Faculty Bibliography

Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation-based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits.

BACKGROUND:Early neurological deterioration (END) and recurrence of vessel blockage frequently complicate intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). Several studies have indicated the potential effectiveness of the early initiation (within < 24 h) of antiplatelet therapy (APT) after IVT. However, conflicting results have been reported by other studies. We aimed to offer a thorough overview of the current literature through a systematic review and meta-analysis. METHODS:Our systematic review and meta-analysis were prospectively registered on PROSPERO (ID: CRD42023488173) following the PRISMA guidelines. We systematically searched Web of Science, SCOPUS, PubMed, and Cochrane Library until May 5, 2024. Rayyan. ai facilitated the screening process. The R statistical programming language was used to calculate the odds ratios and conduct a meta-analysis. Our primary outcomes were excellent functional recovery (modified Rankin Scale score 0-1), symptomatic intracranial hemorrhage (sICH), and mortality. RESULTS:Eight studies involving 2,134 participants were included in the meta-analysis. Early APT showed statistically significant increased odds of excellent functional recovery (mRS 0-1) compared to the standard APT group (OR, 1.81; [95% CI: 1.10, 2.98], p = 0.02). However, we found no differences between the early and standard APT groups regarding sICH (OR, 1.74; [95% CI: 0.91, 3.33], p = 0.10) and mortality (OR, 0.88; [95% CI: 0.62, 1.24]; p = 0.47). CONCLUSION/CONCLUSIONS:Early APT within 24 h of IVT in stroke patients is safe, with no increase in bleeding risk, and has a positive effect on excellent functional recovery. However, there was a statistically insignificant trend of increased sICH with early APT, and the current evidence is based on highly heterogeneous studies. Further large-scale RCTs are warranted.

OBJECTIVE:This study examines the American Headache Society First Contact-Headache in Primary Care program metrics to date in order to assess the program's reach and provide direction for future initiatives. BACKGROUND:Approximately 4 million primary care office visits annually are headache-specific encounters. Therefore, it is important that primary care providers are knowledgeable about headache management. Recognizing the need, the American Headache Society First Contact designed the comprehensive First Contact-Headache in Primary Care program with input from an advisory board comprised of a diverse group of physicians and advanced practice providers with backgrounds in family and internal medicine, pediatrics, obstetrics and gynecology, and neurology. This is the first study to assess the reach of the program and critically examine how to best meet the needs of clinicians and patients going forward. METHODS:We report descriptive statistics for the First Contact website metrics from October 2020 to June 2023 and grand rounds program data from May 2020 to December 2023. We also conducted a cross-sectional analysis of survey data from presentations conducted at two large national family medicine symposia, as well as a thematic analysis of the question: "Please indicate what areas of your practice could be enhanced or improved with additional education?" RESULTS:The First Contact program homepage was the second most visited page on the American Headache Society website (>100,000 views). A total of 20 podcast episodes were created for the program (>3500 plays). The First Contact program held 99 events (72 institutional grand rounds, 22 State-level meetings, and five national meetings), reaching >7000 clinicians. The institutional grand rounds and state-level meetings were held across 27 States and Washington D.C. Only 31.9% (30/94) of First Contact program events (excluding national meetings) occurred in the West census region, which has the fewest headache subspecialists and lowest headache subspecialist density in the United States. When examining survey data of participants who attended the two virtual national family medicine symposia (39.3% response rate, N = 636/1620), 85.7% (544/635) reported being "completely confident" or "very confident" in their ability to recognize and accurately diagnose patients presenting with a primary complaint of headache and 81.5% (517/634) reported being "completely confident" or "very confident" in their ability to develop evidence-based treatment plans that are tailored to the needs of individual patients. The use of diagnostic tools to recognize patients with migraine (60.4%, 384/636) and translating standards of care to the practice setting (42.5%, 270/636) were the most reported intended changes by participants. Most participants reported that program content was of clinical relevance and would improve their patients' outcomes (90.5% [571/631] and 90.6% [572/631], respectively). Over three-quarters (77.8%, 495/636) of participants reported areas of their practice that can be improved by additional education specifically regarding workflow, diagnosis, and management. CONCLUSION/CONCLUSIONS:This study evaluates one of the first national initiatives for primary care education. Data from the two First Contact Family Medicine national symposia indicate the program is generally well received with most participants reporting improved confidence and intention to implement key changes in practice to improve care for patients with headache; however, there remain areas of exploration for education that could further enhance participant experience and expand the reach of the initiatives. Areas for future programming include continued education on multifactorial approaches to headache treatment and suggestions for addressing cost, insurance, and time constraints. Also, future work may examine where the First Contact program might focus initiatives based on specific areas of need in headache care, such as geographic "desert" areas, racial and ethnic disparities, and uninsured/underinsured populations.

