Suja S. Rajan PhD, Jose-Miguel Yamal PhD, Mengxi Wang PhD, MS, Jeffrey L. Saver MD, Asha P. Jacob MD, MPH, Nicole R. Gonzales MD, Nneka Ifejika MD, Stephanie A. Parker MHA, BSN, RN, Christopher Ganey PharmD, MS, Michael O. Gonzalez MS, David R. Lairson PhD, Patti L. Bratina RN, William J. Jones MD, Jason S. Mackey MD, Mackenzie P. Lerario MD, LMSW, Babak B. Navi MD, Ann W. Alexandrov PhD, Andrei Alexandrov MD, May Nour MD, PhD, Ilana Spokoyny MD, Ritvij Bowry MD, Alexandra L. Czap MD, James C. Grotta MD
Objective
Given the high disease and cost burden of ischemic stroke, evaluating the clinical efficacy and cost-effectiveness of new approaches to prevent and treat ischemic stroke is critical. Effective ischemic stroke management depends on timely administration of thrombolytics after stroke onset. This study evaluates the cost-effectiveness associated with the use of mobile stroke units (MSUs) to expedite tissue plasminogen activator (tPA) administration, as compared with standard management through emergency medical services (EMS).
Methods
This study is a prospective, multicenter, alternating-week, cluster-controlled trial of MSU versus EMS. One-year and life-time cost-effectiveness analyses, using the incremental cost-effectiveness ratio (ICER) method, were performed from the perspective of CMS's Medicare. Quality-adjusted life years (QALYs) estimated using patient-reported EQ-5D-5L data were used as the effectiveness measure. Health care utilizations were converted to costs using average national Medicare reimbursements. ICERs excluding patients with pre-existing disability, and limited to stroke-related costs were also calculated.
Results
The first-year ICER for all tPA-eligible patients using total cost differences between MSU and EMS groups was $238,873/QALY; for patients without pre-existing disability was $61,199/QALY. The lifetime ICERs for all tPA-eligible patients and for those without pre-existing disability were $94,710 and $31,259/QALY, respectively. All ICERs were lower when restricted to stroke-related costs and were highly dependent on the number of patients treated per year in an MSU.
Interpretation
MSUs' cost-effectiveness is borderline if we consider total first-year costs and outcomes in all tPA-eligible patients. MSUs are cost-effective to highly cost-effective when calculations are based on patients without pre-existing disability, patients' lifetime horizon, stroke-related costs, and more patients treated per year in an MSU. ANN NEUROL 2025;97:209–221
{"title":"A Prospective Multicenter Analysis of Mobile Stroke Unit Cost-Effectiveness","authors":"Suja S. Rajan PhD, Jose-Miguel Yamal PhD, Mengxi Wang PhD, MS, Jeffrey L. Saver MD, Asha P. Jacob MD, MPH, Nicole R. Gonzales MD, Nneka Ifejika MD, Stephanie A. Parker MHA, BSN, RN, Christopher Ganey PharmD, MS, Michael O. Gonzalez MS, David R. Lairson PhD, Patti L. Bratina RN, William J. Jones MD, Jason S. Mackey MD, Mackenzie P. Lerario MD, LMSW, Babak B. Navi MD, Ann W. Alexandrov PhD, Andrei Alexandrov MD, May Nour MD, PhD, Ilana Spokoyny MD, Ritvij Bowry MD, Alexandra L. Czap MD, James C. Grotta MD","doi":"10.1002/ana.27105","DOIUrl":"10.1002/ana.27105","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Given the high disease and cost burden of ischemic stroke, evaluating the clinical efficacy and cost-effectiveness of new approaches to prevent and treat ischemic stroke is critical. Effective ischemic stroke management depends on timely administration of thrombolytics after stroke onset. This study evaluates the cost-effectiveness associated with the use of mobile stroke units (MSUs) to expedite tissue plasminogen activator (tPA) administration, as compared with standard management through emergency medical services (EMS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study is a prospective, multicenter, alternating-week, cluster-controlled trial of MSU versus EMS. One-year and life-time cost-effectiveness analyses, using the incremental cost-effectiveness ratio (ICER) method, were performed from the perspective of CMS's Medicare. Quality-adjusted life years (QALYs) estimated using patient-reported EQ-5D-5L data were used as the effectiveness measure. Health care utilizations were converted to costs using average national Medicare reimbursements. ICERs excluding patients with pre-existing disability, and limited to stroke-related costs were also calculated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The first-year ICER for all tPA-eligible patients using total cost differences between MSU and EMS groups was $238,873/QALY; for patients without pre-existing disability was $61,199/QALY. The lifetime ICERs for all tPA-eligible patients and for those without pre-existing disability were $94,710 and $31,259/QALY, respectively. All ICERs were lower when restricted to stroke-related costs and were highly dependent on the number of patients treated per year in an MSU.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>MSUs' cost-effectiveness is borderline if we consider total first-year costs and outcomes in all tPA-eligible patients. MSUs are cost-effective to highly cost-effective when calculations are based on patients without pre-existing disability, patients' lifetime horizon, stroke-related costs, and more patients treated per year in an MSU. ANN NEUROL 2025;97:209–221</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"209-221"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764605","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}
Elodie Berthet MD, Antoine Guillonnet MD, Caroline Houillier MD, Renata Ursu MD, Carole Soussain MD, Mehdi Touat MD, Antoine Gueguen MD, Benoît de Renzis MD, Kevin Bigaut MD, Guido Ahle MD, Pierre Durozard MD, Deborah Grosset-Janin MD, Lucie Oberic MD, Antoine Bonnet MD, Anne-Pascale Grandjean MD, Cécile Moluçon-Chabrot MD, Khê Hoang-Xuan MD, PhD, Hugues Chabriat MD, PhD, Stéphanie Guey MD, PhD
Objective
Intravascular lymphoma is a rare subtype of B-cell lymphoma characterized by a clonal proliferation restricted to the lumen of small vessels. Over 50% of patients exhibit central nervous system (CNS) involvement, but diagnosis is often delayed due to the lack of distinctive features. We aimed to identify key phenotypic features for early diagnosis of intravascular lymphoma with CNS involvement through an in-depth cohort study.
