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Optic Nerve in Multiple Sclerosis Diagnostic Criteria: An Aye to the Eyes?.
Brownlee, Wallace J. MD, PhD; Galetta, Steven MD
doi : 10.1212/WNL.0000000000011344
pg. 139-140
Ibudilast: A Paradigm Shift for Progressive Multiple Sclerosis?.
Sormani, Maria Pia PhD; Tur, Carmen MD, MSc, PhD; Barkhof, Frederik MD, PhD
doi : 10.1212/WNL.0000000000011312
pg. 141-142
Cancer and Stroke: A Relationship Thicker Than Blood.
Hurford, Robert MSc, MRCP, DPhil; Strowd, Roy E. III MD, MS, MEd
doi : 10.1212/WNL.0000000000011263
pg. 143-144
Optic Nerve Topography in Multiple Sclerosis Diagnosis: The Utility of Visual Evoked Potentials.
Vidal-Jordana, Angela MD, PhD; Rovira, Alex MD; Arrambide, Georgina MD, PhD; Otero-Romero, Susana MD, PhD; Rio, Jordi MD, PhD; Comabella, Manuel MD, PhD; Nos, Carlos MD; Castillo, Joaquin MD, PhD; Galan, Ingrid MD; Cabello, Sergio; Moncho, Dulce MD; Rahnama, Kimia MD; Thonon, Vanessa MD; Rodriguez-Acevedo, Breogan MD; Zabalza, Ana MD; Midaglia, Luciana MD; Auger, Cristina MD; Sastre-Garriga, Jaume MD, PhD; Montalban, Xavier MD, PhD *; Tintore, Mar MD, PhD *
doi : 10.1212/WNL.0000000000011339
pg. e482-e490
AB Objective: To assess the added value of the optic nerve region (by using visual evoked potentials [VEPs]) to the current diagnostic criteria. Methods: From the Barcelona clinically isolated syndrome (CIS) cohort, patients with complete information to assess dissemination in space (DIS), the optic nerve region, and dissemination in time at baseline (n = 388) were selected. Modified DIS (modDIS) criteria were constructed by adding the optic nerve to the current DIS regions. The DIS and modDIS criteria were evaluated with univariable Cox proportional hazard regression analyses with the time to the second attack as the outcome. A subset of these patients who had at least 10 years of follow-up or a second attack occurring within 10 years (n = 151) were selected to assess the diagnostic performance. The analyses were also performed according to CIS topography (optic neuritis vs non-optic neuritis). Results: The addition of the optic nerve as a fifth region improved the diagnostic performance by slightly increasing the accuracy (2017 DIS 75.5%, modDIS 78.1%) and the sensitivity (2017 DIS 79.2%, modDIS 82.3%) without lowering the specificity (2017 DIS 52.4%, modDIS 52.4%). When the analysis was conducted according to CIS topography, the modDIS criteria performed similarly in both optic neuritis and non-optic neuritis CIS. Conclusion: The addition of the optic nerve, assessed by VEP, as a fifth region in the current DIS criteria slightly improves the diagnostic performance because it increases sensitivity without losing specificity. (C) 2021 American Academy of Neurology
Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study.
Naismith, Robert T. MD; Bermel, Robert A. MD; Coffey, Christopher S. PhD; Goodman, Andrew D. MD; Fedler, Janel PhD; Kearney, Marianne; Klawiter, Eric C. MD; Nakamura, Kunio PhD; Narayanan, Sridar PhD; Goebel, Christopher; Yankey, Jon MS; Klingner, Elizabeth MS; Fox, Robert J. MD; on behalf of the SPRINT-MS investigators; Shinnar, Shlomo MD; Ontaneda, Daniel MD; Riley, Claire S. MD; Perumal, Jai MD; Lava, Neil MD; Klawiter, Eric MD; Cohen, Bruce MD; Racke, Michael MD; Yadav, Vijayshree MD; Jubelt, Burk MD; WeinstockGutman, Bianca MD; Coyle, Patricia MD; Repovic, Pavle MD, PhD; Bashir, Khurram MD; Apperson, Michelle MD; Giesser, Barbara MD; Zabeti, Aram MD; Miravalle, Augusto MD; Lynch, Sharon MD; Delgado, Silvia MD; Suski, Valerie MD; Goodman, Andrew MD; Flores, Angela MD; DeWitt, Dana MD; Goldman, Myla MD; Moses, Harold MD; Naismith, Robert MD; Peng, Qi PhD; Sakaie, Ken PhD; Jambawalikar, Sachin PhD; Dyke, Jonathan P. PhD; Kitajima, Hiroumi PhD; Panych, Lawrence PhD; Witzel, Thomas PhD; Parrish, Todd PhD; Layman, Rick PhD; Yang, Xiangyu PhD; Yee, Seonghwan MD; Shah, Dhaval PhD; Button, Terry Ph.D; Williams, Tony; Buonocore, Mike MD, PhD; Tanase, Costin PhD; Ellingson, Ben PhD; GaskillShipley, Mary MD; Morton, Ray; Brown, Mark PhD; Lee, Phil PhD; Pattany, Pradip PhD; Hetherington, Hoby MD; Zhang, Jianhui PhD; Varghese, Shijn PhD; Lee, James PhD; Mugler, John P. PhD; Price, Ron PhD; Thomas, Betsy RN; Welch, Mary MD; Liff, Jeremy MD; Smith, Andrew MD; Ian, Rossman MD; Vargas, Wendy MD; Cioroiu, Comana MD; Nealon, Nancy MD; Vargas, Diana MD; Cook, Calli DNP; Baharnoori, Moogeh MD; Reda, Haatem MD; Mateen, Farrah MD, PhD; Patel, Kevin MD; Kay-Stacey, Margaret MD; Kisanuki, Yasushi MD; Brett, Alldredge DO; Bogda, Christine MSN; Mass, Michele MD; Kim, Edward MD; Duleep, Anuradha MD; Grosso, Megan DPT, PA; Bucello, Meg ANP; McLinkskey, Nancy MD; Mayadev, Angeli MD; Peiqing, Qian MD; Meador, William MD; Richman, David MD; Dorsch, Andrew MD; Nygren, Kristin MD; Obeidat, Ahmed MD; Wall, Anastacia PA; Hammond, Nancy MD; Andersen, Heather MD; Mittal, Manoj MD; Tornes, Leticia MD; Lizarraga, Alexis MD; Zaydan, Islam MD; Hyland, Megan MD; Munoz, Shanan MD; Wright, Katy PA-C; Smith, Gordon MD; Bruen, Denise NP; Brenton, James Nicholas; Pawate, Siddharama MD; Sriram, Subramaniam MD; Oddis, Kerry; Scheid, Eileen; Thayer, William; Duodova, Mariana; Keller, Margaret RN; Scott, Jennifer RN; Teshome, Mengesha MD
doi : 10.1212/WNL.0000000000011314
pg. e491-e500
AB Objective: To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS). Methods: A randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis. Results: A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo (p = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p = 0.08). Conclusion: Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes. Classification of Evidence: This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions. (C) 2021 American Academy of Neurology
Cancer Incidence and Mortality Rates in Multiple Sclerosis: A Matched Cohort Study.
