Neurology International

Background/Objectives: Migraine may be associated with structural changes in the brain, including the cerebellum and brainstem. Some of these changes reflect the brain’s plasticity in adapting to migraine-related alterations, but others may influence the severity of migraines and resistance to treatment. Some studies report changes in cortical thickness among migraine patients, and focal cortical dysplasia (FCD) has been considered a possible cause of these changes. We argued that FCD could contribute to the development of migraine and the severity of its symptoms. To date, there has been no consistent report of FCD occurring in migraine patients. Case: A 29-year-old woman presented with a history of at least 19 years of high-frequency episodic migraine without aura. She experienced motion sickness during childhood and adolescence. Her condition worsened last year, evolving into chronic migraine, which was partially controlled by medications such as amitriptyline and rizatriptan, leading to high-frequency episodic migraines. An MRI conducted in 2024 showed a small area of signal abnormality in the left occipital lobe, believed to represent cortical dysplasia. A follow-up MRI after three months showed no changes in this area. She is currently diagnosed with high-frequency episodic migraine and demonstrated severe migraine-related disability, with a MIDAS score of 25, and a severe impact on daily functioning, with a HIT-6 score of 65. Conclusions: The case involves a worsening migraine that was somewhat alleviated by a pharmacological intervention. FCD may contribute to brain hyperexcitability in this case and her motion-related problems during childhood and adolescence. FCD could also play a role in the increasing severity of her migraines and her partial resistance to medication. Full article

Brachial plexus injuries are challenging conditions. Over the past decades, nerve transfer surgery has progressively evolved from proximal nerve reconstruction toward selective distal neurotization strategies, considerably expanding the possibilities for functional restoration. As the number of described donor–recipient combinations has increased, the literature has become increasingly fragmented, often focusing on isolated techniques or specific functional targets. The aim of the present study was to provide a comprehensive state-of-the-art overview of currently available motor nerve transfer strategies for upper-limb reinnervation in BPI. A literature review was conducted according to PRISMA guidelines using PubMed/MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science databases. Studies concerning motor nerve transfers for upper-limb reconstruction were systematically reviewed and categorized according to recipient nerve and functional target, including shoulder function, scapular stabilization, elbow flexion and extension, wrist and finger extension, wrist and finger flexion, intrinsic hand function, and extraplexal donor nerve reconstruction. A total of 250 studies met the inclusion criteria. Both intraplexal and extraplexal donor strategies were identified for most reconstructive targets. Intraplexal distal nerve transfers currently represent the preferred approach whenever feasible because of shorter reinnervation distances and more predictable outcomes. Extraplexal donors, including the spinal accessory, intercostal, contralateral C7, and phrenic nerves, remain essential in complete BPIs and root avulsion injuries. Despite substantial advances, restoration of intrinsic hand function and reliable distal reinnervation remain major reconstructive challenges. Motor nerve transfers represent an increasingly versatile and function-oriented reconstructive strategy that should be tailored to the individual injury pattern, available donor nerves, and functional priorities. Full article

Introduction: Congenital myasthenic syndrome (CMS) is a rare hereditary disorder of the neuromuscular junction caused by pathogenic variants that affect acetylcholine transmission. We report three pediatric cases with CMS, including a rare homozygous CHRNE mutation previously described only once, a novel CHRNE compound heterozygous variant, and two novel DPAGT1 variants associated with limb-girdle CMS (LG-CMS), thereby expanding the known genetic and phenotypic spectrum of the disorder. Case presentation: The first patient, a 4-year-old girl born to consanguineous parents, presented with bilateral ptosis and fatigable weakness since infancy. Whole-genome sequencing revealed a homozygous CHRNE variant, c.991C>T. The second patient, a 4-year-old boy born to non-consanguineous parents, presented with congenital bilateral ptosis and ophthalmoplegia without generalized weakness. Genetic analysis identified compound heterozygous CHRNE variants, c.905C>G and c.1040T>C. Both patients demonstrated marked improvement with pyridostigmine therapy. The third patient, a 3-year-old girl born to non-consanguineous parents, presented with severe limb weakness requiring assistance in walking and performing daily activities with minimal ocular involvement, suggesting a diagnosis of LG-CMS. Genetic testing identified two novel variants in the DPAGT1 gene in the compound heterozygous form, c.710G>T and c.858C>A. The initial response to pyridostigmine diminished over time. Conclusions: These cases underscore the phenotypic heterogeneity of CMS, even within the same genetic subtype, and expand the existing mutational spectrum of CHRNE and DPAGT1 genes. This study also highlights the essential role of molecular diagnosis in distinguishing CMS from other neuromuscular disorders. Early genetic confirmation facilitates genotype-targeted therapy, prevents inappropriate immunosuppression, and enables informed reproductive counseling. Full article

