Dong W, Cabulong A, Vu L
… +7 more, Al-Kindi SG, Warner DF, Schiltz NK, Fein HL, Ghearing GR, Sajatovic M, Koroukian SM
JAMA Neurol
· 2026 Feb · PMID 41212547
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IMPORTANCE: Geographic variation in epilepsy incidence among older adults may reflect contextual risk factors and point to opportunities for targeted prevention. However, privacy constraints and sparse case counts have h...IMPORTANCE: Geographic variation in epilepsy incidence among older adults may reflect contextual risk factors and point to opportunities for targeted prevention. However, privacy constraints and sparse case counts have historically limited small-area analyses. OBJECTIVE: To map incident epilepsy among older adults at the smallest geography permissible by privacy constraints and identify contextual social and environmental determinants associated with high-incidence areas. DESIGN, SETTING, AND PARTICIPANTS: This cohort study examined Medicare administrative claims from 2016 to 2019 for all counties in the contiguous United States. A random sample of 4 999 999 Medicare Fee-for-Service beneficiaries 65 years or older with non-Hispanic Black and Hispanic beneficiaries oversampled at rates of 1.50 and 1.75 times their representation in the study population. Beneficiaries with incident epilepsy were identified by claims criteria and codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, in 2019 and had no epilepsy claims during the period 2016 to 2018. Data were analyzed from January to March 2025. EXPOSURES: Area-level social and environmental determinants of health (SEDH), obtained from publicly available sources and linked to beneficiaries' residences. MAIN OUTCOMES AND MEASURES: The outcome was area-level epilepsy incidence rate in 2019. To comply with data privacy requirements, the Max-P regionalization method was used to aggregate 3108 counties into 692 "MaxCounties," each containing at least 11 incident cases. Incidence rates per 100 000 persons were mapped. Associations between SEDH variables and epilepsy incidence were estimated using random forest and multivariable logistic regression. RESULTS: Among 4 817 147 beneficiaries, 20 263 incident epilepsy cases were identified in 2019 (mean [SD] age, 78.7 [7.5] years; 54.6% women). Incidence rates across MaxCounties varied more than 10-fold (range, 141-1476 per 100 000). In random forest models, higher incidence was associated with insufficient sleep, heat index, physical inactivity, uninsured rate, proportion of non-Hispanic Black residents, and obesity prevalence. In multivariable regression, MaxCounties in the highest tertile for insufficient sleep had nearly double the odds of high epilepsy incidence compared to the lowest tertile (odds ratio [OR], 1.99; 95% CI, 1.10-3.60). Lack of household vehicle access was similarly associated with high incidence (OR, 1.93; 95% CI, 1.16-3.25). CONCLUSIONS AND RELEVANCE: Our findings highlight the spatial heterogeneity of epilepsy burden in the US Medicare population and underscore the importance of contextual SEDH factors, such as sleep, mobility, and infrastructure, in shaping disease patterns. These insights may help guide targeted public health interventions and resource allocation.
Knopman DS, Koltai D, Laskowitz DT
… +46 more, Becker J, Charvet L, Wisnivesky J, Federman A, Silverstein A, Lokhnygina Y, Pilloni G, Haddad M, Mahncke H, Van Vleet T, Huang R, Cox W, Terry D, Karwowski J, McCray N, Lin JJ, McComsey GA, Singh U, Geng LN, Chu HY, Reece R, Moy J, Arvanitakis Z, Parthasarathy S, Patterson TF, Gupta A, Ostrosky-Zeichner L, Parsonnet J, Kiriakopoulos ET, Fong TG, Mullington J, Jolley S, Shah NS, Morimoto SS, Lee-Iannotti JK, Killgore WDS, Dwyer B, Stringer W, Isache C, Frontera JA, Krishnan JA, O'Steen A, James M, Harper BL, Zimmerman KO, RECOVER-NEURO Clinical Trial Group
JAMA Neurol
· 2026 Jan · PMID 41212544
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IMPORTANCE: Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a sign...IMPORTANCE: Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. OBJECTIVE: To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. DESIGN, SETTING, AND PARTICIPANTS: This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. INTERVENTIONS: Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. MAIN OUTCOMES AND MEASURES: Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. RESULTS: A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05965739.
