Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.

Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study).

BACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

Six-month follow-up of multidomain cognitive impairment in non-hospitalized individuals with post-COVID-19 syndrome.

Some people infected with SARS-CoV-2 report persisting symptoms following acute infection. If these persist for over three months, they are classified as post-COVID-19 syndrome (PCS). Although PCS is frequently reported, detailed longitudinal neuropsychological characterization remains scarce. We aimed to describe the trajectory of cognitive and neuropsychiatric PCS symptoms. 42 individuals with persisting cognitive deficits after asymptomatic to mild/moderate acute COVID-19 at study inclusion received neuropsychological assessment at baseline (BL) and follow-up (FU; six months after BL). Assessments included comprehensive testing of five neurocognitive domains, two cognitive screening tests, and questionnaires on depression, anxiety, sleep, fatigue, and health-related quality of life. Results showed high rates of subjective cognitive complaints at BL and FU (95.2% versus 88.1%) without significant change over time. However, objectively measured neurocognitive disorder (NCD) decreased (61.9% versus 42.9%). All cognitive domains were affected, yet most deficits were found in learning and memory, followed by executive functions, complex attention, language, and perceptual motor functions. In individuals with NCD, the first three domains mentioned improved significantly over time, while the last two domains remained unchanged. Cognitive screening tests did not prove valuable in detecting impairment. Neuropsychiatric symptoms remained constant except for quality of life, which improved. This study emphasizes the importance of comprehensive neuropsychological assessment in longitudinal research and provides valuable insights into the trajectory of long-term neuropsychological impairments in PCS. While cognitive performance significantly improved in many domains, neuropsychiatric symptoms remained unchanged.

"So at least now I know how to deal with things myself, what I can do if it gets really bad again"-experiences with a long-term cross-sectoral advocacy care and case management for severe multiple sclerosis: a qualitative study.

BACKGROUND: Persons with severe Multiple Sclerosis (PwsMS) face complex needs and daily limitations that make it challenging to receive optimal care. The implementation and coordination of health care, social services, and support in financial affairs can be particularly time consuming and burdensome for both PwsMS and caregivers. Care and case management (CCM) helps ensure optimal individual care as well as care at a higher-level. The goal of the current qualitative study was to determine the experiences of PwsMS, caregivers and health care specialists (HCSs) with the CCM. METHODS: In the current qualitative sub study, as part of a larger trial, in-depth semi-structured interviews with PwsMS, caregivers and HCSs who had been in contact with the CCM were conducted between 02/2022 and 01/2023. Data was transcribed, pseudonymized, tested for saturation and analyzed using structuring content analysis according to Kuckartz. Sociodemographic and interview characteristics were analyzed descriptively. RESULTS: Thirteen PwsMS, 12 caregivers and 10 HCSs completed interviews. Main categories of CCM functions were derived deductively: (1) gatekeeper function, (2) broker function, (3) advocacy function, (4) outlook on CCM in standard care. Subcategories were then derived inductively from the interview material. 852 segments were coded. Participants appreciated the CCM as a continuous and objective contact person, a person of trust (92 codes), a competent source of information and advice (on MS) (68 codes) and comprehensive cross-insurance support (128 codes), relieving and supporting PwsMS, their caregivers and HCSs (67 codes). CONCLUSIONS: Through the cross-sectoral continuous support in health-related, social, financial and everyday bureaucratic matters, the CCM provides comprehensive and overriding support and relief for PwsMS, caregivers and HCSs. This intervention bears the potential to be fine-tuned and applied to similar complex patient groups. TRIAL REGISTRATION: The study was approved by the Ethics Committee of the University of Cologne (#20-1436), registered at the German Register for Clinical Studies (DRKS00022771) and in accordance with the Declaration of Helsinki.

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.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome.

BACKGROUND: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role. DESIGN: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment. RESULTS: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004). CONCLUSIONS: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Cultural adaptation of the Integrated Palliative care Outcome Scale for neurological symptoms.

OBJECTIVES: Standardized measures for assessing neurological patients needing palliative care remain scarce. The Integrated Palliative care Outcome Scale for neurological patients in its short form (IPOS Neuro-S8) helps assess and identify patients' symptom burden and needs early but has not yet been validated in German. The aim was to culturally adapt and translate the IPOS Neuro-S8 into the German health-care context and evaluate its face and content validity. METHODS: Cultural adaptation study following the first 6 out of 8 phases of the Palliative care Outcome Scale measures manual: (1) conceptual definition, (2) forward translation to German, (3) backward translation to English, (4) expert review, (5) cognitive debriefing, (6) proofreading. Neurological patients needing palliative care and clinical staff of the Department of Palliative Medicine or Neurology of the University Hospital of Cologne were included. Data were analyzed using thematic content analysis and descriptive statistics. RESULTS: A total of 13 patients and 16 clinical staff participated in this study. The expert review panel (phase 4) consisted of 11 additional members. While patients (n = 9) and clinical staff (n = 11) confirmed that the IPOS Neuro-S8 is an intelligible tool that is well accepted (phase 5), some linguistic and cultural differences were found between the original English and German versions. These mainly concerned the items mouth problems and spasms. SIGNIFICANCE OF RESULTS: The German version of the IPOS Neuro-S8 has demonstrated face and content validity and captures relevant symptoms of neurological patients needing palliative care. Its psychometric properties, including construct and criterion validity, will be investigated next.

