Pub Date : 2025-10-20DOI: 10.1001/jamaneurol.2025.3905
William G Ondo,Wen Lv,Xiaodong Zhu,Yongsheng Hu,Stuart H Isaacson,Yuan Yuan,Alberto J Espay,David Kreitzman,Sheng-Han Kuo,Salima Brillman,Holly A Shill,Kelly E Lyons,Zhi Yang,Qi Zhao,Zhen Zhang,Rajesh Pahwa
ImportanceEssential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network.ObjectiveTo investigate whether an artificial intelligence (AI)-driven TPNS device is superior to a sham device in reducing ET.Design, Setting, and ParticipantsA 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.InterventionA 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 MeasuresThe 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.ResultsOf 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 RelevanceThe TPNS device improved activities related to upper limb tremor at 90 days and could be an effective noninvasive ET treatment.Trial RegistrationClinicalTrials.gov Identifier: NCT06235190.
{"title":"Transcutaneous Peripheral Nerve Stimulation for Essential Tremor: A Randomized Clinical Trial.","authors":"William G Ondo,Wen Lv,Xiaodong Zhu,Yongsheng Hu,Stuart H Isaacson,Yuan Yuan,Alberto J Espay,David Kreitzman,Sheng-Han Kuo,Salima Brillman,Holly A Shill,Kelly E Lyons,Zhi Yang,Qi Zhao,Zhen Zhang,Rajesh Pahwa","doi":"10.1001/jamaneurol.2025.3905","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3905","url":null,"abstract":"ImportanceEssential tremor (ET) is the most common form of arm tremor. Transcutaneous peripheral nerve stimulation (TPNS) can modulate the central tremor-generating network.ObjectiveTo investigate whether an artificial intelligence (AI)-driven TPNS device is superior to a sham device in reducing ET.Design, Setting, and ParticipantsA 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.InterventionA 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 MeasuresThe 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.ResultsOf 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 RelevanceThe TPNS device improved activities related to upper limb tremor at 90 days and could be an effective noninvasive ET treatment.Trial RegistrationClinicalTrials.gov Identifier: NCT06235190.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"51 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1001/jamaneurol.2025.3869
Ming Lu,Min Jung Kim,Emily C Collins,Sergey Shcherbinin,Amy K Ellinwood,Yuma Yokoi,Dawn A Brooks,Oskar Hansson,David S Knopman,John R Sims,Mark A Mintun
ImportanceAccumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.ObjectiveTo assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.Design, Setting, and ParticipantsThis was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.InterventionsParticipants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.Main Outcomes and MeasuresParticipants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.ResultsAnalyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).Conclusions and RelevanceThe findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.Trial Registra
{"title":"Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.","authors":"Ming Lu,Min Jung Kim,Emily C Collins,Sergey Shcherbinin,Amy K Ellinwood,Yuma Yokoi,Dawn A Brooks,Oskar Hansson,David S Knopman,John R Sims,Mark A Mintun","doi":"10.1001/jamaneurol.2025.3869","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3869","url":null,"abstract":"ImportanceAccumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.ObjectiveTo assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.Design, Setting, and ParticipantsThis was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.InterventionsParticipants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.Main Outcomes and MeasuresParticipants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.ResultsAnalyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).Conclusions and RelevanceThe findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.Trial Registra","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1001/jamaneurol.2025.3775
Peng Roc Chen,Carlos A Artime,Sunil A Sheth,Claudia Pedroza,Santiago Ortega-Gutierrez,Stacey Wolfe,Clark Sitton,Peter Kan,Omar Tanweer,Alex Chebl,Clemens M Schirmer,Jay T Morrow,Yazan J Alderazi,Bradley Bohnstedt,Kadir Erkmen,Edgar A Samaniego,Elena Garrido,Sean I Savitz,Allison Engstrom,Eddie Aguilar,Tien Nguyen,Andrew D Barreto,
