Annals of Clinical and Translational Neurology最新文献

The placebo response in clinical trials in ataxias complicates outcome interpretation and potentially obscures genuine treatment effects. We analyzed placebo group data from past trials in Friedreich Ataxia and observed notable responses in appendicular items, in contrast to minimal changes in axial function, as measured by respective subscores of the modified Friedreich Ataxia Rating Scale (mFARS). The effect increased with the number of consecutive tests, shorter testing intervals, and older group ages. This has implications for trial design and endpoint selection, thus strengthening the utility of the Upright Stability Score (USS), a sub-score of mFARS, as an independent measure.

Objective: Myotonic dystrophy type 2 (proximal myotonic myopathy, PROMM) is a progressive multisystem disorder with muscular symptoms (proximal weakness, pain, myotonia) and systemic manifestations such as diabetes mellitus, cataracts, and cardiac arrhythmias. A hallmark feature is the selective degeneration of type-II fibers, likely driven by chronic myotonia and sustained metabolic stress. In this study, proton magnetic resonance spectroscopy (¹H-MRS) was applied to assess intramuscular carnosine as a potential noninvasive marker of type-II fiber integrity, alongside extramyocellular lipids (EMCL) and intracellular pH. We hypothesized that carnosine would be reduced in PROMM as a consequence of type-II fiber loss.

Methods: Seventy participants (27 genetically confirmed PROMM patients, 43 healthy volunteers) underwent localized ¹H-MRS of the quadriceps muscle at 3 T using a short-TE PRESS sequence. To ensure reliable carnosine quantification, spectra with voxel fat fraction ≥ 40% were excluded, yielding a final cohort of 19 patients and 19 matched healthy volunteers. Metabolites were quantified relative to total creatine, and exploratory correlations were assessed.

Results: PROMM patients showed significantly reduced carnosine compared with healthy volunteers (-50%, 0.05 ± 0.03 vs. 0.10 ± 0.05; p = 0.0022) and markedly elevated EMCL (threefold, 150.6 ± 80.5 vs. 48.6 ± 38.4; p = 0.0007). Intracellular pH did not differ between groups. Exploratory analysis revealed a negative correlation between carnosine and EMCL (r = -0.50, p = 0.03).

Interpretation: This pilot study demonstrates that ¹H-MRS can detect reduced intramuscular carnosine in PROMM, consistent with selective type-II-fiber loss. Carnosine thus emerges as a potential in vivo biomarker of fiber-type-specific degeneration. Validation in larger, longitudinal cohorts is warranted to establish its clinical and translational relevance.

Objective: Neuropsychiatric symptoms are among the most prevalent sequelae of COVID-19, particularly among hospitalized patients. Recent research has identified volumetric brain changes associated with COVID-19. However, it currently remains poorly understood how brain changes relate to post-COVID fatigue and cognitive deficits. We, therefore, aimed to assess structural brain changes after hospitalization for COVID-19 and their associations with cognitive performance and fatigue.

Methods: We analyzed data from n = 57 patients previously hospitalized for COVID-19 (63% male, mean age 52 years) from the prospective, multicentric high-resolution platform of the German National Pandemic Cohort Network (NAPKON-HAP) and n = 57 matched healthy control participants (HC). We assessed cortical thickness and subcortical volumes in high-resolution T1-weighted MRI and their associations with cognitive performance (Montreal Cognitive Assessment) and fatigue (Fatigue Severity Scale).

Results: Patients exhibited statistically significant reductions of cortical thickness in parahippocampal gyri and the temporal lobe (all p[FDR-corrected] < 0.05) as well as reduced hippocampal volumes compared to HC (left, Cohen's d [95% CI] = 0.50 [0.12-0.8]; right d = 0.43 [0.05-0.80]). Higher acute COVID-19 severity was associated with reduced cortical thickness, particularly in the olfactory system. Furthermore, reduced cortical thickness of the temporal poles and the anterior and posterior cingulate gyrus was associated with more severe post-acute fatigue.

Interpretation: Our results identify long-lasting macrostructural brain changes after moderate to severe COVID-19 that correlate with acute disease severity and long-term fatigue. Early identification and targeted interventions for patients at risk of persistent brain changes are needed.

Trial registration: NAPKON-HAP is registered at clinicaltrials.gov (NCT04747366).

Objective: To evaluate whether add-on memantine would exacerbate seizures in people with epilepsy.

Methods: This was a prospective cohort study. People with epilepsy diagnosed with cognitive impairment were consecutively invited. Those who agreed were followed up for at least 24 weeks. Participants were required to be adherent to their antiseizure medication regimens, which had remained unchanged for at least 24 weeks before recruitment. Participants were prescribed memantine and categorized according to their treatment decisions (memantine group vs. non-memantine group). Primary outcome measures were the occurrence of new-onset bilateral tonic-clonic seizure, new-onset status epilepticus, and increased seizure frequency (≥ 25%). The incidence of other adverse events (AEs) and 24-week retention rate were secondary outcome measures.

