis were present in 65%, 14% and 21%; OCB in 95% of patients. WBC were higher in relapsing than progressive MS and predicted, together with monocytes, the conversion from CIS to clinically definite MS. Intrathecal IgG fraction was highest in secondary progressive MS.ConclusionsCSF profile in MS varies across disease courses. Blood-CSF-barrier dysfunction and intrathecal IgA/IgM synthesis are less frequent when the novel RL are applied.

BackgroundThe COVID-19 pandemic challenges neurologists in counselling patients with multiple sclerosis (pwMS) regarding their risk by SARS-CoV-2 and in guiding disease-modifying treatment (DMT).ObjectiveTo characterize the prevalence and outcome of COVID-19 in pwMS specifically associated with different DMT in a nationwide population-based study.MethodsWe included patients aged ≥18 years with a confirmed diagnosis of MS and a diagnosis of COVID-19 established between January 1, 2020 and December 31, 2020. We classified COVID-19 course as either mild, severe or fatal. Impact of DMT and specifically immunosuppressants (alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab) on COVID-19 outcome was determined by multivariable models, adjusted for a-priori-risk.ResultsOf 126 MS patients with COVID-19 (mean age 43.2 years [SD 13.4], 71% female), 86.5% had a mild course, 9.5% a severe course and 3.2% died from COVID-19. A-priori-risk significantly predicted COVID-19 severity (R2 0.814; pConclusionsIn a population-based MS cohort, COVID-19 outcome was not associated with exposure to DMT and immunosuppressive DMT when accounting for other already known risk factors. This provides reassuring evidence that COVID-19 risk can be individually anticipated in MS and-except for a very small proportion of high-risk patients-treatment decisions should be primarily focused on treating MS rather than the pandemic.

Highly sensitive reporter-gene assays have been developed that allow both the direct vascular endothelial growth factor (VEGF) neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity (ADCC) to be quantified rapidly and in a highly specific manner. The use of these assays has shown that in 46 patients with ovarian cancer following four cycle of bevacizumab treatment, and in longitudinal samples from the two patients that respond to bevacizumab therapy from a small cohort of patients with glioblastoma, that there is a reasonably good correlation between bevacizumab drug levels determined by ELISA and bevacizumab activity, determined using either the VEGF-responsive reporter gene, or the ADCC assays. One of the two primary non-responders with glioblastoma exhibited high levels of ADCC activity suggesting reduced bevacizumab Fc engagement in vivo in contrast to the other primary non-responder, and the two secondary non-responders with a decreasing bevacizumab PK profile, determined by ELISA that exhibited low to undetectable ADCC activity. Drug levels were consistently higher than bevacizumab activity determined using the reporter gene assay in serial samples from one of the secondary non-responders and lower in some samples from the other secondary non-responder and ADCC activity was markedly lower in all samples from these patients suggesting that bevacizumab activity may be partially neutralized by anti-drug neutralizing antibodies (NAbs). These results suggest that ADCC activity may be correlated with the ability of some patients to respond to treatment with bevacizumab while the use of the VEGF-responsive reporter-gene assay may allow the appearance of anti-bevacizumab NAbs to be used as a surrogate maker of treatment failure prior to the clinical signs of disease progression.

Objectives: To analyze safety and impact of natalizumab (NTZ) exposure on the disease course, pregnancy, and newborn outcomes of relapsing-remitting multiple sclerosis (RRMS) patients from the Austrian Multiple Sclerosis Treatment Registry (AMSTR).Materials and Methods: Twelve pregnancies of 11 women with RRMS exposed to treatment with NTZ were identified from the AMSTR. Exposure to NTZ was defined as treatment with NTZ from 8 weeks prior to the start of the last menstrual period and onward. All patients completed a standardized questionnaire regarding pregnancy and newborn outcomes until the postpartum period for up to 12 months.Results: NTZ was stopped on average 46 days after the last menstrual period. There were 11 live births and one elective termination due to ectopic pregnancy. Mean gestational age of live born individuals was 39.0 weeks [standard deviation (SD) ± 1.1]. Mean birth weight and length were 3,426 g (SD ± 348) and 51.9 cm (SD ± 1.9), respectively. Apgar scores 1 min after birth were normal, with 9.2 points on average. One child displayed hip dysplasia as the only congenital malformation documented in this cohort. Three patients experienced relapses during pregnancy and three patients in the postpartum period, resulting in confirmed Expanded Disability Status Scale (EDSS) progression in four of them.Conclusion: In this cohort, there was no increased risk concerning pregnancy and newborn outcomes due to NTZ exposure. However, relapses occurring during pregnancy and postpartum period resulted in confirmed disability.

