Annals of Neurology最新文献

{"title":"Laser Ablation of Periventricular Nodular Heterotopia for Medically Refractory Epilepsy","authors":"Ryan M. McCormack MD, PhD,&nbsp;Arjun S. Chandran MD,&nbsp;Samden D. Lhatoo MD,&nbsp;Sandipan Pati MD,&nbsp;Zhouxuan Li MS,&nbsp;Katherine Harris MD,&nbsp;Nuria Lacuey MD, PhD,&nbsp;Giridhar Kalamangalam MD, DPhil,&nbsp;Stephen Thompson MD,&nbsp;Nitin Tandon MD","doi":"10.1002/ana.27059","DOIUrl":"10.1002/ana.27059","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Periventricular nodular heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco-resistant epilepsy. Here, we characterize variables that predict good epilepsy outcomes following surgical intervention using stereo-electroencephalography (SEEG) -informed magnetic resonance-guided laser interstitial thermal therapy (MRgLITT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective review of consecutive cases from a single high-volume epilepsy referral center identified patients who underwent SEEG evaluation for PVNH to characterize the intervention and outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Thirty-nine patients underwent SEEG-guided MRgLITT of the seizure onset zone (SoZ) in PVNH and associated epileptic tissue. PVNH and polymicrogyria (PMG) were densely sampled with a mean of 16.5 (SD = 2)/209.4 (SD = 36.9) SEEG probes/recording contacts per patient. Ablation principally targeted just the PVNH and cortex that was abnormal on imaging was ablated (5 patients) only if implicated in the SoZ. Volumetric analyses revealed a high percentage of PVNH SoZ ablation (96.6%, SD = 5.3%) in unilateral and bilateral (92.9%, SD = 7.2%) cases. Mean follow-up duration was 31.4 months (SD = 20.9). Seizure freedom (ILAE 1) was excellent: unilateral PVNH without other imaging abnormalities, 80%; PVNH with mesial temporal sclerosis (MTS) or PMG, 63%; bilateral PVNH, 50%. SoZ ablation percentage significantly impacted surgical outcomes (<i>p</i> &lt; 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>PVNH plays a central role in seizure genesis as revealed by dense recordings and selective targeting by LITT. MRgLITT represents a transformative technological advance in PVNH-associated epilepsy with seizure control outcomes consistent with those seen in focal lesional epilepsies. In localized unilateral cases and otherwise normal imaging, PVNH ablation without invasive recordings may be considered, and this approach deserves to be explored further. ANN NEUROL 2024;96:1174–1184</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1174-1184"},"PeriodicalIF":8.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266402","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":"Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B)","authors":"Widad Abou Chaar MD,&nbsp;Anirudh N. Eranki,&nbsp;Hannah A. Stevens,&nbsp;Sonya L. Watson MS,&nbsp;Darice Y. Wong PhD,&nbsp;Veronica S. Avila,&nbsp;Megan Delfeld,&nbsp;Alexander J. Gary,&nbsp;Sanjukta Tawde MS,&nbsp;Malia Triebold MS,&nbsp;Marcello Cherchi MD, PhD,&nbsp;Tao Xie MD, PhD,&nbsp;Paul J. Lockhart PhD,&nbsp;Melanie Bahlo PhD,&nbsp;David Pellerin MD, MSc,&nbsp;Marie-Josée Dicaire,&nbsp;Matt Danzi PhD,&nbsp;Stephan Zuchner MD, PhD,&nbsp;Bernard C. Brais MD, PhD,&nbsp;Susan Perlman MD,&nbsp;Margit Burmeister PhD,&nbsp;Henry Paulson MD, PhD,&nbsp;Sharan Srinivasan MD, PhD,&nbsp;Lawrence Schut MD,&nbsp;Matthew Bower MS,&nbsp;Khalaf Bushara MD,&nbsp;Chuanhong Liao MS,&nbsp;Vikram G. Shakkottai MD, PhD,&nbsp;John Collins MD, PhD,&nbsp;H. Brent Clark MD, PhD,&nbsp;Soma Das PhD,&nbsp;Brent L. Fogel MD, PhD,&nbsp;Christopher M. Gomez MD, PhD","doi":"10.1002/ana.27060","DOIUrl":"10.1002/ana.27060","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (<i>FGF14</i>) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024;96:1092–1103</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1092-1103"},"PeriodicalIF":8.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224663","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":"Slowly Expanding Lesions Differentiate Pediatric Multiple Sclerosis from Myelin Oligodendrocyte Glycoprotein Antibody Disease","authors":"Giulia Fadda MD,&nbsp;Brenda Banwell MD,&nbsp;Colm Elliott PhD,&nbsp;Dumitru Fetco MD,&nbsp;Douglas L. Arnold MD,&nbsp;Patrick Waters PhD,&nbsp;E. Ann Yeh MD,&nbsp;Ruth Ann Marrie MD PhD,&nbsp;Amit Bar-Or MD,&nbsp;Sridar Narayanan PhD,&nbsp;the Canadian Pediatric Demyelinating Disease Network","doi":"10.1002/ana.27066","DOIUrl":"10.1002/ana.27066","url":null,"abstract":"<p>Slowly expanding lesions (SELs) in adults with multiple sclerosis (MS) indicate a progressive pathological process. Whether SELs are present in pediatric-onset MS (POMS) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is unknown. We studied 19 children with POMS and 14 with MOGAD (median age 14.3 and 9.4 years, respectively) recruited to the Canadian Pediatric Demyelinating Disease Study with: (1) ≥3 research scans 12 months apart; and (2) ≥1 T2-lesions on the earliest scan. A total of 70 SELs from 16 POMS participants and 1 SEL in the MOGAD group were detected. SELs are an early feature of POMS and essentially not a feature of MOGAD. ANN NEUROL 2024;96:1086–1091</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1086-1091"},"PeriodicalIF":8.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144500","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":"Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease","authors":"Agustin Hidalgo-Gutierrez PhD,&nbsp;Jonathan Shintaku,&nbsp;Javier Ramon,&nbsp;Eliana Barriocanal-Casado,&nbsp;Alba Pesini,&nbsp;Russell P. Saneto,&nbsp;Gloria Garrabou,&nbsp;Jose Cesar Milisenda,&nbsp;Ana Matas-Garcia,&nbsp;Laura Gort,&nbsp;Olatz Ugarteburu,&nbsp;Yue Gu,&nbsp;Lahari Koganti,&nbsp;Tian Wang,&nbsp;Saba Tadesse,&nbsp;Megi Meneri,&nbsp;Monica Sciacco,&nbsp;Shuang Wang,&nbsp;Kurenai Tanji,&nbsp;Marshall S. Horwitz,&nbsp;Michael O. Dorschner,&nbsp;Mahesh Mansukhani,&nbsp;Giacomo Pietro Comi,&nbsp;Dario Ronchi,&nbsp;Ramon Marti,&nbsp;Antonia Ribes,&nbsp;Frederic Tort,&nbsp;Michio Hirano MD","doi":"10.1002/ana.27071","DOIUrl":"10.1002/ana.27071","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified biallelic <i>GUK1</i> pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. <i>GUK1</i> encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands’ fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1209-1224"},"PeriodicalIF":8.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124302","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":"Comparison of Perfusion Imaging Definitions of the No-Reflow Phenomenon after Thrombectomy—What Is the Best Perfusion Imaging Definition?","authors":"Chloe A. Mutimer MD,&nbsp;Adnan Mujanovic MD,&nbsp;Johannes Kaesmacher MD,&nbsp;Leonid Churilov PhD,&nbsp;Timothy J. Kleinig PhD,&nbsp;Mark W. Parsons PhD,&nbsp;Peter J. Mitchell MMed,&nbsp;Bruce C.V. Campbell PhD,&nbsp;Felix Ng PhD","doi":"10.1002/ana.27073","DOIUrl":"10.1002/ana.27073","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>The no-reflow phenomenon is a potential contributor to poor outcome despite successful thrombectomy. There are multiple proposed imaging-based definitions of no-reflow leading to wide variations in reported prevalence. We investigated the agreement between existing imaging definitions and compared the characteristics and outcomes of patients identified as having no-reflow.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed an external validation of 4 existing published definitions of no-reflow in thrombectomy patients with extended Thrombolysis in Cerebral Infarction scale 2c to 3 (eTICI2c-3) angiographic reperfusion who underwent 24-hour perfusion imaging from 2 international randomized controlled trials (EXTEND-IA TNK part-1 and 2) and a multicenter prospective observational study. Receiver-operating-characteristic and Bayesian-information-criterion (BIC) analyses were performed with the outcome variable being dependent-or-dead at 90-days (modified Rankin Score [mRS] ≥3).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 131 patients analyzed, the prevalence of no-reflow significantly varied between definitions (0.8–22.1%; <i>p</i> &lt; 0.001). There was poor agreement between definitions (kappa 5/6 comparisons &lt;0.212). Among patients with no-reflow according to at least 1 definition, there were significant differences between definitions in the intralesional interside differences in cerebral blood flow (CBF) (<i>p</i> = 0.006), cerebral blood volume (CBV) (<i>p</i> &lt; 0.001), and mean-transit-time (MTT) (<i>p</i> = 0.005). No-reflow defined by 3 definitions was associated with mRS ≥3 at 90 days. The definition of &gt;15% CBV or CBF asymmetry was the only definition that improved model fit on BIC analysis (ΔBIC = −8.105) and demonstrated an association between no-reflow and clinical outcome among patients with eTICI3 reperfusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, potentially explaining the variable prevalence of no-reflow reported in literature. The definition of &gt;15% CBV or CBF asymmetry best discriminated for functional outcome at 90 days, including patients with eTICI3 reperfusion. ANN NEUROL 2024;96:1104–1114</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1104-1114"},"PeriodicalIF":8.