Faculty Bibliography

The gene SPG7 codes for the protein paraplegin, a subunit of the m-AAA protease in the inner mitochondrial membrane involved in protein quality control. SPG7 was initially identified as causing autosomal recessive hereditary spastic paraplegia (HSP), with a pure (insidiously progressive bilateral leg weakness and spasticity) and complex (with additional neurologic features including cerebellar signs and optic atrophy) forms. Now identified as one of the most common causes of HSP, SPG7-associated disease has been linked to additional neuro-ophthalmologic features, including isolated dominant optic atrophy, cerebellar eye signs (various forms of nystagmus, dysmetric saccades), progressive external ophthalmoplegia (PEO), and supranuclear vertical palsy. This review describes in detail the various neuro-ophthalmologic presentations of SPG7-associated disease, illustrating the role of mitochondrial dysfunction in the pathophysiology of these different entities. Knowledge of the different manifestations of SPG7-associated disease is crucial for both neurologists and ophthalmologists, and SPG7 should be considered in the work-up of patients presenting with entities such as optic atrophy, PEO, and cerebellar eye signs.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described inflammatory disorder of the central nervous system. Unlike other demyelinating disorders of the central nervous system, the impact of pregnancy and the postpartum period on MOGAD disease activity remains uncertain. A better understanding of pregnancy-related relapse risk in MOGAD is essential to inform management. METHODS:We conducted a retrospective chart review of all patients followed in two large referral centers in the Northeastern United States with a confirmed diagnosis of MOGAD and at least one post-MOGAD onset pregnancy carried to the third trimester. Demographic, neurological, obstetric, and treatment-related data were extracted from electronic medical records, centered around the 12-month pre-pregnancy, pregnancy, and 12-month post-pregnancy periods, for each of which the annualized relapse rates (ARRs) were calculated. RESULTS:We identified 15 women diagnosed with MOGAD who had 22 post-MOGAD onset pregnancies. No relapses were observed during any of the 22 pregnancies, but 2 relapses were observed in the postpartum period in a single patient with a steroid-dependent relapsing course. The mean ARR was 0.26 ± 0.86 during the 12-month pre-pregnancy period, 0 during pregnancy, and 0.09 ± 0.42 in the 12-month postpartum period. Twelve of 22 pregnancies (55 %) were exposed to disease-modifying therapy (DMT) at conception, and 59 % were continued on DMT into the postpartum period. Obstetric complications were recorded in 5 of 22 pregnancies (22 %). CONCLUSIONS:The two main findings of our retrospective study are: 1) the relapse risk is very low during pregnancy in women with MOGAD, and 2) postpartum relapse risk does not appear to be elevated in patients with a low pre-pregnancy relapse rate. Approximately half of the women in our series were receiving disease-modifying therapies during the postpartum period, which may have decreased relapse rates. Larger prospective studies are needed to validate our observations.

The CSF-BAM assay, developed by Pearlman, Wang, and colleagues, integrates the detection of somatic mutations, genome aneuploidy, and B- and T-cell receptor clonality from a single cerebrospinal fluid DNA library to increase the sensitivity of cerebrospinal fluid to diagnosis and track brain tumors. See related article by Pearlman et al., p. 2002.

BACKGROUND:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up. METHODS:This prospective, multicentre, observational cohort study, conducted at nine centres (eight in the USA and one in the UK), recruited children and adults with epilepsy who were undergoing prolonged video-electroencephalographic (EEG) monitoring. Inclusion criteria were diagnosis of epilepsy by an epilepsy specialist, with or without drug resistance; age older than 2 months; admission to the epilepsy monitoring unit of a participating centre, with video-EEG monitoring; and completion of at least one 6-month follow-up. Demographic, electroclinical, and cardiorespiratory data were collected at baseline. Participants were followed up long term through routine clinic visits, review of electronic health records, and telephone interviews to collect information about seizure frequency, medication status, and mortality. The primary endpoint was time to SUDEP. Cox proportional hazards models were used to assess significant risk factors. FINDINGS/RESULTS:Between Sept 17, 2011, and Dec, 30, 2021, 2632 children and adults with epilepsy were enrolled in this study; 164 were lost to follow-up. 38 (1·54%) of 2468 participants died from SUDEP (12 definite, 18 probable, and eight possible SUDEP cases) and two had near-SUDEP events. Incident SUDEP mortality rate was 4·76 (95% CI 3·37-6·53) cases per 1000 person-years, from a cohort of 7982 person-years. Living alone (hazard ratio 7·62, 95% CI 3·94-14·71), three or more generalised convulsive seizures in the previous year (3·1, 1·64-5·87]), longer ictal central apnoea (1·11, 1·05-1·18), and longer postictal central apnoea (1·32, 1·14-1·54]) were significant predictors of increased SUDEP risk. In a subanalysis excluding possible and near-SUDEP cases, longer ictal central apnoea was not significant. INTERPRETATION/CONCLUSIONS:This study shows an association between premortem peri-ictal apnoea and increased SUDEP risk. Cardiorespiratory monitoring during seizures might benefit assessments of epilepsy mortality risk. Together with solitary living and convulsive seizure frequency, peri-ictal apnoea (>14 s for postictal central apnoea and >17 s for ictal central apnoea) could inform the development of a validatable SUDEP risk index. FUNDING/BACKGROUND:US National Institutes of Health.

