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Introduction: The post-COVID-19 condition (PCC) is characterized by debilitating persistent symptoms, including symptoms suggesting neurological aberrations such as concentration difficulties, impaired memory, pain, and sleep disturbances. The underlying mechanisms remain elusive. This study aimed to investigate brain injury biomarkers, neurocognitive test performance, and selfreported neurological and neuropsychological symptoms in young people with PCC. Methods: A total of 404 non-hospitalized adolescents and young adults aged 12-25 years who tested positive for SARS-CoV-2, along with 105 matched SARS-CoV-2 negative individuals, were prospectively enrolled and followed-up for 6 months (Clinical Trials ID: NCT04686734). All participants underwent comprehensive assessment encompassing clinical examinations, questionnaires, neurocognitive testing and blood sampling. Serum samples were immunoassayed for the brain injury biomarkers neurofilament light chain (Nfl) and glial fibrillary acidic protein (GFAp). At 6 months, cross-sectional analyses of serum Nfl/GFAp, neurocognitive test results and symptom scores were performed across groups based on adherence to PCC criteria as well as initial SARS-CoV-2 test results. Also, associations between Nfl/GFAp, neurocognitive test results, and symptom scores were explored. Results: A total of 381 SARS-CoV-2 positive and 85 SARS-CoV-2 negative were included in the final analysis at 6 months, of whom 48% and 47%, respectively, adhered to the PCC criteria. Serum levels of Nfl and GFAp were almost equal across groups and did not differ from reference values in healthy populations. Also, neurocognitive test results were not different across groups, whereas symptom scores were significantly higher in patients fulfilling PCC criteria (independent of initial SARS-CoV-2 status). No significant associations between Nfl/GFAp, neurocognitive test results, and symptom scores were found. Conclusion: Normal brain injury biomarkers and neurocognitive performance 6 months after mild COVID-19 implies that the persistent symptoms associated with PCC are not concurrent with ongoing central nervous system damage or permanent disruption of cognitive functions. This finding contradicts the notion of neuroinflammation as a likely explanation for the persistent symptoms. [ABSTRACT FROM AUTHOR]

Genetic variants in SPAST are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic SPAST variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in SPAST. A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in SPAST, c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a "hot spot", have been reported previously in adult-onset HSP. This report describes a novel SPAST variant in a female with HSP without a known family history of the disorder. [ABSTRACT FROM AUTHOR]

Skogholt's disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt's disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ1––42, Aβ1–40, Aβx–38, Aβx–40, Aβx–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette-Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk.Methods: Using data from a Norwegian tuberculosis screening programme (1963-1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship.Results: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76-0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST.Conclusion: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades. [ABSTRACT FROM AUTHOR]

Background: High serum levels of 25-hydroxyvitamin D (25(OH)D) have been found among patients with a favorable disease course in relapsing-remitting MS (RRMS), indicating that this may limit clinical deterioration. Clinical deterioration in RRMS correlates with increasing serum levels of neurofilament light chain (NfL). Objectives: To examine the association between physiological variations in serum 25(OH)D and NfL levels in RRMS patients before and during disease modifying therapy (DMT). Material and Methods: Serum 25(OH)D and NfL concentrations were measured in 85 newly diagnosed RRMS patients enrolled in a 24-month randomized double-blinded placebo-controlled trial of ω-3 fatty acid supplementation without vitamin D. Patients were without DMT until interferon β-1a (IFN-β) initiation at study month 6. Longitudinal serum measurements and brain magnetic resonance imaging (MRI) were obtained. Associations between 25(OH)D and NfL levels were analyzed with linear regression models for the whole study period and the periods before and during IFN-β treatment. Analyses with adjustment for inflammatory MRI disease activity were also performed. Results: No significant associations were found between variations in 25(OH)D and NfL levels during the whole study period (p = 0.95), or the periods without (p = 0.78) or with (p = 0.33) IFN-β therapy. Patients with inflammatory MRI disease activity had significantly higher serum NfL levels than patients without inflammatory MRI disease activity [mean (SD) difference 12.6 (2.0) pg/mL, p < 0.01]. Adjustment for this did not change the relationship between 25(OH)D and NfL concentrations. Conclusion: Natural variations in serum 25(OH)D values do not seem to be associated with alterations in serum NfL concentrations in RRMS patients. [ABSTRACT FROM AUTHOR]

B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3+CD4+ T cells phenotyped as memory (CD45RO+) or naïve (CD45RO−), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and -CD8 were utilized to exclude monocytes and CD8+ T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4+ T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4+ T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes. [ABSTRACT FROM AUTHOR]

We have previously shown that plasmablasts of the G1m1 allotype of IgG1 are selectively enriched in the cerebrospinal fluid of G1m1/G1m3 heterozygous patients with multiple sclerosis, whereas both allotypes are equally used in neuroborreliosis. Here, we demonstrate a strong preference for the G1m1 allotype in the intrathecal humoral immune responses against measles, rubella, and varicella zoster virus in G1m1/G1m3 heterozygous multiple sclerosis patients. Conversely, intrathecally synthesized varicella zoster virus‐specific IgG1 in varicella zoster virus meningoencephalitis comprised both allotypes. This implies that G1m1 B cells are selected to the central nervous system of multiple sclerosis patients regardless of specificity and suggests that an antigen‐independent mechanism could drive the intrathecal humoral immune response. [ABSTRACT FROM AUTHOR]

Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS), but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA) class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs), to assess whether the prerequisites for such idiotope-driven T-B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR) 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF) B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses. [ABSTRACT FROM AUTHOR]

Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis ( MS) and IgG levels in the cerebrospinal fluid ( CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease-specific mechanism involved in B-cell establishment within the central nervous system in MS. [ABSTRACT FROM AUTHOR]

Background: People with multiple sclerosis have high risk of osteoporosis and fractures. A poor vitamin D status is a risk factor for MS, and vitamin D supplementation has been recommended both to prevent MS progression and to maintain bone health.Methods: We assessed the effect of 20,000 IU vitamin D3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis.Results: Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group, and parathyroid hormone decreased in the vitamin D group compared to the placebo group at week 48 and week 96. There was however no effect on bone formation as measured by procollagen type I N propeptide (PINP), or on bone resorption as measured by C-terminal cross-linking telopeptide of type I collagen (CTX1). Neither PINP nor CTX1 predicted bone loss from baseline to week 96.Conclusions: These findings corroborate the previously reported lack of effect of weekly high dose vitamin D supplementation on bone mass density in the same patients, and suggest that such vitamin D supplementation does not prevent bone loss in persons with MS who are not vitamin D deficient.Trial Registration: The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473 . [ABSTRACT FROM AUTHOR]

Background: The mortality of septicaemia, meningitis and encephalitis caused by Listeria monocytogenes is 20-40%. Twenty-one cases of invasive listeriosis associated with alemtuzumab, including at least 16 in patients with multiple sclerosis, have been published or reported to the World Health Organization Case Safety Reports Database. Three cases were fatal, including at least one patient treated for multiple sclerosis in 2016.Case Presentation: We report a patient with multiple sclerosis who developed pyrexia, nausea and abdominal discomfort few hours after the third and last infusion of her second alemtuzumab cycle. An infusion related reaction was suspected. The patient had however eaten soft cheese and raw sausage 3 days prior to treatment, and L. monocytogenes septicaemia was diagnosed based on positive blood cultures.Conclusion: Listeriosis associated with alemtuzumab is a potentially fatal condition that can mimic an infusion related reaction. As in most other previously reported cases symptoms started rapidly after the last infusion, suggesting that the patient already carried the bacteria prior to the alemtuzumab infusions. The summary of product characteristics recommends patients to avoid foods associated with listeria at least 1 month after treatment. This recommendation should include also the last weeks prior to treatment. [ABSTRACT FROM AUTHOR]

Background: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA). Methods: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years. Results: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score≤-2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers. Conclusion: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases. [ABSTRACT FROM AUTHOR]

Background: Leber's hereditary optic neuropathy (LHON) co-occuring with multiple sclerosis-like disease (LHON-MS) is suggested to be a separate disease entity denoted Harding's disease. Little is known about the response to initiation and discontinuation of potent immunomodulatory treatment in LHON-MS. Case presentation: We describe a LHON-MS patient with 27 years disease duration who developed severe disease activity peaking 14 months after discontinuation of natalizumab, with extensive new inflammatory lesions throughout the brain and in the spinal cord resembling immune inflammatory reconstitution syndrome. She had previously been clinically and radiologically stable on natalizumab treatment for 6 years, and before that only experienced subtle clinical activity during 9 years on interferon beta1a. Conclusion: This is the first report on severe exacerbation of inflammatory disease activity after discontinuation of natalizumab in LHON-MS, and suggests that late rebound activity can occur in these patients. [ABSTRACT FROM AUTHOR]

T cells and B cells are crucial in the initiation and maintenance of multiple sclerosis (MS), and the activation of these cells is believed to be mediated through specific recognition of antigens by the T- and B-cell receptors. The antigen receptors are highly polymorphic due to recombination (T- and B-cell receptors) and mutation (B-cell receptors) of the encoding genes, which can therefore be used as fingerprints to track individual T- and B-cell clones. Such studies can shed light on mechanisms driving the immune responses and provide new insights into the pathogenesis. Here, we summarize studies that have explored the T- and B-cell receptor repertoires using earlier methodological approaches, and we focus on how high-throughput sequencing has provided new knowledge by surveying the immune repertoires in MS in even greater detail and with unprecedented depth. [ABSTRACT FROM AUTHOR]

During treatment with fingolimod, B cells are redistributed from blood to secondary lymphoid organs, where they are protected from the effect of anti-CD20 and other cell-depleting therapies.We describe a multiple sclerosis patient who had almost complete depletion of B cells in blood during and shortly after treatment with fingolimod. He developed severe disease activity resembling immune reconstitution syndrome after switching from fingolimod to rituximab, with first dose being six weeks after fingolimod cessation. Following recommendations from the Swedish MS Association, rituximab treatment was started as one single dose of 1000 mg. In patients treated with fingolimod, pathogenic B cells may still be sequestered in secondary lymph nodes if this dose is given early. To deplete such B cells as they egress from the lymph nodes, we propose that a second dose of rituximab a few weeks after the first dose should be considered. [ABSTRACT FROM AUTHOR]

