Faculty Bibliography

BACKGROUND:Many survivors of hemorrhagic stroke have impaired communication. We aimed to identify preadmission, admission, and post-discharge factors associated with self-reported impaired communication after hemorrhagic stroke. DESIGN/METHODS:Patients with intracerebral or subarachnoid hemorrhage (ICH or SAH) admitted at an urban academic medical center were assessed 3-months post-bleed using the communication Quality of Life in Neurological Disorders (Neuro-QoL) short form inventory. Multivariate analysis was performed to evaluate the relationship between impaired communication (Neuro-QoL scaled score < 100) and preadmission, admission, and post-discharge factors. RESULTS:Of 108 patients (68 ICH and 40 SAH), 59 (54.6%) had impaired communication 3-months post-bleed. On multivariate analysis of the full cohort, when controlling for NIHSS score on admission, impaired communication was associated with: retirement prior to admission (OR: 8.18, 95% CI 1.95-40.5, p = 0.005), hospital length-of-stay (OR: 1.11, 95% CI 1.03-1.22, p = 0.012), and cognitive impairment post-bleed (OR: 32.1, 95% CI 8.93-146, p < 0.001). There were 43 (63.2%) ICH patients with impaired communication 3-months post-bleed. On multivariate analysis, impaired communication was associated with: retirement prior to admission (OR: 9.46, 95% CI 1.76-71.8, p = 0.014), supratentorial location (OR: 8.93, 95% CI 1.22-93.6, p = 0.043), hospital length-of-stay (OR: 1.21, 95% CI 1.01-1.45, p = 0.018), and cognitive impairment post-bleed (OR: 16.3, 95% CI 3.58-102, p < 0.001). CONCLUSIONS:Impaired communication after hemorrhagic stroke is more common in patients who were retired prior to admission and who have post-bleed comorbid cognitive impairment. Increased surveillance is recommended for retired and cognitively impaired patients. Additional investigation into the relationship between communication and both retirement status and cognitive impairment is needed.

Three-dimensional (3D) ex vivo imaging of cleared tissue from intact brains from animal models, human brain surgical specimens, and large postmortem human and non-human primate brain specimens is essential for understanding physiological neural connectivity and pathological alterations underlying neurological and neuropsychiatric disorders. Contemporary light-sheet microscopy enables rapid, high-resolution imaging of large, cleared samples but is limited by the orthogonal arrangement of illumination and detection optics, which constrains specimen size. Light-sheet theta microscopy (LSTM) overcomes this limitation by employing two oblique illumination paths while maintaining a perpendicular detection geometry. Here, we report the development of a next-generation, fully integrated and user-friendly LSTM system that enables uniform subcellular-resolution imaging (with subcellular resolution determined by the lateral performance of the system) throughout large specimens without constraining lateral (XY) dimensions. The system provides a seamless workflow encompassing image acquisition, data storage, pre- and post-processing, enhancement and quantitative analysis. Performance is demonstrated by high-resolution 3D imaging of intact mouse brains and human brain samples, including complete downstream analyses such as digital neuron tracing, vascular reconstruction and design-based stereological analysis. This enhanced and accessible LSTM implementation enables rapid quantitative mapping of molecular and cellular features in very large biological specimens.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related deaths in people with epilepsy. Despite evidence that SUDEP counseling does not cause stress, improves treatment adherence, and empowers people with epilepsy and their caregivers, it remains underdiscussed. This study aimed to explore the in-depth perspectives of parents who have lost a child to SUDEP, focusing on their experiences, grief, and coping strategies, while factoring in their demographics, the clinical features of their deceased children, and their previous awareness of SUDEP, all aspects that have not been systematically investigated before. METHODS:This qualitative phenomenological study involved in-depth semistructured interviews with 51 parents of 43 children who died of SUDEP. Transcripts were analyzed using immersion/crystallization qualitative methodology with Dedoose software, using an iterative consensus-building process. Thematic analysis revealed common perspectives, grief narratives, coping strategies, and perceived needs among parents after their child's SUDEP. RESULTS:Of the 51 participating parents (mean age 54.1 ± 9.4 years, 71% female), 27 reported being unaware of SUDEP before it occurred, whereas 24 reported previous awareness of it. These groups shared similar demographics and clinical characteristics. However, "unaware" parents expressed more intense trauma and prolonged maladaptive grief, characterized by guilt, extreme anger, and medical distrust. By contrast, "aware" parents described mitigated trauma, with less guilt- and anger-ridden grief, and reduced reliance on specialized support groups. Previous SUDEP awareness provided emotional preparation, buffering the devastating reality and fostering agency and acceptance. Another theme highlighted the struggles parents faced immediately after SUDEP, particularly with law enforcement and treating physicians. Unanimously, parents emphasized the paramount importance of counseling about the known relationship between epilepsy and SUDEP. DISCUSSION/CONCLUSIONS:Previous awareness of SUDEP (or lack thereof) has complex and far-reaching effects on the subsequent parental perceived trauma, grief, and coping processes. Furthermore, emergency responders, official personnel, and treating physicians may mishandle the aftermath of SUDEP. This study's findings strongly advocate for a paradigm shift in SUDEP-related practices across multiple disciplines, including legislation. Emphasis should be placed on increasing proactive SUDEP counseling to mitigate the traumatic effect and subsequent grieving process when SUDEP occurs.