Background: As survival improves in transfusion-dependent β-thalassemia, long-term adult morbidity, including cognitive dysfunction, has become increasingly relevant. Adult data remain limited, particularly in Eastern Europe, and many studies rely on single screening tools with limited control for confounding. Methods: We conducted a single-center case–control study (2024–2025) at the Congenital Hemolytic Anemia Treatment Center, University Hospital “Sv. Georgi” Plovdiv, Bulgaria. Fifty adults with transfusion-dependent β-thalassemia (86% thalassemia major; 14% transfusion-dependent intermedia) and 30 frequency-matched healthy controls completed a multi-domain cognitive battery: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Trail Making Test (TMT-A/B), and timed verbal fluency. Associations between thalassemia status and cognitive outcomes were estimated using three prespecified models: unadjusted, adjusted for age and sex, and a doubly robust model combining covariate balancing propensity score inverse probability weighting (balancing BMI, smoking, education, and comorbidity) with age/sex regression adjustment. Results: Patients performed worse than controls on global cognition and executive/visuospatial measures. MoCA scores were lower in patients (−2.26 unadjusted, p = 0.016; −2.83 doubly robust, p = 0.001), as were MMSE scores (−1.64, p = 0.015; −1.87, p = 0.002). CDT performance was consistently poorer (OR ≈ 0.28–0.30 across models). Patients were slower on TMT-B (time ratio 1.35 unadjusted, p = 0.003; 1.42 doubly robust, p < 0.001); TMT-A reached significance only after weighting (ratio 1.32, p = 0.001). Verbal fluency was modestly lower with borderline significance (p ≈ 0.05–0.06). Conclusions: Transfusion-dependent β-thalassemia in adults is associated with poorer cognitive performance, particularly in global cognition and executive/visuospatial domains, with results robust across adjustment strategies. Routine multi-domain cognitive screening may be warranted in adult thalassemia care. Full article

Background/Objectives: Artificial intelligence (AI) tools are increasingly integrated into acute stroke imaging workflows, but real-world performance for ischemia detection on non-contrast CT (NCCT) remains incompletely validated by investigators independent of the developer. This study externally validated the BrainScan AI system in an unselected, consecutively enrolled emergency cohort. Methods: Consecutive adult patients undergoing NCCT under the routine acute stroke protocol at a single tertiary centre between January and December 2025 were prospectively enrolled. The reference standard was the post-consensus radiological diagnosis, supplemented where available by follow-up imaging and clinical course. Primary outcomes were diagnostic accuracy for ischemia and intracranial haemorrhage detection, assessed by sensitivity, specificity, predictive values, likelihood ratios, and area under the ROC curve (AUC; DeLong). Pre-specified secondary analyses included regional sensitivity, confidence-score behaviour, artefact robustness, threshold sensitivity, a cluster-robust bootstrap for within-patient correlation, and a quantitative bias analysis under non-differential reference-standard misclassification. Sample size adequacy was assessed using a precision-based framework. Results: A total of 1419 NCCT examinations from 1260 patients were analysed. Ischemia sensitivity was 59.2% (95% CI 52.1–66.1) and specificity was 99.8% (99.4–100), with an AUC of 0.930 (0.906–0.954). The Youden-optimal threshold (0.055) recovered sensitivity to 86.1% with negligible specificity loss, reflecting a markedly bimodal score distribution. Regional sensitivity was lower in infratentorial structures. Bias-corrected estimates were stable across all reference-standard parameters consistent with the data. Haemorrhage detection performed substantially better (sensitivity 96.7%; AUC 0.983). Conclusions: The system shows excellent specificity and strong discrimination but moderate sensitivity for ischemia, supporting its role as a rule-in adjunct rather than a stand-alone tool, pending multicentre validation and site-specific threshold recalibration. Full article

Background: Trigeminal neuralgia (TN) is clinically defined, but patients presenting to tertiary practice with trigeminal-region pain are often diagnostically heterogeneous and may follow prolonged medication, dental, imaging, and procedural pathways before a stable phenotype is established. We aimed to characterize diagnostic phenotypes, secondary causes, and treatment-escalation patterns in a large retrospective tertiary-center trigeminal pain cohort derived from routine free-text clinical documentation. Methods: We conducted a retrospective single-center cohort study based on a clinical dataset containing 18,007 note fragments linked to 672 unique patient records between 12 October 2010 and 21 April 2026. A rule-based natural-language-processing-assisted chart review framework was used to identify patients with trigeminal pain and to extract documentation-derived demographic features, pain distribution, secondary causes, dental pathway variables, imaging signals, medication exposure, procedures, and outcome language. Patients were grouped into primary/classical TN, secondary TN/trigeminal pain, and dental-first or mimic pathways using predefined operational criteria. Results: A total of 455 patients met criteria for the analytic trigeminal pain cohort; 311 (68.4%) carried explicit TN terminology. Mean age was 58.7 years, median age 60 years, and 267 of 428 patients with recoverable sex data (62.4%) were women. Trigeminal branch involvement could be extracted in 351 patients (77.1%), with V2 involvement documented in 256 (56.3%), V3 involvement in 218 (47.9%), and V1 involvement in 138 (30.3%). The final NLP-derived phenotypic distribution comprised 201 primary/classical TN cases (44.2%), 146 secondary TN/trigeminal pain cases (32.1%), and 108 dental-first or mimic presentations (23.7%). MRI was documented in 384 patients (84.4%), neurovascular conflict or vascular loop in 253 (55.6%), multiple-sclerosis-related disease in 69 (15.2%), and tumor-related trigeminal involvement in 84 (18.5%). Prior dental evaluation was identified in 169 patients (37.1%), and prior dental procedures in 114 (25.1%). Carbamazepine exposure was documented in 367 patients (80.7%), pregabalin in 221 (48.6%), gabapentin in 150 (33.0%), oxcarbazepine in 116 (25.5%), and phenytoin in 73 (16.0%). At least one invasive or image-guided procedure was documented in 390 patients (85.7%), including nerve blocks/injections in 355 (78.0%), radiofrequency procedures in 126 (27.7%), balloon compression in 90 (19.8%), microvascular decompression in 113 (24.8%), and stereotactic radiosurgery in 55 (12.1%). Dental-first patients were significantly more likely to have undergone prior dental procedures (65.7% vs. 3.5% in primary/classical TN and 24.7% in secondary TN; p < 0.001), whereas secondary TN/trigeminal pain was associated with higher use of radiofrequency procedures (36.3%; p = 0.017), higher use of stereotactic radiosurgery (19.9%; p = 0.002), higher recurrence documentation (70.5%; p = 0.001), and a higher rate of complete pain relief documented at last follow-up (46.6%; p = 0.004). Conclusions: In tertiary practice, trigeminal pain is substantially broader than a formal TN label. Secondary disease and dental-first pathways account for a large fraction of referrals, and management is characterized by heavy medication burden, frequent escalation, and recurrent retreatment. A structured phenotyping approach may help convert routine clinical documentation into a clinically meaningful framework for diagnostic triage and treatment selection, although imaging and outcome variables require cautious interpretation when derived from retrospective free text. Full article

Background: Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS. Materials and Methods: We used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures. Results: Before matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52–0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26–0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39–0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles. Conclusions: In this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation. Full article

Background/Objectives: Cortical spreading depolarization (SD) is recognized as the pathophysiological substrate of migraine aura. Suppression of ongoing cortical activity produced by SD is thought to underlie the transient neurological deficits characteristic of the aura phase. While cortical hyperexcitability is a well-established feature of migraine brain, the effect of SD on spontaneous electrical activity in the hyperexcitable cortex remains poorly understood. Here, we investigate how SD and SD-induced depression of cortical activity are modulated by a state of mildly enhanced excitability. Methods: Using freely behaving rats, we assessed characteristics of SDs, electrocorticographic spectral power in the frontal and occipital cortices during interictal period and after SD initiation, under both drug-free conditions and following mild pharmacological disinhibition. Results: Mild cortical disinhibition resulted in a significant increase in baseline oscillatory power relative to control conditions. While cortical hyperexcitability did not alter the properties of SD itself, it differentially modulated the impact of SD on spontaneous activity in a region-specific manner. Notably, under conditions of enhanced excitability, the duration of SD-induced depression was markedly reduced in the frontal cortex but prolonged in the occipital cortex. Conclusions: These findings demonstrate that the effects of SD on spontaneous cortical activity are critically dependent on the baseline level of cortical excitability and exhibit distinct regional heterogeneity. In the awake, hyperexcitable state, the occipital cortex shows heightened vulnerability to SD-induced depression, a finding that may provide a mechanistic basis for the disproportionate involvement of the occipital cortex in aura generation and the predominance of visual symptoms in migraine aura. Full article

Background/Objectives: Yes-associated protein 1 (YAP1) is a transcriptional cofactor that coordinates the complex interplay between cell proliferation, survival, differentiation, metabolism, biomechanics, and tissue regeneration. Previous studies have shown that YAP1 activity is reduced during aging, and replacing YAP1 function has been shown to rejuvenate old cells by mitigating senescence and its associated inflammation. Methods: As YAP1 is now confirmed to exert a profound regenerative influence on multiple organs, we wanted to gain more insight into the molecular signature of YAP1 expression relevant to brain cells. Since proteomics is a very powerful tool for discoveries, we generated SH-SY5Y cells stably expressing GFP-YAP1 and screened 8000 human proteins using multiplex arrays that utilize biotin-label-based antibody arrays. Results: We found YAP1 expression in astrocytes, microglia, neuronal and neuroblastoma cell lines, as well as human neurons. Importantly, YAP1 protein levels were significantly reduced selectively in the nuclear fractions of the brains of patients with Alzheimer’s disease (AD) relative to normal control (NC) subjects. The screen resulted in the identification of 283 differentially expressed proteins. In line with YAP1’s known role in the regulation of actin and cytoskeleton, we found a 2.53-fold upregulated level of Rho guanine nucleotide exchange factor 1 (ARHGEF1), a guanine nucleotide exchange factor (GEF) for the RhoA GTPase, which is crucial for dendritic spine regulation. A 6.19-fold upregulated level of NECAP endocytosis-associated 2 (NECAP2), the highest known increase for any protein in this screen, plays an essential role in clathrin-mediated endocytosis. Most importantly, another upregulated protein was Neudesin Neurotrophic Factor (NENF) (3.07-fold increase), also known as Neudesin, which primarily acts as a neurotrophic factor, and it promotes neuronal survival, enhances cell proliferation, and neurogenesis in neural progenitor cells. Neural Precursor Cell Expressed, Developmentally Down-Regulated 9(NEDD9) levels were also upregulated by 2.46-fold, and it affects neuronal cell number and synaptic connections through its role in neurite formation. However, it should be noted that these proteomic results are preliminary in nature as they are derived from single-sample data. The upregulated levels of ARHGEF1 and NEDD9 were confirmed by immunoblots. We also found a drastic reduction in the levels of p16INK4a, a marker of senescence. Conclusions: Thus, the anti-senescence effect of YAP1 may be mediated through p16INK4a, which in turn may be crucial for YAP1’s regenerative functions through NENF and NEDD9. Full article