Marrie, Ruth Ann MD, PhD; Maxwell, Colleen PhD; Mahar, Alyson PhD; Ekuma, Okechukwu MSc; McClintock, Chad MSc; Seitz, Dallas MD, PhD; Webber, Colleen PhD; Groome, Patti A. PhD
doi : 10.1212/WNL.0000000000011219
pg. e501-e512
AB Objective: To determine whether cancer risk differs in people with and without multiple sclerosis (MS), we compared incidence rates and cancer-specific mortality rates in MS and matched cohorts using population-based data sources. Methods: We conducted a retrospective matched cohort study using population-based administrative data from Manitoba and Ontario, Canada. We applied a validated case definition to identify MS cases, then selected 5 controls without MS matched on birth year, sex, and region. We linked these cohorts to cancer registries, and estimated incidence of breast, colorectal, and 13 other cancers. For breast and colorectal cancers, we constructed Cox models adjusting for age at the index date, area-level socioeconomic status, region, birth cohort year, and comorbidity. We pooled findings across provinces using meta-analysis. Results: We included 53,983 MS cases and 269,915 controls. Multivariable analyses showed no difference in breast cancer risk (pooled hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.78-1.09]) or colorectal cancer risk (pooled HR 0.83 [95% CI 0.64-1.07]) between the cohorts. Mortality rates for breast and colorectal did not differ between cohorts. Bladder cancer incidence and mortality rates were higher among the MS cohort. Although the incidence of prostate, uterine, and CNS cancers differed between the MS and matched cohorts, mortality rates did not. Conclusion: The incidence of breast and colorectal cancers does not differ between persons with and without MS; however, the incidence of bladder cancer is increased. Reported differences in the incidence of some cancers in the MS population may reflect ascertainment differences rather than true differences. (C) 2021 American Academy of Neurology
Risk of Stroke in Cancer Survivors: A Meta-analysis of Population-Based Cohort Studies.
Zhang, Fangfang MD; Wang, Kuanhong MD; Du, Peixin RN; Yang, Wei MD; He, Yazhou MD; Li, Tian MD; Mei, Zubing MD, PhD
doi : 10.1212/WNL.0000000000011264
pg. e513-e526
AB Objective: Accumulating evidence suggests that cancer survivors may have a relatively higher risk of stroke. The aim of this meta-analysis was to determine whether cancer survivors have a relatively higher risk of stroke than cancer-free populations on the basis of published data from population-based cohort studies. Methods: PubMed, Embase, and Cochrane Library were searched from inception to February 8, 2020, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results. Results: Twenty population-based cohort studies involving 10,479,530 participants were identified. Overall, the relative risk (RR) for stroke in cancer survivors was 1.66 (95% CI 1.35-2.04; p < 0.001) compared with that in cancer-free controls; survivors of head and neck, hematologic, lung, pancreas, and stomach cancer (all p < 0.05) showed consistently significant results, whereas no significant increased risk was observed for patients with other cancer types. The effects were more prominent in cancer survivors with female sex (RR 1.38, 95% CI 1.18-1.61; p < 0.001), younger age at cancer diagnosis (<45 years) (RR 2.57, 95% CI 1.27-5.19; p = 0.009), and shorter cancer survival duration (>=1-2 years) (RR 1.69, 95% CI 1.18-2.42; p = 0.004). Moreover, cancer survivors had a significantly increased risk of ischemic stroke (RR 1.53, 95% CI 1.28-1.84; p < 0.001) compared with hemorrhagic stroke. Conclusions: Cancer plays a critical role in the etiologic of stroke. Due to the existence of substantial heterogeneity among the included studies, the results should be interpreted with caution. However, early prevention and effective intervention of stroke in cancer survivors require attention from health policy makers. (C) 2021 American Academy of Neurology
Cerebral Small Vessel Disease MRI Features Do Not Improve the Prediction of Stroke Outcome.
Coutureau, Juliette MD; Asselineau, Julien MSc; Perez, Paul MD, PhD; Kuchcinski, Gregory MD; Sagnier, Sharmila MD, PhD; Renou, Pauline MD; Munsch, Fanny PhD; Lopes, Renaud PhD; Henon, Hilde MD; Bordet, Regis MD, PhD; Dousset, Vincent MD, PhD; Sibon, Igor MD, PhD; Tourdias, Thomas MD, PhD
doi : 10.1212/WNL.0000000000011208
pg. e527-e537
AB Objective: To determine whether the total small vessel disease (SVD) score adds information to the prediction of stroke outcome compared to validated predictors, we tested different predictive models of outcome in patients with stroke. Methods: White matter hyperintensity, lacunes, perivascular spaces, microbleeds, and atrophy were quantified in 2 prospective datasets of 428 and 197 patients with first-ever stroke, using MRI collected 24 to 72 hours after stroke onset. Functional, cognitive, and psychological status were assessed at the 3- to 6-month follow-up. The predictive accuracy (in terms of calibration and discrimination) of age, baseline NIH Stroke Scale score (NIHSS), and infarct volume was quantified (model 1) on dataset 1, the total SVD score was added (model 2), and the improvement in predictive accuracy was evaluated. These 2 models were also developed in dataset 2 for replication. Finally, in model 3, the MRI features of cerebral SVD were included rather than the total SVD score. Results: Model 1 showed excellent performance for discriminating poor vs good functional outcomes (area under the curve [AUC] 0.915), and fair performance for identifying cognitively impaired and depressed patients (AUCs 0.750 and 0.688, respectively). A higher SVD score was associated with a poorer outcome (odds ratio 1.30 [1.07-1.58], p = 0.0090 at best for functional outcome). However, adding the total SVD score (model 2) or individual MRI features (model 3) did not improve the prediction over model 1. Results for dataset 2 were similar. Conclusions: Cerebral SVD was independently associated with functional, cognitive, and psychological outcomes, but had no clinically relevant added value to predict the individual outcomes of patients when compared to the usual predictors, such as age and baseline NIHSS. (C) 2021 American Academy of Neurology
Cerebrovascular Disease Progression in Patients With ACTA2 Arg179 Pathogenic Variants.