Methods
We built up a multicenter retrospective cohort of 17 patients recruited in collaboration with the French Expert Network for Oculo-Cerebral Lymphomas (LOC network), and retrospectively analyzed data from medical records.
Results
In this cohort, 15 of 17 (88%) patients developed focal neurological episodes, often fluctuating and/or recurrent, with a sudden onset in 68% of episodes, suggesting a vascular origin. Rapid cognitive deterioration occurred in 15 of 17 (88%) patients, psychiatric manifestations in 8 of 17 (47%), and “B signs” in 14 of 17 (82%). Brain MRI showed polymorphic FLAIR hyperintensities in 14 of 16 (87%) patients, and DWI-positive lesions in 13 of 16 (81%) of patients, which accumulated over time and had unusual characteristics for ischemic lesions (progressive growth, persistent DWI-hyperintensity over 1 month, surrounded by a wider FLAIR hyperintensity). Early-onset inflammatory syndrome, and elevated lactate dehydrogenase (LDH) levels were observed in over 90% of cases. Mild and inconsistent meningitis contrasted with a nearly-constant hyperproteinorachia. An increased interleukin 10/6 ratio over 0,7 was found in 4 of 7 (57%) patients, and skin biopsy led to a pathological diagnosis in 3 of 6 (50%) patients.
Interpretation
The results of this study highlight “red flags” that could help accelerate the diagnosis of intravascular lymphoma involving the CNS. ANN NEUROL 2025;97:435–448
{"title":"Unveiling the Clinical and Imaging Signatures of Intravascular Lymphoma of the Central Nervous System: A Multicentric Cohort Study","authors":"Elodie Berthet MD, Antoine Guillonnet MD, Caroline Houillier MD, Renata Ursu MD, Carole Soussain MD, Mehdi Touat MD, Antoine Gueguen MD, Benoît de Renzis MD, Kevin Bigaut MD, Guido Ahle MD, Pierre Durozard MD, Deborah Grosset-Janin MD, Lucie Oberic MD, Antoine Bonnet MD, Anne-Pascale Grandjean MD, Cécile Moluçon-Chabrot MD, Khê Hoang-Xuan MD, PhD, Hugues Chabriat MD, PhD, Stéphanie Guey MD, PhD","doi":"10.1002/ana.27132","DOIUrl":"10.1002/ana.27132","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Intravascular lymphoma is a rare subtype of B-cell lymphoma characterized by a clonal proliferation restricted to the lumen of small vessels. Over 50% of patients exhibit central nervous system (CNS) involvement, but diagnosis is often delayed due to the lack of distinctive features. We aimed to identify key phenotypic features for early diagnosis of intravascular lymphoma with CNS involvement through an in-depth cohort study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We built up a multicenter retrospective cohort of 17 patients recruited in collaboration with the French Expert Network for Oculo-Cerebral Lymphomas (LOC network), and retrospectively analyzed data from medical records.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In this cohort, 15 of 17 (88%) patients developed focal neurological episodes, often fluctuating and/or recurrent, with a sudden onset in 68% of episodes, suggesting a vascular origin. Rapid cognitive deterioration occurred in 15 of 17 (88%) patients, psychiatric manifestations in 8 of 17 (47%), and “B signs” in 14 of 17 (82%). Brain MRI showed polymorphic FLAIR hyperintensities in 14 of 16 (87%) patients, and DWI-positive lesions in 13 of 16 (81%) of patients, which accumulated over time and had unusual characteristics for ischemic lesions (progressive growth, persistent DWI-hyperintensity over 1 month, surrounded by a wider FLAIR hyperintensity). Early-onset inflammatory syndrome, and elevated lactate dehydrogenase (LDH) levels were observed in over 90% of cases. Mild and inconsistent meningitis contrasted with a nearly-constant hyperproteinorachia. An increased interleukin 10/6 ratio over 0,7 was found in 4 of 7 (57%) patients, and skin biopsy led to a pathological diagnosis in 3 of 6 (50%) patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The results of this study highlight “red flags” that could help accelerate the diagnosis of intravascular lymphoma involving the CNS. ANN NEUROL 2025;97:435–448</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"435-448"},"PeriodicalIF":8.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wallace J. Brownlee MD, PhD, Angela Vidal-Jordana MD, PhD, Madiha Shatila MD, Eva Strijbis MD, PhD, Lisa Schoof MD, PhD, Joep Killestein MD, PhD, Frederik Barkhof MD, PhD, Luca Bollo MD, Alex Rovira MD, Jaume Sastre-Garriga MD, PhD, Mar Tintore MD, PhD, Maria A. Rocca MD, Federica Esposito MD, PhD, Matteo Azzimonti MD, Massimo Filippi MD, Benedetta Bodini MD, PhD, Andrea Lazzarotto MD, PhD, Bruno Stankoff MD, PhD, Xavier Montalban MD, PhD, Ahmed T. Toosy MD, PhD, Alan J. Thompson MD, Olga Ciccarelli MD, PhD, for the MAGNIMS Study Group
Objective
The 2017 McDonald criteria continued the separation of diagnostic criteria for relapsing–remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS) for historical, rather than biological, reasons. We aimed to explore the feasibility of a single, unified set of diagnostic criteria when applied to patients with suspected PPMS.
