Journal of Neurology最新文献

Background: Orthostatic tremor (OT) is a rare, heterogenous disorder, recently sub-classified into primary OT (isolated 13-18 Hz tremor), OT-plus (OT with additional neurological features) and pseudo-OT (OT with frequencies < 13 Hz). However, to our knowledge no study to date has compared clinical characteristics between all three subgroups.

Objectives: We aim to further define and compare the clinical characteristics of the three different OT subgroups, utilising one of the largest described single centre cohorts to date.

Methods: A retrospective analysis was undertaken of clinical records from 74 OT patients at Charing Cross Hospital between 1999 and 2023, enabling categorisation into subgroups. Clinical characteristics, including treatment efficacy and overall disability, were subsequently described and compared between subgroups.

Results: 61 primary OT, 5 OT-plus and 8 pseudo-OT patients were identified. Baseline demographics were comparable between subgroups. Logistic regression suggested age of onset (OR = 1.02, p = 0.229), symptom duration (OR = 1.05, p = 0.083), tremor frequency (OR = 1.02, p = 0.826) and subgroup (OT-plus (OR = 1.86, p = 0.565) and pseudo-OT (OR = 1.41, p = 0.683)) were not significant predictors of disability. Treatment response varied between subgroup, with primary OT and pseudo-OT patients more frequently reporting symptomatic improvement with clonazepam, gabapentin and/or alprazolam than OT-plus patients.

Conclusions: We provide further insight into the clinical phenotypes of the OT subgroups and encourage future studies to validate these findings with larger sample sizes and establish reliable tools to measure OT severity to better assess disease progression and treatment response.

Background: Although many patients with Parkinson's disease (PD) report experiencing episodes of freezing of gait (FOG) at home under ON medication ("On-meds") conditions, objective and accurate diagnosis of different types of FOG events remains an extremely challenging task.

Methods: We conducted an observational, case-control study enrolling 75 consecutive PD patients, who were classified into "freezer" (n = 50) and "non-freezer" (n = 25) group, based on responses to the FOG Questionnaire and clinical confirmation. A modified timed up and go (TUG) protocol comprised one single‑task TUG (sTUG) and two dual‑task TUGs (cognitive, manual). Synchronized video and a single wearable sensor (Ambulosono) provided parallel capture for real‑time detection and subtyping of FOG.

Results: In the "freezers" group, 337 FOG episodes occurred during TUG testing, whereas none were recorded in the "non‑freezers" group (p < 0.01). The mean frequency was 2.25 FOG episodes per person per test. Compared with the sTUG test (74 FOG episodes), dual-task trials identified 263 FOG episodes, representing a 255% increase (p < 0.01). Trembling, shuffling and akinetic subtypes were identifiable on the device display (GMGI), with sensitivity 87.2% and specificity 89.5% versus video. Wearable data also localized subtypes by gait phase (initiation, turning, midway and ending).

Conclusions: "On-meds" FOGs can be objectively diagnosed among self-reported freezers using a dual task protocol during gait tests. Parallel video and wearable sensor recordings facilitate the real-time detection and subtyping of "On-meds" FOGs, which can substantially improve the current clinical practice.

Introduction: Hereditary spastic paraplegias (HSP) are rare inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. This study aimed to characterize an Austrian HSP cohort and prospectively assess disease progression using the Spastic Paraplegia Rating Scale (SPRS), addressing the knowledge gap regarding its longitudinal capabilities in a real-world setting.

Methods: Data from 126 patients were collected at the Center for Rare Movement Disorders Innsbruck. Baseline clinical data were available for 103 individuals. Follow-up extended up to 5 years (mean 2.3 ± 1.9). Disease severity was assessed with the SPRS, and longitudinal progression analyzed using generalized linear mixed models.

Results: The cohort (64.3% male, mean age 47.1 years) included 54.8% patients with complicated HSP. Genetic confirmation was achieved in 54.0%, with SPAST being the most frequent genotype (36.8%). Mean baseline SPRS was 18.2 points. SPRS scores increased significantly with disease duration, with an overall annual progression of 0.9 points (p < 0.001). Progression was faster in complicated versus pure HSP (1.3 vs. 0.6 points/year; p < 0.001). Most patients received symptomatic medication (69.8%) and neurorehabilitation (84.1%).

