NeurologyPub Date : 2025-07-08Epub Date: 2025-06-11DOI: 10.1212/WNL.0000000000213640
Samuel W Terman, Colin Bruce Josephson, Parag Goyal, Arturo Gonzalez-Izquierdo, Jean Morrison, Spiros Denaxas, Samuel Wiebe
{"title":"Lamotrigine and Cardiac Arrhythmias: A Target Trial Approach.","authors":"Samuel W Terman, Colin Bruce Josephson, Parag Goyal, Arturo Gonzalez-Izquierdo, Jean Morrison, Spiros Denaxas, Samuel Wiebe","doi":"10.1212/WNL.0000000000213640","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213640","url":null,"abstract":"<p><strong>Background and objectives: </strong>While lamotrigine is an effective, well-tolerated antiseizure medication (ASM), a recent warning raised the possibility of ventricular arrhythmias. We compared arrhythmia incidence between patients newly treated for seizures with lamotrigine and those with levetiracetam (presumed cardiac-inert control).</p><p><strong>Methods: </strong>We included patients whose first ASM prescription fill was after the first seizure or epilepsy ICD code in the study period, with no ASM in the previous year. We conducted retrospective cohort studies to emulate a target trial using 2 datasets: (1) 2009-2018 Medicare claims (United States) and (2) Clinical Practice Research Datalink (CPRD), a population-based cohort (United Kingdom). We examined cumulative incidence curves for ventricular tachycardia or fibrillation (VT/VF) from Cox proportional hazard models.</p><p><strong>Results: </strong>We included 40,554 patients (lamotrigine: 3,038; levetiracetam: 37,516) from Medicare and 13,098 (lamotrigine: 8,694; levetiracetam: 4,404) from CPRD. In Medicare, the median (interquartile range) age was 61 (44-74) years and 60% were female in the lamotrigine group vs 74 (65-82) years and 57% female in the levetiracetam group. In CPRD, the median (interquartile range) age was 34 (23-53) years and 63% were female in the lamotrigine group vs 48 (29-66) years and 50% female in the levetiracetam group. After adjusting for demographics, comorbidities, and medication use, the hazard ratio for VT/VF comparing patients whose first ASM was lamotrigine vs levetiracetam was 0.73 (95% CI 0.50-1.08) for Medicare and 0.75 (95% CI 0.35-1.59) for CPRD, with a 2-year cumulative incidence of 1.7% (95% CI 1.0%-2.3%) vs 2.3% (95% CI 2.1%-2.4%) for Medicare and 0.2% (95% CI 0.1%-0.4%) vs 0.3% (95% CI 0.2%-0.6%) for CPRD. In both datasets, lamotrigine showed a slightly but nonsignificantly lower 2-year absolute difference in cumulative incidence of VT/VF compared with levetiracetam (Medicare: -0.6%, 95% CI -1.2% to 0.0%; CPRD: -0.1%, 95% CI -0.3% to 0.1%). Numerous sensitivity analyses modifying the outcome (atrial arrhythmias or any arrhythmias), censorship procedure (further censoring patients on discontinuing their initial ASM akin to a \"per-protocol\" analysis), or population (patients with existing cardiovascular diagnoses) found similar results.</p><p><strong>Discussion: </strong>These data do not support concerns regarding lamotrigine increasing arrhythmias. Limitations include possible residual confounding and lack of generalizability to other populations.</p><p><strong>Classification of evidence: </strong>This study provides Class III evidence that lamotrigine compared with levetiracetam did not significantly increase the 2-year cumulative incidence of VT/VF in adult patients with epilepsy.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 1","pages":"e213640"},"PeriodicalIF":7.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275467","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}
NeurologyPub Date : 2025-07-02DOI: 10.1212/wnl.0000000000213873
Bhooma Rajagopalan Aravamuthan,Luke Moretti,Diana Cejas,Divya Singhal,Roy H Hamilton,Nimish A Mohile,Lisa I Iezzoni,
{"title":"Advancing Disability Equity in Neurology: An AAN Position Statement.","authors":"Bhooma Rajagopalan Aravamuthan,Luke Moretti,Diana Cejas,Divya Singhal,Roy H Hamilton,Nimish A Mohile,Lisa I Iezzoni,","doi":"10.1212/wnl.0000000000213873","DOIUrl":"https://doi.org/10.1212/wnl.0000000000213873","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"283 1","pages":"e213873"},"PeriodicalIF":9.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547656","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}
NeurologyPub Date : 2025-07-01Epub Date: 2025-06-05DOI: 10.1212/WNL.0000000000213769