Lauer, Arne MD *; Speroni, Samantha L. BA *; Patel, Jay B. PhD; Regalado, Ellen MS; Choi, Myoung MD; Smith, Edward MD; Kalpathy-Kramer, Jayashree PhD; Caruso, Paul MD; Milewicz, Dianna M. MD, PhD; Musolino, Patricia L. MD, PhD
doi : 10.1212/WNL.0000000000011210
pg. e538-e552
AB Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the ACTA2 gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with ACTA2 Arg179 pathogenic variants. Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury. Results: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis. Conclusions: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with ACTA2 Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies. (C) 2021 American Academy of Neurology
Machine Learning to Predict Delayed Cerebral Ischemia and Outcomes in Subarachnoid Hemorrhage.
Savarraj, Jude P.J. PhD; Hergenroeder, Georgene W. PhD; Zhu, Liang PhD; Chang, Tiffany MD; Park, Soojin MD; Megjhani, Murad PhD; Vahidy, Farhaan S. PhD; Zhao, Zhongming PhD; Kitagawa, Ryan S. MD; Choi, H. Alex MD
doi : 10.1212/WNL.0000000000011211
pg. e553-e562
AB Objective: To determine whether machine learning (ML) algorithms can improve the prediction of delayed cerebral ischemia (DCI) and functional outcomes after subarachnoid hemorrhage (SAH). Methods: ML models and standard models (SMs) were trained to predict DCI and functional outcomes with data collected within 3 days of admission. Functional outcomes at discharge and at 3 months were quantified using the modified Rankin Scale (mRS) for neurologic disability (dichotomized as good [mRS <= 3] vs poor [mRS >= 4] outcomes). Concurrently, clinicians prospectively prognosticated 3-month outcomes of patients. The performance of ML, SMs, and clinicians were retrospectively compared. Results: DCI status, discharge, and 3-month outcomes were available for 399, 393, and 240 participants, respectively. Prospective clinician (an attending, a fellow, and a nurse) prognostication of 3-month outcomes was available for 90 participants. ML models yielded predictions with the following area under the receiver operating characteristic curve (AUC) scores: 0.75 +/- 0.07 (95% confidence interval [CI] 0.64-0.84) for DCI, 0.85 +/- 0.05 (95% CI 0.75-0.92) for discharge outcome, and 0.89 +/- 0.03 (95% CI 0.81-0.94) for 3-month outcome. ML outperformed SMs, improving AUC by 0.20 (95% CI -0.02 to 0.4) for DCI, by 0.07 +/- 0.03 (95% CI -0.0018 to 0.14) for discharge outcomes, and by 0.14 (95% CI 0.03-0.24) for 3-month outcomes and matched physician's performance in predicting 3-month outcomes. Conclusion: ML models significantly outperform SMs in predicting DCI and functional outcomes and has the potential to improve SAH management. (C) 2021 American Academy of Neurology
Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.
Shaikh, Aasef G. MD, PhD; Beylergil, Sinem Balta PhD; Scorr, Laura MD; Kilic-Berkmen, Gamze PhD; Freeman, Alan MD; Klein, Christine MD; Junker, Johanna MD; Loens, Sebastian MD; Bruggemann, Norbert MD; Munchau, Alexander MD; Baumer, Tobias MD; Vidailhet, Marie MD, PhD; Roze, Emmanuel MD, PhD; Bonnet, Cecilia MD, PhD; Jankovic, Joseph MD; Jimenez-Shahed, Joohi MD; Patel, Neepa MD; Marsh, Laura MD; Comella, Cynthia MD; Barbano, Richard L. MD; Berman, Brian D. MD; Malaty, Irene MD; Wagle Shukla, Aparna MD; Reich, Stephen G. MD; Ledoux, Mark S. MD, PhD; Berardelli, Alfredo MD; Ferrazzano, Gina MD; Stover, Natividad MD; Ondo, William MD; Pirio Richardson, Sarah MD; Saunders-Pullman, Rachel MD, MPH; Mari, Zoltan MD; Agarwal, Pinky MD; Adler, Charles MD; Chouinard, Sylvain MD; Fox, Susan H. MBChB, MRCP, PhD; Brashear, Allison MD; Truong, Daniel MD; Suchowersky, Oksana MD; Frank, Samuel MD; Factor, Stewart DO; Perlmutter, Joel MD; Jinnah, Hyder Azad MD, PhD
doi : 10.1212/WNL.0000000000011049
pg. e563-e574
AB Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia. Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition. Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics. Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia. (C) 2021 American Academy of Neurology
A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City.