IMPORTANCE/UNASSIGNED:The emergency department (ED) is a critical point of contact within the health care system and an opportunity to initiate nonpharmacologic migraine treatment. OBJECTIVE/UNASSIGNED:To examine whether progressive muscle relaxation (PMR) smartphone-based migraine self-management improved patient-reported outcomes for migraine compared with enhanced usual care. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized clinical trial of the smartphone application RELAXaHEAD with and without PMR. Patients aged 18 to 65 years visiting New York University Langone Health EDs for headache who met migraine criteria and self reported 4 or more migraine days per month were recruited from June 2019 to October 2021 with follow-up at 3 months. Data were analyzed from June 2022 to June 2025. INTERVENTION/UNASSIGNED:Participants in the intervention group were asked to listen to the app-based PMR for 60 days. Participants in the control group were asked to use the app as a symptom diary. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcome was change in migraine-related disability (MIDAS). Secondary outcomes were change in migraine-specific quality of life (MSQv2) and monthly headache days (MHDs). Adherence (number of days of diary use, PMR use and total minutes of PMR use over 90-day period) was measured using back-end analytics. RESULTS/UNASSIGNED:Of the 94 patients (median [IQR] age, 33 [26-45] years; 57 [82.6%] female) randomized (48 control patients and 46 PMR patients), 69 of 94 (73%) had 1 or more follow-up MIDAS scores and constituted the modified intent-to-treat population (35 control patients and 34 PMR patients). The mean (SD) change in MIDAS scores from baseline to 3 months (last observation carried forward [LOCF] used if missing 3-month follow-up data) differed between groups (PMR, 25.09 [29.64] vs control, 6.86 [59.61]; P = .01). PMR had nearly double the number of respondents improving by 5 or more MIDAS points (28 of 34 [82.4%] vs 16 of 35 [45.7%] respondents; P = .002). There was no difference in MSQv2 domains from baseline to LOCF between PMR and control (mean [SD] role function preventive domain for PMR, 16.9 [24.5] vs control, 11.3 [25.9]); emotional function domain (mean [SD] for PMR, 26.5 [26.9] vs control, 19.8 [38.5]); and role function restrictive domain (mean [SD] for PMR, 18.1 [22.7] vs control, 18.7 [26.8]). Mean (SD) change in MHDs (baseline to 3 months) did not differ between groups (PMR, 2.9 [8.0]; 23 days vs control, -1.6 [6.5]; 25 days). CONCLUSION AND RELEVANCE/UNASSIGNED:A PMR-based self-management program offered to patients with migraine after ED discharge yielded clinically significant reductions in migraine-related disability. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04281030.

IMPORTANCE/UNASSIGNED:Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. OBJECTIVE/UNASSIGNED:To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. EXPOSURE/UNASSIGNED:ASM (variable). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). RESULTS/UNASSIGNED:Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21-44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33-3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7-16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8-3.2) than those who did (median, 7.4 months; 95% CI, 4.0-10.7). Those with infrequent pretreatment seizures were 0.41-fold more likely to be treatment resistant than those with very frequent seizures (relative risk [RR], 0.41; 95% CI, 0.18-0.89; P = .03; HB-corrected P = .02). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (RR, 1.78; 95% CI, 1.26-2.52; P = .001). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02126774.

BACKGROUND AND OBJECTIVES/UNASSIGNED:With more women entering the medical workforce, caregiving challenges and family-work conflicts are of growing importance to today's neurologists. The aim of this study was to assess the impact of caregiver (CG) status on academic achievements in neurology, analyze the division of labor and time devoted to domestic responsibilities, and measure family-work conflict in US academic neurology faculty. METHODS/UNASSIGNED:analyses as appropriate, with CGs vs noncaregivers (N-CGs) serving as the independent groups. RESULTS/UNASSIGNED:= 0.034). DISCUSSION/UNASSIGNED:Although the caregiving burden did not directly affect academic productivity, it significantly increased FWC in US academic neurology faculty surveyed. Female CG faculty disproportionately shouldered domestic and household responsibilities. Beyond recognizing CG challenges, advocating for a change in paradigm and providing solutions to these pervasive issues could be instrumental in preventing further attrition of professionals from our field, particularly women with caregiving roles.