Methods
We retrospectively identified patients evaluated for suspected PPMS at 5 European centers. The 2017 McDonald PPMS criteria was the gold standard against which the 2017 McDonald RRMS dissemination in space (DIS) and dissemination in time criteria were evaluated. We also investigated modified RRMS DIS criteria, including: (i) optic nerve lesions; (ii) ≥2 spinal cord lesions; and (iii) higher fulfilment of DIS criteria alone (lesions in ≥3 regions) without dissemination in time/positive cerebrospinal fluid, for a diagnosis of PPMS.
Results
A total of 282 patients were diagnosed with PPMS using the 2017 McDonald criteria, and 40 with alternate disorders. The 2017 McDonald RRMS DIS criteria and the modified DIS criteria including the optic nerve or ≥2 spinal cord lesions performed well in PPMS diagnosis when combined with dissemination in time/positive cerebrospinal fluid (sensitivity 92.9–95.4%, specificity 95%, accuracy 93.2–95.3%). A diagnosis of PPMS based on high fulfillment of modified RRMS DIS criteria had high specificity, but low sensitivity. A diagnostic algorithm applicable to patients evaluated for suspected MS is proposed.
Interpretation
The 2017 McDonald RRMS criteria and modifications to DIS criteria, currently under consideration, performed well in PPMS diagnosis. Forthcoming revisions to the McDonald criteria should consider a single, unified set of diagnostic criteria for MS. ANN NEUROL 2025;97:571–582
{"title":"Towards a Unified Set of Diagnostic Criteria for Multiple Sclerosis","authors":"Wallace J. Brownlee MD, PhD, Angela Vidal-Jordana MD, PhD, Madiha Shatila MD, Eva Strijbis MD, PhD, Lisa Schoof MD, PhD, Joep Killestein MD, PhD, Frederik Barkhof MD, PhD, Luca Bollo MD, Alex Rovira MD, Jaume Sastre-Garriga MD, PhD, Mar Tintore MD, PhD, Maria A. Rocca MD, Federica Esposito MD, PhD, Matteo Azzimonti MD, Massimo Filippi MD, Benedetta Bodini MD, PhD, Andrea Lazzarotto MD, PhD, Bruno Stankoff MD, PhD, Xavier Montalban MD, PhD, Ahmed T. Toosy MD, PhD, Alan J. Thompson MD, Olga Ciccarelli MD, PhD, for the MAGNIMS Study Group","doi":"10.1002/ana.27145","DOIUrl":"10.1002/ana.27145","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The 2017 McDonald criteria continued the separation of diagnostic criteria for relapsing–remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS) for historical, rather than biological, reasons. We aimed to explore the feasibility of a single, unified set of diagnostic criteria when applied to patients with suspected PPMS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively identified patients evaluated for suspected PPMS at 5 European centers. The 2017 McDonald PPMS criteria was the gold standard against which the 2017 McDonald RRMS dissemination in space (DIS) and dissemination in time criteria were evaluated. We also investigated modified RRMS DIS criteria, including: (i) optic nerve lesions; (ii) ≥2 spinal cord lesions; and (iii) higher fulfilment of DIS criteria alone (lesions in ≥3 regions) without dissemination in time/positive cerebrospinal fluid, for a diagnosis of PPMS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 282 patients were diagnosed with PPMS using the 2017 McDonald criteria, and 40 with alternate disorders. The 2017 McDonald RRMS DIS criteria and the modified DIS criteria including the optic nerve or ≥2 spinal cord lesions performed well in PPMS diagnosis when combined with dissemination in time/positive cerebrospinal fluid (sensitivity 92.9–95.4%, specificity 95%, accuracy 93.2–95.3%). A diagnosis of PPMS based on high fulfillment of modified RRMS DIS criteria had high specificity, but low sensitivity. A diagnostic algorithm applicable to patients evaluated for suspected MS is proposed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The 2017 McDonald RRMS criteria and modifications to DIS criteria, currently under consideration, performed well in PPMS diagnosis. Forthcoming revisions to the McDonald criteria should consider a single, unified set of diagnostic criteria for MS. ANN NEUROL 2025;97:571–582</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"571-582"},"PeriodicalIF":8.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marta Caballero-Ávila, Lorena Martín-Aguilar, Elba Pascual-Goñi, Milou R. Michael, Marleen J.A. Koel-Simmelink, Romana Höftberger, Julia Wanschitz, Alicia Alonso-Jiménez, Thais Armangué, Adája Elisabeth Baars, Álvaro Carbayo, Barbara Castek, Roger Collet-Vidiella, Jonathan De Winter, Maria Ángeles del Real, Emilien Delmont, Luca Diamanti, Pietro Emiliano Doneddu, Fu Liong Hiew, Eduard Gallardo, Amaia Gonzalez, Susanne Grinzinger, Alejandro Horga, Stephan Iglseder, Bart C. Jacobs, Amaia Jauregui, Joep Killestein, Elisabeth Lindeck Pozza, Laura Martínez-Martínez, Eduardo Nobile-Orazio, Nicolau Ortiz, Helena Pérez-Pérez, Kai-Nicolas Poppert, Paolo Ripellino, Jose Carlos Roche, Franscisco Javier Rodriguez de Rivera, Kevin Rostasy, Davide Sparasci, Clara Tejada-Illa, Charlotte C.E. Teunissen, Elisa Vegezzi, Tomàs Xuclà-Ferrarons, Fabian Zach, Luuk Wieske, Filip Eftimov, Cinta Lleixà, Luis Querol
Objective
To analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN).
