Annals of Neurology最新文献

{"title":"Towards a Unified Set of Diagnostic Criteria for Multiple Sclerosis.","authors":"Wallace J Brownlee, Angela Vidal-Jordana, Madiha Shatila, Eva Strijbis, Lisa Schoof, Joep Killestein, Frederik Barkhof, Luca Bollo, Alex Rovira, Jaume Sastre-Garriga, Mar Tintore, Maria A Rocca, Federica Esposito, Matteo Azzimonti, Massimo Filippi, Benedetta Bodini, Andrea Lazzarotto, Bruno Stankoff, Xavier Montalban, Ahmed T Toosy, Alan J Thompson, Olga Ciccarelli","doi":"10.1002/ana.27145","DOIUrl":"https://doi.org/10.1002/ana.27145","url":null,"abstract":"<p><strong>Objective: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Interpretation: </strong>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 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/10.1002/ana.27142","url":null,"abstract":"<p><strong>Objective: </strong>To analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Interpretation: </strong>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 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"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}

{"title":"Increased Disability Progression in rs10191329^AA 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":"https://doi.org/10.1002/ana.27144","url":null,"abstract":"<p><strong>Objective: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Interpretation: </strong>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 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different Treatment Outcomes of Multiple Sclerosis Patients Receiving Ocrelizumab or Ofatumumab.","authors":"Sven G Meuth, Stephanie Wolff, Anna Mück, Alice Willison, Konstanze Kleinschnitz, Saskia Räuber, Marc Pawlitzki, Franz Felix Konen, Thomas Skripuletz, Matthias Grothe, Tobias Ruck, Hagen B Huttner, Christoph Kleinschnitz, Tobias Bopp, Refik Pul, Bruce A C Cree, Hans-Peter Hartung, Kathrin Möllenhoff, Steffen Pfeuffer","doi":"10.1002/ana.27143","DOIUrl":"https://doi.org/10.1002/ana.27143","url":null,"abstract":"<p><strong>Objective: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Conclusion: </strong>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 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurologic Manifestations of Long COVID Disproportionately Affect Young and Middle-Age Adults","authors":"Natasha A. Choudhury MD,&nbsp;Shreya Mukherjee BA,&nbsp;Tracey Singer BS,&nbsp;Aditi Venkatesh BS,&nbsp;Gina S. Perez Giraldo MD,&nbsp;Millenia Jimenez BS,&nbsp;Janet Miller BS,&nbsp;Melissa Lopez MPH,&nbsp;Barbara A. Hanson PhD,&nbsp;Aasheeta P. Bawa PA-C,&nbsp;Ayush Batra MD,&nbsp;Eric M. Liotta MD,&nbsp;Igor J. Koralnik MD","doi":"10.1002/ana.27128","DOIUrl":"10.1002/ana.27128","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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]; &lt;i&gt;p&lt;/i&gt; = 0.04) and sleep disturbance (median [IQR] PROMIS score: younger 57 [51–63], middle-age 56 [53–63], older 54 [46.8–58]; &lt;i&gt;p&lt;/i&gt; = 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]; &lt;i&gt;p&lt;/i&gt; = 0.01), and working memory (median [IQR] NIH toolbox score: younger 47 [40–53], middle-age 50 [44–57], older 48 [43–58]; &lt;i&gt;p&lt;/i&gt; = 0.0002) in NNP patients, with the worst performance coming from the younger group.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Interpretation&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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}

{"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,&nbsp;Yuhang Zhou MS,&nbsp;Chujun Wu MD PhD,&nbsp;Naian Xiao MD PhD,&nbsp;Jianpeng Li MD PhD,&nbsp;Xin Li MS,&nbsp;Yanfang Li PhD,&nbsp;Xian Zhang PhD,&nbsp;Xiaohua Huang MS,&nbsp;Yabin Song MD,&nbsp;Zhanxiang Wang MD, PhD,&nbsp;Yun-Wu Zhang PhD,&nbsp;Zaiqiang Zhang MD, PhD,&nbsp;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>^+/− 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}

