Faculty Bibliography

Importance/UNASSIGNED:Elevated systolic blood pressure (SBP) after acute ischemic stroke and transient ischemic attack (TIA) is associated with future stroke risk. Objective/UNASSIGNED:To explore the association of dual antiplatelet therapy (DAPT) with stroke recurrence among patients with acute ischemic stroke and TIA with or without elevated baseline SBP. Design, Setting, and Participants/UNASSIGNED:This cohort study performed a post hoc subgroup analysis of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which was a multicenter trial conducted from 2010 to 2018 at 269 sites in 10 countries in North America, Europe, Australia, and New Zealand. Patients enrolled in POINT with available blood pressure and outcome data were included in this cohort. Statistical analysis was performed from November 2020 to January 2021. Exposures/UNASSIGNED:Baseline SBP less than 140 mm Hg vs greater than or equal to 140 mm Hg and the interaction term of SBP (<140 mm Hg vs ≥140 mm Hg) × treatment group (aspirin vs DAPT). Main Outcomes and Measures/UNASSIGNED:The primary outcome was ischemic stroke during 90 days of follow-up. The statistical analysis fit Cox proportional hazards models adjusted for patient age, race, premorbid hypertension, diabetes, and final diagnosis of the qualifying event (stroke vs TIA). Results/UNASSIGNED:Among 4781 patients in the cohort, the mean (SD) age was 64.6 (13.1) years; 2142 (44.8%) were male individuals, 3487 (72.9%) were White individuals, and 266 (5.6%) had a primary outcome of ischemic stroke during follow-up. There were 946 patients (19.8%) with baseline SBP less than 140 mm Hg and 3835 (80.2%) with SBP greater than or equal to 140 mm Hg. The interaction term (SBP × treatment) was significant (P for interaction = .03). In the subgroup of patients with SBP less than 140 mm Hg, the hazard ratio (HR) of DAPT vs aspirin alone for ischemic stroke was 0.36 (95% CI, 0.18-0.72; P = .004), whereas the HR in the subgroup with SBP greater than or equal to 140 mm Hg was 0.79 (95% CI, 0.60-1.02; P = .08). When evaluating the outcome of ischemic stroke within 7 days of randomization, the interaction term was significant (P for interaction = .02), and the HR for patients with DAPT with SBP less than 140 mm Hg was 0.19 (95% CI, 0.07-0.55; P = .002). Conclusions and Relevance/UNASSIGNED:In the POINT trial, patients with SBP less than 140 mm Hg at presentation received a greater benefit from 90 days of DAPT than those with higher baseline SBP, particularly for reduction of early ischemic stroke recurrence. Additional research is needed to replicate these findings and potentially test whether mild SBP reduction and DAPT within 12 hours of stroke onset lowers early risk of stroke recurrence.

PURPOSE OF REVIEW:Central and peripheral nervous system manifestations of coronavirus disease 2019 (COVID-19) have been frequently reported and may cause significant morbidity and mortality. This review details the latest evidence on the neuropathogenesis and neurologic complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RECENT FINDINGS:Commonly reported neurologic complications include toxic-metabolic encephalopathy, acute cerebrovascular disorders, seizures, and anoxic-brain injury. These complications represent secondary injury due to COVID-19 related hypoxia, sepsis, hypercoagulability, or hyperinflammation. Postinfectious complications, such as encephalitis, postinfectious demyelination, and Guillain-Barré syndrome have been reported, but are rare. Recent reports of persistent neurocognitive symptoms highlight the possibility of lasting impairment. SUMMARY:Although some neurologic complications should be treated with standard practices, further investigations are still needed to determine the optimal treatment of COVID-related neurologic complications, such as ischemic stroke. Entering into the next phase of the pandemic, investigations into the long-term neurologic and cognitive impacts of SARS-CoV-2 infection will be needed. Clinicians must have a high clinical suspicion for both acute and chronic neurologic complications among COVID-19 patients.