ImportanceThe optimal anesthetic strategy for patients undergoing endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusion (LVO) remains unclear.ObjectiveTo determine if general anesthesia (GA) or moderate sedation for patients who undergo EVT for AIS with LVO is associated with a different functional outcome in 90 days.Design, Setting, and ParticipantsThis was a multicenter randomized clinical trial conducted from July 2018 to August 2023 of patients with AIS who were receiving EVT due to LVO. Patients were recruited from 10 comprehensive stroke centers in the US. Adult patients with occlusion of the carotid artery and the proximal middle and anterior cerebral artery who underwent EVT were eligible for enrollment.InterventionsPatients were randomized to receive either moderate sedation or GA in 1:1 ratio.Main Outcomes and MeasuresThe primary outcome was the ordinal modified Rankin Scale (mRS) score at 90 days.ResultsA total of 1931 patients were screened for eligibility, and 1671 were excluded due to failure meeting the inclusion criteria. Among 260 individuals with a mean (SD) age of 66.8 (13.3) years included in this intention-to-treat study, 133 were male (52%), and 130 (50%) were randomized to GA and sedation each. At 90 days, a shift in the distribution of ordinal mRS was found favoring GA (odds ratio [OR], 1.22; 95% credible interval [CrI], 0.79-1.87) with an 81% posterior probability of GA superiority. The probability that GA was superior to sedation was 89% (relative risk [RR], 1.2; 95% CrI, 0.9-1.66) and 69% (RR, 1.01; 95% CrI, 0.96-1.08) for 90-day mRS 0 to 2 and successful reperfusion, respectively. Other secondary outcomes were similar. Symptomatic intracerebral hemorrhage was 0.8% (1 of 125 patients) in GA vs 2.4% (3 of 125 patients) in sedation with a posterior probability of GA was superior to sedation of 72% (RR, 0.71; 95% CrI, 0.23-2.16).Conclusions and RelevanceThis randomized clinical trial found that patients with LVO AIS who were treated with EVT using GA had improved rates of 90-day outcomes and higher rates of successful reperfusion compared with those treated using moderate sedation.Trial RegistrationClinicalTrials.gov Identifier: NCT03263117.
{"title":"Sedation vs General Anesthesia for Endovascular Therapy in Acute Ischemic Stroke: The SEGA Randomized Clinical Trial.","authors":"Peng Roc Chen,Carlos A Artime,Sunil A Sheth,Claudia Pedroza,Santiago Ortega-Gutierrez,Stacey Wolfe,Clark Sitton,Peter Kan,Omar Tanweer,Alex Chebl,Clemens M Schirmer,Jay T Morrow,Yazan J Alderazi,Bradley Bohnstedt,Kadir Erkmen,Edgar A Samaniego,Elena Garrido,Sean I Savitz,Allison Engstrom,Eddie Aguilar,Tien Nguyen,Andrew D Barreto, ","doi":"10.1001/jamaneurol.2025.3775","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3775","url":null,"abstract":"ImportanceThe optimal anesthetic strategy for patients undergoing endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusion (LVO) remains unclear.ObjectiveTo determine if general anesthesia (GA) or moderate sedation for patients who undergo EVT for AIS with LVO is associated with a different functional outcome in 90 days.Design, Setting, and ParticipantsThis was a multicenter randomized clinical trial conducted from July 2018 to August 2023 of patients with AIS who were receiving EVT due to LVO. Patients were recruited from 10 comprehensive stroke centers in the US. Adult patients with occlusion of the carotid artery and the proximal middle and anterior cerebral artery who underwent EVT were eligible for enrollment.InterventionsPatients were randomized to receive either moderate sedation or GA in 1:1 ratio.Main Outcomes and MeasuresThe primary outcome was the ordinal modified Rankin Scale (mRS) score at 90 days.ResultsA total of 1931 patients were screened for eligibility, and 1671 were excluded due to failure meeting the inclusion criteria. Among 260 individuals with a mean (SD) age of 66.8 (13.3) years included in this intention-to-treat study, 133 were male (52%), and 130 (50%) were randomized to GA and sedation each. At 90 days, a shift in the distribution of ordinal mRS was found favoring GA (odds ratio [OR], 1.22; 95% credible interval [CrI], 0.79-1.87) with an 81% posterior probability of GA superiority. The probability that GA was superior to sedation was 89% (relative risk [RR], 1.2; 95% CrI, 0.9-1.66) and 69% (RR, 1.01; 95% CrI, 0.96-1.08) for 90-day mRS 0 to 2 and successful reperfusion, respectively. Other secondary outcomes were similar. Symptomatic intracerebral hemorrhage was 0.8% (1 of 125 patients) in GA vs 2.4% (3 of 125 patients) in sedation with a posterior probability of GA was superior to sedation of 72% (RR, 0.71; 95% CrI, 0.23-2.16).Conclusions and RelevanceThis randomized clinical trial found that patients with LVO AIS who were treated with EVT using GA had improved rates of 90-day outcomes and higher rates of successful reperfusion compared with those treated using moderate sedation.Trial RegistrationClinicalTrials.gov Identifier: NCT03263117.