[Diagnostic workup for polyneuropathy]. / Diagnostische Abklärung bei Polyneuropathie.

Polyneuropathy is a disease of the peripheral nervous system that usually results in distally emphasized, often symmetrical sensory and motor stimulation and deficits. These are often extremely painful. They can be divided into hereditary and acquired causes; inflammatory and infectious causes should be further differentiated among the acquired causes. A careful diagnostic workup is essential. Clinical signs and distribution patterns of symptoms can often already provide clues to the underlying aetiology. This review describes this workup, which in addition to the medical history and clinical examination always includes thorough laboratory diagnostics, electrophysiological examination and cerebrospinal fluid diagnostics. In individual cases, further diagnostic steps may be necessary in order to make the correct diagnosis.

Patient-reported benefits from nabiximols treatment in multiple sclerosis-related spasticity exceed conventional measures.

Aim: This prospective, multicenter, open-label, noninterventional 12-week study investigated the effectiveness and tolerability of add-on nabiximols oromucosal spray (Sativex®) in the real-world setting in Germany. Patients & methods: The main analysis set comprised 51 adult patients (49 nabiximols responders) with multiple sclerosis (MS) spasticity. Results: The mean overall goal attainment scale score (primary outcome measure) increased by 46% from baseline to week 12 (35.2 vs 51.4; p < 0.001). Mean gait speed was improved by 23% at 4 and 12 weeks. Clinically meaningful improvements in mean 0-10 numerical rating scale scores for spasticity, pain, sleep quality and urinary bladder dysfunction were recorded at 4 and 12 weeks. Conclusion: Nabiximols is a useful therapeutic option for patients with MS spasticity.

People with multiple sclerosis (MS) spasticity experience a variety of symptoms and have individual expectations about a new treatment. This study investigated patients' perceptions about the effectiveness and tolerability of nabiximols oromucosal spray (Sativex^®) when added to current medications for spasticity. Common treatment goals for patients (n = 51) were less pain, better walking and improved sleep. After 12 weeks of treatment, 62% of selected treatment goals were achieved 'as expected' or 'better than expected' and 65% of patients considered their spasticity to be 'much improved'. Meaningful improvements were recorded in spasticity-related symptoms of pain, sleep quality and bladder problems. Few side effects were reported. Nabiximols may be useful for MS patients with a poor response to usual spasticity medications.

Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage.

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unravelled, nor directly compared to anti-neurofascin-155 IgG4-related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicentre combined prospective and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin-associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-associated neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an intra- and interindividual marker for acuteness, severity and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible, nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care.

Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4.

INTRODUCTION: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis (RMS) since 2017. A full treatment course comprises two treatment cycles given 1 year apart, followed by two treatment-free years. The management of cladribine-treated patients beyond year 4 needs to be addressed as patients have now passed the initial 4 years since European Medical Agency approval. AREAS COVERED: A panel of neurologists and a neuroradiologist experienced in MS treatment/monitoring evaluated clinical trial data and real-world evidence and proposed recommendations for the management of cladribine-treated patients beyond year 4. EXPERT OPINION: Continuous monitoring of disease activity during the treatment-free period is important. Subsequent management depends on the presence or absence of inflammatory disease activity, determined in the absence of consistent guidelines via practice-driven neurological decision criteria. Persisting or newly occurring inflammatory disease activity is an indication for further treatment, i.e. either re-initiation of cladribine or switching to another highly effective disease-modifying therapy. The decision to retreat or switch should be based on clinical and radiological evaluation considering disease course, treatment history, and safety aspects. In the absence of disease activity, either retreatment can be offered, or the treatment-free period can be extended under structured monitoring.

OzEAN Study to Collect Real-World Evidence of Persistent Use, Effectiveness, and Safety of Ozanimod Over 5 Years in Patients With Relapsing-Remitting Multiple Sclerosis in Germany.

