Faculty Bibliography

PURPOSE/OBJECTIVE:Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). BACKGROUND:Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. METHODS:We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). RESULTS:The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. CONCLUSIONS:These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.

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.

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

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.

IMPORTANCE/UNASSIGNED:Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses. OBJECTIVE/UNASSIGNED:To determine whether seizure frequency in FTRE improves over time. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample. EXPOSURES/UNASSIGNED:Participants were treated with multiple interventions at their physicians' discretion. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes. RESULTS/UNASSIGNED:Of 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Findings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretation of open-label studies positing disease-modifying effects and further research into FTRE treatment response.

BACKGROUND:Primary brain calcifications are observed in several inherited diseases due to different pathogenic mechanisms, including the disruption of the neurovascular unit, mitochondrial dysfunction, and impaired nucleic acid metabolism. OBJECTIVE:The aim of the study was to identify a novel genetic cause of brain calcifications in genetically unresolved cases. METHODS:Exome sequencing data from two unrelated Pakistani patients with generalized dystonia and primary brain calcifications were analyzed. The best candidate gene (ie, RRP12) was then investigated in two large cohorts of patients with brain calcifications from France (n = 111) and China (n = 543). RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model. RESULTS:A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Screening of two large cohorts of patients with unresolved brain calcifications revealed two affected French siblings and one unrelated Chinese individual, each carrying rare, biallelic, missense variants in the RRP12 gene (c.1429G>A, p.E477K and c.2634T>G, p.F878L, respectively). Molecular studies revealed a significant reduction in RRP12 protein and abnormal nucleolar morphology in patient'derived fibroblasts. Consistent with its essential role in RNA metabolism, rrp12 knockdown in zebrafish caused severe developmental delay, crimping, and early lethality. CONCLUSIONS:RRP12 is a novel candidate gene for autosomal recessive brain calcifications, possibly associated with a wide clinical spectrum ranging from early-onset severe forms to adult-onset paucisymptomatic presentations. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.