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Neurology
Journal Prestige (SJR): 3.399
Citation Impact (citeScore): 4
Number of Followers: 101  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0028-3878 - ISSN (Online) 1526-632X
Published by LWW Wolters Kluwer Homepage  [301 journals]
  • Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive
           Multiple Sclerosis

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      Authors: Hauser, S. L; Kappos, L, Montalban, X, Craveiro, L, Chognot, C, Hughes, R, Koendgen, H, Pasquarelli, N, Pradhan, A, Prajapati, K, Wolinsky, J. S.
      Abstract: Background and ObjectivesTo report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.MethodsSafety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.ResultsAt data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data.DiscussionContinuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population.Classification of EvidenceThis analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.
      Keywords: Medical care, All Clinical Neurology, All Clinical trials, Patient safety, Class II, Multiple sclerosis
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012700
      Issue No: Vol. 97, No. 16 (2021)
       
  • Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as
           Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis

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      Authors: Koch, M. W; Mostert, J. P, Wolinsky, J. S, Lublin, F. D, Uitdehaag, B, Cutter, G. R.
      Abstract: Background and ObjectivesClinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25-ft walk (T25FW) and 9-hole peg test (NHPT) may be more useful and patient relevant. The objective of this work was to compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset.MethodsWe used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening.ResultsCombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of
      Keywords: All Clinical trials, Clinical trials Methodology/study design, Clinical trials Observational study (Cohort, Case control), Multiple sclerosis
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012690
      Issue No: Vol. 97, No. 16 (2021)
       
  • Multicenter Validation of a Deep Learning Detection Algorithm for Focal
           Cortical Dysplasia

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      Authors: Gill, R. S; Lee, H.-M, Caldairou, B, Hong, S.-J, Barba, C, Deleo, F, D'Incerti, L, Mendes Coelho, V. C, Lenge, M, Semmelroch, M, Schrader, D. V, Bartolomei, F, Guye, M, Schulze-Bonhage, A, Urbach, H, Cho, K. H, Cendes, F, Guerrini, R, Jackson, G, Hogan, R. E, Bernasconi, N, Bernasconi, A.
      Abstract: Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).MethodsWe used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.ResultsOverall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.DiscussionThis first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy.Classification of EvidenceThis study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.
      Keywords: MRI, Class III, Epilepsy surgery, Cortical dysplasia
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012698
      Issue No: Vol. 97, No. 16 (2021)
       
  • MRI-Based Machine Learning Prediction Framework to Lateralize Hippocampal
           Sclerosis in Patients With Temporal Lobe Epilepsy

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      Authors: Caldairou, B; Foit, N. A, Mutti, C, Fadaie, F, Gill, R, Lee, H. M, Demerath, T, Urbach, H, Schulze-Bonhage, A, Bernasconi, A, Bernasconi, N.
      Abstract: Background and ObjectivesMRI fails to reveal hippocampal pathology in 30% to 50% of temporal lobe epilepsy (TLE) surgical candidates. To address this clinical challenge, we developed an automated MRI-based classifier that lateralizes the side of covert hippocampal pathology in TLE.MethodsWe trained a surface-based linear discriminant classifier that uses T1-weighted (morphology) and T2-weighted and fluid-attenuated inversion recovery (FLAIR)/T1 (intensity) features. The classifier was trained on 60 patients with TLE (mean age 35.6 years, 58% female) with histologically verified hippocampal sclerosis (HS). Images were deemed to be MRI negative in 42% of cases on the basis of neuroradiologic reading (40% based on hippocampal volumetry). The predictive model automatically labeled patients as having left or right TLE. Lateralization accuracy was compared to electroclinical data, including side of surgery. Accuracy of the classifier was further assessed in 2 independent TLE cohorts with similar demographics and electroclinical characteristics (n = 57, 58% MRI negative).ResultsThe overall lateralization accuracy was 93% (95% confidence interval 92%–94%), regardless of HS visibility. In MRI-negative TLE, the combination of T2 and FLAIR/T1 intensities provided the highest accuracy in both the training (84%, area under the curve [AUC] 0.95 ± 0.02) and validation (cohort 1 90%, AUC 0.99; cohort 2 76%, AUC 0.94) cohorts.DiscussionThis prediction model for TLE lateralization operates on readily available conventional MRI contrasts and offers gain in accuracy over visual radiologic assessment. The combined contribution of decreased T1- and increased T2-weighted intensities makes the synthetic FLAIR/T1 contrast particularly effective in MRI-negative HS, setting the basis for broad clinical translation.Classification of EvidenceThis study provides Class II evidence that in people with TLE and MRI-negative HS, an automated MRI-based classifier accurately determines the side of pathology.
      Keywords: MRI, Class II, Epilepsy surgery, Hippocampal sclerosis
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012699
      Issue No: Vol. 97, No. 16 (2021)
       