Judit Selma-Gonzalez, Sara Rubio-Guerra, Jesús García-Castro, Elena Vera-Campuzano, Isabel Sala, María Belén Sánchez-Saudinós, Nuole Zhu, Javier Arranz, José Enrique Arriola-Infante, Íñigo Rodríguez-Baz, Lucía Maure-Blesa, Oriol Dols-Icardo, Laura Videla, Sílvia Valldeneu, Isabel Barroeta, Miguel Santos-Santos, Maria Carmona-Iragui, Lídia Vaqué-Alcázar, Esther Alvarez-Sanchez, Oriol Lorente, Mireia Carreras, Olivia Belbin, Burak Arslan, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Laia Montoliu-Gaya, Alexandre Bejanin, Alberto Lleó, Juan Fortea, Daniel Alcolea, Ignacio Illan-Gala
{"title":"Association of Plasma Phosphorylated Tau 217 With Clinical Deterioration Across Alzheimer Disease Stages.","authors":"Judit Selma-Gonzalez, Sara Rubio-Guerra, Jesús García-Castro, Elena Vera-Campuzano, Isabel Sala, María Belén Sánchez-Saudinós, Nuole Zhu, Javier Arranz, José Enrique Arriola-Infante, Íñigo Rodríguez-Baz, Lucía Maure-Blesa, Oriol Dols-Icardo, Laura Videla, Sílvia Valldeneu, Isabel Barroeta, Miguel Santos-Santos, Maria Carmona-Iragui, Lídia Vaqué-Alcázar, Esther Alvarez-Sanchez, Oriol Lorente, Mireia Carreras, Olivia Belbin, Burak Arslan, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Laia Montoliu-Gaya, Alexandre Bejanin, Alberto Lleó, Juan Fortea, Daniel Alcolea, Ignacio Illan-Gala","doi":"10.1212/WNL.0000000000213769","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213769","url":null,"abstract":"<p><strong>Background and objectives: </strong>Phosphorylated tau at threonine 217 (p-tau217) is a highly sensitive blood-based biomarker for Alzheimer disease (AD) pathology, showing high diagnostic accuracy. However, its prognostic value across different clinical stages of AD remains unclear. The aim of this study was to assess the prognostic utility of plasma p-tau217, measured using a commercially available immunoassay, regarding clinical and functional decline across the clinical stages of AD in a cohort with up to 10 years of follow-up.</p><p><strong>Methods: </strong>We conducted a retrospective longitudinal cohort study using data from the Sant Pau Initiative on Neurodegeneration, a research project performed at the Sant Pau Memory Unit between 2011 and 2022. Participants were classified into clinical stages 1-6 based on AD pathology status in CSF, determined by the p-tau181/Aβ1-42 ratio. The primary outcomes were cognitive decline, measured by changes in the Mini-Mental State Examination (MMSE), and progression to dementia. Plasma p-tau217 and CSF p-tau181 levels were assessed, and statistical analysis was performed using linear mixed-effects models for longitudinal changes in MMSE scores and Cox proportional hazard regression was used to examine progression to dementia.</p><p><strong>Results: </strong>A total of 731 participants (mean age 71.5 ± 10.1 years; 60% female) were included. Plasma p-tau217 levels showed a significant increase across advancing AD stages, with all between-group comparisons remaining significant after false discovery rate adjustment (<i>p</i> < 0.05). Longitudinal analysis showed a significant increase in plasma p-tau217 (β = 7.7, 95% CI 3.0-12.5, <i>p</i> = 0.002) and CSF p-tau181 (β = 3.2, 95% CI 1.4-5.0, <i>p</i> = 0.001). Baseline plasma p-tau217 levels were associated with faster MMSE decline (β = -0.08, 95% CI -0.11 to -0.05, <i>p</i> < 0.001) and progression to dementia (hazard ratio 1.03, 95% CI 1.01-1.05, <i>p</i> < 0.001), independent of clinical stage.</p><p><strong>Discussion: </strong>Plasma p-tau217 was significantly associated with cognitive and functional decline in AD. These findings support the potential use of plasma p-tau217 as a prognostic marker for monitoring AD progression in clinical practice. Future studies should validate these results across diverse cohorts and explore their utility in early-stage detection and monitoring.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 1","pages":"e213769"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234640","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}
NeurologyPub Date : 2025-07-01Epub Date: 2025-06-06DOI: 10.1212/WNL.0000000000213659
Zhimin Xu, Subhan Khan, Ahya Ali, Terry Park, Fang Yu, Jon Rosenberg, Fawaz Al-Mufti
{"title":"Clinical Reasoning: A 64-Year-Old Man With Confusion, Nausea, Seizure, and Fever.","authors":"Zhimin Xu, Subhan Khan, Ahya Ali, Terry Park, Fang Yu, Jon Rosenberg, Fawaz Al-Mufti","doi":"10.1212/WNL.0000000000213659","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213659","url":null,"abstract":"<p><p>Evaluating patients with encephalitis is common, but it can be complicated in immunocompromised patients. In this case, a 64-year-old man with a medical history of multiple myeloma and previous Lyme disease presented with acute onset of confusion, nausea, and fever; developed generalized tonic-clonic seizures; and subsequently became comatose. This case highlights the importance of thinking broadly beyond common viral and bacterial encephalitides and developing a comprehensive differential diagnosis.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 1","pages":"e213659"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248936","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}