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118506","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":"RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy","authors":"David J. Burrows PhD,&nbsp;Alexander McGown PhD,&nbsp;Olfat Abduljabbar PhD,&nbsp;Lydia M. Castelli PhD,&nbsp;Pamela J. Shaw MBBS, MD,&nbsp;Guillaume M. Hautbergue PhD,&nbsp;Tennore M. Ramesh DVM, PhD","doi":"10.1002/ana.27068","DOIUrl":"10.1002/ana.27068","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Hexanucleotide repeat expansions in the <i>C9orf72</i> gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058–1069</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1058-1069"},"PeriodicalIF":8.1,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102525","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":"Fetal Intraparenchymal Hemorrhage Imaging Patterns, Etiology, and Outcomes: A Single Center Cohort Study","authors":"Rachel Vassar MD,&nbsp;Elizabeth George MBBS,&nbsp;Andrew Mogga BS,&nbsp;Yi Li MD,&nbsp;Mary E. Norton MD,&nbsp;Orit Glenn MD,&nbsp;Dawn Gano MD, MAS","doi":"10.1002/ana.27072","DOIUrl":"10.1002/ana.27072","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a retrospective, single-center cohort study of IPH diagnosed on fetal MRI (1996–2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Forty-four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22–28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin-twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty-two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow-up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>An etiology for fetal IPH with or without GMH-IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024;96:1137–1147</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1137-1147"},"PeriodicalIF":8.1,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102524","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":"Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy","authors":"Zhihao Xie PhD,&nbsp;Chang Liu MD,&nbsp;Chengyue Sun MD, PhD,&nbsp;Yilin Liu MD, PhD,&nbsp;Jieru Peng MD,&nbsp;Lingchao Meng MD,&nbsp;Jianwen Deng PhD,&nbsp;Zhaoxia Wang MD, PhD,&nbsp;Chunxia Yang PhD,&nbsp;Yun Yuan MD, PhD,&nbsp;Zhiying Xie MD, PhD","doi":"10.1002/ana.27070","DOIUrl":"10.1002/ana.27070","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The transcriptional heterogeneity at a single-nucleus level in human Becker muscular dystrophy (BMD) dystrophic muscle has not been explored. Here, we aimed to understand the transcriptional heterogeneity associated with myonuclei, as well as other mononucleated cell types that underly BMD pathogenesis by performing single-nucleus RNA sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We profiled single-nucleus transcriptional profiles of skeletal muscle samples from 7 BMD patients and 3 normal controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 17,216 nuclei (12,879 from BMD patients and 4,337 from controls) were classified into 13 known cell types, including 9 myogenic lineages and 4 non-myogenic lineages, and 1 unclassified nuclear type according to their cell identities. Among them, type IIx myonuclei were the first to degenerate in response to dystrophin reduction. Differential expression analysis revealed that the fibro-adipogenic progenitors (FAPs) population had the largest transcriptional changes among all cell types. Sub-clustering analysis identified a significantly compositional increase in the activated FAPs (aFAPs) subpopulation in BMD muscles. Pseudotime analysis, regulon inference, and deconvolution analysis of bulk RNA-sequencing data derived from 29 BMD patients revealed that the aFAPs subpopulation, a distinctive and previously unrecognized mononuclear subtype, was profibrogenic and expanded in BMD patients. Muscle quantitative real-time polymerase chain reaction and immunofluorescence analysis confirmed that the mRNA and protein levels of the aFAPs markers including <i>LUM</i>, <i>DCN</i>, and <i>COL1A1</i> in BMD patients were significantly higher than those in controls, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our results provide insights into the transcriptional diversity of human BMD muscle at a single-nucleus resolution and new potential targets for anti-fibrosis therapies in BMD. ANN NEUROL 2024;96:1070–1085</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1070-1085"},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078526","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":"Miyazaki Syndrome as a Complication of Shunt Drainage","authors":"Rick H. G. J. van Lanen MD, MSc,&nbsp;Jasper van Aalst MD, PhD,&nbsp;Mariël P. Ter Laak-Poort MD, PhD","doi":"10.1002/ana.27067","DOIUrl":"10.1002/ana.27067","url":null,"abstract":"&lt;p&gt;A 41-year-old female was referred to the neurosurgery outpatient clinic with progressive bipyramidal syndrome. Medical history included premature birth and prior intraventricular hemorrhage with hydrocephalus. Ventricular-peritoneal (VP) shunting was performed in the management of hydrocephalus. However, complications related to over-drainage, along with hyperostosis of the skull and craniosynostosis, caused scaphocephaly.