OBJECTIVE:Palatable food (PF) intake is significantly greater in females than males and increases during adolescence. Previous data suggest that puberty and ovarian hormones may contribute to these sex and developmental differences, but few studies have examined this possibility. The aim of the current study was to address these gaps by examining trajectories of PF and chow intake during pre-puberty, puberty, and adulthood in intact female rats (Study 1) as well as in those receiving pre-pubertal ovariectomies (P-OVX) (Study 2). METHOD:We examined our study aims using archival data from 66 intact Sprague-Dawley female rats (Study 1) and 77 P-OVX and 79 intact Sprague-Dawley female rats (Study 2). PF and chow intake were measured using a free-choice, intermittent exposure paradigm in which rats were exposed to both food types starting in pre-puberty and continuing into adulthood. RESULTS:Mixed linear models revealed a specific effect of puberty on PF intake in both studies. PF intake increased substantially during puberty in all rats, but increases were particularly pronounced in P-OVX rats in Study 2. By contrast, chow intake increased significantly during pre-puberty (rather than puberty) in both studies, and these increases were relatively unaffected by P-OVX. DISCUSSION:Findings confirm a specific effect of puberty and ovarian hormone removal on PF intake in female rats. Differential trajectories of PF versus chow intake highlight potential reward-based processes in pubertal and ovarian hormone effects on PF intake in females.

Importance:Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab. Objective:To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation. Design, Setting, and Participant:This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy. Exposures:Ocrelizumab monotherapy. Results:A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy. Conclusions and Relevance:In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

BACKGROUND:Over the past 2 decades, a growing number of large-scale clinical trials have helped expand the toolkit for emergency management of acute ischemic stroke. This article is intended to be an up-to-date resource to aid nonstroke specialist neurology providers and ophthalmologists in identifying situations and patient populations in which urgent stroke evaluation should be completed with options for emergent reperfusion therapy considered. EVIDENCE ACQUISITION/METHODS:The literature forming the foundation of the guidelines for early management of patients with acute ischemic stroke was reviewed, annotated, and summarized. RESULTS:Data from both initial and follow-up trials investigating the benefits and indications for use of intravenous thrombolysis and endovascular intervention for stroke are reviewed systematically, with an emphasis on new updates to qualifying patient populations and time periods for treatment. CONCLUSIONS:Recent studies underscore the conclusion that timely reperfusion in acute ischemic stroke is the most effective available treatment and that there are a growing number of new scenarios and patients for which interventions maybe applied.

Importance/UNASSIGNED:Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments. Objective/UNASSIGNED:To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). Design, Setting, and Participants/UNASSIGNED:The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated. Interventions/UNASSIGNED:Implanted medical device delivering 10-kHz SCS. Main Outcomes and Measures/UNASSIGNED:The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. Results/UNASSIGNED:Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001). Conclusions and Relevance/UNASSIGNED:Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN. Trial Registration/UNASSIGNED:ClincalTrials.gov Identifier: NCT03228420.

The main aim of this study was to explore the etiology of relations between general cognitive ability (g) and different hierarchical phenotypic levels of the Five Factor Model (FFM), including the General Factor of Personality (GFP), the Big Two, the five domains of the FFM, and their 30 facets. The second aim was to detect personality facets that contribute to the prediction of general intelligence. The sample consisted of 424 young adult twins (134 pairs of monozygotic twins) on whom the NEO-PI-R and Advanced Progressive Matrices were administered. The results did not support hierarchical solutions above the FFM. Thus, five-domain and facet level of personality were analyzed, showing that only Openness and Neuroticism had significant genetic or environmental correlations with intelligence. The several facets from all domains had significant associations, among which Ideas and Positive Emotions showed the highest positive correlations, while Order and Modesty showed the highest negative genetic correlations with intelligence. Furthermore, seven facets significantly predicted g factor (35%), with higher genetic (0.52) than environmental (0.13) correlations with intelligence. The results reveal the common genetic basis of narrow traits and intelligence, highlighting the importance of specific traits in the explanation of general cognitive abilities.

OBJECTIVE:To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB). METHODS:In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer. RESULTS:/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen. CONCLUSIONS:Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.

OBJECTIVE:Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS:A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS:Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE/CONCLUSIONS:This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.