  • Structural MRI Signatures in Genetic Presentations of the Frontotemporal
           Dementia/Motor Neuron Disease Spectrum

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      Authors: Spinelli, E. G; Ghirelli, A, Basaia, S, Cividini, C, Riva, N, Canu, E, Castelnovo, V, Domi, T, Magnani, G, Caso, F, Caroppo, P, Prioni, S, Rossi, G, Tremolizzo, L, Appollonio, I, Silani, V, Carrera, P, Filippi, M, Agosta, F.
      Abstract: Background and ObjectivesTo assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.MethodsSixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.ResultsCompared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.DiscussionMeasures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.
      Keywords: MRI, Volumetric MRI, Amyotrophic lateral sclerosis, Frontotemporal dementia, All Genetics
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012702
      Issue No: Vol. 97, No. 16 (2021)
       
  • Atrial Fibrillation, Stroke, and Silent Cerebrovascular Disease: A
           Population-based MRI Study

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      Authors: Ryden, L; Sacuiu, S, Wetterberg, H, Najar, J, Guo, X, Kern, S, Zettergren, A, Shams, S, Pereira, J. B, Wahlund, L.-O, Westman, E, Skoog, I.
      Abstract: Background and ObjectivesAtrial fibrillation (AF) has been associated with cognitive decline and dementia. However, the mechanisms behind these associations are not clear. Examination of cerebrovascular pathology on MRI may shed light on how AF affects the brain. This study aimed to determine whether AF is associated with a broad range of cerebrovascular diseases beyond the well-known association with symptomatic stroke, including silent infarcts and markers of small vessel disease, i.e., cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and lacunes, in a population-based sample of 70-year-olds.MethodsData were obtained from the Gothenburg H70 Birth Cohort Studies, in which individuals are invited based on birthdate. This study has a cross-sectional design and includes individuals born in 1944 who underwent structural brain MRI in 2014 to 2017. AF diagnoses were based on self-report, ECG, and register data. Symptomatic stroke was based on self-report, proxy interviews, and register data. Brain infarcts and CMBs were assessed by a radiologist. WMH volumes were measured on fluid-attenuated inversion recovery images with the Lesion Segmentation Tool. Multivariable logistic regression was used to study the association between AF and infarcts/CMBs, and multivariable linear regression was used to study the association between AF and WMHs.ResultsA total of 776 individuals were included, and 65 (8.4%) had AF. AF was associated with symptomatic stroke (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.1–9.5) and MRI findings of large infarcts (OR 5.0, 95% CI 1.5–15.9), lacunes (OR 2.7, 95% CI 1.2–5.6), and silent brain infarcts (OR 3.5; 95% CI 1.6–7.4). Among those with symptomatic stroke, individuals with AF had larger WMH volumes (0.0137 mL/total intracranial volume [TIV], 95% CI 0.0074–0.0252) compared to those without AF (0.0043 mL/TIV, 95% CI 0.0029–0.0064). There was no association between AF and WMH volumes among those without symptomatic stroke. In addition, AF was associated to CMBs in the frontal lobe.DiscussionAF was associated with a broad range of cerebrovascular pathologies. Further research is needed to establish whether cerebrovascular MRI markers can be added to current treatment guidelines to further personalize anticoagulant treatment in patients with AF and to further characterize the pathogenetic processes underlying the associations between AF and cerebrovascular diseases, as well as dementia.
      Keywords: MRI, All Cerebrovascular disease/Stroke, Cardiac
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012675
      Issue No: Vol. 97, No. 16 (2021)
       
  • Subjective Sleep Quality and Sleep Architecture in Patients With Migraine:
           A Meta-analysis