Frontera, Jennifer A. MD; Sabadia, Sakinah MD; Lalchan, Rebecca DO; Fang, Taolin MD; Flusty, Brent DO; Millar-Vernetti, Patricio MD; Snyder, Thomas MD; Berger, Stephen MD; Yang, Dixon MD; Granger, Andre MD; Morgan, Nicole MD; Patel, Palak MD; Gutman, Josef MD; Melmed, Kara MD; Agarwal, Shashank MD; Bokhari, Matthew MD; Andino, Andres MD; Valdes, Eduard MD; Omari, Mirza MD; Kvernland, Alexandra MD; Lillemoe, Kaitlyn MD; Chou, Sherry H.-Y. MD, MSc; McNett, Molly RN, PhD; Helbok, Raimund MD, PhD; Mainali, Shraddha MD; Fink, Ericka L. MD; Robertson, Courtney MD; Schober, Michelle MD; Suarez, Jose I. MD; Ziai, Wendy MD; Menon, David MD, PhD; Friedman, Daniel MD; Friedman, David MD; Holmes, Manisha MD; Huang, Joshua MSc; Thawani, Sujata MD; Howard, Jonathan MD; Abou-Fayssal, Nada MD; Krieger, Penina MPhil; Lewis, Ariane MD; Lord, Aaron S. MD; Zhou, Ting MD; Kahn, D. Ethan DO; Czeisler, Barry M. MD; Torres, Jose MD; Yaghi, Shadi MD; Ishida, Koto MD; Scher, Erica RN, MPH; de Havenon, Adam MD; Placantonakis, Dimitris MD, PhD; Liu, Mengling PhD; Wisniewski, Thomas MD; Troxel, Andrea B. ScD; Balcer, Laura MD, MSCE; Galetta, Steven MD
doi : 10.1212/WNL.0000000000010979
pg. e575-e586
AB Objective: To determine the prevalence and associated mortality of well-defined neurologic diagnoses among patients with coronavirus disease 2019 (COVID-19), we prospectively followed hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients and recorded new neurologic disorders and hospital outcomes. Methods: We conducted a prospective, multicenter, observational study of consecutive hospitalized adults in the New York City metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between patients with COVID-19 with and without neurologic disorders. Results: Of 4,491 patients with COVID-19 hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were reverse transcriptase PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all p < 0.05). After adjusting for age, sex, SOFA scores, intubation, history, medical complications, medications, and comfort care status, patients with COVID-19 with neurologic disorders had increased risk of in-hospital mortality (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.17-1.62, p < 0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, p < 0.001). Conclusions: Neurologic disorders were detected in 13.5% of patients with COVID-19 and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness. (C) 2021 American Academy of Neurology
Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study.
Trucco, Federica MD; Ridout, Deborah MSc; Scoto, Mariacristina MD, PhD; Coratti, Giorgia PT; Main, Marion L. PT; Muni Lofra, Robert PT; Mayhew, Anna G. PT; Montes, Jacqueline PT, EdD; Pane, Marika MD, PhD; Sansone, Valeria MD, PhD; Albamonte, Emilio MD; D'Amico, Adele MD; Bertini, Enrico MD, PhD; Messina, Sonia MD, PhD; Bruno, Claudio MD, PhD; Parasuraman, Deepak MD; Childs, Anne-Marie MD, PhD; Gowda, Vasantha MD; Willis, Tracey MD, PhD; Ong, Min MD; Marini-Bettolo, Chiara MD, PhD; De Vivo, Darryl C. MD; Darras, Basil T. MD; Day, John MD, PhD; Kichula, Elizabeth A. MD; Mayer, Oscar H. MD; Navas Nazario, Aledie A. MD; Finkel, Richard S. MD; Mercuri, Eugenio MD, PhD; Muntoni, Francesco MD; on behalf of the International SMA Consortium (iSMAc); De Sanctis, Roberto PT; Pirola, Alice PT; Longo, Antonella MD; Sframeli, Maria MD, PhD; Pedemonte, Marina MD, PhD; Pallant, Lindsey PT; Wraige, Elizabeth MD; Turner, Sarah PT; White, Kay PT; Glanzman, Allan M. PT; Civitello, Matthew PT; Berardinelli, Angela MD PhD; Baranello, Giovanni MD, PhD; Spinty, Stefan MD; Majumbdar, Anirban MD; Huges, Imelda MD; Krishnakumar, Deepa MD; Chow, Gabriel MD; Thomas, Neil MD; Ramdas, Sithara MD
doi : 10.1212/WNL.0000000000011051
pg. e587-e599
AB Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA). Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy. Results: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (+/-4.4) and 11.1 (+/-4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes. Conclusions: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA. (C) 2021 American Academy of Neurology
Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort.
Grassano, Maurizio MD; Calvo, Andrea MD, PhD; Moglia, Cristina MD, PhD; Brunetti, Maura BSc; Barberis, Marco BSc; Sbaiz, Luca BSc; Canosa, Antonio MD, PhD; Manera, Umberto MD; Vasta, Rosario MD; Corrado, Lucia PhD; D'Alfonso, Sandra PhD; Mazzini, Letizia MD; Scholz, Sonja W. MD, PhD; Dalgard, Clifton PhD; Ding, Jinhui PhD; Gibbs, Raphael J. BSc; Chia, Ruth PhD; Traynor, Bryan J. MD, PhD; Chio, Adriano MD, FAAN; The American Genomic Center
doi : 10.1212/WNL.0000000000011209
pg. e600-e609
AB Objective: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls. Methods: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population. Results: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited. Conclusions: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool. (C) 2021 American Academy of Neurology
Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension.