Time to diagnosis in multiple sclerosis: Epidemiological data from the German Multiple Sclerosis Registry.

OBJECTIVE: To investigate the time to diagnosis in multiple sclerosis (MS) in Germany. METHODS: Analysis of real-world registry data from the German Multiple Sclerosis Registry (GMSR) and performing a primary analysis in patients where month-specific registration of the dates of onset and diagnosis was available. RESULTS: As of January 2020, data of a total of 28,658 patients with MS were extracted from the GMSR, with 9836 patients included in the primary analysis. The mean time to diagnosis was shorter following the introduction of the first magnetic resonance imaging (MRI)-based McDonald criteria in 2001. This effect was most pronounced in younger adults below the age of 40 years with relapsing onset multiple sclerosis (ROMS), with a decrease from 1.9 years in 2010 to 0.9 years in 2020, while unchanged in patients aged 40-50 years (1.4 years in 2010 and 1.3 years in 2020). In the limited number of paediatric onset MS patients, the time to diagnosis was longer and did not change (2.9 years). CONCLUSION: The current sensitive MRI-based diagnostic criteria have likely contributed to an earlier diagnosis of MS in Germany in younger adults aged 18-39 years with ROMS. Whether this translated to earlier initiation of disease-modifying treatment or had a beneficial effect on patient outcomes remains to be demonstrated.

Neuro-COVID-19 is more than anosmia: clinical presentation, neurodiagnostics, therapies, and prognosis.

PURPOSE OF REVIEW: To provide an overview on current knowledge of neurological symptoms and complications of COVID-19, and to suggest management concepts. RECENT FINDINGS: Headache, dizziness, excessive tiredness, myalgia, anosmia/hyposmia, and ageusia/dysgeusia are common nonspecific neurological manifestations during early COVID-19 disease found in the majority of patients. Less frequent but more severe and specific neurological manifestations include Guillain--Barré syndrome, encephalopathy, encephalitis/meningitis, epileptic seizures, and cerebrovascular events. Beyond standard neurological examination, these require a more extensive work-up, including cerebrospinal fluid assessment, neurophysiological evaluation, neuroimaging, and cognitive testing. Symptomatic treatment is advisable unless the neurological complication's immune pathogenesis is proven. SUMMARY: Neurological manifestations of COVID-19 occur during the acute, para-infectious, and 'recovery' phase. Therapeutic management depends on the clinical presentation and neurological work-up.

Pharmacovigilance during treatment of multiple sclerosis: early recognition of CNS complications.

An increasing number of highly effective disease-modifying therapies for people with multiple sclerosis (MS) have recently gained marketing approval. While the beneficial effects of these drugs in terms of clinical and imaging outcome measures is welcomed, these therapeutics are associated with substance-specific or group-specific adverse events that include severe and fatal complications. These adverse events comprise both infectious and non-infectious complications that can occur within, or outside of the central nervous system (CNS). Awareness and risk assessment strategies thus require interdisciplinary management, and robust clinical and paraclinical surveillance strategies. In this review, we discuss the current role of MRI in safety monitoring during pharmacovigilance of patients treated with (selective) immune suppressive therapies for MS. MRI, particularly brain MRI, has a pivotal role in the early diagnosis of CNS complications that potentially are severely debilitating and may even be lethal. Early recognition of such CNS complications may improve functional outcome and survival, and thus knowledge on MRI features of treatment-associated complications is of paramount importance to MS clinicians, but also of relevance to general neurologists and radiologists.

High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation.

In persons with multiple sclerosis (PwMS), the neutrophil-to-lymphocyte ratio (NLR) is associated with disability status, symptomatology and disease activity. High-intensity interval training (HIIT) improves many symptoms in PwMS and may positively influence disease progression. Here, we present results from a randomized controlled trial during inpatient rehabilitation on immediate (single bout) and training (3-week intervention) effects of HIIT versus moderate continuous training on NLR and related cellular inflammation markers. Only HIIT reduced the NLR over the 3-week intervention period. These training effects might be due to repetitive inflammatory states with compensatory anti-inflammatory counterbalancing after each HIIT session.

Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS).

BACKGROUND AND PURPOSE: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. METHODS: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. RESULTS: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. CONCLUSION: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.

[Dysphagia in Multiple Sclerosis - an underestimated symptom?] / Dysphagie bei Multipler Sklerose ­ ein unterschätztes Symptom?