Methods
Patients with anti-CNTN1+ autoimmune nodopathy detected in our laboratory from which clinical information was available were included. Clinical features and treatment response were retrospectively collected. Autoantibody, serum neurofilament light chain (sNfL), and serum CNTN1 levels (sCNTN1) were analyzed at baseline and follow up.
Results
A total of 31 patients were included. Patients presented with progressive sensory motor neuropathy (76.7%) with proximal (74.2%) and distal involvement (87.1%), ataxia (71.4%), and severe disability (median INCAT at nadir of 8). A total of 11 patients (35%) showed kidney involvement. Most patients (97%) received intravenous immunoglobulin, but only 1 achieved remission with intravenous immunoglobulin. A total of 22 patients (71%) received corticosteroids, and 3 of them (14%) did not need further treatments. Rituximab was effective in 21 of 22 patients (95.5%), with most of them (72%) receiving a single course. Four patients (12.9%) relapsed after a median follow up of 25 months after effective treatment (12–48 months). Anti-CNTN1 titers correlated with clinical scales at sampling and were negative after treatment in all patients, but 1 (20/21). sNfL levels were significantly higher and sCNTN1 significantly lower in anti-CNTN1+ patients than in healthy controls (sNfL: 135.9 pg/ml vs 7.48 pg/ml, sCNTN1: 25.03 pg/ml vs 22,186 pg/ml, p < 0.0001). Both sNfL and sCNTN1 returned to normal levels after successful treatment.
Interpretation
Patients with anti-CNTN1+ autoimmune nodopathy have a characteristic clinical profile. Clinical and immunological relapses are infrequent after successful treatment, suggesting that continuous treatment is unnecessary. Anti-CNTN1 antibodies, sNfL, and sCNTN1 levels are useful to monitor disease status in these patients. ANN NEUROL 2025;97:529–541
{"title":"Long-Term Follow Up in Anti-Contactin-1 Autoimmune Nodopathy","authors":"Marta Caballero-Ávila, Lorena Martín-Aguilar, Elba Pascual-Goñi, Milou R. Michael, Marleen J.A. Koel-Simmelink, Romana Höftberger, Julia Wanschitz, Alicia Alonso-Jiménez, Thais Armangué, Adája Elisabeth Baars, Álvaro Carbayo, Barbara Castek, Roger Collet-Vidiella, Jonathan De Winter, Maria Ángeles del Real, Emilien Delmont, Luca Diamanti, Pietro Emiliano Doneddu, Fu Liong Hiew, Eduard Gallardo, Amaia Gonzalez, Susanne Grinzinger, Alejandro Horga, Stephan Iglseder, Bart C. Jacobs, Amaia Jauregui, Joep Killestein, Elisabeth Lindeck Pozza, Laura Martínez-Martínez, Eduardo Nobile-Orazio, Nicolau Ortiz, Helena Pérez-Pérez, Kai-Nicolas Poppert, Paolo Ripellino, Jose Carlos Roche, Franscisco Javier Rodriguez de Rivera, Kevin Rostasy, Davide Sparasci, Clara Tejada-Illa, Charlotte C.E. Teunissen, Elisa Vegezzi, Tomàs Xuclà-Ferrarons, Fabian Zach, Luuk Wieske, Filip Eftimov, Cinta Lleixà, Luis Querol","doi":"10.1002/ana.27142","DOIUrl":"10.1002/ana.27142","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with anti-CNTN1<sup>+</sup> autoimmune nodopathy detected in our laboratory from which clinical information was available were included. Clinical features and treatment response were retrospectively collected. Autoantibody, serum neurofilament light chain (sNfL), and serum CNTN1 levels (sCNTN1) were analyzed at baseline and follow up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 31 patients were included. Patients presented with progressive sensory motor neuropathy (76.7%) with proximal (74.2%) and distal involvement (87.1%), ataxia (71.4%), and severe disability (median INCAT at nadir of 8). A total of 11 patients (35%) showed kidney involvement. Most patients (97%) received intravenous immunoglobulin, but only 1 achieved remission with intravenous immunoglobulin. A total of 22 patients (71%) received corticosteroids, and 3 of them (14%) did not need further treatments. Rituximab was effective in 21 of 22 patients (95.5%), with most of them (72%) receiving a single course. Four patients (12.9%) relapsed after a median follow up of 25 months after effective treatment (12–48 months). Anti-CNTN1 titers correlated with clinical scales at sampling and were negative after treatment in all patients, but 1 (20/21). sNfL levels were significantly higher and sCNTN1 significantly lower in anti-CNTN1<sup>+</sup> patients than in healthy controls (sNfL: 135.9 pg/ml vs 7.48 pg/ml, sCNTN1: 25.03 pg/ml vs 22,186 pg/ml, <i>p</i> < 0.0001). Both sNfL and sCNTN1 returned to normal levels after successful treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Patients with anti-CNTN1<sup>+</sup> autoimmune nodopathy have a characteristic clinical profile. Clinical and immunological relapses are infrequent after successful treatment, suggesting that continuous treatment is unnecessary. Anti-CNTN1 antibodies, sNfL, and sCNTN1 levels are useful to monitor disease status in these patients. ANN NEUROL 2025;97:529–541</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"529-541"},"PeriodicalIF":8.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724339","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}
Maria Protopapa, Falk Steffen, Muriel Schraad, Tobias Ruck, Menekse Öztürk, Nicholas Hanuscheck, Josef Shin, Tobias Brummer, Katrin Pape, Timo Uphaus, Sven G. Meuth, Vinzenz Fleischer, Charlotte E. Teunissen, Philip L. De Jager, Felix Luessi, Stefan Bittner, Frauke Zipp
Objective
We examined the impact of the rs10191329 genetic risk variant on neuroaxonal damage as measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with multiple sclerosis (pwMS).
Methods
In a cohort of pwMS (n = 740), 658 participants were prospectively monitored every 2 years for less than a decade while 82 of 740 pwMS were monitored retrospectively for up to 40 years. We investigated associations between rs10191329 variants and clinical outcome, including Expanded Disability Status Scale (EDSS), disability accrual (defined by EDSS-increase of at least 1.5 for patients starting at EDSS 0, at least 1.0 EDSS-points for patients with an initial EDSS between 1 and 4.5 and at least 0.5 points for patients starting with an EDSS equal or greater than 5) and progression to secondary progressive MS (SPMS). Clinical outcomes were analyzed using Kaplan–Meier and Cox proportional hazards analyses. Disability accumulation over time was depicted using a generalized mixed-effect model. Single-molecule array was used to assess sNfL levels.
Results
Homozygous, heterozygous, and non-carriers of the rs10191329 risk variant displayed comparable sNfL levels indicating similar neuroaxonal damage at the time of diagnosis. Importantly, in homozygous carriers we found highest sNfL levels in follow-up visits preceding elevated disease progression later in the disease course, a steeper increase in overall disability measures and higher probability of SPMS development.
Interpretation
These findings highlight how genetic variants may serve as new biomarkers for disease progression and can be used for personalized medicine and risk assessment in MS. ANN NEUROL 2025;97:596–605
{"title":"Increased Disability Progression in rs10191329AA Carriers with Multiple Sclerosis Is Preceded by Neurofilament Light Chain Elevations","authors":"Maria Protopapa, Falk Steffen, Muriel Schraad, Tobias Ruck, Menekse Öztürk, Nicholas Hanuscheck, Josef Shin, Tobias Brummer, Katrin Pape, Timo Uphaus, Sven G. Meuth, Vinzenz Fleischer, Charlotte E. Teunissen, Philip L. De Jager, Felix Luessi, Stefan Bittner, Frauke Zipp","doi":"10.1002/ana.27144","DOIUrl":"10.1002/ana.27144","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We examined the impact of the rs10191329 genetic risk variant on neuroaxonal damage as measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with multiple sclerosis (pwMS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a cohort of pwMS (n = 740), 658 participants were prospectively monitored every 2 years for less than a decade while 82 of 740 pwMS were monitored retrospectively for up to 40 years. We investigated associations between rs10191329 variants and clinical outcome, including Expanded Disability Status Scale (EDSS), disability accrual (defined by EDSS-increase of at least 1.5 for patients starting at EDSS 0, at least 1.0 EDSS-points for patients with an initial EDSS between 1 and 4.5 and at least 0.5 points for patients starting with an EDSS equal or greater than 5) and progression to secondary progressive MS (SPMS). Clinical outcomes were analyzed using Kaplan–Meier and Cox proportional hazards analyses. Disability accumulation over time was depicted using a generalized mixed-effect model. Single-molecule array was used to assess sNfL levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Homozygous, heterozygous, and non-carriers of the rs10191329 risk variant displayed comparable sNfL levels indicating similar neuroaxonal damage at the time of diagnosis. Importantly, in homozygous carriers we found highest sNfL levels in follow-up visits preceding elevated disease progression later in the disease course, a steeper increase in overall disability measures and higher probability of SPMS development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings highlight how genetic variants may serve as new biomarkers for disease progression and can be used for personalized medicine and risk assessment in MS. ANN NEUROL 2025;97:596–605</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"596-605"},"PeriodicalIF":8.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sven G. Meuth MD, PhD, Stephanie Wolff MD, Anna Mück MD, Alice Willison MD, Konstanze Kleinschnitz PhD, Saskia Räuber MD, Marc Pawlitzki MD, Franz Felix Konen MD, Thomas Skripuletz MD, Matthias Grothe MD, Tobias Ruck MD, Hagen B. Huttner MD, PhD, Christoph Kleinschnitz MD, Tobias Bopp PhD, Refik Pul MD, Bruce A. C. Cree MD, Hans-Peter Hartung MD, Kathrin Möllenhoff PhD, Steffen Pfeuffer MD
Objective
B-cell–depletion via CD20 antibodies is a safe and effective treatment for active relapsing multiple sclerosis (RMS). Both ocrelizumab (OCR) and ofatumumab (OFA) have demonstrated efficacy in randomized controlled trials and are approved for treatment of RMS, yet nothing is known on their comparative effectiveness, especially in the real-world setting.
Methods
This prospective cohort study includes patients that were started on either OCR or OFA between September 2021 and December 2023. Patients were followed until June 2024 and recruited at 3 large tertiary centers in Germany (Duesseldorf, Essen, and Giessen). Propensity-score-matching was used to address baseline imbalances among patients. Clinical relapses, presence of new or enlarging MRI lesions and 6-month confirmed disability worsening were evaluated. Non-inferiority of OFA compared to OCR was evaluated through comparison of Kaplan–Meier-estimates.