Mantegazza, Renato MD; Wolfe, Gil I. MD; Muppidi, Srikanth MD; Wiendl, Heinz MD; Fujita, Kenji P. MD; O'Brien, Fanny L. PhD; Booth, Heather D.E. DPhil; Howard, James F. Jr MD; on behalf of the CReATe Consortium; Mazia, Claudio Gabriel; Wilken, Miguel; Barroso, Fabio; Saba, Juliet; Rugiero, Marcelo; Bettini, Mariela; Chaves, Marcelo; Vidal, Gonzalo; Garcia, Alejandra Dalila; De Bleecker, Jan; Van den Abeele, Guy; de Koning, Kathy; De Mey, Katrien; Mercelis, Rudy; Mahieu, Delphine; Wagemaekers, Linda; Van Damme, Philip; Depreitere, Annelies; Schotte, Caroline; Smetcoren, Charlotte; Stevens, Olivier; Van Daele, Sien; Vandenbussche, Nicolas; Vanhee, Annelies; Verjans, Sarah; Vynckier, Jan; D'Hont, Ann; Tilkin, Petra; Alves de Siqueira Carvalho, Alzira; Brockhausen, Igor Dias; Feder, David; Ambrosio, Daniel; Cesar, Gabor Lovasamela; Melo, Ana Paula; Ribeiro, Renata Martins; Rocha, Rosana; Rosa, Bruno Bezerra; Veiga, Thabata; Augusto da Silva, Luiz; Engel, Murilo Santos; Geraldo, Jordana Goncalves; da Penha Ananias Morita, Maria; Coelho, Erica Nogueira; Paiva, Gabriel; Pozo, Marina; Prando, Natalia; Martineli Torres, Debora Dada; Butinhao, Cristiani Fernanda; Duran, Gustavo; Suriane Fialho, Tomas Augusto; Gomes da Silva, Tamires Cristina; Maia Goncalves, Luiz Otavio; Pazetto, Lucas Eduardo; Cubas Volpe, Luciana Renata; Duca, Luciana Souza; AndreGheller Friedrich, Mauricio; Guerreiro, Alexandre; Guerreiro, Alexandre; Mohr, Henrique; Martins, Maurer Pereira; da Cruz Pacheco, Daiane; Ferreira, Luciana; Macagnan, Ana Paula; Pinto, Graziela; de Cassia Santos, Aline; Bulle Oliveira, Acary Souza; Amaral de Andrade, Ana Carolina; Annes, Marcelo; Silva, Liene Duarte; Lino, Valeria Cavalcante; Pinto, Wladimir; Assis, Natalia; Carrara, Fernanda; Miranda, Carolina; Souza, Iandra; Fernandes, Patricia; Siddiqi, Zaeem; Phan, Cecile; Narayan, Jeffrey; Blackmore, Derrick; Mallon, Ashley; Roderus, Rikki; Watt, Elizabeth; Vohanka, Stanislav; Bednarik, Josef; Chmelikova, Magda; Cierny, Marek; Toncrova, Stanislava; Junkerova, Jana; Kurkova, Barbora; Reguliova, Katarina; Zapletalova, Olga; Pitha, Jiri; Novakova, Iveta; Tyblova, Michaela; Jurajdova, Ivana; Wolfova, Marcela; Andersen, Henning; Harbo, Thomas; Vinge, Lotte; Krogh, Susanne; Mogensen, Anita; Vissing, John; Hojgaard, Joan; Witting, Nanna; Ostergaard Autzen, Anne Mette; Pedersen, Jane; Eralinna, Juha-Pekka; Laaksonen, Mikko; Oksaranta, Olli; Harrison, Tuula; Eriksson, Jaana; Rozsa, Csilla; Horvath, Melinda; Lovas, Gabor; Matolcsi, Judit; Jakab, Gedeonne; Szabo, Gyorgyi; Jakab, Gedeonne; Szabadosne, Brigitta; Vecsei, Laszlo; Dezsi, Livia; Varga, Edina; Konyane, Monika; Antonini, Giovanni; Di Pasquale, Antonella; Garibaldi, Matteo; Morino, Stefania; Troili, Fernanda; Fionda, Laura; Di Pasquale, Antonella; Evoli, Amelia; Alboini, Paolo Emilio; D'Amato, Valentina; Iorio, Raffaele; Inghilleri, Maurizio; Fionda, Laura; Frasca, Vittorio; Giacomelli, Elena; Gori, Maria; Lopergolo, Diego; Onesti, Emanuela; Frasca, Vittorio; Gabriele, Maria; Sacca, Francesco; Filla, Alessandro; Costabile, Teresa; Marano, Enrico; Fasanaro, Angiola; Marsili, Angela; Puorro, Giorgia; Antozzi, Carlo; Bonanno, Silvia; Camera, Giorgia; Locatelli, Alberta; Maggi, Lorenzo; Pasanisi, Maria; Campanella, Angela; Uzawa, Akiyuki; Kanai, Tetsuya; Kawaguchi, Naoki; Mori, Masahiro; Kaneko, Yoko; Kanzaki, Akiko; Kobayashi, Eri; Murai, Hiroyuki; Masaki, Katsuhisa; Matsuse, Dai; Matsushita, Takuya; Uehara, Taira; Shimpo, Misa; Jingu, Maki; Kikutake, Keiko; Nakamura, Yumiko; Sano, Yoshiko; Utsugisawa, Kimiaki; Nagane, Yuriko; Kamegamori, Ikuko; Tsuda, Tomoko; Fujii, Yuko; Futono, Kazumi; Ozawa, Yukiko; Mizugami, Aya; Saito, Yuka; Samukawa, Makoto; Suzuki, Hidekazu; Morikawa, Miyuki; Kamakura, Sachiko; Miyawaki, Eriko; Okumura, Meinoshin; Funaka, Soichiro; Kawamura, Tomohiro; Nakamori, Masayuki; Takahashi, Masanori; Taichi, Namie; Hasuike, Tomoya; Higuchi, Eriko; Kobayashi, Hisako; Osakada, Kaori; Shiraishi, Hirokazu; Miyazaki, Teiichiro; Motomura, Masakatsu; Mukaino, Akihiro; Yoshimura, Shunsuke; Asada, Shizuka; Yoshida, Seiko; Amamoto, Shoko; Kobashikawa, Tomomi; Koga, Megumi; Yasuko, Maeda; Takada, Kazumi; Takada, Mihoko; Tsurumaru, Masako; Yamashita, Yumi; Suzuki, Yasushi; Akiyama, Tetsuya; Narikawa, Koichi; Tano, Ohito; Tsukita, Kenichi; Kurihara, Rikako; Meguro, Fumie; Fukuda, Yusuke; Sato, Miwako; Imai, Tomihiro; Tsuda, Emiko; Shimohama, Shun; Hayashi, Takashi; Hisahara, Shin; Imai, Tomihiro; Kawamata, Jun; Murahara, Takashi; Saitoh, Masaki; Shimohama, Shun; Suzuki, Shuichiro; Yamamoto, Daisuke; Ishiyama, Yoko; Ishiyama, Naoko; Noshiro, Mayuko; Takeyama, Rumi; Uwasa, Kaori; Yasuda, Ikuko; van der Kooi, Anneke; de Visser, Marianne; Gibson, Tamar; Kim, Byung-Jo; Lee, Chang Nyoung; Koo, Yong Seo; Seok, Hung Youl; Kang, Hoo Nam; Ra, HyeJin; Kim, Byoung Joon; Cho, Eun Bin; Choi, MiSong; Lee, HyeLim; Min, Ju-Hong; Seok, Jinmyoung; Lee, JiEun; Koh, Da