BACKGROUND: It is estimated that 240,000 people suffer from multiple sclerosis in Germany. In addition to sensory, motor, vegetative, and neuropsychological functional deficits, dysphagia is a highly relevant and disabling, although not well studied symptom of MS. OBJECTIVES: The purpose of this article is to provide an overview of the scientific background, increase awareness of the symptoms of dysphagia, and to introduce diagnostic tools for its management, overall aiming at alleviating symptoms of dysphagia in persons with MS, and improving their quality of life. METHODS: A structured literature review was conducted of what is currently known on the development, manifestation, diagnosis and treatment options for MS-related dysphagia. Due to the lack of class 1 evidence, in particular for diagnosis and treatment options of dysphagia, also smaller studies or pilot projects were included and discussed in this review. RESULTS: Data from imaging methods such as Flexible Endoscopic Evaluation of Swallowing and Videofluoroscopic Swallowing Evaluation enabled the diagnosis. There was a high variablity in the reported frequency of dysphagia in published studies, largely related to differences in methodology to evaluate the swallowing (from 38 % up to 81 %). Overall, dysphagia as a symptom of multiple sclerosis was underestimated at the patient and the physician level. According to current data from the German MS register, specific treatments were only carried out in 30% of the affected patients.

[Toxicity after chimeric antigen receptor T-cell therapy : Overview and management of early and late onset side effects]. / Toxizitäten nach Chimärer-Antigenrezeptor-T-Zell-Therapie : Übersicht und Management früher und verzögerter Nebenwirkungen.

BACKGROUND: The transfusion of chimeric antigen receptor (CAR) T­cells has become established as a new treatment option in oncology; however, this is regularly associated with immune-mediated side effects, which can also run a severe course and necessitate a specific treatment and intensive medical treatment. MATERIAL AND METHODS: A literature review was carried out on CAR T-cell therapy, toxicities and the management of side effects. RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) regularly occur shortly after CAR T-cell treatment. The symptoms of CRS can range from mild flu-like symptoms to multiorgan failure. In addition to mild symptoms, such as disorientation and aphasia, ICANS can also lead to convulsive seizures and brain edema. The management of CRS and ICANS is based on the severity according to the grading of the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab and corticosteroids are recommended for CRS and corticosteroids are used for ICANS. In the further course persisting hypogammaglobulinemia and cytopenia are frequent even months after the initial treatment and promote infections even months after CAR T­cell therapy. DISCUSSION: Potentially severe complications regularly occur after CAR T-cell therapy. An interdisciplinary cooperation between intensive care physicians, hematologists, neurologists and specialists in other disciplines is of decisive importance for the optimal care of patients after CAR T­cell therapy.

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

OBJECTIVE: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS). METHODS: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany. RESULTS: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts. CONCLUSION: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.

Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis.

PURPOSE OF REVIEW: A variety of high-efficacy disease-modifying therapies (DMTs) are available for the treatment of multiple sclerosis (MS). After evaluation and approval by regulatory agencies, DMTs are likely to be administered to patients whose characteristics differ from those enrolled in clinical trials. This may contribute to the emergence of unexpected adverse events observed in the real-world setting. Higher age may be a relevant factor that could change the benefit-risk balance of DMTs, as it may associate with lower efficiency and higher frequency of adverse events. RECENT FINDINGS: The absolute and relative number of patients with MS who reach the age of 55 and higher increases. Growing evidence demonstrates lower efficacy of DMTs in older persons with MS. Specific risks during DMTs for MS, such as the risk of developing progressive multifocal leukoencephalopathy (PML) or the outcome following PML, have been associated with age. It is hypothesized that age-related and therapy-induced alterations to the immune system may have (super)additive effects, resulting in an acceleration of physiological immunosenescence and inflamm-aging. SUMMARY: In this article, we review the risks of high-efficacy DMTs in MS with a specific focus on age-related efficacy and risks, including opportunistic infections, malignancies, and autoimmune reactions.

Performance of PML diagnostic criteria in natalizumab-associated PML: data from the Dutch-Belgian cohort.

OBJECTIVE: To test the current progressive multifocal leukoencephalopathy (PML) diagnostic criteria by applying them to patients previously diagnosed with natalizumab (NTZ)-associated PML in a real-world clinical setting. METHODS: Patients from the Dutch-Belgian NTZ-PML cohort (n=28) were reviewed at the time of first diagnostic work-up and during follow-up, using the PML diagnostic criteria as proposed in a consensus statement from the American Academy of Neurology. RESULTS: At first diagnostic work-up, 18 patients (64.3%) met the criteria for high diagnostic certainty for PML ('definite PML' or 'probable PML'). During follow-up, this increased to 20 patients (71.4%) as JC virus DNA was detected in cerebrospinal fluid of two additional patients. Nonetheless, 28.6% of patients were still classified as 'possible PML' or 'not PML' (6 (21.5%) and 2 (7.1%) patients, respectively) despite a very high suspicion for PML based on lesion evolution and signs of PML-immune reconstitution inflammatory syndrome on MRI, and development of compatible symptoms. CONCLUSIONS: The current case definition of PML has low sensitivity for diagnosis of NTZ-PML in a real-world clinical setting in which MRI is frequently used for PML screening. This may delay diagnosis and appropriate management of PML, and may complicate a valid estimation of PML incidence during NTZ therapy.

Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis - a community-based randomized controlled trial.

BACKGROUND: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. METHODS: In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. DISCUSSION: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. TRIAL REGISTRATION: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform.