SRPK3/TTN-digenic myopathy was recently established as a skeletal muscle myopathy caused by digenic inheritance. This study characterizes the early clinical presentation of SRPK3/TTN-digenic myopathy in one previously reported and seven newly identified pediatric patients. Next generation sequencing and deep clinical phenotyping provide detailed genetic, clinical, imaging, and histopathological characterization of SRPK3/TTN-digenic myopathy. From the cohort of eight male patients (5-19 years at last evaluation), five presented prenatally with reduced fetal movements. At the time of birth, five had hypotonia, two had contractures, and two had respiratory distress. All patients demonstrated motor delay and muscle weakness within the first 15 months of life. Independent ambulation was achieved in six patients (ages 1.5-4 years); three could run. Variable respiratory compromise was documented as early as 5 years of age, with one patient requiring non-invasive nocturnal ventilation support. Cardiac evaluation was normal in all except one patient who had left ventricular non-compaction cardiomyopathy. Muscle MRI demonstrated mild, slowly progressive fibroadipose replacement of muscle with striking early selective involvement of the semitendinosus muscle. Histopathologic and ultrastructural features mimicked TTN-related myopathy (titinopathy), showing abnormal fiber size variation, increased internally placed nuclei, type 1 fiber predominance, and cores/minicores. This work highlights the early clinical manifestations of SRPK3/TTN-digenic myopathy and demonstrates early muscle imaging patterns and histopathological features that are indistinct from those observed in monogenic biallelic titinopathy cases. These features could help with the potentially challenging interpretation of digenic SRPK3 and TTN variants to allow for a confident clinical diagnosis of this novel congenital myopathy.
Neurochemical levels measured by brain MR spectroscopy (MRS) have been proposed as endpoints for clinical trials in early-stage spinocerebellar ataxia (SCA) trials. We tested their trial-readiness by quantifying neurochemicals in three affected brain regions in early-stage cohorts of SCA2 and SCA3, examining their reproducibility in both patients and controls in a multisite/multivendor setting, and determining if the same neurochemical outcomes can be used as endpoints for different SCA genotypes. Seventy-two participants (18 SCA2, mean Scale for the Assessment and Rating of Ataxia (SARA) = 9 +/- 5; 25 SCA3, mean SARA = 10 +/- 6; 29 controls) underwent 3 T scans at four sites using scanners from two vendors and a harmonized MRS protocol. Scans were performed twice with a maximum 2-week interval. We measured neurochemical concentrations in the cerebellum, pons, and putamen, and assessed their within- and between-site reproducibility and associations with clinician- and patient-reported outcomes. Test-retest coefficients of variance were comparable across sites and vendors, but concentration estimates had to be adjusted for sites to account for small vendor-based biases. Total N-acetylaspartate (tNAA) and glutamate were lower, and myo-inositol (mI) and total creatine (tCr) were higher in the cerebellum and pons in both SCAs vs. controls. Pontine tNAA and mI, and cerebellar tNAA, mI, and glutamate levels were significantly different between SCA2 and SCA3, with strong effect sizes (|Cohen's d| = 1.1-2.1). The tNAA/tCr ratio had the strongest associations with clinical outcomes (|r| ≥ 0.5), with stronger associations in the cerebellum for SCA2 and in the pons for SCA3. These data support the use of tNAA and its ratios in a genotype-specific manner in early-stage SCA2 and SCA3 trials in the multisite/multivendor setting.
We aimed to determine the frequency of subclinical optic nerve (ON) lesions using MRI, optical coherence tomography (OCT), and visual evoked potentials (VEP) in radiologically isolated syndrome (RIS), and to assess their diagnostic and prognostic significance. We conducted a retrospective, multicenter study of 179 RIS individuals followed in clinical practice who met the 2023 RISC criteria. The diagnostic performance of the 2024 McDonald criteria, with and without optic nerve assessment, was evaluated and compared with that of the 2017 criteria. Associations with clinical conversion, comorbidities, and MRI disease activity were analyzed using multivariate models. Silent ON lesions appeared in 107/179 (59.8%) individuals, mainly detected by VEP (100/164; 61.0%) and OCT (69/118; 58.5%), with routine MRI identifying 31/166 (18.7%). During follow-up, 71 (39.7%) had a first clinical event. The presence, laterality, or number of silent ON lesions did not correlate with clinical conversion, event type, or MRI activity. Younger age and the absence of comorbidities associated with other MRI lesions, rather than with ON lesions, were associated with clinical conversion. Including ON in the 2024 McDonald criteria increased sensitivity but decreased specificity, with 17/179 (9.5%) meeting dissemination-in-space criteria solely due to ON lesions. Subclinical ON lesions are common in RIS and are mainly found by OCT and VEP, not routine MRI. Including ON increases sensitivity but does not predict clinical conversion and may lower specificity. These findings suggest cautious interpretation of ON and support a multimodal assessment approach in RIS.
We aim to comprehensively analyze how regional tumor and edema characteristics are associated with clinical presentations and survival outcomes in a large cohort of glioblastoma patients. Patients with IDH-wildtype glioblastoma who received brain MRI from 2010 to 2023 were included. The enhancing tumor, necrotic core, and edema/infiltration volumes were automatically segmented across brain regions. Multivariable regression assessed associations between regional volumes, presenting symptomatology, and survival outcomes. Of 526 patients analyzed, initial presentations included seizure (29%), aphasia (26%), confusion (25%), headache (24%), focal weakness (22%), memory problems (20%), ataxia (16%), visual field deficits (11%), personality change (10%), and focal sensory abnormalities (7%). Distinct regional tumor patterns emerged: seizures were associated with smaller overall tumor burden but with relatively greater cortical involvement, headache with increased subcortical volumes, confusion with left hemisphere and temporal involvement, personality changes with frontal-cingulate-basal ganglia involvement, and focal neurologic deficits with mostly predictable patterns. While no initial presentation correlated with survival, the presence of postoperative seizures was associated with improved overall survival. Increased volume of enhancing tumor, particularly in the insula and brainstem, was associated with worse overall survival. Anatomical tumor distribution provided prognostic information beyond overall tumor burden in glioblastoma. Regional patterns expand on the anatomical basis of symptoms. The survival benefit associated with postoperative seizures suggests distinct tumor biology or microenvironmental factors. Incorporating regional characteristics into clinical and prognostic models may improve risk stratification and inform treatment planning.
Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS). This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures. Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants). The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.
Oxysterols (cholestane-3β,5α,6β-triol and 7-ketocholesterol) and N-palmitoyl-O-phosphocholineserine (PPCS) are sensitive biomarkers for Niemann-Pick disease type C (NPC) screening. However, false-positive results occur, with a biomarker profile suggestive of NPC despite the absence of pathogenic variants in genes involved in NPC or other inborn errors of metabolism. To identify causes of false-positive biomarker profiles mimicking NPC. We conducted a multicenter retrospective study of 15 patients with false-positive oxysterols and PPCS profiles referred between 2017 and 2022 to two French NPC reference laboratories. Clinical data were collected via standardized chart review. The impact of Sertraline on NPC-like biological features was evaluated using the filipin test in fibroblasts and biomarker analysis in sertraline-treated patients. Thirteen of 15 patients with false-positive biomarkers were treated with sertraline. Two patients who discontinued sertraline showed normalization of biomarkers. The filipin test revealed that Sertraline disrupts intracellular cholesterol trafficking, a hallmark of NPC cellular features. Finally, among 47 sertraline-treated patients without NPC-suspicion, 26 (55%) had biomarker profile mimicking NPC. Sertraline use is frequently associated with elevated biomarkers that mimic NPC, representing a primary cause of false-positive results in NPC screening. Genetic analysis of NPC1 and NPC2 remains essential to confirm NPC diagnosis. Most sertraline-treated patients with false-positive biomarkers presented predominantly atypical psychiatric symptoms, though one exhibited a clinical picture highly suggestive of NPC following prolonged sertraline exposure. The long-term clinical effects of sertraline use need further evaluation.
Ischemic stroke, a major cause of mortality and long-term disability, results from the abrupt cessation of cerebral blood flow due to vascular occlusion or rupture. Icosapent Ethyl (EPA-EE), approved for hypertriglyceridemia, has anti-inflammatory and antithrombotic properties that may lessen ischemic damage. This trial evaluates the impact of EPA-EE on functional recovery and inflammatory markers in patients with acute ischemic stroke. In a blinded, randomized controlled trial (RCT), adults (≥ 18 years) with acute ischemic stroke were assigned to receive either 2000 mg/day EPA-EE (EPA group) or a matched placebo alongside standard treatment for 12 weeks. Functional outcomes were measured using the modified Rankin scale (mRS) and national institutes of health stroke scale (NIHSS), while inflammatory biomarkers, interleukin-6 (IL-6) and C-reactive protein (CRP), were assessed at baseline and at the 7th day. Of 178 patients screened, 90 were randomized, and 80 completed the 12-week intervention. The EPA group showed significantly greater functional improvement, with mean mRS score reductions of 2.18 ± 0.61 compared to 1.38 ± 0.66 in the placebo group (p = 0.001) and NIHSS score reductions of 5.00 ± 1.83 versus 3.38 ± 1.38 (p = 0.001). IL-6 levels decreased by 6.32 ± 5.69 pg/mL in the EPA group compared to 2.95 ± 4.11 pg/mL in the placebo group (p = 0.003). Changes in CRP levels were not statistically significant (p = 0.142). EPA-EE at 2000 mg/day was well tolerated, with no serious adverse events reported. EPA-EE administration significantly improves functional outcomes and reduces IL-6 levels in patients with acute ischemic stroke, suggesting its potential as an effective add-on therapy. CLINICALTRIALS. IRCT20170608034390N15.
This report presents a case of behavioral variant frontotemporal dementia caused by mutations in the MATR3 and NOS3 genes, aiming to analyze its clinical manifestations and genetic characteristics. For a case presenting with personality changes and gait abnormalities as the initial symptoms, this study conducted a comprehensive analysis of its clinical manifestations, neuropsychological assessments, cerebrospinal fluid biomarkers, head imaging changes, and genetic test results. It also discussed the possible causes based on the literature. Its main manifestations include personality changes, gait disorders, and a decline in executive functions. 18F-FDG PET shows decreased FDG metabolism in both bilateral frontal lobes, temporal lobes, and anterior cingulate gyrus, accompanied by corresponding brain atrophy, and no abnormal deposition of Aβ in both cerebral hemispheres. The related gene detection indicates mutations in the MATR3 gene (NM_018834.6: intron 11: c.1778 + 3A > G) and NOS3 gene (NM_000603.5: exon 20: c.2435C > A). There is no report of the coexistence of these two genes. The clinical diagnosis is behavioral variant frontotemporal dementia(bvFTD). The conclusion is that the mutations in MATR3 and NOS3 are likely to be associated with the pathological process of frontotemporal dementia by altering the structure and function of the encoded proteins. The identification of these variations provides new candidate gene combinations for the genetic variation spectrum of frontotemporal dementia, which should be regarded as hypothetical generative observation results. The clinical significance of these results needs to be further verified.
Epilepsy surgery is severely underutilized despite proven efficacy, with substantial under-referral of eligible patients in routine clinical practice. This study evaluated the potential role of large language models (LLMs) as decision-support tools for screening unstructured clinical notes to identify epilepsy surgery candidates and stratify them according to prognostic indicators. We retrospectively analyzed free-text medical records in a non-English language (Hebrew) from 110 patients in a tertiary epilepsy clinic. Six LLMs (Gemini 2.5 Pro, 2.5 Flash, 2.0 Flash; GPT-5, GPT-5 mini; and o4-mini) were prompted to extract surgical eligibility criteria, parameters of the Seizure Freedom Scale (SFS) for surgical prognostication, completion of presurgical evaluations, and previous surgical consideration. Model outputs were compared with expert manual review. Model performance in identifying core eligibility parameters demonstrated high sensitivity (up to 1.00) and specificity (up to 0.96), with favorable predictive values (PPV up to 0.92, NPV up to 1.00). Majority voting yielded near-perfect sensitivity (1.00 in this cohort) for identifying surgical eligibility. Notably, 45% (13/29) of patients meeting surgical criteria had no prior consideration of surgery. Models demonstrated high accuracy in SFS score evaluation (sensitivity 0.95, specificity 0.93) and strong performance in identifying completed presurgical evaluations. These findings suggest the potential role of LLMs to act as decision-support tools for identifying patients who may benefit from surgical evaluation but have not been recognized in routine care. This is supported by the models' high performance in correctly identifying eligible patients, as well as prognostic parameters. As this performance was achieved using off-the-shelf general-purpose models applied directly to raw, non-English clinical notes, it suggests a practical and scalable screening approach across diverse clinical settings.
Early risk stratification may support clinical decision-making in spontaneous intracerebral hemorrhage (ICH). We aimed to develop and internally validate HAGIV, a score integrating frequency of imaging markers (FIM), a time-adjusted non-contrast computed tomography (CT) metric of hematoma expansion, with established predictors for 90-day functional outcome in supratentorial ICH. This prespecified prognostic modeling study used a multicenter retrospective cohort of consecutive supratentorial ICH patients with baseline non-contrast CT within 6 h of onset (January 2018-August 2022). The HAGIV score was constructed by assigning integer points according to regression coefficients from multivariable logistic regression. Discrimination for poor functional outcome (modified Rankin Scale score 3-6) was assessed using area under the curve (AUC) and compared with established ICH prognostic scores. HAGIV incorporated baseline hematoma volume (H), age (A), Glasgow Coma Scale score (G), frequency of imaging markers (I), and presence of intraventricular hemorrhage (V). In the derivation cohort, HAGIV achieved an AUC of 0.86, significantly outperforming the ICH (0.81), MICH (0.81), Outcome (0.72), and Landseed ICH (0.79) scores (all p < 0.001, DeLong's test). This superiority was confirmed in the validation cohort, where HAGIV maintained an AUC of 0.84 compared with 0.76, 0.78, 0.75, and 0.75, respectively. In this predominantly small-to-moderate, supratentorial ICH cohort, HAGIV integrated FIM with established prognostic variables and improved discrimination for 90-day outcome. It may support interpretable early risk stratification for counseling and trial design, but prospective external validation is required before broader clinical implementation.
Down syndrome regression disorder is a syndrome characterized by subacute loss of cognitive, behavioral, and functional abilities in individuals with Down syndrome. Electroencephalography abnormalities are frequently observed during evaluation, but it remains unclear whether these findings represent a dynamic marker of disease activity. We evaluated longitudinal changes in electroencephalography and examined whether normalization is associated with clinical improvement. We conducted a retrospective longitudinal cohort study of individuals with Down syndrome regression disorder who underwent electroencephalography within 2 months of symptom onset and repeat studies at six and 12 months. Active epilepsy, antiseizure medication use, or seizures during follow-up were exclusionary. Changes in electroencephalography were assessed over time. Among participants with abnormal baseline electroencephalography, associations between treatment exposures, electroencephalography normalization, and changes in clinical severity were evaluated. Among 589 eligible individuals, 181 met inclusion criteria and 69 (38.1%) had abnormal baseline electroencephalography. Abnormal electroencephalography prevalence decreased to 20.4% at 6 months and 16.6% at 12 months (both p < 0.001 versus baseline). Among participants with abnormal baseline electroencephalography, normalization occurred in 49.3% by 6 months and 56.5% by 12 months. Immunotherapy exposure during the first 6 months was associated with higher odds of normalization (p < 0.001, 95% CI: 20.0-676.1) and faster time to normalization (HR: 15.35, p < 0.001, 95% CI: 4.90-48.09). Normalization was associated with reduced disease severity (all p ≤ 0.01). Electroencephalography abnormalities frequently improve over time in Down syndrome regression disorder. Normalization is associated with greater clinical recovery, supporting serial electroencephalography as a potential biomarker of neurophysiologic recovery in this condition.
Despite its monogenic origin, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy exhibits marked variability in clinical expression and severity. Variants in the NOTCH3 gene, within epidermal growth factor-like repeat domains 1-6 or 7-34, are known to influence disease onset, but their impact on long-term progression remains unclear. This study assesses mutation location effects on post-first stroke clinical trajectories. Clinical data from a large cohort were analyzed (Patients EGFR 1-6 mutation group n = 210 and 7-34 mutation group n = 116) with target emulated trial framework. To study the impact of mutation location on stroke recurrence, disability (modified Rankin score ≥ 3) and mortality, following a first stroke event. Propensity score matching was used to balance covariates between mutation location groups and principal stratification to consider truncation by death. Events occurrence differences were compared using Restricted Mean Survival Time at 2, 5, 10 and 15 years. At first stroke, patients with mutation in domains 1-6 were younger than those in the 7-34 mutation group (49.51 ± 7.4 vs. 55.00 ± 7.4 years). Ten years after first stroke event, mortality occurred slightly later in the 7-34 group (9.63 [9.33-9.92] vs. 9.11 [8.71-9.52] years, p = 0.04), also at 15 years (14.0 [13.42-14.63] vs. 12.4 [11.62-13.24] years; p = 0.002). Second stroke occurrence did not differ between groups. Time beyond modified Rankin of 3 slightly differed between groups at 5 and 10 years, with a difference of 0.22 [0.01-0.044] and 0.72 [0.14-1.30] year respectively (p = 0.044 and 0.017). Although NOTCH3 variants location influences the delay to the first stroke, it has no or little impact on the recurrence of stroke, risk of disability and death after the first stroke manifestation.
Chimeric antigen receptor (CAR) T-cell therapy has been investigated in neurological diseases, encompassing both central nervous system malignancies and autoimmune disorders, thereby extending its application beyond hematological cancers. This scoping review evaluates CAR T-cell therapy applications in neurological conditions, assessing therapeutic efficacy, safety profiles, and neurotoxicity management strategies. A literature search across four databases (January 2020-December 2025) identified 33 studies meeting the inclusion criteria, encompassing original and secondary research from international centers. CAR T-cell therapy demonstrated promising efficacy across diverse neurological conditions. In glioblastoma trials, 44% of patients (n = 128) achieved partial or complete clinical/radiographic responses with favorable safety profiles. Moreover, compelling results emerged from neuromyelitis optica spectrum disorder studies, in which 92% of patients (11/12) achieved sustained relapse-free remission over a median follow-up of 5.5 months. Multiple sclerosis, myasthenia gravis, and stiff-person syndrome cases exhibited excellent treatment tolerance without significant immune effector cell-associated neurotoxicity syndrome (ICANS), which is a major concern affecting 27% of patients with hematological malignancies. Overall, CAR T-cell therapy emerges as a novel therapeutic strategy in neurology, encompassing both oncological and autoimmune conditions. Toxicity profiles in neurological CAR T-cell applications differ substantially from those observed in hematologic malignancies, underscoring the need for condition-specific risk assessment frameworks and customized management approaches. Future research should prioritize larger multicenter trials with extended follow-up to establish definitive efficacy and safety profiles in neurological indications.
Cutaneous phosphorylated α-synuclein (p-syn) and α-synuclein seeding activity are promising biomarkers for Parkinson's disease (PD), but their clinical value remains uncertain due to disease heterogeneity. This study evaluates these two biomarkers in PD patients to inform phenotype-specific diagnosis and disease severity assessment. We compared the diagnostic performance of cutaneous p-syn immunostaining and α-synuclein seed amplification assay (syn-SAA) in 108 PD patients and 60 controls. Additional analyses assessed the influence of clinical subtypes on p-syn distribution (positive rates and diffusion coefficients across regions), and syn-SAA characteristics, along with their correlations with clinical scales. Cutaneous p-syn immunostaining showed 100% specificity and 75% sensitivity, whereas syn-SAA showed 93.3% specificity and 86.1% sensitivity. Among the clinical subtypes, a significant regional difference in the diffusion coefficient was observed only in the suspected REM sleep behavior disorder subgroup, with higher values in the distal leg than in the posterior cervical region (p = 0.001). The diffusion coefficient correlated with the severity of both motor and non-motor symptoms (all p < 0.05). No significant differences in syn-SAA positivity rates or parameters were found across clinical subtypes. Syn-SAA parameters were consistent across biopsy sites and associated with disease duration and non-motor symptom severity, but not with motor symptom severity. These findings highlight complementary roles for skin biomarkers in PD. P-syn deposition shows regional α-synuclein aggregation, reflecting clinical heterogeneity and supporting phenotype-specific diagnosis and severity assessment, whereas α-synuclein seeding activity enables early diagnosis and may serve as a potential biomarker for monitoring disease progression.
Acute intracranial stenting during endovascular thrombectomy (EVT) for ischemic stroke requires intraprocedural antiplatelet therapy (APT) to maintain patency. However, the hemorrhagic risk of combining APT with intravenous thrombolysis (IVT) remains uncertain. We evaluated the safety of IVT combined with conservative versus aggressive intraprocedural APT in patients requiring stenting during EVT. This multicenter RESISTANT registry subanalysis (2016-2023) included 823 adults. APT was categorized as conservative (aspirin +/- oral P2Y12) or aggressive (including GPIIb/IIIa inhibitors or cangrelor). The primary outcome was a composite of symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma (PH1/PH2). Multivariable logistic regression assessed associations and interactions between IVT and APT. A total of 823 patients were included: 44 (5.3%) received IVT + conservative APT, 130 (15.8%) No IVT + conservative APT, 145 (17.6%) IVT + aggressive APT, and 504 (61.2%) No IVT + aggressive APT. Frequencies of sICH-PH1-PH2 were 9.3% with IVT + conservative APT, 10.7% with IVT + aggressive APT, 3.2% with No IVT + conservative APT, and 9.9% with No IVT + aggressive APT. In multivariable analysis without interaction terms, neither IVT (aOR 1.18, 95% CI 0.58-2.27; p = 0.64) nor aggressive APT (aOR 2.10, 95% CI 0.92-5.69; p = 0.10) was independently associated with increased risk of sICH-PH1-PH2. However, in the interaction model, IVT within the conservative-APT stratum (aOR 5.84, 95% CI 1.07-43.92; p = 0.05) and aggressive APT within the no-IVT stratum (aOR 4.81, 95% CI 1.41-30.22; p = 0.03) were each associated with higher odds of sICH-PH1-PH2, while the IVT-by-APT interaction term was < 1 (aOR 0.15, 95% CI 0.02-0.94; p = 0.05), indicating attenuation of the joint effect on the multiplicative odds scale. Among patients requiring intracranial stenting during EVT, we found no evidence that IVT and aggressive intraprocedural APT act synergistically to increase hemorrhagic risk. Rather, the negative IVT-by-APT interaction suggested attenuation of the joint effect on the multiplicative odds scale, although patients receiving both therapies remained at increased hemorrhagic risk relative to the reference group.
To characterize the demographic, clinical, and laboratory features of the Chinese patients of genetic Creutzfeldt-Jakob disease with T188K variant (T188K-gCJD), the most common subtype of genetic prion diseases (gPrDs) in China. In this nationwide retrospective study, data from 98 genetically confirmed T188K-gCJD patients were collected via Chinese National Surveillance for CJD (CNS-CJD) from 2007 to 2025. The features of demography, clinical manifestations, MRI and EEG, cerebrospinal fluid (CSF) tests (14-3-3, CaM, RT-QuIC) and PRNP sequencing were comprehensively analyzed. The onset ages of 98 Chinese T188K-gCJD patients ranged from 40 to 80 years old (y) (median: 61 years), with a male-to-female ratio of 1:0.85. The geographic distribution of T188K-gCJD patients showed a significant north-south disparity (cumulative incidence: 0.1217 vs. 0.0534 per million, p = 0.0227). Clinical phenotype of T188K-gCJD resembled closely that of sporadic CJD (sCJD), but positive rates of periodic sharp wave complexes (PSWC) on EEG (29.9%) and CSF RT-QuIC (53.2%) were relatively low. Majority of the patients progressed rapidly with the median survival of 5.0 months, which was associated only with a shorter onset-to-report interval. The phenotype of T188K-gCJD is extremely similar to that of sCJD, underscoring the critical importance of PRNP sequencing for accurate diagnosis.
Stroke clinical trials are essential for advancing stroke care but can face challenges with recruitment, retention, clinical relevance, and translation into real-world practice. We propose that integrating community engagement and implementation science approaches into stroke trials can help address these needs. We conceptualize clinical trials as an evidence-based practice and highlight that implementation frameworks linked to implementation strategies can be used to anticipate and address multilevel trial determinants. We also describe how engaging constituents across the trial lifecycle can support negotiation of inevitable trade-offs and alignment of trial decisions with the needs, capacities, and priorities of those affected, including those responsible for implementing findings. We propose that integrating community engagement and implementation science has the potential to improve trial efficiency, strengthen relevance, accelerate translation into real-world practice, and advance stroke health for all.
Evaluate clinical and laboratory correlates of abnormal neurologic exam findings after acute HIV infection (AHI). Participants from the RV254/SEARCH 010 cohort in Bangkok underwent standardized neurologic examinations at Weeks 0 (AHI), 12, 96, and 288 following antiretroviral therapy (ART). A subset of participants completed 3T neuroimaging. Associations between neuroimaging, clinical and HIV parameters, and abnormal neurologic exam were analyzed using chi-square tests and multinomial regression. At AHI, 703 participants (median age 26.5 years, 97.6% male) had neurologic exams, with follow-up data available for 493, 667, and 560 participants at Weeks 12, 96, and 288, respectively. Viral suppression (≤ 50 copies/mL) was 0% at Week 0, 65% at Week 12, 98% at Week 96, and 99% at Week 288. Abnormalities in any neurologic exam domain were observed in 26%, 28%, 17%, and 8% of participants at each time point. Most findings occurred in sensory and fine motor domains. During AHI, history of HCV co-infection associated with abnormal exam (p = 0.006). At Weeks 96 and 288, higher CD4:CD8 ratio correlated with abnormal exam at the same visit (p = 0.040 Week 96, p = 0.018 Week 288). In a longitudinal model, higher Fiebig stage associated with conversion from abnormal to normal neurologic exam (p < 0.035). Of participants with MRIs, 14% at Week 0 and 36% at Week 96 demonstrated abnormalities; abnormal MRI at Week 0 associated with abnormal fine motor performance (p = 0.045). Objective neurologic abnormalities are common during AHI, though few persist with long-term ART. Coinfections, immunologic state, and demographic factors modify these outcomes.
Focal cortical dysplasia (FCD) is the most common etiology of drug-resistant epilepsy in children. Focal to bilateral tonic-clonic seizures (FBTCS) mark a high risk of drug-resistant epilepsy and involve thalamocortical circuitry in their generation and propagation. Using FCD as a model of focal epilepsy, we examined the integrity of thalamocortical circuitry to characterize thalamo-lesional connectivity signatures of FBTCS. Forty-three patients (14 with FBTCS) range 5-22 years, and 116 age- and sex-matched healthy controls were included. A network-driven thalamic functional parcellation was developed in healthy controls using Yeo 7-network atlas. We calculated z-scored thalamo-lesional functional connectivity between thalamic functional parcels and dysplasia masks in reference to controls, which was used to classify the presence of FBTCS. Clinical associations of thalamo-lesional connectivity were evaluated. Z-scored thalamo-lesional connectivity classified the presence of FBTCS with a median accuracy of 0.72. The thalamic parcel preferentially connected to the somatomotor-network (SMN), comprising ventral-posterolateral, pulvinar-medial and intralaminar nuclei, contributed most to classification. Lower ipsilateral SMN-thalamus connectivity was related to postsurgical seizure freedom and preserved ipsilateral thalamic volume. Thalamocortical circuitry was examined between the seizure generator (lesion) and the amplifier (thalamus) in FCD patients. FBTCS are associated with thalamo-lesional connectivity abnormalities that correlate to postsurgical outcomes, and demonstrate the SMN-thalamus as a primary gatekeeper for secondary generalization. The successful implementation of our classifier suggests that these thalamo-lesional signatures can serve as a potential neuromarker for seizure phenotyping, marking a step toward network-informed, personalized treatment.
There are limited real-world data regarding the safety and effectiveness of onasemnogene abeparvovec (OA; Zolgensma) infusion, a one-time gene replacement therapy, for Japanese patients with spinal muscular atrophy (SMA). We aimed to improve understanding of the real-world outcomes for OA in Japan. We report interim, 5-year results of Japanese post-marketing surveillance of OA (part of the RESTORE registry: NCT04174157). Eighty patients were registered and treated with OA (monotherapy: 30%; bridge or switch to OA: 54%). The median (min, max) age (months) was 3.0 (0, 18) at symptom onset and 10.0 (0, 24) at OA infusion. Forty patients each (50.0%) had two or three survival motor neuron 2 (SMN2) gene copies. Ten patients were identified by newborn screening. Adverse events related to OA were reported in 98.8% (serious: 26.3%; no deaths). Adverse events of special interest occurred in 92.5%, including hepatotoxicity (90.0%), transient thrombocytopenia (62.5%), cardiac adverse events (33.8%), and thrombotic microangiopathy (5.0%). Event-free survival at 3 years since OA administration was 93.0%. There was one death from disease progression. Of 39 patients with two or more developmental milestones, 64.1% achieved new developmental milestones and 15.4% maintained their milestones. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by ≥ 4 points in 81.8% (54/66). The safety profile of OA in Japanese patients with SMA mirrored that of earlier studies. In our real-world observations, patients showed gains in or maintenance of motor milestones or motor function scores that were sustained over the observation period. NCT04174157 (ClinicalTrials.gov).