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ObjectiveTo determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsThis was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase.ResultsSixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%–7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%–7.4%) or relapses (95% CI 0%–7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0–5.0) and after follow-up (3.0, IQR 2.0–5.0).ConclusionPersonalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations.Classification of evidenceThis study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.

Objective To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening. Methods Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS). Results The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1–1.8) and 1.7 (95% CI: 1.4–2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2–1.8) and 1.55 (95% CI: 1.3–1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant. Conclusions Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.

Objective:To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS).Methods:We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared.Results:Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p Conclusions:Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Objectives:To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).Methods:We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.Results:High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types

Progressive spinal muscular atrophy (PMA) is a disorder characterized by loss of lower motor neurons resulting in progressive muscle weakness. It has been debated whether PMA is a distinct disease entity or should be considered a subtype of amyotrophic lateral sclerosis (ALS). PMA can progress to ALS and the disease course of PMA can be equally relentless, with death due to respiratory failure within 3 years.1 Familiar patients with ALS with mutations in SOD1 can lack UMN signs. Furthermore, pathologic studies of PMA have shown involvement of the corticospinal tract and ubiquinated inclusions, as also observed in ALS. Sporadic ALS and PMA are complex diseases, with environmental and genetic factors contributing to disease susceptibility. Mutations in ALS cases have been found in SOD1 , ANG , and TDP-43 . However, in the majority of cases the genetic background of sporadic ALS is unknown. Over the last 2 years, several genome-wide association studies (GWAS) have been performed in ALS and have highlighted the discovery of three novel candidate genes, including DPP6 .2 This association has now been replicated twice by independent studies.3,4 Considering the clinical and pathologic overlap between ALS and PMA, we investigated the hypothesis that genetic variation in DPP6 may be a risk factor for PMA. ### Methods. A total of 155 …

We studied acetaminophen sulfation, plasma sulfate levels, and the activity of sulfotransferase in blood platelets in patients with Parkinson's disease, Huntington's disease, and in controls and did not find any abnormality in the patient groups, independent of the use of medication.

We studied pathologic changes in sural nerve biopsies from four patients with probable autosomal recessive (AR) hereditary motor and sensory neuropathy (HMSN) type I with a median motor nerve conduction velocity greater than 10 m/sec, comparing them with the pathologic features in autosomal dominant (AD) HMSN type I. The four recessive and two sporadic cases showed segmental demyelination. However, the classic onion bulbs of concentric Schwann cell processes, which occur in AD type I, were rare; many axons, also of a smaller size, were surrounded by onion bulbs of basal laminae. Schwann cells of the myelinated and unmyelinated types were involved in these onion bulb formations. Patients with HMSN type I who have many basal lamina onion bulbs should be considered as having AR inheritance.

To investigate systemic serotonin (5-HT) metabolism in migraine, we determined platelet and platelet-free plasma concentrations of 5-HT, its precursors tryptophan and 5-hydroxytryptophan, and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA), as well as the activities of the platelet enzymes monoamine oxidase and phenolsulfotransferase in classic and common migraineurs. Between attacks, migraineurs had lower plasma 5-HT and higher 5-HIAA levels than did healthy controls and patients with tension headache. During migraine attacks, plasma 5-HT levels were substantially higher than during attack-free periods, while 5-HIAA concentrations and platelet enzyme activities were lower. Platelet 5-HT was reduced only during common, but not classic, migraine attacks. We hypothesize that systemic 5-HT metabolism is enhanced in migraineurs during headache-free periods and transiently decreases during attacks, presumably due to a fall in enzymatic degradation. Furthermore, platelet behavior differs during migraine attacks with and without aura, and release of platelet 5-HT cannot (exclusively) be held accountable for the rise of plasma 5-HT during migraine attacks.