Faculty Bibliography

Parsonage-Turner syndrome (PTS) is a spontaneous neuropathy characterized by severe upper extremity pain and muscle denervation and is considered to be a rare disease that is under-recognized. Quantitative MRI (qMRI) characterizes muscle denervation but has not been previously assessed in a longitudinal PTS cohort. The aims of this study are to prospectively and longitudinally characterize qMRI changes in PTS patients at baseline (< 6 months' symptom onset) and at follow-up timepoints (3, 6, and 12 months), to measure associations against electromyography (EMG) and muscle strength, and to predict muscle strength at follow-up. A total of 49 subjects (age = 47.2 ± 14.0 years, 31 M/18 F) underwent 3-Tesla qMRI with T2-mapping, diffusion-based muscle fiber diameter, volumetry, and fat fraction (FF) mapping. Image segmentation of involved muscles was performed by two raters. Linear regression between qMRI metrics and days from symptom onset (DSO) was performed. Pearson's correlation quantified correlations between qMRI metrics, and Kendall's tau assessed correlations between qMRI and EMG and muscle strength. For predictive modeling of muscle strength, a generalized linear model was used, and the coefficient of determination (r²) was compared for combinations of baseline inputs. Regression detected a mean T2 increase of 0.66 ms/week and a mean muscle fiber diameter decrease of 0.96 μm/week within DSO of 100. Muscle fiber diameter correlated with muscle volume (r = 0.850). T2 correlated with EMG (|τ| = 0.34-0.78) and muscle strength (|τ| = 0.40-0.83) in most muscles that could be analyzed. Muscle fiber diameter was correlated to EMG (|τ| = 0.43-0.72) and muscle strength in some muscles (|τ| = 0.39-0.56). The addition of baseline T2 values improved the prediction of muscle strength at 3-month (from r² = 0.57 to 0.67, with -0.057 to -0.068 muscle grade per ms T2), at 6-month (r² = 0.40-0.59, -0.057 to -0.071 grade per ms), and at 12-month follow-up (r² = 0.40-0.62, -0.053 to -0.080 grade per ms). Muscle qMRI measurements in PTS depict muscle denervation and provide complementary characterization of muscle quality for diagnosis and follow-up assessment.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Epilepsy is a common neurologic disorder. Although antiseizure medications (ASMs) are the first-line treatment, identifying the most effective ASM for each individual remains a trial-and-error process. Genetic variation may influence treatment response. We aimed to develop and validate a multimodal deep learning model that integrates clinical and genomic features to predict response to the initial ASM in people with newly diagnosed epilepsy. METHODS:We used data from individuals with newly diagnosed epilepsy in Australia as the development cohort and participants from the Human Epilepsy Project 1 (recruited in the United States, Europe, and Australia) as the external validation cohort. All participants initiated ASM treatment and were followed prospectively for at least 1 year. We included 16 clinical factors and constructed 4 genomic feature types related to epilepsy and ASM pharmacogenomics, with and without functional impact annotations. We evaluated various machine learning architectures and multimodal fusion strategies to predict seizure freedom while taking the initial ASM at 1 year. RESULTS:< 0.05). Applying this model to the development cohort, if all participants took the highest ranked ASMs, the mean predicted seizure-free probability would be 68.05% (95% CI 65.79%-70.35%) compared with the observed seizure-free rate of 47.2% (95% CI 41.3%-53.2%). DISCUSSION/CONCLUSIONS:Integrating genomic data with clinical features enhances the ability of deep learning models in predicting ASM response in newly diagnosed epilepsy. This approach may support personalized treatment selection and improve clinical outcomes.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

This position statement provides updated member guidance from the American Academy of Neurology (AAN) regarding (1) communication with surrogate decision makers about brain death/death by neurologic criteria (BD/DNC), (2) management of surrogate decision-maker objections to BD/DNC, (3) the ethical considerations associated with BD/DNC determination in a pregnant person, and (4) enhancing public trust in BD/DNC. This position statement is intended to complement recommendations in the 2023 "Pediatric and Adult Brain Death/Death by Neurologic Criteria Consensus Guideline" published by the AAN, American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine, as well as the 2021 AAN Code of Professional Conduct. It replaces the 2019 AAN position statement, "Brain death, the determination of brain death, and member guidance for brain death accommodation requests."

Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.

BACKGROUND AND PURPOSE/OBJECTIVE:Mild traumatic brain injury (MTBI) is a common public health concern with potential long-term consequences, yet its underlying pathophysiology remains poorly understood. Clinical heterogeneity of individuals having diverse extent and array of symptoms has impeded the identification of reliable imaging biomarkers. Traditional group-level analyses may obscure biologically meaningful subtypes. This study uses latent class analysis (LCA) to classify MTBI subjects into symptom-defined subgroups and examines corresponding WM microstructural alterations using advanced diffusion MRI. MATERIALS AND METHODS/METHODS:Sixty-one MTBI patients within one month of injury completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). LCA was used to identify symptom-based subgroups. Of these, 54 MTBI patients underwent multi-shell diffusion MRI and were compared with 31 controls. WM changes were assessed across subgroups using ROI-based diffusion analyses. RESULTS:LCA identified three distinct MTBI subgroups: those with minimal to no symptoms (31.5%), the cognitively symptomatic (38.9%), and the more globally symptomatic (29.6%). The three groups were associated with different patterns of diffusion MRI differences compared with controls. The cognitively symptomatic subgroup showed predominantly central WM differences, the globally symptomatic subgroup exhibited more peripheral differences with right-hemisphere predominance and sparing the corpus callosum, marked by reduced fractional anisotropy and kurtosis and elevated diffusivities, the less symptomatic subgroup demonstrated focal differences in the callosal genu, with increased fractional anisotropy and kurtosis and decreased diffusivity measures. CONCLUSIONS:MTBI comprises biologically distinct phenotypes with subgroup-specific WM signatures on diffusion MRI. Even individuals with minimal to no symptoms show WM differences compared with controls, underscoring the limitations of symptom reporting alone. Integrating symptom-based classification with advanced diffusion MRI may improve diagnostic precision to help risk stratification and provide insight into mechanisms of injury. ABBREVIATIONS/BACKGROUND:LCA = latent class analysis; MTBI = mild traumatic brain injury; RPQ = Rivermead post-concussion symptoms questionnaire.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Trans-sonolucent cranioplasty ultrasonography (TCUS) has been explored as a noninvasive tool for evaluating superficial temporal artery (STA)-middle cerebral artery (MCA) bypass patency. Previous research has focused on early postoperative feasibility. Data on its long-term utility and correlation with formal angiography remain scarce. We aimed to evaluate TCUS' role in postoperative STA-MCA bypass graft monitoring and its concordance with formal angiography. METHODS:This retrospective study included 46 consecutive direct STA-MCA anastomoses in 40 patients (March 2021-May 2024), all with sonolucent polymethyl methacrylate cranioplasty. Patient records were reviewed for demographics, disease and surgical characteristics, and outcomes. Postoperative TCUS was performed outpatient to monitor anastomotic patency. Formal follow-up angiography was also conducted, and radiographic data were reviewed for graft patency assessment and qualitative correlation with TCUS. RESULTS:Follow-up angiography was performed for 41 of 46 anastomoses (digital subtraction angiography, n = 34; computed tomography angiography, n = 4; magnetic resonance angiography, n = 3) at a median of 1.1 years, demonstrating 97.6% patency (40/41). Outpatient TCUS was performed in 32 of 46 bypasses (69.6%) with 100% patency at first scan (median 28.5 days). A second TCUS (n = 19, 41.3%) at a median of 8.4 months (3.9-13.6 months) showed robust flow in 94.7% of cases. One bypass had asymptomatic slow flow with a narrowed anastomosis, and another showed a severely stenosed STA correlating with later digital subtraction angiography. In the broader cohort, third (n = 5, median 1.2 years) and fourth (n = 1, 1.4 years) TCUS assessments demonstrated 100% patency. Among bypasses undergoing both TCUS and angiography (n = 31, 67.4%), findings were concordant in all cases. CONCLUSION/CONCLUSIONS:TCUS demonstrated complete agreement with formal angiography in assessing bypass patency, supporting TCUS as a reliable, noninvasive monitoring tool. Future research should explore quantitative TCUS flow measurements and their relationship to intraoperative flow and long-term graft remodeling.

INTRODUCTION/BACKGROUND:The Curing Coma Campaign Ethics Working Group sought to understand informed consent practices for research involving persons with disorders of consciousness (DoC) to establish an empirical foundation to formulate common consent elements for research regarding this vulnerable population. METHODS:Consent forms for research involving persons with DoC were collected from the Curing Coma Campaign members and Clinicaltrials.gov in the fall of 2024. We abstracted data about study specifics, the consent process, and unique considerations related to persons with DoC and then reviewed and collated them using descriptive statistics. RESULTS:The collection process yielded 58 consent forms: 40 (69%) from member submissions and 18 (31%) from Clinicaltrials.gov. After excluding duplicates and studies that did not pertain to persons with DoC, there were 43 forms, which included 62 unique terms to describe acute brain injury/consciousness/DoC. Of 41 studies that enrolled persons with DoC, there were 4 (10%) that mentioned an evaluation for covert consciousness. Although only 3 (7%) forms mentioned an evaluation for capacity of the person with DoC/recovered from DoC, 16 (39%) referenced first-person consent if the person with DoC regained capacity. Most studies that involved study-specific medications/interventions/tests included some mention of experiential risks (26/32, 81%), but only 2 (6%) specifically addressed the challenges associated with these risks in a person with DoC. CONCLUSIONS:Consent forms for research involving persons with DoC include inconsistent terminology to describe acute brain injury/consciousness/DoC, the capacity to consent, and the potential experiential risks of study participation in the context of a DoC. There are opportunities to improve transparency and consistency of communication about research involving persons with DoC via creation of common consent elements to ensure the informed consent process protects individual autonomy.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.

PURPOSE/OBJECTIVE:Many studies estimate that more than 50% of non-hospitalized patients with long-COVID develop moderate to severe autonomic dysfunction. However, the specific impact of autonomic dysfunction as it relates to quality of life in long-COVID is not fully understood. The aim of the current study is to assess autonomic symptoms and quality-of-life in patients with Post-Acute Sequelae of COVID-19 (PASC) recruited from a neurology department outpatient setting. METHODOLOGY/METHODS:In a two-year follow-up study of a baseline cohort of 93 non-hospitalized SARS-CoV-2 laboratory-positive patients evaluated for PASC between November 2020-August 2021, 44 participants completed follow-up telephone questionnaires examining quality-of-life as well as neurologic and autonomic symptoms. RESULTS:Among 93 participants, 44 (47 %) completed the two-year follow-up evaluation and 27 (61 %) were female with a median age of 55 years (IQR = 24-88). Most participants (95 %, 42/44) were vaccinated against COVID-19 and 43 % (19/44) had a pre-existing neurological disorder. Median time from index COVID-19 infection to follow-up was 26 months (IQR = 23-17), with a median of 15 months (IQR = 15-16) between visits. Fatigue, word finding difficulty, and changes in memory were the most commonly reported PASC symptoms. Sixty-six percent (29/44) of individuals met criteria for autonomic dysfunction as defined by the Composite Autonomic Symptom Score-31 (COMPASS-31) scale. Secretomotor and gastrointestinal subdomains demonstrated significant associations with Neuro-QoL metrics for Anxiety, Depression, and Fatigue. For every 1 additional PASC symptom reported at a follow-up study visit, there was an average increase of 1.5 points on the COMPASS-31 composite score. In addition, visual disturbances and sleep impairment were both associated with increased autonomic dysfunction. CONCLUSION/CONCLUSIONS:The strong association between autonomic dysfunction and reduced QoL in PASC and the relation to insomnia, visual dysfunction, and functional impairment are valuable findings, reinforcing the clinical impact of these symptoms longitudinally after index COVID-19 infection.