Journal of Neurology最新文献

Background: Vamorolone is a dissociative glucocorticoid receptor agonist for treating Duchenne muscular dystrophy (DMD). The VBP15-006 study assessed vamorolone safety, tolerability, and pharmacokinetics in 2- to < 4 and 7- to < 18-year-old boys with DMD. Results for 7- to < 18-year-old boys, either corticosteroid (CS)-untreated or switching from prior CS treatment, are reported here. Exploratory objectives included efficacy and pharmacodynamic biomarkers related to safety.

Methods: In this phase II, open-label, multiple-dose study, participants received 2 or 6 mg/kg/day vamorolone for 12 weeks, followed by treatment in an expanded access protocol (EAP Canada).

Results: 34 participants (12 CS-untreated, 22 CS-treated) aged 7- to < 18 years were enrolled. Most treatment-emergent adverse events were mild. All 34 participants completed VBP15-006 and entered EAP Canada. During EAP Canada, CS-untreated participants maintained stable linear growth, while CS-treated participants exhibited catch-up growth consistent with serum bone biomarkers (median total vamorolone exposure 1.3 and 1.7 years, respectively). Some weight gain occurred, especially in CS-untreated participants receiving 6 mg/kg/day. Dose-dependent adrenal suppression occurred in CS-untreated and CS-treated participants; 2 individuals who switched from deflazacort to vamorolone 2 mg/kg/day had generalized weakness consistent with adrenal insufficiency. Vamorolone showed dose-dependent pharmacokinetics, rapid clearance, and no accumulation. There were no relevant efficacy changes in CS-treated and CS-untreated groups at either dose.

Conclusions: Vamorolone demonstrated a consistent safety profile in 7- to < 18-year-old boys with DMD. Switching to 6 mg/kg/day vamorolone appeared to mitigate adrenal insufficiency risk. There was no negative effect on growth, and catch-up growth occurred in previously CS-treated individuals switching to vamorolone.

Trial registration: ClinicalTrials.gov: NCT05185622, NCT03863119. First submitted 09-11-2021.

Primary CNS vasculitis (PCNSV) is uncommon, difficult to diagnose, and potentially fatal or at least likely to cause major and persistent neurological deficits, and yet appears highly treatable (although controlled clinical trials remain to be done). Here, we summarize recent advances in the recognition and diagnosis of PCNSV, the crucial role of biopsy and histopathological confirmation of the diagnosis, and currently recommended approaches to treatment. We also sign post areas of potentially fruitful future collaborative study that might advance this difficult disease.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is defined as a dysimmune disorder of the peripheral nervous system (PNS) resulting in sensorimotor deficits. However, an increasing body of data suggests that CIDP also goes along with features, such as autonomic, circadian, fatigue, mood, and subtle cognitive dysfunctions. Some of these non-sensorimotor symptoms (NSMS) challenge the concept of an exclusive PNS disease. Pragmatically, the high prevalence of NSMS calls for a more holistic disease assessment and surveillance to achieve optimal therapeutic results.

Background: Acute vertigo and dizziness are among the most frequent complaints presenting to the emergency department (ED). If acute-onset and persistent vertigo/dizziness (lasting > 24 h) are accompanied by motion intolerance, gait imbalance, nausea/vomitus, and (usually also) nystagmus, this refers to the acute vestibular syndrome (AVS). We aimed at collecting epidemiologic data about the frequency of AVS etiologies for improving the diagnostic workup.

Methods: We conducted a Prospero-registered systematic literature search (MEDLINE, Embase - in June 2024) retrieving information on AVS's clinical presentation, differential diagnosis, and stroke frequency. Two independent reviewers screened abstracts and full texts. Studies were rated with QUADAS-2 for risk of bias. Due to heterogeneity, we refrained from meta-analysis.