Results
A total of 1,138 patients were initially enrolled in the cohort. Following patient selection and propensity-score-matching, 544 OCR and 417 OFA patients were included in the final analysis. In our primary analysis, OFA was non-inferior to OCR in terms of relapses, disability progression, and accrual of MRI lesions. Subgroup analyses confirmed findings in previously naïve and platform-treated patients. Potential differences between OFA and OCR were seen in patients switching from S1P receptor modulators or natalizumab.
Conclusion
We here provide comparative data on the effectiveness of OCR and OFA in patients with active RMS. OFA was non-inferior to OCR in the overall cohort. Potential differences observed in patients switching from S1P receptor modulators or natalizumab require further validation. ANN NEUROL 2025;97:583–595
{"title":"Different Treatment Outcomes of Multiple Sclerosis Patients Receiving Ocrelizumab or Ofatumumab","authors":"Sven G. Meuth MD, PhD, Stephanie Wolff MD, Anna Mück MD, Alice Willison MD, Konstanze Kleinschnitz PhD, Saskia Räuber MD, Marc Pawlitzki MD, Franz Felix Konen MD, Thomas Skripuletz MD, Matthias Grothe MD, Tobias Ruck MD, Hagen B. Huttner MD, PhD, Christoph Kleinschnitz MD, Tobias Bopp PhD, Refik Pul MD, Bruce A. C. Cree MD, Hans-Peter Hartung MD, Kathrin Möllenhoff PhD, Steffen Pfeuffer MD","doi":"10.1002/ana.27143","DOIUrl":"10.1002/ana.27143","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>B-cell–depletion via CD20 antibodies is a safe and effective treatment for active relapsing multiple sclerosis (RMS). Both ocrelizumab (OCR) and ofatumumab (OFA) have demonstrated efficacy in randomized controlled trials and are approved for treatment of RMS, yet nothing is known on their comparative effectiveness, especially in the real-world setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This prospective cohort study includes patients that were started on either OCR or OFA between September 2021 and December 2023. Patients were followed until June 2024 and recruited at 3 large tertiary centers in Germany (Duesseldorf, Essen, and Giessen). Propensity-score-matching was used to address baseline imbalances among patients. Clinical relapses, presence of new or enlarging MRI lesions and 6-month confirmed disability worsening were evaluated. Non-inferiority of OFA compared to OCR was evaluated through comparison of Kaplan–Meier-estimates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 1,138 patients were initially enrolled in the cohort. Following patient selection and propensity-score-matching, 544 OCR and 417 OFA patients were included in the final analysis. In our primary analysis, OFA was non-inferior to OCR in terms of relapses, disability progression, and accrual of MRI lesions. Subgroup analyses confirmed findings in previously naïve and platform-treated patients. Potential differences between OFA and OCR were seen in patients switching from S1P receptor modulators or natalizumab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We here provide comparative data on the effectiveness of OCR and OFA in patients with active RMS. OFA was non-inferior to OCR in the overall cohort. Potential differences observed in patients switching from S1P receptor modulators or natalizumab require further validation. ANN NEUROL 2025;97:583–595</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"583-595"},"PeriodicalIF":8.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natasha A. Choudhury MD, Shreya Mukherjee BA, Tracey Singer BS, Aditi Venkatesh BS, Gina S. Perez Giraldo MD, Millenia Jimenez BS, Janet Miller BS, Melissa Lopez MPH, Barbara A. Hanson PhD, Aasheeta P. Bawa PA-C, Ayush Batra MD, Eric M. Liotta MD, Igor J. Koralnik MD
<div> <section> <h3> Objective</h3> <p>To investigate neurologic manifestations of post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC) in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients across the adult lifespan.</p> </section> <section> <h3> Methods</h3> <p>Cross-sectional study of the first consecutive 200 PNP and 1,100 NNP patients evaluated at a Neuro-coronavirus disease 2019 (COVID-19) clinic between May 2020 and March 2023. Patients were divided into younger (18–44 years), middle-age (45–64 years), and older (65+ years) age groups.</p> </section> <section> <h3> Results</h3> <p>Younger and middle-age individuals accounted for 142 of 200 (71%) of PNP and 995 of 1100 (90.5%) of NNP patients. Significant age-related differences in the frequencies of comorbidities and abnormal neurologic findings demonstrated higher prevalence in older patients. Conversely, 10 months from COVID-19 onset, we found significant age-related differences in Neuro-PASC symptoms indicating lower prevalence, and therefore, symptom burden, in older individuals. Moreover, there were significant age-related differences in subjective impression of fatigue (median [interquartile range (IQR)] patient-reported outcomes measurement information system [PROMIS] score: younger 64 [57–69], middle-age 63 [57–68], older 60.5 [50.8–68.3]; <i>p</i> = 0.04) and sleep disturbance (median [IQR] PROMIS score: younger 57 [51–63], middle-age 56 [53–63], older 54 [46.8–58]; <i>p</i> = 0.002) in the NNP group, commensurate with higher impairment in quality of life (QoL) among younger patients. Finally, there were significant age-related differences in objective executive function (median [IQR] National Institutes of Health [NIH] toolbox score: younger 48 [35–63], middle-age 49 [38–63], older 54.5 [45–66.3]; <i>p</i> = 0.01), and working memory (median [IQR] NIH toolbox score: younger 47 [40–53], middle-age 50 [44–57], older 48 [43–58]; <i>p</i> = 0.0002) in NNP patients, with the worst performance coming from the younger group.</p> </section> <section> <h3> Interpretation</h3> <p>Younger and middle-age individuals are disproportionally affected by Neuro-PASC regardless of acute COVID-19 severity. Although older people more frequently have abnormal neurologic findings and comorbidities, younger and middle-age patients suffer from a higher burden of Neuro-PASC symptoms and cognitive dysfunction contributing to decreased QoL. Neuro-PASC principally affects adults in their prime, contributing to profound public health and socioeconomic impacts warranting dedicated resourc
