Journal of Neurology最新文献

Objectives: Granulomatous myositis (GM) is a rare entity whose precise clinical features and therapeutic outcomes have not yet been well defined. Given the limited evidence, data from a large cohort of patients is needed to aid in the recognition and management of this condition.

Methods: We retrospectively analyzed our institutional databases to identify patients who had myositis and non-caseating granuloma on muscle biopsy (GM). We collected data on clinical and diagnostic features, management, and outcomes of these cases and compared them with inclusion body myositis (IBM) controls.

Results: 22 GM patients were identified and subdivided into 3 main groups: 13 patients with GM and sarcoidosis (6 of whom subsequently developed suspected or confirmed IBM), 7 patients with idiopathic isolated GM (2 of whom subsequently developed confirmed IBM), 2 patients with GM and Crohn's disease. Patients with GM and sarcoidosis without IBM, as well as patients with isolated GM, exhibited variable clinical presentation ranging from myalgia to mostly symmetrical proximo-distal weakness, with most showing complete or at least partial response to therapies. Patients with GM associated with Crohn's disease had only mild clinical impairment and good therapeutic outcomes. Conversely, patients with GM and IBM presented more severe asymmetric proximo-distal muscle weakness, increased occurrence of dysphagia and poor treatment response, similar to IBM controls.

Conclusions: A frequent association of GM with IBM and/or sarcoidosis was demonstrated in our cohort. When associated with IBM, GM led to treatment refractoriness and more severe clinical impairment, unlike the other GM groups which showed satisfactory outcomes in most cases.

Background: Previous investigations on optical coherence tomography (OCT) in multiple sclerosis (MS) focused on generalizable macular and peri-papillary regions without considering the anatomic variations of the retinal layer thickness.

Objective: This study aimed to assess the utility of parafoveal retinal layer thickness measured by OCT, underscoring its relationships with clinical outcomes in MS.

Methods: In this cross-sectional study, 214 people with MS (pwMS) and 57 age- and sex-matched healthy controls (HCs) were enrolled. Spectral domain OCT evaluation using 1, 3, 6 mm Early Treatment Diabetic Retinopathy Study grid were conducted. The macular and parafoveal thickness (excluding the 1 mm foveal/umbo contribution) of the retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), ganglion cell layer (GCL), inner plexiform layer (IPL), and the peri-papillary RNFL (pRNFL) were measured. Multivariable step-wise logistic, linear and generalized estimating equation (GEE) regression models were used to assess the association between the OCT parameters and clinical MS outcomes.

Results: The parafoveal RNFL thickness (d = 0.27, p = 0.023), GCL (d = 0.87, p < 0.001), IPL (d = 0.82, p < 0.001), and GCIPL (d = 0.85, p < 0.001) were all significantly lower in pwMS than HCs. Optic neuritis history [odds ratio (OR) = 0.84, p < 0.001] and progressive MS (PMS) status (OR = 0.92, p < 0.001) were both best predicted by parafoveal GCL. The Expanded Disability Status Scale (EDSS) was associated with the parafoveal thickness of GCL (standardized β = -0.472, p < 0.001) and pRNFL (standardized β = 0.187, p = 0.021). The parafoveal GCL thickness as predictor of MS disability was also confirmed by the GEE models.

Conclusion: This investigation supports the potential use of parafoveal OCT segmentation as an alternative assessment method in detecting neuroinflammatory and neurodegenerative processes in MS. Averaging of the parafoveal retinal layer thickness into the OCT measures may increase the sensitivity of the standard macular OCT segmentation outcomes. Further studies should aim at exploring the reproducibility of this OCT outcome and its longitudinal responsiveness.

Background: Skeletal and cardiac muscle damage have been increasingly recognized in female carriers of DMD pathogenic variants (DMDc). Little is known about cognitive impairment in these women or whether they have structural brain damage.

Objective: To characterize the cognitive profile in a Brazilian cohort of DMDc and determine whether they have structural brain abnormalities using multimodal MRI.

Methods: Thirty-three DMDc and 33 age-matched healthy women were recruited. The Addenbrooke cognitive examination revised (ACE-R) and the Beck depression inventory (BDI) were used to assess cognition and depressive symptoms. 3T Brain MRI was acquired for both groups. Using volumetric T1 sequence, we computed cerebral cortical thickness (FreeSurfer), basal ganglia (T1 Multi-atlas) and cerebellar (Cerebnet) volumetry. Diffusion tensor imaging (DTI) assessed white-matter integrity (DTI Multi-atlas). Groups were compared using a generalized linear model with Bonferroni-corrected p values < 0.05.

Results: Mean age of DMDc was 38.2 ± 8.2 years, 48.5% of them had abnormal cognition, but only 15% showed meaningful depressive symptoms. Multiple cognitive domains were affected: Attention in 51.5%, Verbal Fluency in 36.4%, Visuospatial Ability in 36.4%, Language in 27.3%, and Memory in 21.2%. Multimodal MRI revealed bilateral, symmetric atrophy in parieto-occipital cortices in DMDc relative to controls, but no basal ganglia, white matter, or cerebellar changes. Parietal cortex thinning correlated with attention, memory, and verbal fluency scores.