IMPORTANCE/UNASSIGNED:Differentiating multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), especially in seronegative cases, remains challenging due to overlapping clinical and imaging features. High-level Epstein-Barr virus (EBV)-derived Epstein-Barr nuclear antigen 1 (EBNA-1) peptide antibody titers may be an MS-specific biomarker that could the improve differential diagnosis. OBJECTIVE/UNASSIGNED:To determine whether longitudinal EBNA-1 peptide antibodies can distinguish MS from MOGAD and NMOSD. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a retrospective, multicenter, longitudinal, case-control study with patients from Austria, Germany, and the US. This study assessed samples from 2 independent retrospective cohorts. A test cohort and a validation cohort assessed longitudinal plasma samples from patients with MS, MOGAD, or NMOSD. Patients were recruited between 2001 and 2023 and followed up for 2 years. A combined analysis of both cohorts was conducted in January 2025. EXPOSURES/UNASSIGNED:Plasma EBNA-1 peptide immunoglobulin G (IgG) titers measured by enzyme-linked immunosorbent assay after diagnosis and in 3 follow-up samples. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Diagnostic utility of persistent EBNA-1 peptide antibody levels across 4 time points in patients with MS compared with patients with MOGAD and NMOSD. RESULTS/UNASSIGNED:This study included the plasma samples of 2091 patients (mean [SD] age, 31.0 [16.9] years; 1137 female [54.4%]) with neuroinflammatory disease and 1976 healthy controls (mean [SD] age, 39.8 [16.2] years; 1120 male [56.7%]) recruited between 2001 and 2023. The test cohort (310 patients; 54.8% female) included 184 patients with MS, 65 with MOGAD, and 61 with NMOSD (including 12 who were seronegative for aquaporin 4 [AQP4] IgG). The validation cohort (183 patients; 126 female [68.8%]) included 142 patients with MS, 24 with MOGAD, and 17 with NMOSD. In the test cohort, 177 patients with MS (96.2%) had high-level titers in 2 or more of 4 follow-up samples compared with 5 patients (7.7%) with MOGAD (odds ratio [OR], 303.4; 95% CI, 94.4-908.6) and 11 patients (18.0%) with NMOSD (OR, 114.9; 95% CI, 43.0-280.0). Among patients with NMOSD who were seronegative for AQP4-IgG, only 1 (11.1%) had persistent high-level EBNA-1 peptide antibody titers compared with 61 matched patients (96.7%) with MS (OR, 236.0; 95% CI, 18.6-2588.0). In the validation cohort, 135 patients (95.1%) with MS had high-level titers in 2 or more of 4 follow-up samples compared with 4 patients (16.7%) with MOGAD (OR, 96.4; 95% CI, 26.6-293.0) and 3 patients (17.6%) with NMOSD (OR, 90.0; 95% CI, 19.7-319.7). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this case-control study reveal that persistent high-level EBNA-1 peptide antibody titers may serve as a reliable biomarker for differentiating MS from MOGAD, and NMOSD.

