Faculty Bibliography

OBJECTIVE:Reduced-channel wearable electroencephalography (EEG) may overcome the accessibility and patient comfort limitations of traditional ambulatory electrographic seizure monitoring during extended-duration use. Automated algorithms are necessary for review of extended-duration reduced-channel EEG, yet current clinical support software is designed only for full-montage recordings. METHODS:The performance of a novel automated seizure detection algorithm for reduced-channel EEG (Epitel) was evaluated in a clinical validation study involving 50 participants (31 with seizures) with diverse demographic and seizure representation. RESULTS:The algorithm demonstrated an event-level sensitivity of 86.2% (95% confidence interval [CI] = 79.5%-93.2%) and a false detection rate of .162 per hour (95% CI = .116-.221), which is comparable to the performance of current clinical software for full-montage EEG. Performance varied by electrographic seizure type, with 91.4% sensitivity for focal evolving to generalized seizures, 86.7% for generalized seizures, and 77.3% for focal seizures. The algorithm maintained robust performance in both pediatric participants aged 6-21 years (83% sensitivity) and adults aged 22+ years (90% sensitivity), as well as in ambulatory (80%) and epilepsy monitoring unit (EMU) monitoring environments (87.5%). The false detection rate in ambulatory monitoring environments (.290 false positive [FP] detections/h), all of which involved pediatric participants, was notably higher than in the EMU (.136 FP/h), indicating an area with clear need for improvement for unrestricted at-home monitoring. The algorithm's supplemental Confidence metric, designed to engender trust in the algorithm, showed a strong correlation with detection precision. SIGNIFICANCE/CONCLUSIONS:These results suggest that this algorithm can provide crucial support for review of extended-duration reduced-channel wearable EEG, enabling electrographic seizure monitoring with no restrictions on a person's daily life.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by adult-onset cerebellar ataxia, and occasionally pyramidal signs, cognitive changes, sensory changes, myoclonus, and tremor. SCA14 results from heterozygous gain-of-function pathogenic variants in PRKCG, which encodes protein kinase Cγ. The aim was to elucidate the molecular mechanism of disease in a 60-year-old man with SCA14 due to a novel heterozygous variant in PRKCG c.154T > C p.(C52R). Next-generation sequencing was completed in the proband, targeted variant analysis was conducted in his family, and biochemical functional assays were performed. The C52R variant segregated with disease. Like other C1A domain variants, it had increased basal activity yet was unresponsive to agonist stimulation and was relatively resistant to down-regulation. This expands the genetic landscape of SCA14 and supports the condition as a gain-of-function disease, with variants in the C1A domain having leaky activity yet unresponsiveness to agonist stimulation.

BACKGROUND:The US Food and Drug Administration approved satralizumab for use in adult patients with aquaporin-4 immunoglobulin G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) in 2020, but real-world data are limited. The objective of this case series is to describe the experience with satralizumab in adult patients with AQP4-IgG+ NMOSD who previously received rituximab. METHODS:Case information for patients with AQP4-IgG+ NMOSD who had received satralizumab for ≥6 months was obtained from US healthcare providers from April 1, 2022, to September 30, 2023. Patient characteristics, examination findings, diagnostic tests, treatment response and adverse events were recorded. Patients who received satralizumab after discontinuing treatment with rituximab were included in this case series. RESULTS:Twenty patients were included, and their ages ranged from 19 to 70 years. Overall, 45 % of patients self-identified as Black/African American, 40 % as White, 10 % as Asian and 5 % as multiracial. Time since confirmed NMOSD diagnosis ranged from 4 to 17 years. Median (range) duration of rituximab treatment was 50 (12-162) months. The main reasons for switching to satralizumab were intolerance (60 %) to and inadequate disease control (25 %) with rituximab. The majority of patients (70 %) received satralizumab for ≥24 months and as monotherapy (90 %). All 20 patients were free from radiographically confirmed relapses with satralizumab. Overall, patients maintained disease control with satralizumab, and adverse events primarily included asymptomatic laboratory abnormalities. Two patients permanently discontinued satralizumab due to adverse events. CONCLUSIONS:In this retrospective case series, satralizumab was effective and well tolerated in patients with NMOSD who switched due to ineffectiveness and/or poor tolerability of rituximab. These outcomes align with the long-term efficacy and safety outcomes with satralizumab in the Phase III SAkura clinical trials.

Depression is a common and debilitating disorder affecting millions. First-line treatments fail to achieve remission in about one-third of patients, highlighting a critical treatment need. Transcranial direct current stimulation (tDCS) has emerged as a novel treatment for depression. Therefore, the aim of this review was to provide a comprehensive overview of the last decade of tDCS trials for depression and propose future research directions. To compile studies of the past decade, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) of tDCS for depression. A total of 21 RCTs were included, presenting a moderate effect for active tDCS compared to placebo. We also provided a description of study designs, stimulation parameters, and patients' characteristics. Following, we proposed possible strategies to enhance clinical effectiveness and reduce variability in results, including 1) optimization/personalization of tDCS via spatial and temporal target localization; 2) optimized methodological strategies, including home-based, accelerated tDCS protocols and novel trial designs; and 3) investigate patient profile to identify features that can predict treatment response. In conclusion, tDCS holds promise as a treatment for depression, but variability in trial parameters and outcomes underscores the need for its further optimization. Refining and standardizing protocols may enhance its effectiveness.

