Faculty Bibliography

BACKGROUND:Endovascular thrombectomy (EVT) is the gold standard for acute ischemic stroke (AIS) with large vessel occlusion (LVO). However, concomitant intracranial hemorrhage (ICH) might render AIS-LVO patients ineligible for EVT in real-life practice. OBJECTIVE:To provide robust evidence regarding the outcomes of EVT in AIS-LVO patients with concomitant ICH. METHODS:We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. Data analysis was performed using OpenMetaAnalyst software. We assessed the pooled incidence rate with a 95 % confidence interval (CI) for qualitative data and analyzed the pooled mean difference (MD) with a 95 % CI for continuous data. The pooled effect size for all outcomes was calculated using the DerSimonian and Laird random-effects model. RESULTS:Six studies were included in the meta-analysis. The overall incidence rate of successful revascularization was 85.3 % (95 % CI: 75.8 %-94.7 %), with rates of 76.1 % for ipsilateral hemorrhages and 66.1 % for contralateral hemorrhages. Functional independence was achieved in 20 % of patients (95 % CI: 4.8 %-36.8 %), with rates of 23 % for ipsilateral and 27.7 % for contralateral hemorrhages. Mortality was reported at 52 % (95 % CI: 34.9 %-69 %), with a higher rate of 52.6 % for ipsilateral hemorrhages compared to 36.8 % for contralateral hemorrhages. CONCLUSION/CONCLUSIONS:This meta-analysis indicates that EVT is feasible in AIS patients with concurrent ICH, yet it is associated with poor functional outcomes and high mortality rates. Careful patient selection is essential to optimize the outcomes, and further research is needed to enhance outcomes for these high-risk patients.

Severe brain injury can result in disorders of consciousness (DoC), including coma, vegetative state/unresponsive wakefulness syndrome, and minimally conscious state. Improved emergency and trauma medicine response, in addition to expanding efforts to prevent premature withdrawal of life-sustaining treatment, has led to an increased number of patients with prolonged DoC. High-quality bedside care of patients with DoC is key to improving long-term functional outcomes. However, there is a paucity of DoC-specific evidence guiding clinicians on efficacious bedside care that can promote medical stability and recovery of consciousness. This Viewpoint describes the state of current DoC bedside care and identifies knowledge and practice gaps related to patient care with DoC collated by the Care of the Patient in Coma scientific workgroup as part of the Neurocritical Care Society's Curing Coma Campaign. The gap analysis identified and organized domains of bedside care that could affect patient outcomes: clinical expertise, assessment and monitoring, timing of intervention, technology, family engagement, cultural considerations, systems of care, and transition to the post-acute continuum. Finally, this Viewpoint recommends future research and education initiatives to address and improve the care of patients with DoC.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the Grading of Recommendations, Assessment, Development and Evaluation approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

The mechanisms behind comorbid symptoms of depression in persons with epilepsy (PWE) remain largely unknown. Our study aimed to learn whether seizures moderate fluctuations in depressive symptoms in PWE when controlling for preictal symptoms of depression. We enrolled 57 adult PWE admitted to the New York University (NYU) Langone Epilepsy Monitoring Unit (EMU) from 2021 to 2024. Thirty-seven participants had a seizure. Twenty of the admitted patients did not have seizures during the admission period and therefore served as controls. All participants were seizure free for > 7 days prior to participation. Upon admission, all participants completed the Montgomery-Asberg Depression Rating Scale (MADRS) to evaluate baseline mood. The MADRS was repeated acutely (4-24 h post seizure or admission) and subacutely (2-7 days post seizure or discharge) for both groups. Linear regression models revealed that individuals with higher baseline MADRS scores (indicating higher depressive symptoms) experienced worse mood acutely post-seizure, while lower baseline MADRS scores were associated with acute mood improvement (R² = 0.59, p < 0.001). Experiencing a seizure was not associated with subacute mood outcomes, which were instead driven by acute mood state (R² = 0.56, p < 0.001). In conclusion, we found that seizures exacerbate pre-ictal depressive symptoms and that post-ictal depressive symptoms persist up to 7 days after seizure resolution. This study may provide evidence for a bidirectional relationship and demonstrate a vicious cycle between depression and epilepsy.

OBJECTIVE:To report interim data from an ongoing, open-label extension (OLE) of a Phase 2b study (X-TOLE) of azetukalner in adults with focal onset seizures (FOS) receiving 1-3 antiseizure medications. METHODS:Eligible participants enrolled in the 7-year OLE at 20 mg azetukalner once daily with food. Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of ≥50%, ≥75%, ≥90%, and 100% seizure reductions. RESULTS:285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the 24-month interim analysis (September 5, 2023), 182 participants had been treated for ≥12 months and 165 for ≥24 months; 152 (55.3%) continued in the study. The median (range) treatment duration in the OLE was 26.3 (0.1-46.6) months. MPC reduction was 83.2% at 24 months in the OLE vs. DBP baseline. For all participants who entered the OLE, 56.4% (155/275) and 44.4% (122/275) achieved a ≥50% seizure reduction, 28.4% (78/275) and 19.6% (54/275) achieved a ≥90% seizure reduction, and 22.2% (61/275) and 14.9% (41/275) achieved seizure freedom (100% seizure reduction) for any consecutive ≥6- and ≥12-month period, respectively. For those who reached ≥24 months in the OLE, seizure freedom was achieved by 34.5% (57/165) and 23.6% (39/165) for any consecutive ≥6- and ≥12-month period, respectively. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Serious AEs were reported in 35 (12.7%) participants. SIGNIFICANCE/CONCLUSIONS:The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis. Azetukalner was generally well tolerated, with no new safety signals compared to the DBP. These data suggest sustained long-term efficacy and safety of azetukalner in a difficult-to-treat population. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:This long-term study assessed the safety and efficacy of azetukalner to treat focal seizures. Patients taking azetukalner daily with food for about 2 years had far fewer focal seizures with azetukalner than before taking the medication. For those who had been treated for 24 months, about a third were seizure-free for a consecutive 6-month period, and about a quarter were seizure-free for a consecutive 12-month period. Most side effects were mild or moderate, and these included dizziness, headache, and somnolence (sleepiness).

OBJECTIVE:This study was an open-label single-arm clinical trial evaluating the fidelity, feasibility, acceptability, and clinical signal of abbreviated mindfulness-based cognitive therapy (MBCT-brief) delivered either via telephone (MBCT-T) or by video conferencing (MBCT-V) for people with migraine and comorbid depressive symptoms. BACKGROUND:Migraine is commonly comorbid with elevated depressive symptoms. MBCT reduces depressive symptoms and shows promise to reduce migraine-related disability. An abbreviated and remotely delivered version of MBCT could increase access to care. METHODS:) at baseline, mid-treatment, and post-treatment. Feasibility and acceptability rates were compared to a priori benchmarks. RESULTS:(pre-treatment median [interquartile range] score 8 [5, 13] vs. post-treatment 4 [3, 6], p = 0.003). CONCLUSION/CONCLUSIONS:We found that remotely delivered MBCT-brief for migraine and depressive symptoms was feasible and acceptable to patients in both the telephone and video modalities. Intervention was associated with significant post-treatment reductions in headache-related disability and depressive symptomatology, findings that must be interpreted cautiously in the absence of a control group.

Presence of focal to bilateral tonic-clonic seizures (FBTCS) in focal epilepsy is associated with increased morbidity and mortality. Risk factors for FBTCS are poorly understood, and little is known regarding FBTCS recurrence after treatment initiation. This study aimed to investigate factors related to FBTCS in newly diagnosed focal epilepsy and their recurrence after starting antiseizure medications (ASMs) in the Human Epilepsy Project (HEP) cohort. HEP was an international, prospective cohort study that enrolled people with newly diagnosed focal epilepsy within 4 months of treatment initiation and followed them for up to 6 years. Baseline characteristics, treatment choices, and seizure outcomes were collected. Descriptive and inferential statistical analysis was conducted to assess the differences between study participants who had FBTCS and those who never experienced FBTCS. A total of 443 participants were included in this analysis; 77% (n = 342) had FBTCS at some point prior to or within the study period. In participants with FBTCS, regardless of initial seizure type, diagnosis was mostly made after FBTCS (335/342, 98%). After treatment initiation, FBTCS did not recur in 57% (n = 194/342) of cases. A higher number of total pretreatment seizures (median = 16 vs. 11, p = .048, Mann-Whitney U-test), predominantly focal aware seizures (FAS) or focal impaired awareness seizures (FIAS; median = 15 vs. 10, p = .049, Mann Whitney U-test), was associated with no recurrence in FBTCS after treatment initiation. Of 108 participants without FBTCS prior to treatment, only seven (6%) developed FBTCS after treatment initiation. There was no significant difference in choice of initial ASM class (levetiracetam vs. sodium channel blockers) between participants who experienced FBTCS and those who did not. This study highlights the significance of FBTCS among individuals with newly diagnosed focal epilepsy. The majority of participants who experienced FBTCS were diagnosed with epilepsy after experiencing their first FBTCS despite preceding FAS/FIAS. The more frequent FAS/FIAS in participants whose FBTCS resolved may be a characteristic of their epilepsy.

BACKGROUND AND OBJECTIVES/UNASSIGNED:Neurosarcoidosis poses a diagnostic and management challenge due to its rarity, phenotypic variability, and lack of randomized controlled studies to guide treatment selection. Recommendations for management based on expert opinion are useful in clinical practice and provide a framework for designing prospective studies. METHODS/UNASSIGNED:In this Delphi survey study, specialists with experience in managing patients with neurosarcoidosis were invited to anonymously complete 2 surveys about key elements of evaluation, diagnosis, treatment, monitoring, and long-term management of neurosarcoidosis. Expert consensus recommendations were adopted if >80% threshold of agreement was reached. RESULTS/UNASSIGNED:Of the 41 invited expert clinicians across the United States, 32 (78%) participated in the study. All round 1 respondents self-identified as neuroimmunologists (except for 1 pulmonologist). Consensus was reached regarding the need to consider neurosarcoidosis phenotype and severity to guide the choice of initial immunosuppression in both the acute (relapse) and maintenance phases. Experts endorsed the use of TNF-α inhibitors as first-line agents in selected phenotypes with poor prognosis. Neuroimaging was recommended to complement clinical surveillance for treatment response. DISCUSSION/UNASSIGNED:There was agreement on several key issues, most importantly on the need to consider neurosarcoidosis phenotype and severity when deciding initial treatment. No consensus was achieved on the dosing and duration of specific immunosuppressants, nor regarding the management of the peripheral nervous system manifestation of neurosarcoidosis. These topics warrant further investigation.

OBJECTIVES/BACKGROUND/OBJECTIVE:This study was undertaken to synthesize evidence on the benefits and harms of behavioral interventions for migraine prevention in children and adults. The efficacy and safety of behavioral interventions for migraine prevention have not been tested in recent systematic reviews. METHODS:An expert panel including clinical psychologists, neurologists, primary care physicians, researchers, funders, individuals with migraine, and their caregivers informed the scope and methods. We searched MEDLINE, Embase, PsycINFO, PubMed, the Cochrane Database of Systematic Reviews, clinicaltrials.gov, and gray literature for English-language randomized trials (January 1, 1975 to August 24, 2023) of behavioral interventions for preventing migraine attacks. Primary outcomes were migraine/headache frequency, migraine disability, and migraine-related quality of life. One reviewer extracted data and rated the risk of bias, and a second verified data for completeness and accuracy. Data were synthesized with meta-analysis when deemed appropriate, and we rated the strength of evidence (SOE) using established methods. RESULTS:For adults, we included 50 trials (77 publications, N = 6024 adults). Most interventions were multicomponent (e.g., cognitive behavioral therapy [CBT], biofeedback, relaxation training, mindfulness-based therapies, and/or education). Most trials were at high risk of bias, primarily due to possible measurement bias and incomplete data. For adults, we found that any of three components (CBT, relaxation training, mindfulness-based therapies) may reduce migraine/headache attack frequency (SOE: low). Education alone that targets behavior may improve migraine-related disability (SOE: low). For three other interventions (biofeedback, acceptance and commitment therapy, and hypnotherapy), evidence was insufficient to permit conclusions. We also found that mindfulness-based therapies may reduce migraine disability more than education, and relaxation + education may improve migraine-related quality of life more than propranolol (SOE: low). For children/adolescents, we included 13 trials (16 publications, N = 1444 children), but the evidence was only sufficient to conclude that CBT + biofeedback + relaxation training may reduce migraine attack frequency and disability more than education alone (SOE: low). CONCLUSION/CONCLUSIONS:Results suggest that for adults, CBT, relaxation training, and mindfulness-based therapies may each reduce the frequency of migraine/headache attacks, and education alone may reduce disability. For children/adolescents, CBT + biofeedback + relaxation training may reduce migraine attack frequency and disability more than education alone. Evidence consisted primarily of underpowered trials of multicomponent interventions compared with various types of control groups. Limitations include semantic inconsistencies in the literature since 1975, differential usage of treatment components, expectation effects for subjectively reported outcomes, incomplete data, and unclear dosing effects. Future research should enroll children and adolescents, standardize intervention components when possible to improve reproducibility, consider smart study designs and personalized therapies based on individual characteristics, use comparison groups that control for expectation, which is a known challenge in behavioral trials, enroll and retain larger samples, study emerging digital and telehealth modes of care delivery, improve the completeness of data collection, and establish or update clinical trial conduct and reporting guidelines that are appropriate for the conduct of studies of behavioral therapies.