Background: Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was approved as a disease-modifying therapy for active relapsing-remitting multiple sclerosis (RRMS) in 2020 and for active ulcerative colitis in 2021. Long-term, real-world studies in a nonselective population are needed. OzEAN is an ongoing study to assess the real-world persistent use, effectiveness, and safety of ozanimod and its impact on quality of life (QoL) in patients with RRMS over a 5-year period. Methods: This prospective, noninterventional, postmarketing authorization study will enroll ~1,300 patients (≥18 years of age) with active RRMS. The decision to initiate ozanimod must have been made before and independent from study participation. Enrollment began in March 2021. Recruitment is ongoing and will last for 36 months across 140 sites in Germany. Treatment-naive patients or those having prior experience with a disease-modifying therapy receive oral ozanimod 0.92 mg/day after an initial dose escalation, per the summary of product characteristics recommendations, for up to 60 months. Persistence with ozanimod treatment (primary endpoint) is assessed at month 60. Secondary endpoints include additional physician-reported outcomes [persistence at earlier time points, annualized relapse rate, Expanded Disability Status Scale score, cognition (Symbol Digit Modalities Test), and incidence of adverse events], and patient-reported outcomes assessing patient satisfaction, adherence, and treatment modalities (Treatment Satisfaction Questionnaire for Medication, v1.4), disability (United Kingdom Neurological Disability Rating Scale), QoL (MSQOL-54 questionnaire), fatigue (Fatigue Scale for Motor and Cognitive Functions), and health economics [Work Productivity and Activity Impairment Questionnaire for Multiple Sclerosis (German v2.1); Multiple Sclerosis Health Resource Survey, v3.0]. A Multiple Sclerosis Documentation System with an internet-based e-health portal allows patients to view files and complete questionnaires. A safety follow-up will occur 3-8 months after the last ozanimod dose for patients who discontinue treatment early. Long-term results are anticipated after study completion in 2029. Yearly interim analyses are planned after enrollment has reached 25%. Conclusion: This is the first long-term, real-world study of ozanimod in patients with RRMS and, to our knowledge, the first noninterventional study utilizing a patient portal. These data will add to the safety/efficacy profile of ozanimod demonstrated in phase 3 trials. Clinical Trial Registration: Clinicaltrials.gov, identifier: NCT05335031.

Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies.

BACKGROUND AND OBJECTIVES: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). METHODS: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. RESULTS: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. DISCUSSION: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.

[New master's program: multiple sclerosis management]. / Neuer Masterstudiengang: Multiple Sklerose Management.

The new study program "Multiple Sclerosis Management" is aimed at physicians, therapists, nurses, scientists, pharmacists, psychologists and biologists who want to specialize in the field of multiple sclerosis (MS). After successful accreditation in 2019, the first students have been in the master's program offered by Dresden International University (DIU) since 2020. Over a period of four semesters, it can be completed part-time and largely digitally. The master's program is divided into six modules focusing on basics, clinical and diagnostic aspects, MS studies and statistics, disease-modifying and symptomatic therapy, disease monitoring and documentation. The teaching includes theoretical parts and numerous practical units. A further goal is to derive therapeutic intervention plans and problem-solving strategies from scientific publications and clinical studies, to develop them further and to apply them in patient care. The lecturers come from Germany, Austria and Switzerland and are predominantly professors. The German Multiple Sclerosis Society is the patron of the course. This article presents the study program in detail.

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

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

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

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

Validity of Consumer Activity Monitors and an Algorithm Using Smartphone Data for Measuring Steps during Different Activity Types.

Background: Consumer activity monitors and smartphones have gained relevance for the assessment and promotion of physical activity. The aim of this study was to determine the concurrent validity of various consumer activity monitor models and smartphone models for measuring steps. Methods: Participants completed three activity protocols: (1) overground walking with three different speeds (comfortable, slow, fast), (2) activities of daily living (ADLs) focusing on arm movements, and (3) intermittent walking. Participants wore 11 activity monitors (wrist: 8; hip: 2; ankle: 1) and four smartphones (hip: 3; calf: 1). Observed steps served as the criterion measure. The mean average percentage error (MAPE) was calculated for each device and protocol. Results: Eighteen healthy adults participated in the study (age: 28.8 ± 4.9 years). MAPEs ranged from 0.3-38.2% during overground walking, 48.2-861.2% during ADLs, and 11.2-47.3% during intermittent walking. Wrist-worn activity monitors tended to misclassify arm movements as steps. Smartphone data collected at the hip, analyzed with a separate algorithm, performed either equally or even superiorly to the research-grade ActiGraph. Conclusion: This study highlights the potential of smartphones for physical activity measurement. Measurement inaccuracies during intermittent walking and arm movements should be considered when interpreting study results and choosing activity monitors for evaluation purposes.

Acute intermittent porphyria (AIP) in a patient with celiac disease.