NeurologyPub Date : 2025-07-01Epub Date: 2025-06-13DOI: 10.1212/WNL.0000000000213589
Marc C Patterson, Uma Ramaswami, Aimee Donald, Tomas Foltan, Matthias Gautschi, Paul Gissen, Andreas Hahn, Simon A Jones, Richard Kay, Miriam Kolniková, Julien Park, Stella Reichmannová, Mark Walterfang, Pierre Wibawa, Marianne Rohrbach, Kyriakos Martakis, Tatiana Bremova-Ertl
{"title":"Disease-Modifying, Neuroprotective Effect of N-Acetyl-l-Leucine in Adult and Pediatric Patients With Niemann-Pick Disease Type C.","authors":"Marc C Patterson, Uma Ramaswami, Aimee Donald, Tomas Foltan, Matthias Gautschi, Paul Gissen, Andreas Hahn, Simon A Jones, Richard Kay, Miriam Kolniková, Julien Park, Stella Reichmannová, Mark Walterfang, Pierre Wibawa, Marianne Rohrbach, Kyriakos Martakis, Tatiana Bremova-Ertl","doi":"10.1212/WNL.0000000000213589","DOIUrl":"10.1212/WNL.0000000000213589","url":null,"abstract":"<p><strong>Background and objectives: </strong>N-acetyl-l-leucine (NALL) has been established to improve the neurologic manifestations of Niemann-Pick disease type C (NPC) after 12 weeks in a placebo-controlled trial. In the open-label extension phase (EP) follow-up, data were obtained after 12 and 18 months to evaluate the long-term effects of NALL for NPC.</p><p><strong>Methods: </strong>This is an ongoing, multinational, multicenter EP. Patients with a genetic diagnosis of NPC aged 4 years or older who completed the placebo-controlled trial were eligible to continue in the EP and receive orally administered NALL 2-3 times per day in 3 tiers of weight-based dosing. The primary end point is the modified 5-domain NPC Clinical Severity Scale (NPC-CSS) (range 0-25 points; lower score representing better neurologic status); data from the EP cohort are compared with the expected annual trajectory of decline (i.e., disease progression) established in natural history studies. Analyses are also performed on exploratory end points, including the 15-domain and 4-domain NPC-CSSs and the Scale for Assessment and Rating of Ataxia (SARA).</p><p><strong>Results: </strong>Fifty-three patients aged 5-67 years (45.3% female, 54.7% male) were enrolled in the EP. After 12 months, the mean (±SD) change from baseline on the 5-domain NPC-CSS was -0.27 (±2.42) with NALL vs +1.5 (±3.16) in the historical cohort (95% CI -3.05 to -0.48; <i>p</i> = 0.009), corresponding to a 118% reduction in annual disease progression. After 18 months, the mean (±SD) change was +0.05 (±2.95) with NALL vs +2.25 (±4.74) in the historical cohort (95% CI -4.06 to -0.35; <i>p</i> = 0.023). The 15-domain and 4-domain NPC-CSSs were consistent with the 5-domain NPC-CSS. The improvements in neurologic manifestations demonstrated in the placebo-controlled trial on the primary SARA end point were sustained over the long-term follow-up. NALL was well tolerated, and no treatment-related adverse events or serious reactions occurred.</p><p><strong>Discussion: </strong>Treatment with NALL was associated with a significant reduction in NPC disease progression after 12 and 18 months, demonstrating a disease-modifying, neuroprotective effect.</p><p><strong>Trial registration information: </strong>The trial is registered with ClinicalTrials.gov (NCT05163288; registered December 6, 2021), EudraCT (2021-005356-10). The first patient was enrolled into the EP on March 8, 2023. The trial was funded by IntraBio Inc.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that NALL reduces disease progression in NPC.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 1","pages":"e213589"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289416","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}
NeurologyPub Date : 2025-07-01Epub Date: 2025-06-13DOI: 10.1212/WNL.0000000000213857
Dakota J S J Peacock, Darius Ebrahimi-Fakhari
{"title":"N-Acetyl-l-Leucine for Niemann-Pick Type C: Cautious Optimism for an Expanded Treatment Toolkit.","authors":"Dakota J S J Peacock, Darius Ebrahimi-Fakhari","doi":"10.1212/WNL.0000000000213857","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213857","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 1","pages":"e213857"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289418","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}