Interpretation: DMDc should no longer be seen as 'asymptomatic'. They have cognitive abnormalities and cerebral structural changes compared to healthy women. These manifestations should be actively identified and managed in clinical practice.

Cognitive impairment (CI) in multiple sclerosis (MS) is only partially explained by whole-brain volume measures, but independent component analysis (ICA) can extract regional patterns of damage in grey matter (GM) or white matter (WM) that have proven more closely associated with CI. Pathology in GM and WM occurs in parallel, and so patterns can span both. This study assessed whether joint-ICA of GM and WM features better explained cognitive function compared to single-tissue ICA. 89 people with MS underwent cognitive testing and magnetic resonance imaging. Structural T1 and diffusion-weighted images were used to measure GM volumes and WM connectomes (based on fractional anisotropy weighted by the number of streamlines). ICA was performed for each tissue type separately and as joint-ICA. For each tissue type and joint-ICA, 20 components were extracted. In stepwise linear regression models, joint-ICA components were significantly associated with all cognitive domains. Joint-ICA showed the highest variance explained for executive function (Adjusted R² = 0.35) and visual memory (Adjusted R² = 0.30), while WM-ICA explained the highest variance for working memory (Adjusted R² = 0.23). No significant differences were found between joint-ICA and single-tissue ICA in information processing speed or verbal memory. This is the first MS study to explore GM and WM features in a joint-ICA approach and shows that joint-ICA outperforms single-tissue analysis in some, but not all cognitive domains. This highlights that cognitive domains are differentially affected by tissue-specific features in MS and that processes spanning GM and WM should be considered when explaining cognition.

Background: The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact.

Methods: This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants' distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress.

Results: A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships.

Conclusions: Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.

Background and objectives: Patients with synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease (PD) frequently display speech and language abnormalities. We explore the diagnostic potential of automated linguistic analysis of natural spontaneous speech to differentiate MSA and PD.

Methods: Spontaneous speech of 39 participants with MSA compared to 39 drug-naive PD and 39 healthy controls matched for age and sex was transcribed and linguistically annotated using automatic speech recognition and natural language processing. A quantitative analysis was performed using 6 lexical and syntactic and 2 acoustic features. Results were compared with human-controlled analysis to assess the robustness of the approach. Diagnostic accuracy was evaluated using sensitivity analysis.

Results: Despite similar disease duration, linguistic abnormalities were generally more severe in MSA than in PD, leading to high diagnostic accuracy with an area under the curve of 0.81. Compared to controls, MSA showed decreased grammatical component usage, more repetitive phrases, shorter sentences, reduced sentence development, slower articulation rate, and increased duration of pauses, whereas PD had only shorter sentences, reduced sentence development, and longer pauses. Only slower articulation rate was distinctive for MSA while unchanged for PD relative to controls. The highest correlation was found between bulbar/pseudobulbar clinical score and sentence length (r = -0.49, p = 0.002). Despite the relatively high severity of dysarthria in MSA, a strong agreement between manually and automatically computed results was achieved.

Discussion: Automated linguistic analysis may offer an objective, cost-effective, and widely applicable biomarker to differentiate synucleinopathies with similar clinical manifestations.

Background: The presented study identified the appropriate ocrelizumab dosing regimen for patients with pediatric-onset multiple sclerosis (POMS).

Methods: Patients with POMS aged 10-17 years were enrolled into cohort 1 (body weight [BW] < 40 kg, ocrelizumab 300 mg) and cohort 2 (BW ≥ 40 kg, ocrelizumab 600 mg) during a 24-week dose-exploration period (DEP), followed by an optional ocrelizumab (given every 24 weeks) extension period.

Primary endpoints: pharmacokinetics, pharmacodynamics (CD19⁺ B-cell count); secondary endpoint: safety; exploratory endpoints: MRI activity, protocol-defined relapses, Expanded Disability Status Scale (EDSS) score change.

Results: A total of 23 patients (cohort 1: n = 6, age 10-12 years, BW 27.0-39.0 kg; cohort 2: n = 17, age 11-17 years, BW 42.1-108.4 kg) were enrolled. Median treatment duration was 120 (range, 24-193) weeks at the primary analysis cutoff (October 5, 2023). Overall, the pharmacokinetic data were within the range observed at 600 mg in adult patients with MS; however, the exposure at 300 mg in patients < 40 kg was lower than with 600 mg in patients ≥ 40 kg. Shifting the cutoff to 35 kg would provide better exposure to patients with 35-40 kg body weight. Sustained, near-complete B-cell depletion was observed. The safety profile was consistent with that in adults. EDSS scores remained stable; no clinical relapses were observed.

Conclusion: A dosing regimen of 300 mg ocrelizumab for patients < 35 kg, and 600 mg for patients ≥ 35 kg (every 24 weeks), was selected for the phase 3 OPERETTA II trial (NCT05123703).

Trial registration: ClinicalTrials.gov: NCT04075266.