Conclusion: This study provides comprehensive real-world data on HSP from an Austrian cohort, including clinical, genetic, management, and imaging findings. We present the first prospective assessment of SPRS progression in a natural history cohort, revealing significant longitudinal change. Taken together, our findings may contribute to the design of future therapeutic trials in HSP.

Background: The central vein sign (CVS) is a promising imaging marker of multiple sclerosis (MS). We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of CVS-based rules in the differential diagnosis of MS and to identify the best cutoffs for these rules.

Methods: PubMed, Embase, and Scopus were systematically searched for available evidence. Data extracted were entered into Bayesian models recommended by the Cochrane network. Summary sensitivity and specificity of CVS-based diagnostic rules across different positivity thresholds were calculated. A meta-regression for the role of gadolinium-based MRI protocols was also performed.

Results: 3434 patients from 28 studies were included. Three CVS-based diagnostic rules were found: the first one considers the percentage of CVS + lesions (relative threshold method), the second one the presence of CVS in a given number of lesions selected in T2 sequences (select-n method), and the third one the presence of a given number of CVS + lesions in gradient-echo sequences (select-n* method). For relative threshold method, the best cutoff was 37.5% (sensitivity 97.3%, 95%CI 90.9-99.6%; specificity 90.4%, 95%CI 83.2-95.9%; Youden index 0.877); for select-n* method, 4 was the best threshold (sensitivity 87.1%, 95%CI 66.9-96.6%; specificity 88.2%, 95%CI 65.1-98.1%; Youden index 0.753). Use of gadolinium-based MRI protocols was irrelevant (for relative threshold method RDOR = 6.62, 95%CI 0.68-71.27; for select-n* method RDOR = 2.52, 95%CI 0.35-15.36).

Conclusions: Relative threshold and select-n* methods are good predictors of MS diagnosis. This synthesis should support the use of CVS in clinical practice and prompt further research.

Introduction and objective: Depending on the methodology used, the prevalence of restless legs syndrome (RLS) in people with multiple sclerosis (PwMS) ranges from 13 to 65%. This study aimed to evaluate the prevalence of RLS in PwMS using a case-control design, with each case confirmed by a sleep disorder specialist.

Methods: Prevalence of RLS was analyzed in a hospital cohort of 440 PwMS and 241 age- and sex-matched control subjects. Cases were identified through two interviews. First, participants answered to a structured questionnaire, and second, those who met the criteria for any cardinal RLS symptoms were interviewed by a sleep disorder specialist to confirm the diagnosis. Multivariate regression was used to analyze the clinical and radiological characteristics of MS associated with RLS.

Results: Of the 86 PwMS who tested positive for RLS using the questionnaire, 67 were diagnosed by a sleep specialist, corresponding to a prevalence of 15.23% (95% CI 11.80-19.34) compared to 19.55% (95% CI 15.63-24.14) based solely on the questionnaire (false positive: 22.09%). PwMS were twice as likely to suffer from this syndrome as the control group (OR 2.148, 95% CI 1.218-3.788, p = 0.008). Family history of RLS (OR 5.291, 95% CI 2.407-11.629, p < 0.0001) and pyramidal tract involvement (OR 4.208 95% CI 1.940-9.128, p < 0.0001) were the only factors associated with RLS.

Conclusion: PwMS are twice as likely to develop RLS as the general population. Pyramidal tract involvement appears to be a risk factor for developing RLS in this disease.

Background and purpose: Dominant PURA variants (encoding purine-rich element-binding protein A) cause a neurodevelopmental disorder with hypotonia, cognitive impairment, and variable neuromuscular symptoms. Clinical presentations and response to pyridostigmine, moreover, highlighted neuromuscular junction (NMJ) involvement. However, NMJ architecture, underlying molecular mechanisms, and potential minimally invasive biomarkers in PURA syndrome remain poorly characterized. This study aimed to profile PURA-related disease using integrated clinical, histological, ultrastructural, transcriptional, and protein analyses of skeletal muscle and blood.