Results: We identified 6731 unique articles and 45 manuscripts (reporting on > 5 Mio. dizzy patients) that were included. 3.45% of all ED visits were related to dizziness/vertigo. One tenth (i.e., 0.3%) met the diagnostic criteria for an AVS. Only about 74% of AVS patients received peripheral or central vestibular diagnoses, while 26% were non-specific. Stroke was the second most common cause (21% in our dedicated review) after acute unilateral vestibulopathy (38%). Selected studies assessing infarction location showed posterior-inferior cerebellar artery (36%) involvement most commonly. Stroke cases were seen at similar rates in patients with or without nystagmus (22 vs. 25%).

Conclusion: Representing 10% of all dizzy patients, AVS in the ED is frequent. With a stroke fraction among all AVS cases of approximately 21%, profound clinical training to differentiate peripheral from central causes reliably should be prioritized.

Background: Spinal muscular atrophy (SMA) types III and IV are the most common late-onset forms, and they progress slowly, making the identification of sensitive biomarkers critical. The Motor Unit Number Index (MUNIX) estimates motor unit loss and may complement traditional electrophysiological measurements such as Compound Muscle Action Potential amplitudes (CMAP). However, their respective performances have never been directly compared in adult SMA.

Methods: In a French multicenter study (NCT04690998), 71 adult patients with SMA and 24 healthy controls underwent clinical and electrophysiological evaluation. MUNIX, CMAP, and Motor Unit Size Index (MUSIX) were recorded in four muscles, and sum scores (SumMUNIX, SumCMAP, SumMUSIX) were calculated. Reliability was assessed using intraclass correlation coefficients (ICCs), and associations with functional outcomes were explored.

Results: MUNIX and CMAP effectively distinguished SMA patients from controls, showing strong test - retest reliability. MUNIX showed the highest discriminative performance (AUC = 0.92), while CMAP demonstrated the strongest and most consistent associations with clinical severity. In multivariate analyses, only CMAP remained independently associated with all functional and strength measures, whereas MUNIX and MUSIX lost significance.

Conclusion: MUNIX demonstrated the highest discriminative performance among biomarkers for differentiating SMA from controls, indicating early motor unit loss even when CMAP values were within normal limits. However, disease burden and functional impairment were better reflected by CMAP, probably due to it integrating both motor unit loss and reinnervation. The complementary nature of these profiles supports their combined use (concurrent application), and longitudinal studies are warranted to assess their responsiveness in adult SMA as well as their appropriateness for clinical trial settings.

Background: Air pollution is linked to an increased risk of multiple sclerosis (MS) in adults.

Objective: To investigate the link between air pollutant exposure and pediatric MS (pedMS) in an Italian cohort.

Methods: PEDIGREE (Pediatric Italian Genetic and Environment Exposure) is a multicenter case-control study investigating genetic and environmental factors in MS before the age of 18. Information on environmental and perinatal exposures was collected through the PEQ-IT questionnaire. Air pollution data during the first, second, and third years prior to MS onset (PM2.5, PM10, O3, NO2, SO2, and CO levels) were obtained from the European Monitoring and Evaluation Program database.

Results: Data were available for 113 pedMS cases and 117 controls. We found statistically significant associations between pedMS and higher exposure to ozone (O₃) in the first (OR = 1.11; 95% CI 1.03-1.19; p = 0.007), second (OR = 1.10; 95% CI 1.02-1.18; p = 0.012), and third (OR = 1.09; 95% CI 1.01-1.17; p = 0.025) year before MS onset, even after adjusting for gender, age at onset, sun exposure, parental smoking habit, and socioeconomic background. A one-unit increase in O₃ exposure was associated with a roughly 10% increase in pedMS risk.

Discussion: O₃ may play a significant role in the development of MS by promoting inflammation and oxidative stress.