Objective. Patients with multiple sclerosis (MS) are often suffering from neuropathic pain. Antiepileptic drugs (AEDs) and tricyclic antidepressants (TCAs) are commonly used and are susceptible to be involved in drug interactions. The aim of this retrospective study was to investigate the prevalence of use of antiepileptic and antidepressive drugs in MS patients and to discuss the theoretical potential for interactions. Methods. Review of the medical records from all patients treated at a dedicated MS rehabilitation centre in Norway between 2009 and 2012. Results. In total 1090 patients attended a rehabilitation stay during the study period. Of these, 342 (31%; 249 females) with mean age of 53 (±10) years and EDSS 4.8 (±1.7) used at least one AED (gabapentin 12.7%, pregabalin 7.7%, clonazepam 7.8%, and carbamazepine 2.6%) or amitriptyline (9.7%). Polypharmacy was widespread (mean 5.4 drugs) with 60% using additional CNS-active drugs with a propensity to be involved in interactions. Age, gender, and EDSS scores did not differ significantly between those using and not using AED/amitriptyline. Conclusion. One-third of MS patients attending a rehabilitation stay receive AED/amitriptyline treatment. The high prevalence of polypharmacy and use of CNS-active drugs calls for awareness of especially pharmacodynamic interactions and possible excessive adverse effects. [ABSTRACT FROM AUTHOR]

Background: Studies have shown the positive effects of multidisciplinary rehabilitation on disability and health-related quality of life in multiple sclerosis (MS). However, many patients do not seek such treatment, even if it is available free of charge. The aim of this study was to identify facilitators and barriers related to use of such treatment options. Methods: Five focus group interviews with 27 MS patients were conducted. Three groups included patients who had been admitted to a multidisciplinary MS rehabilitation institution, and two groups included outpatients of a university hospital who had not applied for specialized rehabilitation. Interviews were audiotaped and transcribed, and were analyzed qualitatively by means of a modified form of systematic text condensation. Results: Important factors influencing the use of an MS rehabilitation service were 1) the availability and suitability of initial information about the disease and the service, 2) assumptions and expectations about such a service, and 3) practical barriers in the patient's life. The prospect of having a retreat from work and family was described as a motivational factor. Lack of reorientation after diagnosis, fears and perceptions of being labeled as an MS patient, or having information overload and being confronted with disabled individuals were identified as barriers. Conclusions: Communication skills, including information-giving skills, of neurologists in relation to newly diagnosed MS patients need improvement. Rehabilitation programs for MS patients should include stays of different durations and purposes to it patients' needs. Health-care authorities should take measures to secure equal access to information about rehabilitation options across institutions and practicing physicians. [ABSTRACT FROM AUTHOR]

Background: Ocrelizumab is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion to 2 hours may reduce the total site stay from 5.5-6 hours (approved infusion duration including mandatory premedication/observation) to 4 hours, which may reduce patient and site staff burden. Objectives: To investigate the safety profile of ocrelizumab when administered over a shorter infusion period, using primary results from ENSEMBLE PLUS. Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (trial registration: NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS (18-55 years; treatment-naive; disease duration ≤3 years; Expanded Disability Status Scale score 0-3.5) receive ocrelizumab 600-mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab (600 mg) administered over the approved infusion time (3.5 hours; conventional duration), is compared with a 2-hour infusion (shorter duration); the initial infusion (2 x 300 mg) duration remains unaffected. The ENSEMBLE PLUS primary end point is the proportion of patients with infusion-related reactions (IRRs) following the first randomized infusion (frequency/severity assessed during and 24 hours postinfusion). Results: As of September 2019, 291 and 289 patients were randomized to the conventional and shorter infusion groups, respectively. Following the first randomized infusion, 67 patients (23.1%) in the conventional and 71 patients (24.6%) in the shorter infusion group had IRRs, from which 17.9% vs 31.0% were throat irritation and 25.4% vs 23.9% were fatigue, respectively. Most IRRs were mild or moderate; >98% of all IRRs resolved without sequelae in both groups. No IRRs were life threatening, serious, or fatal; 1 severe IRR occurred in both the conventional (laryngeal inflammation [second randomized dose]) and shorter duration groups (fatigue [first randomized dose]). No IRR-related discontinuations occurred. During the first randomized dose, 14 (4.8%) and 25 (8.7%) patients in the conventional and shorter infusion groups had IRRs leading to infusion interruption/slowing, respectively. Conclusions: Primary analysis suggests that the frequency/severity of IRRs are comparable between conventional and shorter infusions. No new safety signals were detected. [ABSTRACT FROM AUTHOR]

Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology. [ABSTRACT FROM AUTHOR]

Objective: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. Results: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment. [ABSTRACT FROM AUTHOR]