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      Authors: Stanyer, E. C; Creeney, H, Nesbitt, A. D, Holland, P. R, Hoffmann, J.
      Abstract: Background and ObjectivesSleep disturbance is often associated with migraine. However, there is a paucity of research investigating objective and subjective measures of sleep in patients with migraine. This meta-analysis aims to determine whether there are differences in subjective sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) and objective sleep architecture measured using polysomnography (PSG) between adult and pediatric patients and healthy controls.MethodsThis review was preregistered on PROSPERO (CRD42020209325). A systematic search of 5 databases (Embase, MEDLINE, Global Health, APA PsycINFO, and APA PsycArticles, last searched on December 17, 2020) was conducted to find case–control studies that measured PSG or PSQI in patients with migraine. Pregnant participants and those with other headache disorders were excluded. Effect sizes (Hedges g) were entered into a random effects model meta-analysis. Study quality was evaluated with the Newcastle Ottawa Scale and publication bias with the Egger regression test.ResultsThirty-two studies were eligible, of which 21 measured PSQI or Migraine Disability Assessment Test in adults, 6 measured PSG in adults, and 5 measured PSG in children. The overall mean study quality score was 5/9; this did not moderate any of the results and there was no risk of publication bias. Overall, adults with migraine had higher PSQI scores than healthy controls (g = 0.75, p < 0.001, 95% confidence interval [CI] 0.54–0.96). This effect was larger in those with a chronic rather than episodic condition (g = 1.03, p < 0.001, 95% CI 0.37–1.01; g = 0.63, p < 0.001, 95% CI 0.38–0.88, respectively). For polysomnographic studies, adults and children with migraine displayed a lower percentage of rapid eye movement sleep (g = –0.22, p = 0.017, 95% CI –0.41 to –0.04; g = –0.71, p = 0.025, 95% CI –1.34 to –0.10, respectively) than controls. Pediatric patients displayed less total sleep time (g = –1.37, p = 0.039, 95% CI –2.66 to –0.10), more wake (g = 0.52, p < 0.001, 95% CI 0.08–0.79), and shorter sleep onset latency (g = –0.37, p < 0.001, 95% CI –0.54 to –0.21) than controls.DiscussionPeople with migraine have significantly poorer subjective sleep quality and altered sleep architecture compared to healthy individuals. Further longitudinal empirical studies are required to enhance our understanding of this relationship.
      Keywords: Migraine, Pediatric headache, All Sleep Disorders, Case control studies, EEG
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012701
      Issue No: Vol. 97, No. 16 (2021)
       
  • Clinical Reasoning: An 81-Year-Old Woman Who Insisted the Hospital Was Her
           Home

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      Authors: Carlisle, T. C; Stanley, M. P. H, Singhal, A. B, Caplan, D. N.
      Abstract: An 81-year-old right-handed White non-Hispanic previously healthy woman with glaucoma presented with acute weakness and slurred speech nearly 10 hours after last seen well. She was found to have new onset atrial fibrillation. Her NIH stroke scale (NIHSS) was 18 with points given for failure to answer questions, left lower facial paralysis, right gaze preference with ability to cross midline, left field cut, left hemiplegia, severe dysarthria, mild aphasia, and severe left sensory neglect.
      Keywords: Aphasia, Cardiac, Assessment of cognitive disorders/dementia
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012392
      Issue No: Vol. 97, No. 16 (2021)
       
  • Teaching NeuroImage: Ganglion Cell Patterns Localize Anterior Visual
           Pathway Lesions

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      Authors: Miller, G. D; Vuong, L. N, Hedges, T. R.
      Abstract: Measurement of retinal ganglion cell layer thickness by optical coherence tomography provides an objective and reliable evaluation of anterior visual pathway lesions to complement visual field testing in the management of optic chiasm compression from pituitary tumors.1,2 We demonstrated 3 differing patterns of ganglion cell layer thinning—junctional (figure 1, A and D), binasal (figure 1, B and E), and homonymous (figure 1, C and F)—and illustrated how these patterns correspond to the location of chiasmal compression by pituitary adenomas, anteriorly (figure 2A), centrally (figure 2B), or posteriorly (figure 2C). Consideration of the pattern of ganglion cell layer thinning in conjunction with visual field testing is useful for predicting the location of anterior visual pathway lesions.
      Keywords: MRI, Optic nerve, Visual loss, Visual fields
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012200
      Issue No: Vol. 97, No. 16 (2021)
       
  • Teaching NeuroImage: Isolated Unilateral Hypoglossal Nerve Palsy due to
           Skull Base Meningioma

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      Authors: Coenen, J; Cleaver, J, James, R, Chohan, G.
      Abstract: A 73-year-old woman presented with a 6-month history of intermittent lisp, drooling, and aspiration. Initial assessment showed right hemitongue atrophy (Figure 1) with ipsilateral fasciculations and weakness. Residual neurologic examination was unremarkable. MRI brain confirmed a right hypoglossal nerve palsy (HNP) secondary to a hypoglossal canal meningioma, with classical radiologic appearances (Figure 2).
      Keywords: CT, MRI, Clinical neurology history, Clinical neurology examination
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012232
      Issue No: Vol. 97, No. 16 (2021)
       