GBD 2021 US CNS Cancer Collaborators, Han HJ, Kim YS
… +73 more, Park S, Shin JI, Kim MS, Moon JH, Kim YB, Ababneh HS, Abu-Zaid A, Areda D, Arul S, Azzam AY, Bardhan M, Bayat Tork MA, Behnam B, Bilgin GB, Bhardwaj PV, Bhuyan SS, Lomer NB, Chen MX, Chennapragada SS, Dai X, Dean FE, Deekonda S, Ding X, Doshi OP, E'mar AR, Elhadi M, Fares J, Fazeli P, Fisher JL, Fotouhi M, Gholamrezanezhad A, Ida F, Iwu CD, Jalloh M, Jani CT, Kalani R, Kankam SB, Kazemi F, Keshwani A, Khosla AA, Lim SS, Mehboob R, Mestrovic T, Mokdad AH, Murray CJL, Naik G, Natto ZS, Nguyen D, Nugen F, Orscelik A, Parikh RR, Penberthy L, Pestell RG, Prabhu D, Puvvula J, Ramasamy SK, Sabet CJ, Schumacher AE, Senol YC, Sham S, Sherchan SP, Simegn GL, Singh JA, Solanki R, Srichawla BS, Taiba J, Tanwar M, Amirikah MT, Verma A, Yunusa I, Zheng DX, Yon DK, Park KY
JAMA Neurol
· 2026 Jan · PMID 41182787
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IMPORTANCE: Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. OBJECTIVE:...IMPORTANCE: Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. OBJECTIVE: To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. EXPOSURE: CNS cancer diagnosis. MAIN OUTCOMES AND MEASURES: Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. RESULTS: In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, -17.75% to -13.68%) and 8.41% (95% UI, -11.09% to -6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (-34.42% to -11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = -0.6860 and ρ = -0.6391; P < .001). CONCLUSIONS AND RELEVANCE: These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.
Zhang Y, Buck BH, Barber PA
… +40 more, Chatterjee K, Clarke B, Choi PMC, Hunter G, Ganesh A, Mishra SM, Williams D, Campbell BCV, Dowlatshahi D, Butcher KS, Krishnan K, Wiggam MI, Kleinig TJ, Muir KW, Zerna C, Field TS, Goyal M, Yu AYX, Roffe C, Demchuck AM, Parsons MW, Bazan R, Ankolekar S, Kennedy J, Menon BK, Mandzia JL, Pille A, Kelly PJ, Marko M, Singh N, Vatanpour S, Lima FO, Catanese L, Horn M, Ghia D, Ferrari J, Greisenegger S, Hill MD, Coutts SB, TEMPO-2 Investigators
JAMA Neurol
· 2025 Dec · PMID 41143808
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IMPORTANCE: Outcomes following intravenous thrombolysis for minor ischemic stroke may vary based on the presence of disabling deficits. OBJECTIVE: To determine whether intravenous tenecteplase improves outcomes according...IMPORTANCE: Outcomes following intravenous thrombolysis for minor ischemic stroke may vary based on the presence of disabling deficits. OBJECTIVE: To determine whether intravenous tenecteplase improves outcomes according to US National Institutes of Health Stroke Scale (NIHSS) score-based definitions of pretreatment disabling deficits. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the TEMPO-2 (Tenecteplase vs Standard of Care for Minor Ischemic Stroke With Proven Occlusion) randomized clinical trial, conducted between April 27, 2015, and January 19, 2024. Patients were followed up for 90 days. The TEMPO-2 trial was conducted across 48 sites globally among patients with minor ischemic stroke (NIHSS 0-5) and proven intracranial occlusion within 12 hours of onset. Patients were divided into having nondisabling vs disabling syndromes at presentation as per the TREAT Task Force consensus. Other established definitions of disabling stroke from the ARAMIS trial and the National Institute of Neurological Disorders and Stroke trial were explored. Data analysis was completed from July 2024 to September 2024. INTERVENTIONS: Intravenous tenecteplase (0.25 mg/kg) vs nonthrombolytic standard of care. MAIN OUTCOMES AND MEASURES: The primary outcome was a return to baseline modified Rankin scale score at 90 days. RESULTS: Among 886 enrolled patients, 2 withdrew consent and 884 were included in the secondary analysis. Among 884 patients analyzed (369 women [41.7%]; median [IQR] age, 72 [61-80] years), 100 (11.3%) had disabling and 784 (88.7%) had nondisabling deficits. Patients with disabling deficits had higher median (IQR) baseline NIHSS scores (4 [3-5] vs 2 [1-3]), later presentations (onset to hospital arrival time: 288 [153-412] minutes vs 133 [70-310] minutes), and longer onset to treatment time (411 [307-560] minutes vs 278 [170-462] minutes) than those with nondisabling deficits. In the disabling group, the primary outcome following tenecteplase, compared with standard of care, occurred in 29 patients (54.7%) vs 32 patients (68.1%) (adjusted risk ratio [aRR], 0.81; 95% CI, 0.60-1.10). This neutral treatment effect was consistent in patients without disabling deficits (280 [73.9%] vs 306 [75.6%]; aRR, 0.98; 95% CI, 0.91-1.07; P for interaction = .32). CONCLUSIONS AND RELEVANCE: In this secondary analysis of the TEMPO-2 randomized clinical trial, current definitions of disabling symptoms based on NIHSS score at baseline did not modify the neutral treatment effect of intravenous tenecteplase in patients with minor stroke and intracranial occlusion. Together with converging evidence comparing intravenous thrombolysis to nonthrombolytic standard of care, this analysis suggests the need to reevaluate thrombolysis in minor disabling stroke. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02398656.
Ondo WG, Lv W, Zhu X
… +13 more, Hu Y, Isaacson SH, Yuan Y, Espay AJ, Kreitzman D, Kuo SH, Brillman S, Shill HA, Lyons KE, Yang Z, Zhao Q, Zhang Z, Pahwa R
JAMA Neurol
· 2025 Dec · PMID 41114984
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IMPORTANCE: Essential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network. OBJECTIVE: To investigate whether an artific...IMPORTANCE: Essential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network. OBJECTIVE: To investigate whether an artificial intelligence (AI)-driven TPNS device is superior to a sham device in reducing ET. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was conducted from February 7 through August 9, 2024, in 12 outpatient neurology clinics in the United States and China. Participants were adults with upper-extremity tremor and a clinical diagnosis of ET, a tremor severity score of 2 or higher on 1 of the Essential Tremor Rating Assessment Scale (TETRAS) performance subscale tasks, a total performance subscale score of at least 7, and familiarity with operating a smartphone and connecting to Wi-Fi at home. They were randomized 2:1 to receive active TPNS or sham stimulation, stratified by use of ET medications and tremor severity. After the devices were fitted, the participants were instructed to use them during waking hours for 90 days. INTERVENTION: A wearable neuromodulation device that stimulates the radial, median, and ulnar nerves and uses AI to continuously adjust stimulation settings in real time. MAIN OUTCOME AND MEASURES: The primary outcome was change in daily activities as measured by the modified Activities of Daily Living (mADL) subscale of TETRAS at 90 days in the intention-to-treat population. RESULTS: Of 133 screened, 125 were randomized to receive TPNS (n = 83) or sham (n = 42) treatment. The mean (SD) age was 64.9 (13.1) years, 62 (49.6%) were female and 63 (50.4%) male, and the mean (SD) tremor duration was 11.4 (13.1) years. At 90 days, the mADL score was reduced by 6.9 points (95% CI, 5.4-8.4) in the TPNS group vs 2.7 points (95% CI, 1.3-4.0) in the sham group (P < .001). Skin irritation, the most common device-related adverse event, occurred in 28 of 83 participants (33.7%) in the TPNS group and 2 of 42 (4.8%) in the sham group. Nausea, arthralgia, worsening of existing arthritis in the thumb, muscular weakness, and involuntary muscle contractions each occurred in 1 participant, all in the TPNS group. CONCLUSIONS AND RELEVANCE: The TPNS device improved activities related to upper limb tremor at 90 days and could be an effective noninvasive ET treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06235190.