In most cases, multiple sclerosis (MS) patients reduce physical activity with disease progression and many patients are found to be vitamin D deficient. The aim of this study was to explore correlations between daily physical activity in everyday life and 25-hydroxyvitamin-D3 (25(OH)D3) serum levels in mildly disabled patients with an Expanded Disability Status Scale (EDSS) ≤ 4. We analyzed serum 25(OH)D3 levels and recorded daily physical activity (activity duration, number of steps, distance, energy expenditure) using an activity tracker for 14-days in 25 women and 15 men. Participants recorded their daily sunlight exposure time by diary during the study period. We found a positive correlation between physical activity and 25(OH)D3 levels in both, Pearson correlation (r = 0.221) and multivariate regression analysis (β = 0.236), which was stronger than correlation with sunlight exposure time (β = -0.081). EDSS and physical activity were weakly correlated (r = -0.228), but no correlation between EDSS and 25(OH)D3 levels was found (r = -0.077). There were no relevant differences in physical activity (p = 0.803) and 25(OH)D3 concentrations (p = 0.385) between the EDSS groups 0 - 1.5 and 2.0 - 4.0. In conclusion, physical activity has an effect on vitamin D levels independent of sunlight exposure time in people with MS (pwMS) with low-grade disability.

BackgroundCerebrospinal fluid (CSF) oligoclonal bands (OCB) occur in chronic or post-acute phase of inflammatory diseases of the central nervous system.ObjectiveTo determine whether CSF OCB in patients with neuroborreliosis (NB) are specific for borrelia burgdorferi senso lato.MethodsWe performed isoelectric focusing followed by immunoblotting in CSF of 10 NB patients and 11 controls (7 patients with multiple sclerosis, 2 patients with neuromyelitis optica spectrum disease, 1 patient with dementia and 1 patient with monoclonal gammopathy). Immunoblotting was performed using an uncoated as well as a borrelia antigen pre-coated nitrocellulose membrane (NCM). OCB were counted by visual inspection and photometric analysis. OCB were compared between uncoated und pre-coated NCM both in the NB and control group. For validation purposes inter-assay precision was determined by calculating the coefficient of variation (CV).ResultsBorrelia-specific OCB were found in the CSF of 9 NB patients and in none of the control subjects resulting in a sensitivity of 90% and a specificity of 100%. Number of NB specific OCB were 11±7 bands by photometric analyses compared to 9±5 bands by visual inspection. Validation experiments revealed an inconsistent inter-assay precision between visual and photometric analyses (NB uncoated: visual 28% versus photometric 14%, control subject uncoated: visual 16% versus photometric 24%).ConclusionsIn CSF samples with positive OCB, Borrelia-specific bands were detected in almost all NB patients and in none of the control subjects. Inconsistent inter-assay precision may be explained by a poor comparability of visual and photometric approach.

Abstract Introduction Determination of antibodies against the John Cunningham virus (JCV) is an important tool for risk stratification in Natalizumab‐treated multiple sclerosis (MS) patients. Six‐monthly testing has been suggested for anti‐JCV antibody negative patients and patients with low antibody index in order to detect changes of serostatus. We conducted a prospective study with predefined testing intervals in order to investigate the predictability of anti‐JCV antibody status and the intervals for repetitive testing. Methods Our study included 109 patients at the MS Clinic of the Departments of Neurology, Medical Universities of Innsbruck and Salzburg. Blood withdrawals were performed at five time points: baseline, month 1, 3, 6, and 12. Patients’ sera were sent to Unilabs, Copenhagen, Denmark, where anti‐JCV antibodies were tested by a two‐step enzyme‐linked immunosorbent assay. Qualitative (negative/positive) and quantitative results (anti‐JCV antibody index) were used for statistical analyses. Results In our cohort, 52.3% of the patients were positive for anti‐JCV antibodies at baseline, with a significant correlation with age, but no association with sex or prior disease‐modifying therapy. Seven patients converted and reverted from negative to positive status and vice versa around the cut‐off index of 0.4, but no patient showed a permanent seroconversion from negative to highly positive anti‐JCV antibody status. Conclusion Long‐term anti‐JCV antibody status, including seroconverters/‐reverters around the cut‐off index, is highly predictable by testing three times within short intervals, however, we cannot suggest clearly defined intervals for repetitive testing. The rate of real seroconverters, i.e., new infections with JCV, per year seems lower than previously described.