  • Spotlight on the October 19 Issue

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      Authors: Merino; J. G.
      Pages: 749 - 750
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012697
      Issue No: Vol. 97, No. 16 (2021)
       
  • Longer-term Safety of B-Cell Therapy With Ocrelizumab in Multiple
           Sclerosis

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      Authors: Yeh, E. A; Bourdette, D, Wiendl, H.
      Pages: 751 - 753
      Abstract: Treatment options in multiple sclerosis (MS) have expanded tremendously, with 23 disease-modifying therapies (DMT) approved in the United States since 1993. Along with the increasing number of approved MS DMTs, refinements to diagnostic criteria and recognition of the benefits of early treatment have led clinicians to diagnose and treat patients when they have a first demyelinating episode. Furthermore, treatment approaches have shifted to the use of more powerful, highly efficacious agents, including monoclonal antibodies (mAbs), at onset.1 The newer therapies, such as natalizumab, alemtuzumab, and the anti-B-cell mAb ocrelizumab, have made "no evidence of disease activity" a realistic therapeutic target, delayed the onset of progressive disease, and led to improved quality of life of individuals with MS. Yet these agents are a double-edged sword: with higher efficacy comes potential risks, particularly with long-term use of these therapies.2
      Keywords: All Clinical Neurology, All Clinical trials, Multiple sclerosis
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012716
      Issue No: Vol. 97, No. 16 (2021)
       
  • Mapping Epileptogenic Tissues in MRI-Negative Focal Epilepsy: Can Deep
           Learning Uncover Hidden Lesions'

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      Authors: Sinha, N; Davis, K. A.
      Pages: 754 - 755
      Abstract: In patients with drug-resistant focal epilepsy, pathologies such as focal cortical dysplasia (FCD), hippocampal sclerosis, polymicrogyria, or ganglioglioma typically appear as structural lesions on MRI. Mapping these structural lesions is fundamental to planning epilepsy surgery for controlling seizures. These lesions are part of the epileptogenic zone, and their incomplete removal is associated with seizure recurrence. A major diagnostic challenge occurs when patients with focal epilepsy do not have demonstrable lesions on MRI.1 The surgical outcomes in these patients are considerably less favorable if their pathology is missed by traditional visual inspection.
      Keywords: Epilepsy surgery, Epileptogenic zone, Cortical localization, Volumetric MRI use in epilepsy, Cortical dysplasia
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012696
      Issue No: Vol. 97, No. 16 (2021)
       
  • Neuropathologic Findings in a Patient With Juvenile-Onset
           Levodopa-Responsive Parkinsonism Due to ATP13A2 Mutation

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      Authors: Chien, H. F; Rodriguez, R. D, Bonifati, V, Nitrini, R, Pasqualucci, C. A, Gelpi, E, Barbosa, E. R.
      Pages: 763 - 766
      Abstract: ObjectiveTo describe the postmortem neuropathologic findings of a patient with Kufor Rakeb syndrome (KRS) due to ATP13A2 mutation. KRS is characterized by juvenile-onset levodopa-responsive parkinsonism associated with pyramidal signs, supranuclear gaze palsy, and cognitive impairment.MethodsA detailed neuropathologic analysis of the brain was performed. The patient had a genetically confirmed ATP13A2 homozygous missense mutation and died at age 38 years, which was 26 years after the onset of his symptoms.ResultsThe main brain neuropathologic findings were widespread neuronal and glial lipofuscin accumulation with no Lewy body–type inclusions and absence of α-synuclein–positive, tau-positive, β-amyloid–positive, and TDP-43 protein–positive pathologies. Sparse iron deposits were observed in several brain areas, but no obvious axonal spheroids were identified.DiscussionThis is to our knowledge the first KRS postmortem neuropathologic description. Iron deposits were found but not associated with increased axonal spheroids, as frequently observed in neurodegeneration with brain iron accumulation. ATP13A2 mutations have been described in patients with neuronal ceroid lipofuscinosis (CLN). Moreover, animal models with these mutations develop neurodegenerative disorders with CLN pathology. Therefore, our findings support that ATP13A2 mutations may be considered a genetic etiology of neuronal lipofuscinosis.
      Keywords: Metabolic disease (inherited), Gait disorders/ataxia, Parkinson's disease/Parkinsonism, Gene expression studies, Motor Control
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012705
      Issue No: Vol. 97, No. 16 (2021)
       