Results: Two hundred and eleven participants were enrolled (median age, 63; male, 65%). Among them, one hundred and one (48%) started memantine. Baseline seizure characteristics were comparable between the two groups. During follow-up, no new-onset bilateral tonic-clonic seizure was recorded; there was one status epilepticus in the non-memantine group. Increased seizure frequency was reported by 12 (6%) participants (memantine vs. non-memantine, seven vs. five). Other AEs in the memantine group included headache (7%), dizziness (5%), fatigue (4%), drowsiness (2%), and anorexia (2%). The 24-week retention rate was 91%.

Interpretation: Adjunctive memantine was well tolerated in people with epilepsy regarding seizure control and other AEs. Previous warnings might have been disproportionate. Large-scale, randomized trials are required to confirm this and further elucidate its efficacy profiles in epilepsy.

Objective: To elucidate the features of plexin D1-immunoglobulin (Ig)G-associated neuropathic pain and its relationship to atopic myelitis (AM) in a nationwide Japanese survey.

Methods: A preliminary survey questionnaire was sent to 1574 selected departments (neurology and pediatrics/pediatric neurology) to explore the numbers of AM and plexin D1-IgG-positive patients between 2018 and 2022. A secondary survey collected detailed patient data via a questionnaire.

Results: In the preliminary survey, 987 (62.7%) institutions responded, reporting 87 AM patients (49 women) and 11 plexin D1-IgG-positive non-AM patients (8 women). The secondary survey collected 71 AM (plexin D1-IgG-positive: 6/31) and 11 plexin D1-IgG-positive non-AM patients (83.7% recovery rate). In AM, paresthesia/dysesthesia was most frequently experienced (> 90%), followed by pain (> 70%). The underlying diseases in 17 plexin D1-IgG-positive patients, all of whom had neuropathic pain, were AM and small fiber neuropathy in 6 each, neuromyelitis optica spectrum disorder with aquaporin-4-IgG in 2, and painful trigeminal neuropathy, erythromelalgia, and multiple sclerosis in 1 each. When 14 plexin D1-IgG-positive patients (excluding 3 patients with established demyelinating diseases) were compared with 25 plexin D1-IgG-negative AM patients, onset ≥ 50 years old, pain at onset, and allodynia/erythromelalgia/facial pain during the entire disease course were significantly more common in the plexin D1-IgG-positive group. Conversely, atopic disorders and hyperIgEemia were associated with plexin D1-IgG-negative AM but not plexin D1-IgG-positive patients.

Interpretation: Both AM and plexin D1-IgG-positive patients present long-standing neuropathic pain, whereas plexin D1-IgG is particularly associated with aged-onset neuropathic pain, allodynia, erythromelalgia, and facial pain, but not atopy.

Background: Inflammation is a critical risk factor for poor outcomes in cerebral infarction. Prior studies focused primarily on baseline inflammation status, neglecting dynamic longitudinal changes. We try to investigate the association between immune-inflammation status alterations and stroke prognosis, and evaluated three systemic biomarkers' predictive efficacy.

Methods: In this prospective cohort study of ischemic stroke patients, C-reactive protein-albumin-lymphocyte (CALLY), Systemic Immune-Inflammation Index (SII), and Systemic Inflammation Response Index (SIRI) were assessed. Immune-inflammation changes were measured between baseline and a second survey. The primary outcome was death or major disability (modified Rankin Scale score ≥ 3) after stroke onset. Prognostic performance for poor outcomes was evaluated at baseline. The association was calculated by Cox proportional hazard models.

Results: Elevated baseline CALLY correlated with reduced poor outcome risk (OR 0.33, 95% CI 0.20-0.53), while higher SII and SIRI indicated increased risk (SII OR 2.54, 95% CI 1.61-4.06; SIRI OR 2.37, 95% CI 1.47-3.87). Adding these markers to conventional risk factors significantly improved prediction, with CALLY showing the greatest enhancement (C-statistic 0.882 vs. 0.862; p = 0.004; NRI = 29.68%; IDI = 0.39%). Compared to stable mild status, progression to severe status increased poor outcome risk, while recovery to mild status reduced risk (CALLY OR 14.2, 95% CI 2.31-64.27; SII OR 1.27, 95% CI 1.01-7.10; SIRI OR 4.10, 95% CI 1.61-10.71). High inflammatory indices and significant changes predicted poor outcomes.

Conclusions: CALLY demonstrated superior predictive ability for ischemic stroke outcomes versus SII/SIRI. Both baseline levels and dynamic changes in immune-inflammation status significantly correlated with prognosis, suggesting these biomarkers could valuably predict outcomes and guide intervention.