BACKGROUND:Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect. METHODS:We curated a retrospective data set of 635 patients with large middle cerebral artery stroke totaling 95,463 data points for 10 longitudinal covariates and 40 time-independent covariates. We assessed trajectories of the 10 longitudinal variables during the 72 h preceding three outcomes representative of life-threatening mass effect: midline shift ≥ 5 mm, pineal gland shift (PGS) > 4 mm, and decompressive hemicraniectomy (DHC). We used a "backward-looking" trajectory approach. Patients were aligned based on outcome occurrence time and the trajectory of each variable was assessed before that outcome by accounting for cases and noncases, adjusting for confounders. We evaluated longitudinal trajectories with Cox proportional time-dependent regression. RESULTS:Of 635 patients, 49.0% were female, and the mean age was 69 years. Thirty five percent of patients had midline shift ≥ 5 mm, 24.3% of patients had PGS > 4 mm, and 10.7% of patients underwent DHC. Backward-looking trajectories showed mild increases in white blood cell count (10-11 K/UL within 72 h), temperature (up to half a degree within 24 h), and sodium levels (1-3 mEq/L within 24 h) before the three outcomes of interest. We also observed a decrease in heart rate (75-65 beats per minute) 24 h before DHC. We found a significant association between increased white blood cell count with PGS > 4 mm (hazard ratio 1.05, p value 0.007). CONCLUSIONS:Longitudinal profiling adjusted for confounders demonstrated that white blood cell count, temperature, and sodium levels appear to increase before radiographic and clinical indicators of space-occupying mass effect. These findings will inform the development of multivariable dynamic risk models to aid prediction of life-threatening, space-occupying mass effect.

OBJECTIVE:Randomized controlled trials (RCTs) are necessary to evaluate the efficacy of novel treatments for epilepsy. However, there have been concerning increases in the placebo responder rate over time. To understand these trends, we evaluated features associated with increased placebo responder rate. METHODS:Using individual-level data from 20 focal-onset seizure trials provided by seven pharmaceutical companies, we evaluated associations with change in seizure frequency in participants randomized to placebo. We used multivariable logistic regression to evaluate participant and study factors associated with differing rates of 50% reduction in seizure frequency during blinded placebo treatment, as compared to pre-randomization baseline seizure frequency. In addition, we focused on the association of placebo responder rate with pre-randomization baseline seizure frequency and country of recruitment. RESULTS:). In addition, there was a significantly higher 50RR in participants with a baseline seizure frequency of six or fewer seizures per 28 days (29% vs 21%, p = .00018). SIGNIFICANCE/CONCLUSIONS:These results can assist future RCTs in estimating the expected placebo responder rate, which may lead to more reliable power estimates. Higher placebo responder rate was associated with markers of less-refractory epilepsy. There were concerning significant differences in placebo responder rate by country and geographic region as well as an elevated placebo responder rate in participants with baseline seizure frequency close to the minimum eligibility criteria.

T cell receptor (TCR) gene therapy is a potent form of cellular immunotherapy in which patient T cells are genetically engineered to express TCRs with defined tumor reactivity. However, the isolation of therapeutic TCRs is complicated by both the general scarcity of tumor-specific T cells among patient T cell repertoires and the patient-specific nature of T cell epitopes expressed on tumors. Here we describe a high-throughput, personalized TCR discovery pipeline that enables the assembly of complex synthetic TCR libraries in a one-pot reaction, followed by pooled expression in reporter T cells and functional genetic screening against patient-derived tumor or antigen-presenting cells. We applied the method to screen thousands of tumor-infiltrating lymphocyte (TIL)-derived TCRs from multiple patients and identified dozens of CD4⁺ and CD8⁺ T-cell-derived TCRs with potent tumor reactivity, including TCRs that recognized patient-specific neoantigens.

OBJECTIVE:To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD). METHODS:The study was conducted from January 2018 to December 2021, pausing during the COVID-19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH-) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures. RESULTS:Compared to baseline, EtOH+ but not EtOH- patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6-26.9; p = 0.008; EtOH-: 98.75% CI = -6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75-5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7-48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness. INTERPRETATION/CONCLUSIONS:Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2024.