Yoon; Kwon, JuYoung; Park, SangAe; Choi, Eun Haw; Hong, Yoon-Ho; Ahn, So-Hyun; Koo, Dae Lim; Lim, Jae-Sung; Shin, Chae Won; Hwang, Ji Ye; Kim, Miri; Kim, Seung Min; Jeong, Ha-Neul; Jung, JinWoo; Kim, Yool-hee; Lee, Hyung Seok; Shin, Ha Young; Hwang, Eun Bi; Shin, Miju; Casasnovas, Carlos; Alberti Aguilo, Maria Antonia; Homedes-Pedret, Christian; Palacios, Natalia Julia; Porras, Laura Diez; Santamaria, Valentina Velez; Lazaro, Ana; Carbonell, Josep Gamez; Sune, Pilar; Figueras, Maria Salvado; Gili, Gisela; Mazuela, Gonzalo; Illa, Isabel; Vicente, Elena Cortes; Diaz-Manera, Jordi; Querol Gutierrez, Luis Antonio; Garcia, Ricardo Rojas; Vidal, Nuria; Arribas-Ibar, Elisabet; Tejedor, Exuperio Diez; Salcedo, Pilar Gomez; Fernandez-Fournier, Mireya; Ruiz, Pedro Lopez; Rodriguez de Rivera, Francisco Javier; Fernandez-Fournier, Mireya; Sastre, Maria; Piehl, Fredrik; Hietala, Albert; Bjarbo, Lena; Sengun, Ihsan; Meherremova, Arzu; Ozcelik, Pinar; Balkan, Bengu; Tuga, Celal; Ugur, Muzeyyen; Erdem-Ozdamar, Sevim; Bekircan-Kurt, Can Ebru; Acar, Nazire Pinar; Yilmaz, Ezgi; Caliskan, Yagmur; Orsel, Gulsah; Efendi, Husnu; Aydinlik, Seda; Cavus, Hakan; Kutlu, Ayse; Becerikli, Gulsah; Semiz, Cansu; Tun, Ozlem; Terzi, Murat; Dogan, Baki; Onar, Musa Kazim; Sen, Sedat; Cavdar, Tugce Kirbas; Veske, Adife; Norwood, Fiona; Dimitriou, Aikaterini; Gollogly, Jakit; Mahdi-Rogers, Mohamed; Seddigh, Arshira; Sokratous, Giannis; Maier, Gal; Sohail, Faisal; Jacob, Saiju; Sadalage, Girija; Torane, Pravin; Torane, Pravin; Brown, Claire; Shah, Amna; Sathasivam, Sivakumar; Arndt, Heike; Davies, Debbie; Watling, Dave; Amato, Anthony; Cochrane, Thomas; Salajegheh, Mohammed; Roe, Kristen; Amato, Katherine; Toska, Shirli; Silvestri, Nicholas; Patrick, Kara; Zakalik, Karen; Katz, Jonathan; Miller, Robert; Engel, Marguerite; Forshew, Dallas; Bravver, Elena; Brooks, Benjamin; Sanjak, Mohammed; Plevka, Sarah; Burdette, Maryanne; Cunningham, Scott; Kramer, Megan; Nemeth, Joanne; Schommer, Clara; Scott, Tierney; Juel, Vern; Guptill, Jeffrey; Hobson-Webb, Lisa; Massey, Janice; Beck, Kate; Carnes, Donna; Loor, John; Anderson, Amanda; Pascuzzi, Robert; Bodkin, Cynthia; Kincaid, John; Snook, Riley; Guingrich, Sandra; Micheels, Angela; Chaudhry, Vinay; Corse, Andrea; Mosmiller, Betsy; Kelley, Andrea; Ho, Doreen; Srinivasan, Jayashri; Vytopil, Michal; Jara, Jordan; Ventura, Nicholas; Carter, Cynthia; Donahue, Craig; Herbert, Carol; Scala, Stephanie; Weiner, Elaine; Alam, Sharmeen; McKinnon, Jonathan; Haar, Laura; McKinnon, Naya; Alcon, Karan; McKenna, Kaitlyn; Sattar, Nadia; Daniels, Kevin; Jeffery, Dennis; Freimer, Miriam; Hoyle, Joseph Chad; Kissel, John; Agriesti, Julie; Chelnick, Sharon; Mezache, Louisa; Pineda, Colleen; Muharrem, Filiz; Karam, Chafic; Khoury, Julie; Marburger, Tessa; Kaur, Harpreet; Dimitrova, Diana; Gilchrist, James; Agrawal, Brajesh; Elsayed, Mona; Kohlrus, Stephanie; Ardoin, Angela; Darnell, Taylor; Golden, Laura; Lokaitis, Barbara; Seelbach, Jenna; Goyal, Neelam; Sakamuri, Sarada; So, Yuen T; Paulose, Shirley; Pol, Sabrina; Welsh, Lesly; Bhavaraju-Sanka, Ratna; Gonzalez, Alejandro Tobon; Dishman, Lorraine; Jones, Floyd; Gonzalez, Anna; Padilla, Patricia; Saklad, Amy; Silva, Marcela; Nations, Sharon; Trivedi, Jaya; Hopkins, Steve; Kazamel, Mohamed; Alsharabati, Mohammad; Lu, Liang; Nozaki, Kenkichi; Mumfrey-Thomas, Sandi; Woodall, Amy; Mozaffar, Tahseen; Cash, Tiyonnoh; Goyal, Namita; Roy, Gulmohor; Mathew, Veena; Maqsood, Fatima; Minton, Brian; Jones, H. James; Rosenfeld, Jeffrey; Garcia, Rebekah; Echevarria, Laura; Garcia, Sonia; Pulley, Michael; Aranke, Shachie; Berger, Alan Ross; Shah, Jaimin; Shabbir, Yasmeen; Smith, Lisa; Varghese, Mary; Shabbir, Yasmeen; Gutmann, Laurie; Gutmann, Ludwig; Jerath, Nivedita; Nance, Christopher; Swenson, Andrea; Olalde, Heena; Kressin, Nicole; Sieren, Jeri; Barohn, Richard; Dimachkie, Mazen; Glenn, Melanie; McVey, April; Pasnoor, Mamatha; Statland, Jeffery; Wang, Yunxia; Liu, Tina; Emmons, Kelley; Jenci, Nicole; Locheke, Jerry; Fondaw, Alex; Johns, Kathryn; Rico, Gabrielle; Walsh, Maureen; Herbelin, Laura; Hafer-Macko, Charlene; Kwan, Justin; Zilliox, Lindsay; Callison, Karen; Young, Valerie; DiSanzo, Beth; Naunton, Kerry; Benatar, Michael; Bilsker, Martin; Sharma, Khema; Cooley, Anne; Reyes, Eliana; Michon, Sara-Claude; Sheldon, Danielle; Steele, Julie; Karam, Chafic; Traub, Rebecca; Chopra, Manisha; Vu, Tuan; Katzin, Lara; McClain, Terry; Harvey, Brittany; Hart, Adam; Huynh, Kristin; Beydoun, Said; Chilingaryan, Amaiak; Doan, Victor; Droker, Brian; Gong, Hui; Karimi, Sanaz; Lin, Frank; McClain, Terry; Polaka, Krishna; Shah, Akshay; Tran, Anh; Akhter, Salma; Malekniazi, Ali; Tandan, Rup; Hehir, Michael; Waheed, Waqar; Lucy, Shannon; Weiss, Michael; Distad, Jane; Strom, Susan; Downing, Sharon; Kim, Bryan; Bertorini, Tulio; Arnold, Thomas; Henderson, Kendrick; Pillai, Rekha; Liu, Ye; Wheeler, Lauren; Hewlett, Jasmine; Vanderhook, Mollie; Nowak, Richard; Dicapua, Daniel; Keung, Benison; Kumar, Aditya; Patwa, Huned; Robeson, Kimberly; Yang, Irene; Nye, Joan; Vu, Hong
doi : 10.1212/WNL.0000000000011207
pg. e610-e618
AB Objective: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. Methods: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. Results: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. Conclusion: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. ClinicalTrials.gov Identifier: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. Classification of Evidence: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo. (C) 2021 American Academy of Neurology
Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation.
Farrell, Michelle E. PhD *; Jiang, Shu PhD *; Schultz, Aaron P. PhD; Properzi, Michael J. BEng/BCompSci; Price, Julie C. PhD; Becker, J. Alex PhD; Jacobs, Heidi I.L. PhD; Hanseeuw, Bernard J. MD, PhD; Rentz, Dorene M. PsyD; Villemagne, Victor L. MD, PhD; Papp, Kathryn V. PhD; Mormino, Elizabeth C. PhD; Betensky, Rebecca A. PhD; Johnson, Keith A. MD; Sperling, Reisa A. MD; Buckley, Rachel F. PhD
doi : 10.1212/WNL.0000000000011214
pg. e619-e631
AB Introduction: As clinical trials move toward earlier intervention, we sought to redefine the [beta]-amyloid (A[beta])-PET threshold based on the lowest point in a baseline distribution that robustly predicts future A[beta] accumulation and cognitive decline in 3 independent samples of clinically normal individuals. Methods: Sequential A[beta] cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and A[beta]-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). Results: Within samples, cutoffs derived from future A[beta]-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5). Discussion: These optimized thresholds can help to inform future research and clinical trials targeting early A[beta]. Threshold convergence raises the possibility of contemporaneous early changes in A[beta] and cognition. Classification of Evidence: This study provides Class II evidence that among clinically normal individuals a specific A[beta]-PET threshold is predictive of cognitive decline. (C) 2021 American Academy of Neurology
Paraneoplastic Myeloneuropathies: Clinical, Oncologic, and Serologic Accompaniments.
Shah, Shailee MD; Vazquez Do Campo, Rocio MD; Kumar, Neeraj MD; McKeon, Andrew MD; Flanagan, Eoin P. MD; Klein, Christopher MD; Pittock, Sean J. MD; Dubey, Divyanshu MD
doi : 10.1212/WNL.0000000000011218
pg. e632-e639
AB Objective: To test the hypothesis that myeloneuropathy is a presenting phenotype of paraneoplastic neurologic syndromes we retrospectively reviewed clinical, radiologic, and serologic features of 32 patients with concomitant paraneoplastic spinal cord and peripheral nervous system involvement. Methods: Observational study investigating patients with myeloneuropathy and underlying cancer or onconeural antibody seropositivity. Results: Among 32 patients with paraneoplastic myeloneuropathy, 20 (63%) were women with median age 61 years (range 27-84 years). Twenty-six patients (81%) had classified onconeural antibodies (amphiphysin, n = 8; antineuronal nuclear antibody [ANNA] type 1 [anti-Hu], n = 5; collapsin response mediator protein 5 [CRMP5] [anti-CV2], n = 6; Purkinje cell cytoplasmic antibody type 1 [PCA1] [anti-Yo], n = 1; Purkinje cell cytoplasmic antibody type 2 [PCA2], n = 2; kelch-like protein 11 [KLHL11], n = 1; and combinations thereof: ANNA1/CRMP5, n = 1; ANNA1/amphiphysin, n = 1; ANNA3/CRMP5, n = 1). Cancer was confirmed in 25 cases (onconeural antibodies, n = 19; unclassified antibodies, n = 3; no antibodies, n = 3). Paraneoplastic myeloneuropathies had asymmetric paresthesias (84%), neuropathic pain (78%), subacute onset (72%), sensory ataxia (69%), bladder dysfunction (69%), and unintentional weight loss >15 pounds (63%). Neurologic examination demonstrated concomitant distal or asymmetric hyporeflexia and hyperreflexia (81%), impaired vibration and proprioception (69%), Babinski response (68%), and asymmetric weakness (66%). MRI showed longitudinally extensive (45%), tract-specific spinal cord T2 hyperintensities (39%) and lumbar nerve root enhancement (38%). Ten of 28 (36%) were unable to ambulate independently at last follow-up (median 24 months, range 5-133 months). Combined oncologic and immunologic therapy had more favorable modified Rankin Scale scores at post-treatment follow-up compared to those receiving either oncologic or immunologic therapy alone (2 [range 1-4] vs 4 [range 2-6], p < 0.001). Conclusions: Paraneoplastic etiologies should be considered in the evaluation of subacute myeloneuropathies. Recognition of key characteristics of paraneoplastic myeloneuropathy may facilitate early tumor diagnosis and initiation of immunosuppressive treatment. (C) 2021 American Academy of Neurology
What's Happening in Neurology(R) Neuroimmunology & Neuroinflammation.