The cerebellum, a subcortical structure, is traditionally linked to sensorimotor integration and coordination, although its role in cognition and affective behavior, as well as epilepsy, is increasingly recognized. Cerebellar dysfunction in patients with epilepsy can result from genetic disorders, antiseizure medications, seizures, and seizure-related trauma. Impaired cerebellar function, regardless of cause, can cause ataxia (imbalance, impaired coordination, unsteady gait), tremor, gaze-evoked nystagmus, impaired slow gaze pursuit and saccade accuracy, as well as speech deficits (slurred, scanning, or staccato). We explore how cerebellar dysfunction can contribute to epilepsy, reviewing data on genetic, infectious, and neuroinflammatory disorders. Evidence of cerebellar dysfunction in epilepsy comes from animal studies as well as human neuropathology and structural magnetic resonance imaging (MRI), functional and diffusion tensor MRI, positron emission and single photon emission computerized tomography, and depth electrode electro-encephalography studies. Cerebellar lesions can infrequently cause epilepsy, with focal motor, autonomic, and focal to bilateral tonic-clonic seizures. Antiseizure medication-resistant epilepsy typically presents in infancy or before age 1 year with hemifacial clonic or tonic seizures ipsilateral to the cerebellar mass. Lesions are typically asymmetric benign or low-grade tumors in the floor of the fourth ventricle involving the cerebellar peduncles and extending to the cerebellar hemisphere. Electrical stimulation of the cerebellum has yielded conflicting results on efficacy, although methodological issues confound interpretation. Epilepsy-related comorbidities including cognitive and affective disorders, falls, and sudden unexpected death in epilepsy may also be impacted by cerebellar dysfunction. We discuss how cerebellar dysfunction may drive seizures and how genetic epilepsies, seizures and seizure therapies may drive cerebellar dysfunction, and how our understanding of epilepsy-related comorbidities through basic neuroscience, animals models and patient studies can advance our understanding and improve patient outcomes.

OBJECTIVE:We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults. METHODS:Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults. RESULTS:A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively. SIGNIFICANCE/CONCLUSIONS:Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy that may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer's and Huntington's diseases.

After stroke, upper extremity (UE) motor recovery may be mediated in part by transcallosal projections between hemispheres. The interhemispheric competition model posits that transcallosal inhibition (TI) from the contralesional hemisphere is abnormally strengthened following stroke and interferes with motor recovery. This model has recently been questioned. In this longitudinal study, we aimed to definitively confirm or refute a maladaptive role of contralesional TI in subacute motor recovery. We assessed 30 mild-to-moderately impaired subjects over the six months following ischemic stroke. We tracked contralesional TI and motor functions in the proximal and distal segments of the paretic UE. We used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP) in an arm and hand muscle. We used quantitative and clinical testing to examine deficits in muscle strength, motor control, and individuation; UE segmental impairment; and UE activity limitation. We assessed the relationships of contralesional TI to motor functions in the subacute period. Despite recovery of most motor functions in the proximal and distal UE, contralesional TI was largely static and unrelated to recovery of any motor function. There were inconsistent associations between stronger TI, less hand impairment, and less activity limitation in the subacute period overall. We found no compelling evidence to suggest a maladaptive role of contralesional TI in UE motor recovery in mild-to-moderately impaired stroke subjects. The scattered associations between stronger TI and better levels of paretic UE function suggest a potential supportive role rather than a limiting one. These findings challenge the validity of the interhemispheric competition model in the subacute recovery period, and prompt reconsideration of neuromodulatory strategies that subacutely target contralesional TI.

BACKGROUND:Intubated neuroscience ICU patients are at risk for unplanned extubation (premature removal of the endotracheal tube by the patient or during patient care). The incidence of unplanned extubation is an indicator of the quality of ICU care. Unplanned extubation is a risk factor for pneumonia, increased ventilator days, the need for tracheostomy and increased ICU and hospital length-of-stay. After serial unplanned extubations, we introduced a multidisciplinary unit-based practice standard to reduce unplanned extubations as part of a quality improvement initiative in the neuroscience ICU in a large academic medical center at a High Reliability Organization in May 2021. The unit-based practice standard to guide care of intubated neuroscience ICU patients focused on communication, timely escalation of concerns, use of sedation/analgesia targeting RASS ≤ -1, soft wrist restraints (unless specified exclusion criteria met) and continuous observation for patients at high risk of agitation/restlessness. We sought to determine the impact of this initiative on the incidence of unplanned extubations. METHOD/METHODS:Unplanned extubations were identified via retrospective audit of prospective incident reports from our Patient Safety Incident registry pre-initiative (June 2020-May 2021) and prospective audit of incident reports post-initiative (July 2021-March 2024). Chart review facilitated collection of data on patient age, sex, diagnosis, intubation day, RASS goal, sedation/analgesia, restraints, constant observation, shift, and reintubation. The total number of intubated patients and ventilator days during these timeframes was identified retrospectively via an electronic medical record report of all patients on ventilators in the neuroscience ICU. RESULTS:During the pre-initiative audit period, there were 214 intubated patients (968 ventilator days). The audit identified 9 unplanned extubations (0.93/100 ventilator days; 8 males, median age 63-years-old (IQR 47-67)). There were 4 patients who were not ordered for sedation/analgesia or had a RASS goal of 0 and no patients were in nonviolent soft wrist restraints. During the post-initiative audit period, there were 576 intubated patients (2,730 ventilator days). The audit identified 6 unplanned extubations (0.22/100 ventilator days; 6 males, median age 53-years-old (IQR 27-78)). All 6 patients had a RASS goal ≤ -1 and were in nonviolent soft wrist restraints. CONCLUSION/CONCLUSIONS:This quality improvement initiative effectively reduced the incidence of unplanned extubations in our neuroscience ICU.