Evaluation of frequency, severity, and independent risk factors for recurrence of disease activity after fingolimod discontinuation in a large real-world cohort of patients with multiple sclerosis.

Background: Clinical and radiological signs of recurring disease activity (RDA) have been described in patients with multiple sclerosis (pwMS) after discontinuation of fingolimod (FGL). Objective: To describe frequency, severity and potential risk factors for RDA after FGL discontinuation in a large real-world cohort of pwMS. Methods: Post-FGL RDA was defined as evidence of clinical and/or radiological activity within 6 months after FGL discontinuation. Relapses with Expanded Disability Status Scale increase ⩾2 points and/or magnetic resonance imaging (MRI) activity with at least five cerebral gadolinium-enhancing lesions and/or ⩾6 cerebral new T2 lesions were defined as severe recurring disease activity (sRDA). Using a multivariate logistic model, we explored the influence of age, disease duration, sex, clinical, and MRI activity under FGL on the occurrence of RDA. Results: We identified 110 pwMS who discontinued FGL. Thirty-seven (33.6%) developed post-FGL RDA and 13 (11.8%) also fulfilled criteria for sRDA. Younger age at diagnosis [odds ratio (OR) = 1.10, p < 0.01], shorter disease duration (OR = 1.17, p < 0.01), and MRI activity under FGL (OR = 2.92, p = 0.046) were independent risk factors for the occurrence of post-FGL RDA. Conclusion: Individual risk assessment and optimal treatment sequencing can help to minimize the risk of post-FGL RDA. Early switch to highly effective disease-modifying therapy might reduce occurrence of post-FGL RDA.

Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS.

OBJECTIVE: Intrathecal Immunoglobulin M synthesis (IgMIntrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgMIF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS. METHODS: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgGIF + (vs IgGIF - ) or IgMIF + (vs IgMIF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgGIF and IgMIF (>0% vs 0%, respectively): (1) OCGB- /IgGIF - /IgMIF - ; (2) OCGB+ /IgGIF - /IgMIF - ; (3) OCGB+ /IgGIF + /IgMIF - ; and (4) OCGB+ /IgGIF + /IgMIF + . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters. RESULTS: Patients with a spinal syndrome had a 8.36-fold higher odds of IgMIF + (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgMIF + (but not of IgGIF + ); this was not the case for cerebral lesions. OCGB+ /IgGIF + /IgMIF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01). INTERPRETATION: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820.

Exercise and Neuropathy: Systematic Review with Meta-Analysis.

INTRODUCTION: Peripheral neuropathies are a prevalent, heterogeneous group of diseases of the peripheral nervous system. Symptoms are often debilitating, difficult to treat, and usually become chronic. Not only do they diminish patients' quality of life, but they can also affect medical therapy and lead to complications. To date, for most conditions there are no evidence-based causal treatment options available. Research has increased considerably since the last review in 2014 regarding the therapeutic potential of exercise interventions for patients with polyneuropathy. OBJECTIVE: Our objective in this systematic review with meta-analysis was to analyze exercise interventions for neuropathic patients in order to update a systematic review from 2014 and to evaluate the potential benefits of exercise on neuropathies of different origin that can then be translated into practice. METHODS: Two independent reviewers performed a systematic review with meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria according to the PICOS approach were: neuropathic patients, exercise interventions only, an inactive or non-exercising control group, and solely randomized controlled trials with the following outcome parameters: neuropathic symptoms, balance parameters, functional mobility, gait, health-related quality of life, and HbA1c (glycated hemoglobin). RESULTS: A total of 41 randomized, controlled trials met all inclusion criteria, 20 of which could be included in the quantitative analysis. Study quality varied from moderate to high. Current data further support the hypothesis that exercise is beneficial for neuropathic patients. This is best documented for patients with diabetic peripheral neuropathy (DPN) (27 studies) as well as for chemotherapy-induced peripheral neuropathy (CIPN) (nine studies), while there are only few studies (five) on all other causes of neuropathy. We found standardized mean differences in favor of the exercise group of 0.27-2.00 for static balance, Berg Balance Scale, Timed-up-and-go-test, nerve conduction velocity of peroneal and sural nerve as well as for HbA1c in patients with DPN, and standardized mean differences of 0.43-0.75 for static balance, quality of life, and neuropathy-induced symptoms in patients with CIPN. CONCLUSION: For DPN, evidence-based recommendations can now be made, suggesting a combination of endurance and sensorimotor training to be most beneficial. For patients with CIPN, sensorimotor training remains the most crucial component. For all other neuropathies, more high-quality research is needed to derive evidence-based recommendations. Overall, it seems that sensorimotor training has great potential to target most neuropathies and combined with endurance training is therefore currently the best treatment option for neuropathies. REGISTRATION NUMBER: (PROSPERO 2019 CRD42019124583)/16.04.2019.