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"39 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImportancePatients with ischemic stroke and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease are at an elevated risk of recurrent ischemic events. Although combined anticoagulant and antiplatelet therapy may reduce ischemic risk, it also increases bleeding, and the optimal antithrombotic strategy remains uncertain.ObjectiveTo determine whether adding an antiplatelet agent to anticoagulant therapy influences the net clinical benefit in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease.Design, Setting, and ParticipantsThis multicenter, open-label randomized clinical trial was conducted at 41 sites across Japan from November 2016 to March 2025. Eligible patients had an ischemic stroke or transient ischemic attack within 8 to 360 days of onset, nonvalvular atrial fibrillation, and at least 1 manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease). Data were analyzed from April 16, 2024, to October 14, 2024.InterventionsPatients were randomized to receive combination therapy (anticoagulant plus antiplatelet) or anticoagulant monotherapy.Main Outcomes and MeasuresThe primary outcome was a composite of ischemic cardiovascular events and major bleeding within 2 years. Secondary outcomes included ischemic cardiovascular events; safety outcomes included major and clinically relevant nonmajor bleeding.ResultsIn total, 316 patients were randomized to combination therapy (n = 159) or monotherapy (n = 157) (mean [SD] age, 77.2 [7.4] years; 90 female patients [28.5%]). The trial was terminated on July 18, 2023, after an interim analysis for futility. The cumulative incidence of the primary outcome was 17.8% in the combination therapy group and 19.6% in the monotherapy group (hazard ratio [HR], 0.91; 95% CI, 0.53-1.55; P = .64). Ischemic cardiovascular events occurred in 11.1% and 14.2% (HR, 0.76; 95% CI, 0.39-1.48; P = .41), and major and clinically relevant nonmajor bleeding occurred in 19.5% and 8.6% (HR, 2.42; 95% CI, 1.23-4.76; P = .008) of combination therapy and monotherapy groups, respectively.Conclusions and RelevanceIn this randomized clinical trial, in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease, adding an antiplatelet agent to anticoagulant therapy provided no net clinical benefit over anticoagulant monotherapy, with higher bleeding risk.Trial RegistrationClinicalTrials.gov Identifier: NCT03062319.
{"title":"Optimal Antithrombotics for Ischemic Stroke and Concurrent Atrial Fibrillation and Atherosclerosis: A Randomized Clinical Trial.","authors":"Shuhei Okazaki,Kanta Tanaka,Yukako Yazawa,Ryosuke Doijiri,Masatoshi Koga,Masafumi Ihara,Shiro Yamamoto,Kenji Kamiyama,Yuko Honda,Kazutaka Uchida,Takeshi Yoshimoto,Koko Asakura,Katsuhiro Omae,Kenta Tanaka,Hirotada Maeda,Haruko Yamamoto,Teruyuki Hirano,Kazunori Toyoda,Yasuyuki Iguchi,Teruo Noguchi,Yasushi Okada,Kazuo Kitagawa,Nobuyuki Sakai,Hiroshi Yamagami, ","doi":"10.1001/jamaneurol.2025.3662","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3662","url":null,"abstract":"ImportancePatients with ischemic stroke and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease are at an elevated risk of recurrent ischemic events. Although combined anticoagulant and antiplatelet therapy may reduce ischemic risk, it also increases bleeding, and the optimal antithrombotic strategy remains uncertain.ObjectiveTo determine whether adding an antiplatelet agent to anticoagulant therapy influences the net clinical benefit in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease.Design, Setting, and ParticipantsThis multicenter, open-label randomized clinical trial was conducted at 41 sites across Japan from November 2016 to March 2025. Eligible patients had an ischemic stroke or transient ischemic attack within 8 to 360 days of onset, nonvalvular atrial fibrillation, and at least 1 manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease). Data were analyzed from April 16, 2024, to October 14, 2024.InterventionsPatients were randomized to receive combination therapy (anticoagulant plus antiplatelet) or anticoagulant monotherapy.Main Outcomes and MeasuresThe primary outcome was a composite of ischemic cardiovascular events and major bleeding within 2 