doi : 10.1212/WNL.0000000000011346
pg. 160
Sex Differences in Response to Triptans: A Systematic Review and Meta-analysis.
van Casteren, Daphne S. MD; Kurth, Tobias MD, ScD; Danser, A.H. Jan PhD; Terwindt, Gisela M. MD, PhD; MaassenVanDenBrink, Antoinette PhD
doi : 10.1212/WNL.0000000000011216
pg. 162-170
AB Objective: To examine the effect of sex on clinical response to triptans in migraine and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis. Methods: We searched clinical trials distinguishing clinical response to or pharmacokinetic parameters of triptans between sexes in PubMed, MEDLINE, Cochrane Library, Embase, and Web of Science up to Dec 12, 2019. Analysis was based on data extracted from published reports. Male-to-female pooled risk ratios (RR) were calculated for clinical outcomes and pooled ratio of means (RoM) for pharmacokinetic outcomes using random-effects models. Results: Of 1,188 publications on clinical trials with triptans, 244 were identified with sex-related search terms. Only 19 publications presented sex-specific results, comprising n = 2,280 men and n = 13,899 women. No sex differences were revealed for 2-hour headache and pain-free responses, but men had a lower risk for headache recurrence (male-to-female RR 0.64, 95% confidence interval [CI]: 0.55-0.76, Q = 0.81) and adverse events (RR 0.82, 95% CI: 0.72-0.93, Q = 4.93). Men had lower drug exposure with lower area under the curve (RoM 0.69, 95% CI: 0.60-0.81, Q = 18.06) and peak drug concentration (RoM 0.72, 95% CI: 0.64-0.82, Q = 8.24) than women. Conclusions: Remarkably few publications about sex differences in triptan response are available. The limited number of eligible studies show sex differences in adverse event frequency, which may be partly because of drug exposure differences. This higher drug exposure in women is not reflected in different response rates. Despite higher exposure, women have higher headache recurrence rates possibly because of longer attack duration related to sex hormonal changes. (C) 2021 American Academy of Neurology
Increased Large Vessel Occlusive Strokes After the Christchurch March 15, 2019, Terror Attack.
Wu, Teddy Y. PhD; Myall, Daniel PhD; Palmer, David MBChB; Beharry, James MBChB; Lim, Jen Yuh MBChB; Mason, Deborah F. FRACP; Reimers, Jon FRACP; Duncan, Roderick PhD; Weaver, James FACEM; Collecutt, Wayne FRANZCR; Mouthaan, Paul MMIS; Lim, Anthony FRANZCR; Hurrell, Mike A. FRANZCR; Barber, P. Alan PhD; Ranta, Annemarei PhD; Fink, John N. FRACP; Le Heron, Campbell DPhil
doi : 10.1212/WNL.0000000000011341
pg. 171-174
Nelarabine-Induced Myelotoxicity.
Madhavan, Ajay A. MD; Carr, Carrie M. MD; Alkhateeb, Hassan MD; Staff, Nathan P. MD; Naddaf, Elie MD
doi : 10.1212/WNL.0000000000011343
pg. 175-176
Resident & Fellow Rounds.
Strowd, Roy E. III MD, MEd, MS; Editor; Aamodt, Whitley MD, MPH; Deputy Editor
doi : 10.1212/WNL.0000000000011360
pg. 177-179
Clinical Reasoning: A 71-Year-Old Man Presenting With Acute Onset Dysarthria and Dysphagia.
Spagni, Gregorio MD; Tricoli, Luca MD; Modoni, Anna MD, PhD; Monforte, Mauro MD, PhD; Della Marca, Giacomo MD, PhD; Brunetti, Valerio MD
doi : 10.1212/WNL.0000000000010816
pg. 180-184
Pearls & Oy-sters: A Novel Presentation of Ataxia With Vitamin E Deficiency Caused by TTPA Gene Mutation.
Zea Vera, Alonso MD; Liu, Wei MD; Thomas, Cameron MD, MS; Gilbert, Donald L. MD, MS
doi : 10.1212/WNL.0000000000010853
pg. e640-e642
Teaching NeuroImages: Spinal Neurosarcoidosis: An Eccentric Manifestation.
French, David MD; Nascimento, Fabio A. MD; Xu, Ya MD; Dunham, S. Richard MD
doi : 10.1212/WNL.0000000000010802
pg. e643-e644
Teaching NeuroImages: SARS-CoV-2-Related Encephalitis: MRI Pattern of Olfactory Tract Involvement.
Casez, Olivier MD; Willaume, Gauthier; Grand, Sylvie MD; Nemoz, Benjamin MD; Lupo, Julien MD, PhD; Kahane, Philippe MD, PhD; Brion, Jean-Paul MD
doi : 10.1212/WNL.0000000000011150
pg. e645-e646
The Impact of COVID-19 on Developing Neurologic Disorders.
Tekiela, Piotr MD; Majersik, Jennifer J. MD, MS
doi : 10.1212/WNL.0000000000011348
pg. e647-e649
Editors' Note: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies.
Lewis, Ariane MD; Galetta, Steven MD
doi : 10.1212/WNL.0000000000011358
pg. 185
Reader Response: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies.
Lancaster, Eric
doi : 10.1212/WNL.0000000000011361
pg. 185-186
Reader Response: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies.
McKeon, Andrew; Dubey, Divyanshu; Flanagan, Eoin P.; Pittock, Sean J.; Zekeridou, Anastasia
doi : 10.1212/WNL.0000000000011362
pg. 186-188
Author Response: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies.
Dalmau, Josep; Martinez-Hernandez, Eugenia
doi : 10.1212/WNL.0000000000011359
pg. 188-189
