Faculty Bibliography

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.

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.

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This study aimed to evaluate whether a 6-month (limited) course of early IVIG is an effective strategy for relapse prevention in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) versus only acute therapies or other early immunotherapies. METHODS:This was a retrospective multicenter observational study of pediatric MOGAD patients from the US Network of Pediatric Multiple Sclerosis Centers with disease onset between October 1996 and December 2022. Controls were matched to limited early IVIG subjects using a 3:1 ratio. Hazard ratios of time to relapse and rate ratios of annualized relapse rate were calculated. The cumulative probability of remaining relapse-free was evaluated with the Kaplan-Meier method. RESULTS:We identified 130 unique control subjects treated before second attack with acute treatments only used in matching, 18 subjects treated with limited early IVIG, and 23 subjects treated with other early immunotherapy. The time to relapse was not different between either the limited early IVIG group and control group (HR 0.60 [0.22, 1.66], p = 0.32) or other early immunotherapy group (HR 0.98 [0.27, 3.6], p = 0.98). The limited early IVIG group showed a lower annualized relapse rate, although not statistically significant (RR 0.44 [0.17, 1.14], p = 0.09) compared with controls and a similar annualized relapse rate compared with the other early immunotherapy group (RR 0.56 [0.19, 1.69], p = 0.30). DISCUSSION/CONCLUSIONS:Although underpowered, our results suggest that the use of a limited, 6-month course of early IVIG may reduce the risk of multiphasic disease in pediatric MOGAD.

The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this convergence relevant to daily auditory discourse remain poorly understood. Here, we leveraged neurosurgical electrocorticographic (ECoG) recordings from 48 patients and dissociated two key language networks that highly overlap in time and space integral to word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was agnostic to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. Our findings characterize how humans integrate ongoing auditory semantic information over time, a critical linguistic function from passive comprehension to daily discourse.

INTRODUCTION/UNASSIGNED:Huntington's Disease (HD) is a progressive fatal neurodegenerative disease with an unmet need for disease-modifying therapies. Neuroinflammation, particularly astrogliosis, plays a crucial role in the pathogenesis of HD and modulation of this damaging activity and its downstream effects presents a promising therapeutic avenue. Pepinemab, a semaphorin4D (SEMA4D) blocking antibody, has the potential to serve this purpose. AREAS COVERED/UNASSIGNED:We review the proposed mechanisms of action of pepinemab, published safety and efficacy results from the 'SIGNAL' Phase 2 trial in HD and supporting data from a Phase 1 trial in multiple sclerosis (MS). EXPERT OPINION/UNASSIGNED:Pepinemab's potential to reduce reactive gliosis and inflammation is a novel mechanism of action (MOA) that may be effective as a standalone therapy as well as one that may complement other strategies to reduce toxic disease associated processes. Pepinemab has demonstrated a favorable safety profile and treatment benefits in fluid biomarkers, imaging endpoints, and measures of cognitive function that encourage continued development in HD and other neurodegenerative diseases.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Alcohol withdrawal syndrome (AWS) is a serious complication of alcohol use disorder. Although benzodiazepines are the mainstay of treatment, some patients may be resistant to them, requiring rapidly escalating doses. Phenobarbital has emerged as an effective adjunct therapy in severe alcohol withdrawal, but studies have yielded inconsistent results and carry safety risks. The purpose of our study was to examine the effectiveness and the potential harm of phenobarbital in AWS. METHODS:In this multi-center, retrospective cohort study, patients who were admitted for AWS and received phenobarbital with benzodiazepine were compared to patients who received benzodiazepine monotherapy. The primary outcome was time to AWS resolution. Other secondary and safety outcomes included length of stay (LOS), rate of mechanical ventilation, and incidence of aspiration pneumonia. RESULTS:The phenobarbital group received significantly higher doses of benzodiazepines compared to the benzodiazepine monotherapy group (660 mg vs 340 mg, p < 0.0001). After adjustment, the use of phenobarbital was associated with significantly reduced time to AWS resolution (141.65 h vs 165.72 h, p < 0.0001). However, the use of phenobarbital was associated with the likelihood of mechanical ventilation (19.42 %vs. 0.96 %, p < 0.0001), aspiration pneumonia (22.33 % vs 5.77 %, p = 0.0006), and increased hospital LOS (8 days vs. 6 days, p = 0.0197). In the combination group, earlier phenobarbital initiation (within 24 h) was associated with significantly lower cumulative benzodiazepine dose (530 mg vs 887.50 mg, p = 0.002) and hospital LOS (6 days vs 10 days, p = 0.0017). CONCLUSION AND RELEVANCE/CONCLUSIONS:In our study, patients who received phenobarbital in combination with benzodiazepines had a quicker resolution of AWS but also had a higher incidence of mechanical ventilation, prolonged hospital LOS, and an increased risk of aspiration pneumonia. For patients at high risk of severe alcohol withdrawal, earlier initiation of phenobarbital appeared to yield the most optimal benefit.