&lt;/p&gt;&lt;p&gt;Over the course of several months, she experienced progressive difficulties walking and developed right-sided weakness. Neurological examination revealed right-sided hemiparesis, hyperreflexia, and bilateral Babinski's sign. Imaging of the brain and cervical spine (Fig 1) showed scaphocephaly with slit-like ventricles and myelopathy extending from the C1 to C3 levels, along with the presence of spinal epidural venous engorgement. In the absence of a diagnosis, she was placed under long-term follow-up care by her neurologist. Follow-up magnetic resonance imaging (MRI) of the cervical spine revealed progressive myelopathy, before the diagnosis of Miyazaki syndrome was made. She underwent VP-shunt revision, with implantation of a Miethke proGAV 2.0 0-20/20 (programmable valve pressure setting 8). Outpatient clinic follow-up at 6 months showed stabilization of the bipyramidal symptoms. Follow-up MRI showed improvement of the epidural venous engorgement.&lt;/p&gt;&lt;p&gt;Miyazaki syndrome arises as a complication of cerebrospinal fluid (CSF) hypotension caused by excessive drainage through VP-shunting. Although CSF hypotension is often associated with well-known symptoms, like orthostatic headache and cranial nerve palsies, the development of epidural venous engorgement leading to spinal cord compression is a less common but critical manifestation.&lt;/p&gt;&lt;p&gt;The syndrome is characterized by cervical myelopathy or radiculopathy due to cervical epidural venous congestion, results from complex pathophysiological mechanisms.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; These include changes in CSF pressure, consistent with the Monro-Kellie doctrine, and dysfunction in the Starling resistor, leading to the enlargement and dilation of the spinal epidural venous plexus.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Venous congestion can lead to spinal cord or nerve roots compression or circulation hampering,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; causing neurological symptoms, whereas presenting a unique diagnostic challenge. One of the striking features of Miyazaki syndrome is that it can manifest without the typical symptom of orthostatic headache, which is commonly associated with CSF hypotension. Instead, patients with Miyazaki syndrome may develop myelopathy symptoms slowly over time, making it challenging to diagnose, potentially leading to misdiagnosis.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This underlines the importance of considering Miyazaki syndrome in the differential diagnosis of patients with VP-shunts who present with myelopathy but do not experience headaches. Timely recognition is crucial and","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1230-1231"},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071516","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":"Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis","authors":"Simon Witzel MD,&nbsp;André Huss PhD,&nbsp;Gabriele Nagel MD,&nbsp;Angela Rosenbohm MD,&nbsp;Dietrich Rothenbacher MD,&nbsp;Raphael S. Peter PhD,&nbsp;Hansjörg Bäzner MD,&nbsp;Axel Börtlein MD,&nbsp;Silke Dempewolf MD,&nbsp;Martin Schabet MD,&nbsp;Martin Hecht MD,&nbsp;Andreas Kohler MD,&nbsp;Christian Opherk MD,&nbsp;Andrea Naegele MD,&nbsp;Norbert Sommer MD,&nbsp;Alfred Lindner MD,&nbsp;Christoforos Alexudis,&nbsp;Franziska Bachhuber PhD,&nbsp;Steffen Halbgebauer PhD,&nbsp;David Brenner MD,&nbsp;Wolfgang Ruf MD,&nbsp;Ulrike Weiland MD,&nbsp;Benjamin Mayer PhD,&nbsp;Joachim Schuster PhD,&nbsp;Johannes Dorst MD,&nbsp;Hayrettin Tumani MD,&nbsp;Albert C. Ludolph MD,&nbsp;and the ALS Registry Swabia Study Group","doi":"10.1002/ana.27054","DOIUrl":"10.1002/ana.27054","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040–1057</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1040-1057"},"PeriodicalIF":8.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034629","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}