Anxiety or depression are considered prodromes of Parkinson's disease (PD), though their temporal pattern is not fully defined. This study investigates the temporal relationship between drug-treated anxiety or depression and the clinical onset of PD motor symptoms.We used data from the Moli-sani study, which included 23,395 participants (52% women; mean age 55 ± 12 years, 15 year median follow-up). Participants free of PD at baseline were classified as either non-exposed (N = 20,033) or as having anxiety or depression (N = 1,760), based on both self-reporting and documented use of appropriate medications. Individuals with only one criterion (N = 1,602) were analysed separately. Incident PD cases were identified through regional health records and validated by neurologists and medical records. We used Cox models with inverse probability weighting based on propensity scores.A total of 306 PD cases were recorded (337,372 person-years). Individuals with both self-reported anxiety or depression and medication use had double PD hazard versus non-exposed (HR = 2.02, 95%CI: 1.45-2.80). This association was confirmed with validated PD cases (N = 144; HR = 1.96; 95%CI: 1.21-3.17), and was more evident in those treated for both conditions (N = 395; HR = 3.18, 95%CI: 1.90-5.31). No association emerged for those meeting only one criterion. Excluding subjects with a progressively shorter interval between the onset of anxiety or depression and study exit clearly attenuated the association, which nearly disappeared when the interval was > 10 years. The temporal pattern observed suggests that anxiety and depression requiring pharmacological treatment may represent time-dependent prodromal manifestations of clinical PD, emerging up to 10 years before motor symptoms.

Background: To report the genotype-phenotype correlations in neuronal intranuclear inclusion disease (NIID)-related retinopathy.

Methods: 13 patients from 12 families (62-81 years) clinically diagnosed with late-onset NIID were studied. Best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinography (ERGs) were examined. The number of CGG repeats in NOTCH2NLC was determined. Genotype-phenotype correlations between the number of CGG repeats and the age at onset of ocular symptoms, disease duration, ellipsoid zone (EZ) length of photoreceptors in the peripapillary area, and ERGs amplitudes were determined.

Results: All patients had expanded CGG repeats (100-177 repeat units) in the NOTCH2NLC, and 11 patients noticed ocular symptoms before cognitive decline and two noticed them in their 20 s. FAF decrease and EZ absence in the peripapillary area were observed in all cases. ERGs indicated rod-cone dysfunction. The number of repeats was significantly correlated with an amplitude of all components of scotopic and photopic ERGs except for the b-wave in dark-adapted (DA) 0.01 and DA 10.0 ERGs. The highest coefficient of correlation was found between the amplitudes of the d-wave, a-wave, and the b-wave in light-adapted (LA) ON-OFF ERG (ρ = -0.97, P < 0.001, ρ = -0.92, P < 0.01, ρ = -0.84, P < 0.01 respectively), the b-wave in LA 3.0 (ρ = -0.75, P < 0.01), and 30 Hz flicker (ρ = -0.71, P < 0.05).

Conclusions: Expanded CGG repeats in NOTCH2NLC develop ocular symptoms earlier than reported. The number of repeats can be a biomarker for the severity of retinal dysfunction in NIID-related retinopathy.

Background: Autonomic dysfunction is well recognized in hereditary transthyretin amyloidosis (ATTRv), but it has not been systematically studied in wild-type transthyretin amyloidosis (ATTRwt). Because ATTRwt primarily presents with cardiomyopathy, autonomic symptoms may mimic heart failure and lead to inappropriate treatment. Here we aimed to investigate the presence and extent of autonomic dysfunction in ATTRwt.

Methods: In ATTRwt patients and controls, we performed an extensive autonomic examination, including standardized questionnaires, passive and active orthostatic challenges, Valsalva maneuver, deep breathing and sudomotor assessment.

Results: 20 ATTRwt patients and 20 controls were included. Composite Autonomic Symptom Score 31-scores were similar between the groups. Orthostatic challenges revealed impaired blood pressure (BP) and heart rate regulation in ATTRwt compared to controls (for passive orthostatic challenge: HR p = 0.001, systolic BP p = 0.010) and diastolic BP p = 0.006; for active orthostatic challenge: HR p = 0.001, systolic BP p = 0.002, diastolic BP p = 0.002). A lack of late phase 2 BP overshoot during Valsalva maneuver was observed in ATTRwt and Valsalva Ratio was pathological in 83% of ATTRwt versus 30% of controls (p = 0.020). The rate of pathological sweat tests did not differ between ATTRwt patients and controls.

Conclusions: Autonomic symptoms in ATTRwt were infrequently reported. However, detailed assessment revealed cardiovascular autonomic dysfunction, which contributes to the overall clinical phenotype of ATTRwt.