{"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,&nbsp;Lena C. O'Flynn BA,&nbsp;Azadeh Hamzehei Sichani MA,&nbsp;Steven J. Frucht MD,&nbsp;Anna F. Rumbach PhD,&nbsp;Nutan Sharma MD, PhD,&nbsp;Phillip C. Song MD,&nbsp;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}

{"title":"Oropouche Virus: An Emerging Neuroinvasive Arbovirus","authors":"Daniel M. Pastula MD, MHS,&nbsp;J. David Beckham MD,&nbsp;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}

{"title":"Cerebrovascular Function in Sporadic and Genetic Cerebral Small Vessel Disease.","authors":"Michael S Stringer, Gordon W Blair, Anna Kopczak, Danielle Kerkhofs, Michael J Thrippleton, Francesca M Chappell, Susana Muñoz Maniega, Rosalind Brown, Kirsten Shuler, Iona Hamilton, Daniela Jaime Garcia, Fergus N Doubal, Una Clancy, Eleni Sakka, Tetiana Poliakova, Esther Janssen, Marco Duering, Michael Ingrisch, Julie Staals, Walter H Backes, Robert van Oostenbrugge, Geert Jan Biessels, Martin Dichgans, Joanna M Wardlaw","doi":"10.1002/ana.27136","DOIUrl":"https://doi.org/10.1002/ana.27136","url":null,"abstract":"<p><strong>Objective: </strong>Cerebral small vessel diseases (SVDs) are associated with cerebrovascular dysfunction, such as increased blood-brain barrier leakage (permeability surface area product), vascular pulsatility, and decreased cerebrovascular reactivity (CVR). No studies assessed all 3 functions concurrently. We assessed 3 key vascular functions in sporadic and genetic SVD to determine associations with SVD severity, subtype, and interrelations.</p><p><strong>Methods: </strong>In this prospective, cross-sectional, multicenter INVESTIGATE-SVDs study, we acquired brain magnetic resonance imaging in patients with sporadic SVD/cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), including structural, quantitative microstructural, permeability surface area product, blood plasma volume fraction, vascular pulsatility, and CVR (in response to CO₂) scans. We determined vascular function and white matter hyperintensity (WMH) associations, using covariate-adjusted linear regression; normal-appearing white matter and WMH differences, interrelationships between vascular functions, using linear mixed models; and major sources of variance using principal component analyses.</p><p><strong>Results: </strong>We recruited 77 patients (45 sporadic/32 CADASIL) at 3 sites. In adjusted analyses, patients with worse WMH had lower CVR (B = -1.78, 95% CI -3.30, -0.27) and blood plasma volume fraction (B = -0.594, 95% CI -0.987, -0.202). CVR was worse in WMH than normal-appearing white matter (eg, CVR: B = -0.048, 95% CI -0.079, -0.017). Adjusting for WMH severity, SVD subtype had minimal influence on vascular function (eg, CVR in CADASIL vs sporadic: B = 0.0169, 95% CI -0.0247, 0.0584). Different vascular function mechanisms were not generally interrelated (eg, permeability surface area product~CVR: B = -0.85, 95% CI -4.72, 3.02). Principal component analyses identified WMH volume/quantitative microstructural metrics explained most variance in CADASIL and arterial pulsatility in sporadic SVD, but similar main variance sources.</p><p><strong>Interpretation: </strong>Vascular function was worse with higher WMH, and in WMH than normal-appearing white matter. Sporadic SVD-CADASIL differences largely reflect disease severity. Limited vascular function interrelations may suggest disease stage-specific differences. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646030","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}

{"title":"Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.","authors":"Renjia Zhong, Demi L A Dionela, Nina Haeyeon Kim, Erin N Harris, John G Geisler, Lan Wei-LaPierre","doi":"10.1002/ana.27140","DOIUrl":"https://doi.org/10.1002/ana.27140","url":null,"abstract":"<p><strong>Objective: </strong>Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.</p><p><strong>Methods: </strong>hSOD1^G93A mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1^G93A mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.</p><p><strong>Results: </strong>DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1^G93A mice. Strikingly, symptomatic hSOD1^G93A mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.</p><p><strong>Interpretation: </strong>Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646034","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}