Hepatitis E virus infections in patients with MS on oral disease-modifying treatment.

OBJECTIVE: To test whether patients with MS on disease-modifying treatments (DMTs) are at a higher risk of acute or chronic hepatitis E virus (HEV) infections or extrahepatic manifestations, we monitored approximately 1,100 persons with MS (pwMS) during 3 years for HEV infection. METHODS: This is an observational case series study. All pwMS were followed in our MS center between January 2016 and December 2018 with at least annual standardized clinical and laboratory assessments. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection. RESULTS: Four cases of acute HEV under DMT (fingolimod [n = 3]; dimethyl fumarate [n = 1]) were identified. Two presented with fulminant icteric hepatitis and one with a HEV-associated neurologic manifestation (neuralgic amyotrophy). No chronic HEV courses were observed. DMT was continued after clearing of HEV or normalization of liver function tests in all cases. CONCLUSION: HEV infection is an important differential diagnosis of drug-induced liver injury in pwMS under DMT. Our data do not suggest an increased incidence of acute HEV infections or chronification in pwMS. However, epidemiologic studies in immunomodulatory-treated patients are needed to further investigate HEV disease courses and extrahepatic manifestations.

A case of progressive multifocal leukoencephalopathy under dimethyl fumarate treatment without severe lymphopenia or immunosenescence.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is the main safety concern for dimethyl fumarate (DMF) treatment in persons with multiple sclerosis (pwMS). Risk stratification under DMF is currently based on age above 50 years and prolonged lymphopenia below 500 cells/µL. OBJECTIVE: To report a case of PML under DMF without severe lymphopenia or immunosenescence. METHODS: Case report. RESULTS: A 39-year-old female pwMS developed DMF-associated oligosymptomatic PML. The patient had not experienced any repeated lymphocyte counts below 800 cells/µL and was 15 years younger than previously described cases. CONCLUSION: Despite risk stratification, vigilance for PML is advised in all pwMS under DMF. Severe CD8-lymphopenia is a common feature of all published DMF-associated cases.

Individually tailored whole-body vibration training to reduce symptoms of chemotherapy-induced peripheral neuropathy: study protocol of a randomised controlled trial-VANISH.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and clinically meaningful side effect of cancer treatment. CIPN is induced by neurotoxic agents, causing severe sensory and/or motor deficits, resulting in disability and poor recovery, reducing patients' quality of life and limiting medical therapy. To date, effective treatment options are lacking. Whole-body vibration (WBV) training can attenuate motor and sensory deficits. We are conducting a two-armed, multicentre, assessor-blinded, randomised controlled trial, to investigate the effects of WBV on relevant symptoms of CIPN and determine the training characteristics. METHODS AND ANALYSIS: In this ongoing study, 44 patients who have completed therapy in the past 3 months, with a neurologically confirmed CIPN are assessed before and after a 12-week intervention and follow-up. The intervention group receives WBV twice a week. Exercises are individually tailored according to the initially determined optimal neuromuscular response. The control group receives care as usual.Primary endpoint is the patient reported reduction of CIPN-related symptoms (Functional Assessment of Cancer Therapy/Gynaecology Oncology Group-Neurotoxicity). Secondary endpoints are compound muscle action potentials, distal motor latency, conduction velocity, F-waves from the tibial and peroneal nerve, antidromic sensory nerve conduction studies of the sural nerve, normalised electromyographic activity, peripheral deep sensitivity, proprioception, balance, pain, the feasibility of training settings, quality of life and the level of physical activity. AIM, ETHICS AND DISSEMINATION: The study was approved by both responsible ethics committees. (1) Our results may contribute to a better understanding of the effects of WBV on motor and sensory functions and (2) may provide information whether WBV at the most effective setting, is feasible for neuropathic patients. (3) Our results may also contribute to improve supportive care in oncology, thereby enhancing quality of life and enabling the optimal medical therapy. All results will be published in international peer-reviewed journals as well as a manual for clinical practice. TRIAL REGISTRATION NUMBER: NCT03032718.

A case of concomitant psoriasis and multiple sclerosis: Secukinumab and rituximab exert dichotomous effects in two autoimmune conditions.

BACKGROUND: Multiple sclerosis (MS) and psoriasis vulgaris (PV) are two disorders with autoimmune pathophysiology and a supposed altered T helper (TH) cell response. OBJECTIVE: To report a case of concomitant relapsing remitting MS and PV treated with different immunomodulatory medications, particularly secukinumab and rituximab. METHODS: Case report. RESULTS: In a 68-year-old woman diagnosed with MS and PV, secukinumab alleviated the dermatological condition, but could not control neuroinflammation. Rituximab treatment halted MS activity, but led to a flare-up of dermatological inflammation. CONCLUSION: The presented case suggests that the pathomechanisms of MS and PV differ regarding involvement of TH and B cells with implications for therapeutic approaches.