IMPORTANCE/UNASSIGNED:Psychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs). OBJECTIVE/UNASSIGNED:To evaluate the role of psychiatric disturbances at the time of epilepsy diagnosis in predicting risk of future treatment resistance in focal epilepsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Human Epilepsy Project (HEP) is a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. Participants with newly diagnosed focal epilepsy, enrolled within 4 months of initiating ASM treatment, between the ages 18 and 60 years, and without significant other comorbidities were recruited during the open period of 2012 to 2020. Data analysis was performed from January to September 2025. EXPOSURE/UNASSIGNED:Presence of a psychiatric diagnosis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presence of psychiatric diagnosis (mood/anxiety disorders) measured by Mini International Neuropsychiatric Interview (MINI) and/or suicidality measured by Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment. Treatment response included the following outcomes: treatment resistant (TR), defined as failure of first 2 adequate ASM trials (ongoing seizures at/above therapeutic doses); treatment sensitive (TS), defined by a minimum period of seizure freedom on first 2 adequate ASM trials (12 months/3-fold greatest pretreatment seizure-free interval, whichever is longer); and indeterminate (neither TR/TS). RESULTS/UNASSIGNED:Of 376 enrolled adults, 347 (median [IQR] age at seizure onset, 33 [23-44] years; 209 female [60.2%]) completed the MINI and C-SSRS at enrollment. Of these individuals, 191 (55%) were TS, 83 (24%) TR, and 73 (21%) indeterminate. The rate of psychiatric disturbance (mood/anxiety disorder; suicidality) at epilepsy diagnosis was 38% (n = 133). Fifty-seven (16%) had mood/anxiety disorder(s) without suicidality, and 75 (22%) expressed suicidality with or without a psychiatric disorder. Suicidality at epilepsy diagnosis was associated with greater than 2-fold risk of developing TR (relative risk [RR], 2.02; 95% CI, 1.32-3.09; P = .001). There were no significant overall associations between mood/anxiety disorders and TR. Suicidality alone significantly increased TR probability from 16.3% (95% CI, 11.3%-21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65-5.05; P < .001). Anxiety disorder alone increased TR probability to 32.9% (RR, 2.02; 95% CI, 1.10-3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. There was no significant change in TR probability when mood disorder alone was present; however, presence of mood disorder with suicidality increased TR probability to 39.6% (RR, 2.43; 95% CI, 1.26-4.68; P = .008). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology. Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes.

INTRODUCTION/BACKGROUND:This study aimed to explore the experience of living with amyotrophic lateral sclerosis (ALS) and to develop a conceptual model for this rare disease. METHODS:Concept elicitation interviews were conducted (January-September 2024) with people living with ALS (PLwALS; n = 31), caregivers (n = 20), and clinicians (n = 10). Qualitative data were analyzed separately to develop a conceptualization of the experience of living with ALS. Concept saturation was assessed every 5-6 interviews, and a conceptual model was developed. RESULTS:The mean age of PLwALS was 42.4 years (standard deviation [SD] 11.5), 81% were female, 84% were white, and 23% had SOD1-ALS. The mean time since diagnosis was 4.6 years (SD 4.2); mean normed Rasch Overall ALS Disability Scale score was 76 (SD 17.16). Signs, symptoms, and functions reported during PLwALS interviews included neuromuscular, bulbar, speech, neurocognitive (e.g., memory issues), and a range of physical functioning issues (e.g., motor coordination). PLwALS also reported impacts on a range of activities and psychosocial interactions (e.g., eating, depressed mood, and relationships), alongside management strategies they employed. Interviews with caregivers and clinicians supported findings from the PLwALS interviews. Caregivers also identified signs such as drooling/excess salivation, and impacts related to ALS management (e.g., need for writing aids). Clinicians additionally considered loss of speech and neurocognitive signs (e.g., behavior/personality change) as ALS clinical manifestations. Concept saturation was reached, and a consolidated, comprehensive conceptual model was developed. CONCLUSION/CONCLUSIONS:This research provides a holistic understanding of the experience of living with ALS and is the first conceptual model based on in-depth concept elicitation interviews. The findings highlight the range of signs, symptoms, and impacts that PLwALS experience, emphasizing its serious humanistic impact and high unmet need, and will help to guide patient-centric evaluation of clinical outcome assessments in future ALS studies.

BACKGROUND:Spinocerebellar ataxia type 27 B (SCA27B) caused by GAA trinucleotide repeats in the fibroblast growth factor 14 gene is emerging as a common cause of late-onset ataxia. Oscillopsia due to downbeat nystagmus (DBN) and diplopia are common symptoms, yet the causes of diplopia and strabismus patterns are poorly defined. METHODS:Retrospective chart review of 18 patients diagnosed with SCA27B over the past year. RESULTS:Ten of 18 patients had episodic or persistent oscillopsia or diplopia at disease onset, neurologically isolated in 4. Seventeen had detectable DBN, although it was often delayed in onset and was clinically obvious in only 5. Diplopia was present in 14 patients: vertical due to skew deviation (static and or alternating on lateral gaze) (n = 8) and/or horizontal due to vergence dysfunction (n = 11). Symptomatic vergence dysfunction included convergence insufficiency (CI) (n = 4) and divergence insufficiency (n = 5). Thirteen of 16 patients experienced improvement in oscillopsia or imbalance on 4-aminopyridine (4-AP). CONCLUSIONS:Strabismus patterns causing diplopia in patients with SCA27B are, not unexpectedly, largely attributable to cerebellar dysfunction and are not unique to SCA27B. The exceptions to cerebellar localization were CI, sixth nerve palsy, and slow saccades. Careful assessment for DBN in patients presenting with episodic or persistent diplopia from skew deviation or vergence disorders is important, as this may be key to confirming a cerebellar localization, subtle on examination, and guide toward genetic testing and 4-AP treatment.