We present the case of an 18 year old Caucasian with known celiac disease, who suffered a severe first attack of acute intermittent porphyria (AIP) with neuropsychiatric symptoms, severe tetraparesis and respiratory insufficiency. Treatment with heme arginate and high-dose intravenous glucose and rigorous rehabilitation resulted in a slow but almost complete recovery of her motor symptoms. To our knowledge this is the first case of acute intermittent porphyria triggered by malnutrition in the context of celiac disease. It is remarkable that the patient showed a favourable outcome despite the severity of her initial symptoms. This case shows the importance of early and systematic symptomatic treatment in patients with severe neurologic manifestation of AIP.

The Two-Minute Walk Test in Persons with Multiple Sclerosis: Correlations of Cadence with Free-Living Walking Do Not Support Ecological Validity.

The two-minute walk test (2MWT) is a frequently used walking capacity test in persons with multiple sclerosis (pwMS). However, less is known about its relevance with regards to walking capacity during free-living walking performance. Therefore, the ecological validity of the 2MWT was tested by 1. computing free-living minutes with the same intensity (cadence) as during the 2MWT and 2. investigating the relationship between 2MWT cadence and minutes with the same cadence during free-living walking. 20 pwMS aged 44.2 ± 12.2 (Expanded Disability Status Scale (EDSS) score of 3.1 ± 1.4) performed a 2MWT and wore an accelerometer for seven days. The number of pwMS reaching 100%, 90%, 80% or 70% of 2MWT cadence for at least one minute a day and minutes/day with at least 100%, 90%, 80% and 70% of 2MWT cadence during free-living walking was calculated. Six participants reached 100% of the 2MWT cadence for at least one minute/day during free-living walking. A total of 80% 2MWT cadence was the first intensity category that was reached by all participants during free-living walking. No significant correlation was found between cadence in the 2MWT and minutes in which this cadence was reached during free-living walking. Ecological validity with regard to walking intensity could not be confirmed in our study sample.

Effect of Multiple Sclerosis on Daily Activities, Emotional Well-being, and Relationships: The Global vsMS Survey.

BACKGROUND: The vsMS survey was conducted to better understand the negative effects of fatigue, cognitive impairment, emotional burden, and decreased physical functioning on the personal, professional, and social lives of individuals with multiple sclerosis (MS). METHODS: The vsMS survey was an online survey conducted in Australia, Canada, France, Italy, Spain, the United Kingdom, and the United States that assessed the impact of MS on individuals' daily activities, emotional well-being, relationships, and employment. RESULTS: The survey included 1075 participants with relapsing-remitting MS. Almost 42% of participants reported that their ability to perform and manage daily activities had worsened during the previous 2 years. More than 50% reported limitations in daily activities due to fatigue, physical weakness, problems with balance/coordination, heat/cold sensitivity, memory problems, numbness/tingling, trouble concentrating, impaired movement/muscle stiffness, and impaired sleeping. Participants also reported a negative effect on emotional and social factors, including self-esteem, general outlook, well-being, maintaining/starting relationships, ability to progress in their career/keep their job, and ability to cope with life roles. CONCLUSIONS: These data highlight the importance of addressing the impact of MS and the social and emotional disease burdens on daily activities when planning the care of patients with MS.

Autoantibodies against central nervous system antigens in a subset of B cell-dominant multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

Long-term management of multiple sclerosis patients treated with cladribine tablets: an expert opinion.

INTRODUCTION: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4. AREAS COVERED: The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this. EXPERT OPINION: Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

BACKGROUND: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. METHODS: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded. RESULTS: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. CONCLUSIONS: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach "no evidence of disease activity" status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice. METHODS: Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics. RESULTS: On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia. DISCUSSION: Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.

Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis.

OBJECTIVE: To report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab. METHODS: Retrospective case series. RESULTS: Patient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab. Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab. CONCLUSION: This is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease. Whether this is due to different rates of B- and T cell repopulation has to be the subject of further research. Moreover, further effects on the interactions between the adaptive and innate immunity as well as between B and T cell lineages might explain the observed disease activation.

Break-out session highlights.

A popular feature of the Multiple Sclerosis Experts Summit is interactive break-out sessions to discuss various aspects of multiple sclerosis (MS), including MS spasticity and general management of MS patients. The format encourages participation and active discussion, thus providing attendees with the opportunity to exchange their experiences of the day-to-day management of MS in clinical practice. Following feedback provided by each session leader, key messages are summarized and presented in a plenary session by the Summit chair. Topics covered in this year's country break-out sessions included: triggering factors for MS; decision-making in MS and the importance of patients' risk perception; assessment and management of MS spasticity.