years. Secondary outcomes included ischemic cardiovascular events; safety outcomes included major and clinically relevant nonmajor bleeding.ResultsIn total, 316 patients were randomized to combination therapy (n = 159) or monotherapy (n = 157) (mean [SD] age, 77.2 [7.4] years; 90 female patients [28.5%]). The trial was terminated on July 18, 2023, after an interim analysis for futility. The cumulative incidence of the primary outcome was 17.8% in the combination therapy group and 19.6% in the monotherapy group (hazard ratio [HR], 0.91; 95% CI, 0.53-1.55; P = .64). Ischemic cardiovascular events occurred in 11.1% and 14.2% (HR, 0.76; 95% CI, 0.39-1.48; P = .41), and major and clinically relevant nonmajor bleeding occurred in 19.5% and 8.6% (HR, 2.42; 95% CI, 1.23-4.76; P = .008) of combination therapy and monotherapy groups, respectively.Conclusions and RelevanceIn this randomized clinical trial, in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease, adding an antiplatelet agent to anticoagulant therapy provided no net clinical benefit over anticoagulant monotherapy, with higher bleeding risk.Trial RegistrationClinicalTrials.gov Identifier: NCT03062319.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"20 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1001/jamaneurol.2025.3581
Helen Kim,Jeffrey Nelson,Charles E McCulloch,Christopher Hess,Steven W Hetts,Kelly Flemming,Giuseppe S Lanzino,Päivi Koroknay-Pál,Elias Oulasvirta,Aki Laakso,Michael T Lawton,Jay P Mohr,Michael K Morgan,Nicole Moayeri,Jonathan G Zaroff,Marco A Stefani,Xiaolin Chen,Yuanli Zhao,Rustam Al-Shahi Salman
ImportanceAnnual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions.ObjectiveTo provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs.Design, Setting, and ParticipantsThe Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM.ExposuresDemographic, clinical, and angiographic characteristics.Main Outcome and MeasureThe primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort.ResultsA total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01).Conclusions and RelevanceThe annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.
{"title":"Risk of Future Hemorrhage From Unruptured Brain Arteriovenous Malformations: The Multicenter Arteriovenous Malformation Research Study (MARS).","authors":"Helen Kim,Jeffrey Nelson,Charles E McCulloch,Christopher Hess,Steven W Hetts,Kelly Flemming,Giuseppe S Lanzino,Päivi Koroknay-Pál,Elias Oulasvirta,Aki Laakso,Michael T Lawton,Jay P Mohr,Michael K Morgan,Nicole Moayeri,Jonathan G Zaroff,Marco A Stefani,Xiaolin Chen,Yuanli Zhao,Rustam Al-Shahi Salman","doi":"10.1001/jamaneurol.2025.3581","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3581","url":null,"abstract":"ImportanceAnnual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions.ObjectiveTo provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs.Design, Setting, and ParticipantsThe Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM.ExposuresDemographic, clinical, and angiographic characteristics.Main Outcome and MeasureThe primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort.ResultsA total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01).Conclusions and RelevanceThe annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1001/jamaneurol.2025.3534
Richard A Bernstein,Lauren E Previch
{"title":"Anticoagulation and Antiplatelet Therapy in Patients With Atrial Fibrillation and Atherosclerosis.","authors":"Richard A Bernstein,Lauren E Previch","doi":"10.1001/jamaneurol.2025.3534","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3534","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"73 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1001/jamaneurol.2025.3574
M. Travis Caton, Zhe Guan, Paolo Bolognese
This case report describes a case of iatrogenic cerebrospinal fluid–venous fistula as a previously unreported mechanism of cerebrospinal fluid leak following lumbar puncture.
本病例报告描述了一例医源性脑脊液静脉瘘，作为腰椎穿刺后脑脊液泄漏的先前未报道的机制。
{"title":"Iatrogenic Cerebrospinal Fluid–Venous Fistula","authors":"M. Travis Caton, Zhe Guan, Paolo Bolognese","doi":"10.1001/jamaneurol.2025.3574","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.3574","url":null,"abstract":"This case report describes a case of iatrogenic cerebrospinal fluid–venous fistula as a previously unreported mechanism of cerebrospinal fluid leak following lumbar puncture.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"47 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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