{"title":"Neurologic Manifestations of Long COVID Disproportionately Affect Young and Middle-Age Adults","authors":"Natasha A. Choudhury MD, Shreya Mukherjee BA, Tracey Singer BS, Aditi Venkatesh BS, Gina S. Perez Giraldo MD, Millenia Jimenez BS, Janet Miller BS, Melissa Lopez MPH, Barbara A. Hanson PhD, Aasheeta P. Bawa PA-C, Ayush Batra MD, Eric M. Liotta MD, Igor J. Koralnik MD","doi":"10.1002/ana.27128","DOIUrl":"10.1002/ana.27128","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate neurologic manifestations of post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC) in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients across the adult lifespan.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cross-sectional study of the first consecutive 200 PNP and 1,100 NNP patients evaluated at a Neuro-coronavirus disease 2019 (COVID-19) clinic between May 2020 and March 2023. Patients were divided into younger (18–44 years), middle-age (45–64 years), and older (65+ years) age groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Younger and middle-age individuals accounted for 142 of 200 (71%) of PNP and 995 of 1100 (90.5%) of NNP patients. Significant age-related differences in the frequencies of comorbidities and abnormal neurologic findings demonstrated higher prevalence in older patients. Conversely, 10 months from COVID-19 onset, we found significant age-related differences in Neuro-PASC symptoms indicating lower prevalence, and therefore, symptom burden, in older individuals. Moreover, there were significant age-related differences in subjective impression of fatigue (median [interquartile range (IQR)] patient-reported outcomes measurement information system [PROMIS] score: younger 64 [57–69], middle-age 63 [57–68], older 60.5 [50.8–68.3]; <i>p</i> = 0.04) and sleep disturbance (median [IQR] PROMIS score: younger 57 [51–63], middle-age 56 [53–63], older 54 [46.8–58]; <i>p</i> = 0.002) in the NNP group, commensurate with higher impairment in quality of life (QoL) among younger patients. Finally, there were significant age-related differences in objective executive function (median [IQR] National Institutes of Health [NIH] toolbox score: younger 48 [35–63], middle-age 49 [38–63], older 54.5 [45–66.3]; <i>p</i> = 0.01), and working memory (median [IQR] NIH toolbox score: younger 47 [40–53], middle-age 50 [44–57], older 48 [43–58]; <i>p</i> = 0.0002) in NNP patients, with the worst performance coming from the younger group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Younger and middle-age individuals are disproportionally affected by Neuro-PASC regardless of acute COVID-19 severity. Although older people more frequently have abnormal neurologic findings and comorbidities, younger and middle-age patients suffer from a higher burden of Neuro-PASC symptoms and cognitive dysfunction contributing to decreased QoL. Neuro-PASC principally affects adults in their prime, contributing to profound public health and socioeconomic impacts warranting dedicated resourc","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"369-383"},"PeriodicalIF":8.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Banglian Hu BMed, Yuhang Zhou MS, Chujun Wu MD PhD, Naian Xiao MD PhD, Jianpeng Li MD PhD, Xin Li MS, Yanfang Li PhD, Xian Zhang PhD, Xiaohua Huang MS, Yabin Song MD, Zhanxiang Wang MD, PhD, Yun-Wu Zhang PhD, Zaiqiang Zhang MD, PhD, Honghua Zheng MD, PhD
Mutations in colony stimulating factor 1 receptor (CSF1R) result in CSF1R-related disorder (CSF1R-RD). Our previous study demonstrated a proteolytic generation of a soluble CSF1R (sCSF1R) that could potentially serve as a diagnostic biomarker of CSF1R-RD. Herein, we observed that sCSF1R is released into peripheral serum as a highly glycosylated monomer in Csf1r+/− mice that mimic the clinical symptoms of CSF1R-RD patients. Notably, we found that serum sCSF1R could distinguish CSF1R-RD cohorts from controls with high accuracy as evaluated by receiver operating characteristic (ROC) curves. This study demonstrates that reduced sCSF1R in serum may serve as a diagnostic biomarker for CSF1R-RD. ANN NEUROL 2025;97:397–403
{"title":"Evaluation of Soluble Colony Stimulating Factor 1 Receptor (CSF1R) in Peripheral Blood as a Diagnostic Marker of CSF1R-Related Disorder (CSF1R-RD) in a Murine Model and CSF1R-RD Patients","authors":"Banglian Hu BMed, Yuhang Zhou MS, Chujun Wu MD PhD, Naian Xiao MD PhD, Jianpeng Li MD PhD, Xin Li MS, Yanfang Li PhD, Xian Zhang PhD, Xiaohua Huang MS, Yabin Song MD, Zhanxiang Wang MD, PhD, Yun-Wu Zhang PhD, Zaiqiang Zhang MD, PhD, Honghua Zheng MD, PhD","doi":"10.1002/ana.27147","DOIUrl":"10.1002/ana.27147","url":null,"abstract":"<p>Mutations in colony stimulating factor 1 receptor (CSF1R) result in CSF1R-related disorder (CSF1R-RD). Our previous study demonstrated a proteolytic generation of a soluble CSF1R (sCSF1R) that could potentially serve as a diagnostic biomarker of CSF1R-RD. Herein, we observed that sCSF1R is released into peripheral serum as a highly glycosylated monomer in <i>Csf1r</i><sup>+/−</sup> mice that mimic the clinical symptoms of CSF1R-RD patients. Notably, we found that serum sCSF1R could distinguish CSF1R-RD cohorts from controls with high accuracy as evaluated by receiver operating characteristic (ROC) curves. This study demonstrates that reduced sCSF1R in serum may serve as a diagnostic biomarker for CSF1R-RD. ANN NEUROL 2025;97:397–403</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"397-403"},"PeriodicalIF":8.1,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680248","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}
Kristina Simonyan MD, PhD, DrMed, Lena C. O'Flynn BA, Azadeh Hamzehei Sichani MA, Steven J. Frucht MD, Anna F. Rumbach PhD, Nutan Sharma MD, PhD, Phillip C. Song MD, Alexis Worthley BA
Objective
To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD).