Methods: Ten genetically confirmed patients underwent detailed phenotyping with emphasis on congenital myasthenic syndrome (CMS)-like features. Quadriceps biopsy from one patient was analyzed by histology, immunohistochemistry, and electron microscopy. Protein profiling of muscle, serum, and extracellular vesicles (EVs) was performed by ELISA and mass spectrometry, with validation by qPCR.

Results: In line with the recognized classification of PURA syndrome as a CMS subtype, our patients exhibited hypotonia, ptosis, ocular weakness, and myopathic facies, reflecting impaired neuromuscular transmission. Subtle vesicle accumulation and minor NMJ alterations suggest possible neuromuscular involvement in PURA syndrome. Muscle proteomics showed reduced PURA protein and dysregulation of transcriptional regulation, vesicle transport, extracellular matrix remodeling, and complement activation. qPCR confirmed POSTN and PHGDH upregulation among others. Serum analyses demonstrated elevated TSP4, identifying a promising candidate blood biomarker for PURA-associated NMJ dysfunction. EV proteomics revealed dysregulated immunoglobulins, complement components, and novel candidates including NOTCH2, TARSH, and PON1.

Conclusions: Pathogenic PURA variants may impair NMJ structure and vesicle homeostasis, potentially linking molecular and ultrastructural defects with clinical myasthenic features and pyridostigmine responsiveness. Proteomic analysis of skeletal muscle provides initial molecular insights into the consequences of dominant PURA variants in muscle tissue. The identification of TSP4 and extracellular vesicle-associated proteins as potential minimally invasive biomarkers provides a framework for biochemical monitoring of PURA syndrome.

Cerebral amyloid angiopathy (CAA) is a common small vessel disease characterized by Aβ deposition in cortical and leptomeningeal arteries, leading to lobar intracerebral hemorrhage and vascular cognitive impairment. Despite advances in diagnosis, prognosis remains highly heterogeneous, encompassing risks of recurrent hemorrhage and progressive cognitive decline. This review summarizes recent developments in imaging and fluid biomarkers for prognostic stratification in CAA. Imaging markers, including advanced MRI and molecular PET techniques, have evolved from traditional hemorrhagic indicators, such as cerebral micro-bleeds (CMBs) and cortical superficial siderosis (cSS), to non-hemorrhagic including white matter hyper-intensities (WMHs), and enlarged perivascular spaces (ePVS), which sensitively capture microstructural damage after using quantitative measures. Fluid biomarkers provide dynamic insights into vascular and neuronal injury, including altered plasma Aβ42/Aβ40 ratios, MMPs/TIMPs balance, and elevated neuro-filament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels. Integrating these multi-modal indicators may enable individualized prediction of hemorrhagic and cognitive outcomes and inform precision management strategies. Future research should standardize quantification methods and validate multi-modal models across diverse CAA phenotypes to advance toward personalized prognostic frameworks.

Background: Understanding how meaningful symptoms and impacts of Parkinson's change with time is necessary to select endpoints for clinical trials and to support clinical practice.

Objective: This study aimed to longitudinally evaluate the prevalence, bothersomeness, and functional impacts of early Parkinson's symptoms on daily life over a three-year study duration.

Methods: 32 participants with early Parkinson's completed qualitative interviews to map symptoms and impacts of disease annually for three years. Symptom maps were content coded for frequency and bothersomeness of symptoms and presence of related impacts. Non-parametric generalized linear mixed models (GLMM) were used to evaluate change over time.

Results: The most bothersome motor symptoms were tremor, gait difficulties, balance, fine motor, slow movements, and stiffness at all years. Top non-motor symptoms were fatigue, sleep, mood changes, difficulty thinking, and quiet voice. Of these, only gait and balance changed significantly over the study duration. By contrast, many functional impacts changed significantly, with all reporting increased work of living and greater effort to do usual activities by year 3. At the same time, participants reported increased ability to cope and compensate by making positive life changes which mitigated the bothersomeness of symptoms.

Conclusions: Other than gait and balance, few Parkinson's symptoms increased significantly in bothersomeness over three years. However, functional and psychosocial impacts of symptoms, often attributed to more than one cause, were more sensitive to change over time.