Inflammatory demyelinating CNS syndromes include, besides their most common entity multiple sclerosis (MS), several different diseases of either monophasic or recurrent character—including neuromyelitis optica spectrum disorders (NMOSDs) and acute disseminated encephalomyelitis (ADEM). Early diagnostic differentiation is crucial for devising individual treatment strategies. However, due to overlapping clinical and paraclinical features diagnosis at the first demyelinating event is not always possible. A multiplicity of potential biological markers that could discriminate the different diseases was studied. As the use of autoantibodies in patient management of other autoimmune diseases, is well-established and evidence for the critical involvement of B cells/antibodies in disease pathogenesis in inflammatory demyelinating CNS syndromes increases, antibodies seem to be valuable diagnostic tools. Since the detection of antibodies against aquaporin-4 (AQP-4), the understanding of immunopathogenesis and diagnostic management of NMOSDs has dramatically changed. However, for most inflammatory demyelinating CNS syndromes, a potential antigen target is still not known. A further extensively studied possible target structure is myelin oligodendrocyte glycoprotein (MOG), found at the outermost surface of myelin sheaths and oligodendrocyte membranes. With detection methods using cell-based assays with full-length, conformationally correct MOG, antibodies have been described in early studies with a subgroup of patients with ADEM. Recently, a humoral immune reaction against MOG has been found not only in monophasic diseases, but also in recurrent non-MS diseases, particularly in pediatric patients. This review presents the findings regarding MOG antibodies as potential biological markers in discriminating between these different demyelinating CNS diseases, and discusses recent developments, clinical implementations, and data on immunopathogenesis of MOG antibody-associated disorders.

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies.Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index.Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-β, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay.Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-β, glatiramer acetate, or natalizumab.Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.

Paroxysmal (PS) and unusual symptoms (US) account for approximately 1.6% of initial manifestations of multiple sclerosis (MS) and have comparable conversion rates to clinically definite MS (CDMS) as classical bout onset symptoms (CS). However, long-term prognosis and clinical outcome of patients experiencing PS or US as first clinical manifestation are unclear.Clinical, MRI and cerebrospinal fluid data were obtained retrospectively and patients presenting with PS or US were compared to patients with CS presentation.In a cohort of 532 relapsing onset MS patients followed for a mean period of 11.4 years (SD 3.6), 10 (1.9%) patients initially presented with PS/US. PS/US patients received disease modifying treatment (DMT) in a significantly smaller proportion immediately after the first clinical symptom (30% vs. 61.7%; p = 0.021) and during the observation period (60% vs. 83.5%; p = 0.033). In multivariate models correcting for sex, age at initial symptoms, complete remission of initial symptoms, total number of T2 and contrast-enhancing lesions, presence of oligoclonal bands and DMT exposure, PS/US were not associated with lower annualized relapse rate or lower EDSS over time.In addition to a similar conversion rate to CDMS, patients presenting with PS/US at disease onset display very similar relapse and disability rates as patients with CS onset. Consequently, initial presentation with PS/US does not indicate benign or atypical MS, but requires DMT initiation based on the same criteria as in CS patients.

There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS.128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3-10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate.CSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p

BACKGROUND:Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. OBJECTIVE:To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status. METHODS:MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4-6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. RESULTS:154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and

Multiple sclerosis (MS) has a highly heterogenic course making prediction of long term outcome very difficult.The objective was to evaluate current and identify additional clinical factors that are linked to long term outcome of relapsing-remitting MS assessed by disability status 10 years after disease onset.This observational study included 793 patients with relapsing-remitting MS. Clinical factors hypothesized to influence long term outcome measured by EDSS scores 10 years after disease onset were analysed by Kaplan-Meier-estimates. Multinomial logistic regression models regarding mild (EDSS ≤2.5), moderate (EDSS 3.0-5.5) or severe (EDSS ≥6.0) disability were calculated to correct for confounders.Secondary progression was the strongest predictor of severe disability (Hazard ratio [HR] 503.8, 95% confidence interval [CI] 160.0-1580.1); p

BACKGROUND: Neuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses. CONCLUSIONS: Our results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration.