Faculty Bibliography

Huntington's disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was -0.18 (95% confidence interval -0.49 to 0.14; P = 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was -0.11 (95% confidence interval -0.40 to 0.18; P = 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier: NCT04556656 .

OBJECTIVE:People with focal epilepsy experience one or more seizures prior to diagnosis. The Human Epilepsy Project (HEP) was a prospective study enrolling people with newly diagnosed focal epilepsy. It collected information including cognitive testing at the time of enrollment. This was completed utilizing a computerized test battery called the Cogstate Brief Battery (CBB). A prior analysis found that enrollment CBB test scores were below that of age matched controls and that performance on testing was not independently associated with the longer-term development of treatment resistance over the course of the HEP study. The present study assesses the impact of pretreatment seizures on cognition at time of diagnosis, considering time-to-treatment initiation in relation to seizure onset, pre-treatment seizure frequency, and pretreatment seizure classification. METHODS:Participants with newly diagnosed focal epilepsy and no other major medical comorbidities or intellectual disability (estimated IQ > 70) were enrolled between June 29, 2012, and September 1, 2019. A subset of the 448 enrolled participants (N = 183) were over 18 years old, had complete HEP enrollment data that included pre-treatment seizure histories, and complete enrollment CBB testing for analysis in this study. Performance on enrollment CBB testing was modeled using multiple linear regression with pre-treatment seizure characteristics including seizure type and duration between seizure onset and treatment initiation, controlling for other key baseline participant characteristics. RESULTS:There were no independent associations between cognitive measures on the CBB at the time of enrollment and pre-treatment seizures after correcting for potentially confounding variables. Z-scores for the attention composite on CBB (an average of Identification and Detection tests) were not associated with a global pre-treatment seizure score that quantified time with seizures (days) and seizure count by seizure type (motor, non-motor, bilateral tonic clonic) (p = 0.29). Similarly, z-scores for the memory composite (an average of the One Card Learning test and One Back tests) were not associated with the pre-treatment seizure score (p = 0.1). No additional independent associations were found to be significant between z-scores for attention or memory composites and other potential explanatory variables. SIGNIFICANCE/CONCLUSIONS:This study highlights an important finding for people who develop focal epilepsy and otherwise are in good health: pre-treatment time-limited seizures do not have an independent impact on cognition early on, as measured by a brief validated cognitive screening test. This suggests that that cognition at the time of epilepsy diagnosis may be more strongly related to underlying etiology, chronic disease, and comorbidities.

BACKGROUND/UNASSIGNED:Time-to-treatment goals for acute ischemic stroke (AIS) have substantially improved outcomes, yet similar metrics have not been studied in patients with intracerebral hemorrhage (ICH), where mortality rates are much higher. METHODS/UNASSIGNED:Multicenter, observational retrospective study of patients with ICH and AIS between January 1, 2017, and December 31, 2022, in 11 comprehensive stroke centers across the United States participating in Get With The Guidelines. We included patients with ICH who received antihypertensive therapy and anticoagulation reversal, and patients with AIS requiring intravenous thrombolytic and mechanical thrombectomy. The coprimary outcomes included (1) time-to-treatment and (2) the percentage of patients meeting current national time interval goals. Multivariable logistic regression models controlling for age, sex, race and ethnicity, time to arrival, National Institutes of Health Stroke Scale score, arrival systolic blood pressure, and admission international normalized ratio were constructed to assess the likelihood of patients with ICH being treated within goal compared with patients with AIS. Multivariable logistic regression models were constructed to assess the impact of treatment time on mortality or discharge disposition in patients with ICH. RESULTS/UNASSIGNED:<0.01) compared with those treated in >60 minutes. CONCLUSIONS/UNASSIGNED:Time-to-treatment for patients with ICH is significantly longer than for patients with AIS. Faster antihypertensive treatment times are associated with better discharge outcomes in patients with ICH.

Aim To compare the clinical outcome and in-hospital complication risk with chemotherapy and without chemotherapy in patients with inflammatory and immune myopathies (IIM). Methods We obtained data for IIM patients admitted to hospitals in the United States from 2017 to 2018 with a primary diagnosis of IIM using a large national database. We determined the rate and pattern of utilization of associated in-hospital outcomes of chemotherapy in this patient population. Results A total of 5,360 patients had IIM, of which 315 (5.8%) received chemotherapy for the underlying malignancies and 5,045 (94.2%) did not. No significant racial or gender discrepancies were observed between the two groups. Patients who received chemotherapy had more in-hospital complications, including sepsis [79 (25.1%) vs. 585 (11.6%), p<0.01] and acute kidney injury [75 (23.8%) vs. 665 (13.2%), p<0.01]. The number of deaths was higher in the chemotherapy group [125 (39.7%) vs. 190 (3.8%)]. Further analysis of patients who died in the chemotherapy group showed that myocardial infarction [20 (6.3%)] and pneumonia [45 (14.3%)] were the leading causes of death. Conclusion In hospitalization complications such as sepsis and acute kidney injury were higher in patients who received chemotherapy in IIM patients; however, patients who died had a higher risk of myocardial infarction and pneumonia, so routine cardiac and pulmonary evaluation should be done during hospitalization of this patient population.

OBJECTIVE/UNASSIGNED:The authors sought to determine the relationships among cognitive impairment, psychiatric outcome, and functional status 3 months after a hemorrhagic stroke. METHODS/UNASSIGNED:Patients with nontraumatic intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) were assessed by telephone 3 months after discharge by using the Quality of Life in Neurological Disorders (Neuro-QoL) cognitive function, anxiety, depression, and sleep disturbance short forms, as well as the modified Rankin Scale (mRS). The relationships between poor cognition (Neuro-QoL T score≤50), functional status, and psychiatric outcome among patients with ICH or SAH and patients with ICH only were evaluated. RESULTS/UNASSIGNED:Of 101 patients (N=62 with ICH and N=39 with SAH), 51% had poor cognition 3 months posthemorrhage, with 61% having mRS scores of 3-5, 43% having anxiety, 28% having depression, and 31% having sleep disturbance. Univariate analysis of the full cohort indicated that poor cognition was significantly associated with anxiety, depression, sleep disturbance, and mRS scores of 3-5 (p<0.05). Multivariate analysis revealed that poor cognition was significantly associated with anxiety (OR=4.38, 95% CI=1.30-14.74, p=0.017) and mRS scores of 3-5 (OR=6.15, 95% CI=1.96-19.32, p=0.002). Univariate analysis of the 62 patients with ICH indicated that poor cognition was significantly associated with anxiety, sleep disturbance, and mRS scores of 3-5 (p<0.05). Multivariate analysis revealed that poor cognition was significantly associated with anxiety (OR=10.98, 95% CI=2.32-51.99, p=0.003). CONCLUSIONS/UNASSIGNED:Poor cognition was associated with anxiety 3 months after hemorrhagic stroke. Additional research is needed to understand whether treatment for anxiety would improve cognition in this population.

Nusinersen, an antisense oligonucleotide, modulates pre-mRNA splicing to produce full length survival motor neuron protein in spinal muscular atrophy (SMA). It was approved in the US for SMA in all ages based on evidence in children. In adults, studies of nusinersen rely on real-world observational data and show stability or small improvements over time. We performed a prospective, 30 month longitudinal, observational multi-center study of adults initiating nusinersen with SMA types II/III to examine its safety, tolerability, and effectiveness. 43 participants (20 female; 14 ambulatory; 3, 17, and 23 with 2, 3, and ≥4 SMN2 copies, respectively), mean (SD) age 37.1 (11.9) years) enrolled and completed baseline assessments. Serial assessments over 30 months showed small but not significant improvements in the six minute walk test (16.1 m), Revised Upper Limb Module (0.7), Revised Hammersmith Scale (0.8), maximal inspiratory (-2.6 cm H20) and expiratory pressure (12.3 cm H20). Muscle strength and forced vital capacity did not change. The patient reported outcome Total SMA-HI improved (-11 (95% CI: -17,-5); p < 0.001)). No new safety effects were identified. This study of nusinersen in adults with SMA demonstrates stability over time in contrast to the expected decline in untreated patients, with a favorable safety profile.

BACKGROUND:Whether early use of higher-efficacy disease-modifying therapy (DMT) reduces later risk of disability in multiple sclerosis (MS) has not been studied as a prospective treatment strategy. Herein, we describe the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial design and provide the baseline characteristics of the enrolled population. METHODS:TREAT-MS is a pragmatic, randomized, rater-blinded trial of DMT strategies in treatment-naive people aged 18-60 years with relapsing-remitting MS (RRMS). Participants were randomized (1:1, stratified by site and long-term disability risk classification) to one of two treatment strategies: higher-efficacy or traditional DMT; the specific DMT within the assigned strategy was chosen by the clinician/patient pair. Participants could switch DMT for breakthrough disease occurring after 6 months on DMT. The primary outcome is sustained worsening of the Expanded Disability Status Scale (EDSS)-plus, a composite endpoint that includes the EDSS and the timed 25-ft walk and 9-hole peg tests. RESULTS:TREAT-MS includes 900 people with the following baseline characteristics: mean age 36 ± 10 years; 629 (70 %) female gender; 648 (72 %) white, 168 (19 %) Black/African American race, and 105 (12 %) Hispanic or Latino. Mean time since MS symptom onset was 2.6 (± 4.5) years, and mean EDSS score was 2.5 (± 1.3). CONCLUSION/CONCLUSIONS:TREAT-MS seeks to address how early DMT strategy influences MS disability and related outcomes. The results will be generalizable to future individuals newly diagnosed with RRMS who, with their clinicians, will be able to use them to make data-driven DMT decisions about how to maximize their intermediate-term function.

State death determination acts require brain death/death by neurologic criteria (BD/DNC) determination to be in accordance with "accepted medical standards." The American Academy of Neurology/American Academy of Pediatrics/Child Neurology Society/Society of Critical Care Medicine published updated BD/DNC guidelines in October 2023 to replace earlier iterations of separate guidelines for BD/DNC determination in adults and pediatric persons. There are no other medical society guidelines for BD/DNC determination in the United States. As of early 2024, only Nevada, New Jersey, and New York identified the 2023 BD/DNC guidelines as the "accepted medical standards." Delineation of the "accepted medical standards" in state death determination acts or by state health organizations (SHOs) could help facilitate consistency and accuracy in BD/DNC determination, prevent false-positive death determination, and promote public trust. SHOs are comprised of policy experts and medical professionals responsible for addressing medical, ethical, and legislative problems related to health. In April 2024, we began iteratively contacting state health departments, medical boards, medical societies, and hospital associations requesting acknowledgment of the 2023 BD/DNC guidelines as the "accepted medical standards." From April 2024 to March 2025, we contacted 168 SHOs and received responses from 108 of 168 (64%, median: 2 per state, range: 0-4 per state). The effects of this advocacy effort continue to evolve, but as of March 31, 2025, 4 states had an SHO that acknowledged the 2023 BD/DNC guidelines as the "accepted medical standards" (Delaware, Louisiana, Oklahoma, and Vermont), 9 states had an SHO discussing acknowledgment, 4 states had an SHO that would consider a resolution submitted by a member about acknowledgment, and 30 states showed no SHO interest in acknowledgment. The Medical Society of Delaware and the Oklahoma State Medical Association formalized acknowledgment in a resolution while the Louisiana Department of Health and the Vermont Department of Health and Board of Medical Practice disseminated communication about acknowledgment. This effort also prompted discussion about the "accepted medical standards" by the American Medical Association. Ongoing advocacy may expand recognition of the 2023 BD/DNC guidelines as the "accepted medical standards" for BD/DNC determination. Communication to hospitals indicating that adherence to these guidelines is crucial and regulations to ensure adherence are essential.

A 65-year-old woman presented with 3 months of progressive hand weakness, initially with distal-predominant symptoms. EMG was notable for diminished amplitudes in bilateral radial nerves without evidence of conduction block and with normal sensory nerve action potentials. Anti-acetylcholine receptor and antistriated muscle antibodies were positive, but subsequent EMG did not reveal abnormalities on repetitive nerve stimulation. Muscle biopsy was performed, revealing extensive inflammatory infiltrates with significant associated fibrosis. This case discusses the approach to localization within the motor pathway and the use of serologic studies, imaging, and electrodiagnostic testing to supplement history and examination.