Journal of Neurology最新文献

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.

Amyotrophic lateral sclerosis (ALS) is more prevalent in males than in females. However, it is unclear whether the difference in sex ratio is observed similarly in sporadic compared to familial ALS. Here, we conducted a systematic review to investigate the differences in sex ratio between familial and sporadic ALS. Following the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, this study searched Ovid MEDLINE, Embase, Emcare, SCOPUS and Cochrane databases. We used a random-effects meta-analysis to estimate sex ratios in a total of 9269 ALS patients (4135 female, 5134 male) across 20 included studies. We confirmed that ALS is more prevalent in males than in females (sex ratio: 1.25 (95%CI 1.14-1.37). However, when we stratified the analyses, the sex ratio was only different in sporadic ALS. Male-to-female ratios were 1.29 (95% CI 1.16-1.42) for sporadic ALS and 1.05 (95% CI 0.93-1.18) for familial ALS. A further analysis showed a pooled risk ratio of 1.07 (95% CI 1.00-1.15), indicating a 7% higher likelihood of males being diagnosed with sporadic rather than familial ALS. These findings highlight the importance of considering sex-specific factors in ALS research and clinical practice.

Background: Neurological disorders, a leading cause of global disability, often cause debilitating dizziness and imbalance. While subjective symptoms are well-documented, the actual prevalence of vestibulo-ocular reflex (VOR) dysfunction in patients with central nervous system (CNS) damage remains unclear due to inconsistent primary studies. This research aims to determine the prevalence of VOR gain dysfunction, as measured by the video Head Impulse Test (vHIT), across neurological disorders.

Methods: Our systematic review searched MEDLINE, CENTRAL, CINAHL, Scopus, ClinicalTrials.gov, and the WHO ICTRP for original articles from 2009 to September 2025. The JBI Checklist for prevalence studies was used to assess the methodological quality, and descriptive analyses were performed, followed by a meta-analysis of proportions using a random-intercept logistic regression model.

Results: We included 48 studies, of which three reported on the same or overlapping samples. Thus, 45 unique studies (1604 participants, 792 females, mean age 56) were described. A meta-analysis of 33 studies (1129 participants) found an overall prevalence of vestibular dysfunction of 48% (95% CI 31-67%). Given the high heterogeneity, we performed subgroup analyses by condition. We found a pooled prevalence of 98% for CANVAS, 73% for ataxia, 44% for Parkinson's disease, 59% for multiple sclerosis, 15% for traumatic brain injury, 5% for multiple system atrophy, and 77% for superficial siderosis.

Conclusion: Isolated semicircular canal dysfunctions, as documented using vHIT, are prevalent in neurological disorders. Future research must elucidate their etiology and diagnostic potential, utilizing comprehensive vestibular assessments. Eventually, these findings should be translated into improved, evidence-based rehabilitation strategies.

Prospero registration: CRD42024575542.

Spinal muscular atrophy (SMA) is a rare inherited disorder that results in skeletal muscle wasting and weakness with a varying degree of severity. Pregnancy is associated with several changes in respiratory muscle function and respiratory physiology, which can compromise breathing leading to complications during pregnancy and delivery. Pregnant women with SMA are therefore considered to be a high-risk obstetric group. Due to the rare nature of the condition, it is infrequently encountered in pregnancy and this highlights the clinical importance of reporting this current case series. We report, in this retrospective case series, the outcomes of eight pregnancies in six women living with SMA, including, to our knowledge, the first reported successful pregnancy in a woman with SMA type-1, managed in our tertiary multi-professional and multi-speciality centre. All pregnancies, over an 18-year period, resulted in healthy live births between 30 and 39 weeks of gestation, six were pre-term (before 37 weeks gestation) and two were term. Although there were no maternal deaths, four women had a deterioration in respiratory function during the second trimester. All, but one returned to their pre-pregnancy state by three months postpartum. One had an obstetric-related post-partum complication and returned to pre-pregnancy baseline by the first year postpartum. Our case series, of a rare neuromuscular condition in pregnancy, strongly supports that appropriate multi-professional and multi-speciality care for pregnant women living with SMA enhances the outcome for both mother and baby. Indeed, two of our women had the confidence to proceed with a second pregnancy, both of which concluded in good outcomes.