Methods
The study was conducted from January 2018 to December 2021, pausing during the COVID-19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH−) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures.
Results
Compared to baseline, EtOH+ but not EtOH− patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6–26.9; p = 0.008; EtOH−: 98.75% CI = −6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75–5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7–48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness.
Interpretation
Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2025;97:329–343
{"title":"Efficacy and Safety of Sodium Oxybate in Isolated Focal Laryngeal Dystonia: A Phase IIb Double-Blind Placebo-Controlled Cross-Over Randomized Clinical Trial","authors":"Kristina Simonyan MD, PhD, DrMed, Lena C. O'Flynn BA, Azadeh Hamzehei Sichani MA, Steven J. Frucht MD, Anna F. Rumbach PhD, Nutan Sharma MD, PhD, Phillip C. Song MD, Alexis Worthley BA","doi":"10.1002/ana.27121","DOIUrl":"10.1002/ana.27121","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study was conducted from January 2018 to December 2021, pausing during the COVID-19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH−) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to baseline, EtOH+ but not EtOH− patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6–26.9; <i>p</i> = 0.008; EtOH−: 98.75% CI = −6.2 to 18.7; <i>p</i> = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75–5.80; <i>p</i> = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7–48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2025;97:329–343</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"329-343"},"PeriodicalIF":8.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel M. Pastula MD, MHS, J. David Beckham MD, Kenneth L. Tyler MD
Oropouche virus (OROV) is an arthropod-borne virus (arbovirus) in the Orthobunyavirus genus and Peribunyaviridae viral family that is endemic to parts of South America, Central America, and the Caribbean. It has recently emerged in Cuba, and travel-imported cases are recently being reported in the United States and Europe. Typically maintained in a sylvatic cycle between certain forest sloths, non-human primates, birds, and mosquitoes, OROV disease outbreaks can occur in an urban cycle between certain biting midges and/or mosquitoes and humans. Clinically, approximately 60% of infections are symptomatic with an abrupt fever and non-specific influenza-like illness within 3 to 10 days. Many initial OROV infections can present similarly to chikungunya, dengue, and Zika virus infections. Interestingly, OROV infections can follow a biphasic course with recurrence of symptoms approximately 1 week after initial symptom onset. Concerningly, similar to Zika virus, it appears that vertical transmission of OROV may occur with potentially adverse effects on fetal development including miscarriages. Neuroinvasion of OROV occurs in animal models, and human cases of meningitis, encephalitis, and peri-infectious Guillain-Barré syndrome have all been reported. Diagnosis is either through detection of OROV nucleic acid, OROV immunoglobulin M, or OROV neutralizing antibodies in the serum and/or cerebrospinal fluid. No antiviral treatments are available, and there are no current vaccines. Preventing mosquito and biting midge bites is key. Neurologists should be aware of and report any potential neuroinvasive OROV disease cases to local/state/territorial health departments. ANN NEUROL 2025;97:28–33
{"title":"Oropouche Virus: An Emerging Neuroinvasive Arbovirus","authors":"Daniel M. Pastula MD, MHS, J. David Beckham MD, Kenneth L. Tyler MD","doi":"10.1002/ana.27139","DOIUrl":"10.1002/ana.27139","url":null,"abstract":"<p>Oropouche virus (OROV) is an arthropod-borne virus (arbovirus) in the <i>Orthobunyavirus</i> genus and <i>Peribunyaviridae</i> viral family that is endemic to parts of South America, Central America, and the Caribbean. It has recently emerged in Cuba, and travel-imported cases are recently being reported in the United States and Europe. Typically maintained in a sylvatic cycle between certain forest sloths, non-human primates, birds, and mosquitoes, OROV disease outbreaks can occur in an urban cycle between certain biting midges and/or mosquitoes and humans. Clinically, approximately 60% of infections are symptomatic with an abrupt fever and non-specific influenza-like illness within 3 to 10 days. Many initial OROV infections can present similarly to chikungunya, dengue, and Zika virus infections. Interestingly, OROV infections can follow a biphasic course with recurrence of symptoms approximately 1 week after initial symptom onset. Concerningly, similar to Zika virus, it appears that vertical transmission of OROV may occur with potentially adverse effects on fetal development including miscarriages. Neuroinvasion of OROV occurs in animal models, and human cases of meningitis, encephalitis, and peri-infectious Guillain-Barré syndrome have all been reported. Diagnosis is either through detection of OROV nucleic acid, OROV immunoglobulin M, or OROV neutralizing antibodies in the serum and/or cerebrospinal fluid. No antiviral treatments are available, and there are no current vaccines. Preventing mosquito and biting midge bites is key. Neurologists should be aware of and report any potential neuroinvasive OROV disease cases to local/state/territorial health departments. ANN NEUROL 2025;97:28–33</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 1","pages":"28-33"},"PeriodicalIF":8.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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