Background/Objectives: Multiple sclerosis (MS) remains challenging to diagnose due to clinical and radiological overlap with mimicking conditions. The 2024 revisions of the McDonald criteria have incorporated the central vein sign (CVS) and paramagnetic rim lesions (PRLs) as magnetic resonance imaging (MRI) biomarkers to improve diagnostic specificity. This study assessed the prevalence and anatomical distribution of CVS and PRLs in patients with relapsing–remitting MS (RRMS). Methods: This cross-sectional study included 91 patients with RRMS diagnosed according to the 2017 McDonald criteria. MRI scans were obtained using 3T scanners, and T2-FLAIR and susceptibility-weighted angiography (SWAN) sequences were analyzed. CVS and PRLs were identified using established criteria. Patients were stratified by lesion count (<5, 5–9, ≥10), and lesions were categorized by anatomical location. Descriptive statistics, chi-square tests, and multivariable logistic regression adjusted for covariates were performed. Results: CVS was present in 69.2% of patients, while PRLs were identified in 29.7%. Both markers were more frequent in patients with higher lesion burden in univariate analysis. CVS prevalence increased significantly with lesion count (p < 0.001) and remained an independent predictor in multivariable logistic regression. PRL presence was associated with lesion count in univariate analysis but not after adjustment. Most CVS- and PRL-positive lesions were supratentorial and predominantly periventricular. No significant association was observed between CVS and PRL presence. Conclusions: CVS is a highly prevalent MRI feature in RRMS and independently associated with lesion burden, supporting its role as a diagnostically relevant imaging marker. PRLs were less prevalent and showed weaker independent associations. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Background/Objectives: The optimal upfront modality selection for real-world aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We evaluated outcomes after an institutional change from an endovascular treatment (EVT)-first default to a modality-neutral individualized pathway. Methods: This single-center retrospective before-and-after cohort study included consecutive patients with aSAH who underwent aneurysm securing during two fixed time periods (pre-change: 1 May 2023 to 31 July 2024; post-change: 1 August 2024 to 31 October 2025). The primary outcome was a favorable 90-day modified Rankin Scale (mRS) score of 0–2. The primary analysis used Firth penalized logistic regression adjusted for age, pre-morbid mRS ≥ 2, and World Federation of Neurosurgical Societies grade IV–V. Conventional logistic regression and ordinal mRS shift analysis were performed as sensitivity analyses. Results: A total of 104 patients were included (pre-change, n = 48; post-change, n = 56). EVT decreased from 79.2% to 37.5%, and microsurgery increased from 20.8% to 62.5% (p < 0.001). Favorable outcomes occurred in 25/48 patients (52.1%) in the pre-change period and 36/56 patients (64.3%) in the post-change period (p = 0.235). In adjusted analyses, the post-change period was associated with favorable outcome (aOR 3.82; 95% CI, 1.31–12.79; p = 0.009), consistent with the sensitivity analysis (aOR, 4.41; 95% CI, 1.43–15.95; p = 0.009). Shift analysis also favored the post-change period (adjusted common OR, 2.36; 95% CI, 1.15–4.91; p = 0.021). Secondary outcomes and procedure-related complications were similar between the two periods. Conclusions: A shift from an EVT-first default to a modality-neutral individualized pathway was associated with more favorable adjusted 90-day functional outcomes. Multicenter confirmation is warranted. Full article

Background/Objectives: Birth asphyxia is a frequent neonatal complication in humans. Its outcome is variable, and the factors underlying this variability remain incompletely understood. Maternal gut microbiome impairment has been proposed as one factor that may influence offspring neurodevelopment, especially when the immature brain is exposed to additional vulnerability such as perinatal asphyxia (PA). Building on our previous maternal microbiome disruption model and on our prior observation that electroencephalography (EEG) reactivity to photic stimulation under deep anesthesia detects functional impairment two months after PA, we assessed whether this reactivity was further impaired after prolonged gestational antibiotic administration and whether probiotics modulated this effect. Methods: Wistar dams received antibiotics, probiotics, antibiotics with probiotics, or control treatment, and offspring underwent PA. Adult EEG reactivity to photic stimulation was assessed during chloral hydrate-induced burst suppression. Burst count reactivity (BCR) was used as the primary event-based readout of stimulus-evoked burst recruitment and was compared with the suppression-ratio-based burst-suppression reactivity index (BSRi). Results: Burst suppression remained reactive to photic stimulation in all groups. BCR was lower after gestational antibiotic treatment than in controls. The magnitude of the effect was attenuated by probiotics coadministration. BSRi showed the same overall pattern. Conclusions: Prolonged gestational antibiotic exposure increased the severity of perinatal asphyxia as measured by EEG reactivity in the adult offspring. The converging BCR and BSRi results support burst-suppression reactivity as a functional neurophysiological readout in this PA model and support further methodological development of EEG reactivity measures for translational studies of hypoxic–ischemic brain injury. Full article

Background/Objectives: Stroke remains a leading cause of global disability, with upper limb impairment affecting over 80% of patients. During the acute phase (first seven days), a critical neuroplastic window exists where interventions may significantly influence recovery. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of electrical stimulation—specifically Functional Electrical Stimulation (FES) and Neuromuscular Electrical Stimulation (NMES)—on upper limb functional recovery and complication prevention during the acute phase of stroke. Methods: A systematic search was conducted across eight databases (including Medline, PEDRo, and Cochrane) for randomized and non-randomized clinical trials published between 2016 and 2025. Methodological quality was assessed using the PEDRo scale. Quantitative synthesis was performed via meta-analysis using a random-effects model, focusing on the Fugl-Meyer Assessment (FMA-UE). Results: Eight randomized clinical trials were selected with a total of 384 participants. The meta-analysis results showed a positive and statistically significant effect in favor of the experimental group compared to the control group (Z = 2.39; p = 0.02), with a combined Standardized Mean Difference of 0.53 (95% CI: 0.10 to 0.96), indicating a moderate effect size on the Fugl-Meyer Assessment Upper Extremity scale. Although high heterogeneity was detected (I² = 74%), the analysis suggests that Functional Electrical Stimulation (FES) and Neuromuscular Electrical Stimulation (NMES) improve manual dexterity, prevent disuse atrophy, and reduce glenohumeral subluxation. Conclusions: Electrical stimulation shows a positive trend in early stroke recovery; however, it should be considered a promising adjunct rather than a definitive treatment. Further research into standardized protocols is required to confirm their clinical significance. Full article

To this day, the etiology of multiple sclerosis has yet to be fully comprehended by the scientific community. However, the knowledge on mechanisms leading to the development of this neurodegenerative autoimmune disorder increases daily, along with the development of new disease-modifying treatments. A correlation between Epstein–Barr Virus infection and the disease incidence has recently shed light on possible innovative antiviral therapies. Here, we review the literature on Human Endogenous Retroviral sequences as emerging actors for the impairment of remyelination as a major challenge in disease progression. Our primary focus is the HERV-W envelope protein, which has been found at elevated levels in individuals affected by this condition and is suggested here as a potential therapeutic target. We then continue analyzing the clinical cases where antiretroviral drugs have been tested to treat multiple sclerosis patients and, from successes and failures, we finally narrow down our therapeutic hypothesis to the administration of Nucleoside-analog Reverse Transcriptase Inhibitors to target the HERV-W envelope protein, possibly leading to remyelination and significantly improving the condition of those affected by the disease. The main purpose of this review is to present a rationale for the therapeutic potential of this drug class and offer a new perspective for therapeutic options against multiple sclerosis. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects millions globally, particularly those in the elderly population. Several occupational exposures typical of maritime environments are recognized or suspected risk factors for PD, warranting attention within occupational health frameworks. The disease is characterized by motor symptoms such as tremor, rigidity, and bradykinesia, as well as non-motor impairments including speech abnormalities. Objective: Early diagnosis is crucial for effective disease management but remains challenging due to symptoms overlapping with normal aging and other neurological conditions. This study presents a machine learning (ML)-based approach for the early diagnosis of PD using speech signal analysis. Methods: We employed six supervised ML classifiers to differentiate between PD patients and healthy controls based on vocal features. The experimental dataset, MDVR-KCL, consists of speech recordings from both reading tasks and spontaneous dialogs, collected via mobile devices. From these recordings, we extracted Mel-Frequency Cepstral Coefficients (MFCCs), Gammatone Frequency Cepstral Coefficients (GTCCs), and acoustic features such as jitter, shimmer, and harmonic-to-noise ratio. These features capture a broad range of prosodic, spectral, and articulatory characteristics associated with PD-related speech impairments. Speaker diarization was applied in spontaneous dialog recordings to separate participant speech. Hyperparameter tuning was performed using GridSearchCV with 10-fold cross-validation, while final model evaluation was conducted using Leave-One-Subject-Out Cross-Validation (LOSOCV) to ensure subject-independent performance assessment. Results: In the read-text task, the SVM model performed exceptionally, yielding 95.45% accuracy, 94.62% sensitivity, 95.97% specificity, an F1-score of 94.12%, and an AUC of 0.98 with an MCC value of 0.90, for GTCCs with the acoustic features. In the spontaneous dialog task, the XGB model demonstrated the highest overall performance across all metrics, with a test accuracy of 83.7%, a sensitivity of 76.3.9%, a specificity of 88.9%, an F1-score of 79.5%, an AUC value of 0.88, and an MCC value of 0.66. Conclusions: Comparable results were obtained on both spontaneous dialog and reading speech subsets, demonstrating the robustness of the approach across different speaking contexts. These results demonstrate the effectiveness of integrating cepstral and acoustic features with machine learning models for non-invasive PD classification. The findings support the use of speech-based digital biomarkers in early PD detection and highlight the potential for developing scalable tools. This work highlights the potential of speech-based digital diagnostics to support clinical decision-making and improve patient outcomes. Full article

Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions. Full article

The conventional classification of multiple sclerosis (MS) into relapsing–remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy. Full article