Objective: Peripheral neuropathies contribute to patient disability but may be diagnosed late or missed altogether due to late referral, limitation of current diagnostic methods and lack of specialized testing facilities. To address this clinical gap, we developed NeuropathAI, an interpretable deep learning-based multiclass classification system for rapid, automated diagnosis and differentiation of 88 patients with diabetic peripheral neuropathy (DPN), chemotherapy-induced peripheral neuropathy (CIPN), chronic inflammatory demyelinating polyneuropathy (CIDP), and human immunodeficiency virus-associated sensory neuropathy (HIV-SN).

Methods: A deep learning-based multiclass system was developed to analyze corneal nerve images. These images were preprocessed to train and validate the proposed model and the diagnostic utility was evaluated from the accuracy, F1-score and area under the curve to derive sensitivity, specificity and precision.

Results: NeuropathAI achieved excellent results: AUC-96.75%, sensitivity-83.87%, specificity-95.07%, and demonstrated excellent discrimination for CIDP, CIPN, HIV-SN and DPN with one-vs-all AUC scores of 97%, 93.1%, 99.7% and 96.9%, respectively. Explainability visualization through heatmaps demonstrated that regions of decision making by the model localized to areas with nerve fiber loss, enhancing interpretability.

Interpretation: NeuropathAI achieved rapid and accurate diagnosis of four of the most prevalent peripheral neuropathies globally, underscoring the potential of artificial intelligence-driven corneal image analysis for the rapid diagnosis and differentiation of peripheral neuropathies.

Objective: To describe the use of central stimulants and amantadine for fatigue in MS and evaluate a potential association with reduced work loss in people with MS.

Methods: We conducted a nationwide, matched, register-based cohort study in Sweden (2006 to 2023) using national registers with prospective data collection. We included individuals with MS, identified via the Swedish MS register or ≥ 3 MS diagnoses in the National Patient Register, who initiated treatment with modafinil, amantadine, or central stimulants for ADHD (ADHD-Drugs), along with untreated individuals matched on modafinil start date, age, sex, time since MS diagnosis, and prior-year work loss. The main outcome was monthly work loss, defined as the sum of net days on sick leave, disability pension, and activity compensation.

Results: We identified 2162 new modafinil users, 462 amantadine, 424 ADHD drugs, and 9762 untreated. All cohorts showed increasing work loss before index, followed by no change in work loss over the subsequent 24 months. Modafinil users had a significantly greater attenuation, but with low effect size, of the increasing trajectory of average monthly work loss than untreated (-0.17 days; 95% CI: -0.22, -0.12), with no significant differences between modafinil and other treated groups. Modafinil was the most prescribed treatment, with 1-year prevalence of 8.5% in 2006 and 7% in 2023.

Interpretation: A potential minor treatment benefit is suggested by the statistically significant, small attenuation of worsening work loss following fatigue treatment initiation compared with untreated people with MS. No differences in treatment benefit were observed across fatigue treatments.

We present the case of a 28-year-old right-handed woman with medically refractory focal epilepsy. Her seizure semiology and electroencephalography (EEG) indicated a seizure onset zone in the right central-parietal area. However, both MRI and PET scans were unremarkable, showing no focal lesions or areas of altered metabolism. Intracranial monitoring, with extensive evaluation of both hemispheres, confirmed the seizure onset zone in the right central-parietal region. This area not only served as the site of seizure onset but also encompassed the primary sensory cortex.

Background: Myasthenia gravis (MG) is a rare disorder characterized by fluctuating muscle weakness with potential life-threatening crises. Timely interventions may be delayed by limited access to care and fragmented documentation. Our objective was to develop predictive algorithms for MG deterioration using multimodal telemedicine data.

Methods: In this 12-week randomized controlled study, 30 MG patients recorded symptoms using patient-reported outcome measures (PROMs) and patient-performed measures via a mobile app, alongside data from wearables. MG deterioration was defined as a ≥ 3-point worsening in the Quantitative Myasthenia Gravis score, occurrence of MG-related hospitalization or exacerbation. A machine learning linear classifier was trained to predict deterioration and cross-validated. The area under the receiver operator characteristic curve (AUROC) was calculated, accepting 1-2 false alarms (FAs) per week.

Results: The model achieved the best predictive performance when using all input signals (AUROC 0.85 (95% confidence interval 0.77-0.91)) and remained stable across look-back windows of 4-10 days. Model sensitivity was 0.65 (0.48-0.83) to 0.82 (0.60-1.00) (1 and 2 FAs per week, respectively). PROMs reflected worsening symptoms before deterioration; wearables alone showed higher AUROCs.

Interpretation: Multimodal self-monitoring via MyaLink predicted MG deterioration with good performance at acceptable FA rates. This approach may enable earlier clinical interventions of MG worsening.

Trial registration: The study was registered under the German Clinical Trial Registry (DRKS00029907).