  • Neurologic Safety Monitoring of COVID-19 Vaccines: Lessons From the Past
           to Inform the Present

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      Authors: Thakur, K. T; Epstein, S, Bilski, A, Balbi, A, Boehme, A. K, Brannagan, T. H, Wesley, S. F, Riley, C. S.
      Pages: 767 - 775
      Abstract: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).
      Keywords: All Clinical Neurology, COVID-19, All Demyelinating disease (CNS), All epidemiology
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012703
      Issue No: Vol. 97, No. 16 (2021)
       
  • What Is the Role of Oligodendrocytes in Amyotrophic Lateral Sclerosis'

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      Authors: Benarroch; E.
      Pages: 776 - 779
      Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. There is growing evidence that astrocytes, microglia, and oligodendrocytes participate in the pathodynamics of ALS via both loss-of-function and toxic gain-of-function mechanisms.1 Whereas most studies have focused on the role of microglia and astrocytes,1,2 oligodendrocytes may also have a major pathogenic role in this disorder3-6 (Figure). A recent analysis applying a polygenic risk score approach indicated that variation in genes involved in neuronal morphogenesis and membrane trafficking are a major genetic risk for ALS.7 This study also showed that subtypes of oligodendrocytes, as well as parvalbumin-expressing GABAergic neurons in the motor cortex, were significantly enriched in ALS risk genes in humans.7 Oligodendrocytes are the targets of mutations affecting ALS-related genes and their dysfunction may affect motor neuron survival by several mechanisms. Experimental models of ALS indicate that the inability of oligodendrocyte precursors to fully differentiate into mature oligodendrocytes renders them unable to provide metabolic support and myelinate the axons.3-6 In vitro co-culture studies show that oligodendrocytes derived from induced pluripotent or neural progenitor cells from patients with familial ALS associated with superoxide dismutase 1 (SOD1) or other mutations, as well as those from patients with sporadic ALS, may also have an active role in motor neuron death via cell-contact mechanisms.5 These findings expand the potential cellular targets for neuroprotection in ALS.6
      Keywords: Amyotrophic lateral sclerosis
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012706
      Issue No: Vol. 97, No. 16 (2021)
       
  • Building a Fence Around Brain Death: The Shielded-Brain Formulation

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      Authors: Gelb; D. J.
      Pages: 780 - 784
      Abstract: The concept of brain death was proposed more than 50 years ago, and it has been incorporated in laws and clinical practice, but it remains a source of confusion, debate, and litigation. Because of persistent variability in clinical standards and ongoing controversies regarding policies, the Uniform Law Commission, which drafted the Uniform Determination of Death Act in 1980, has appointed a committee to study whether the act should be revised. This article reviews the history of the concept of brain death and its philosophical underpinnings, summarizes the objections that have been raised to the prevailing philosophical formulations, and proposes a new formulation that addresses those objections while preserving current practices.
      Keywords: Coma, Critical care, Brain death
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012641
      Issue No: Vol. 97, No. 16 (2021)
       
  • Clinical and Neuroimaging Features of Encephalocraniocutaneous Lipomatosis

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      Authors: de Moraes, M. P. M; Ferreira de Abrantes, F, Tonholo Silva, T. Y, Pedroso, J. L, Marussi, V. H. R, Meneses, A, Barsottini, O. G. P.
      Pages: 785 - 786
      Abstract: A 60-year-old woman with cognitive developmental delay presented with childhood-onset seizures and cutaneous abnormalities evolving over the left hemiface and eye. Examination showed alopecia, naevus psiloliparus, subcutaneous fat accumulation, and proptosis (Figure 1). Brain MRI disclosed intracranial lipomatosis and left hemimegalencephaly (Figure 2), and encephalocraniocutaneous lipomatosis (ECCL) was confirmed.
      Keywords: Clinical neurology examination, Intelligence, EEG; see Epilepsy/Seizures, Other neurocutaneous disorders
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012704
      Issue No: Vol. 97, No. 16 (2021)
       
  • Pearls & Oy-sters: Labyrinthine Infarction Mimicking Vestibular Neuritis

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      Authors: Nam, H.-W; Yoo, D, Lee, S.-U, Choi, J.-Y, Yu, S, Kim, J.-S.
      Pages: 787 - 790
      Abstract: Acute unilateral audiovestibulopathy is often caused by inflammatory disorders involving the labyrinth.
      Keywords: All Neurotology, Audition, Tinnitus, Vertigo, Infarction
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012297
      Issue No: Vol. 97, No. 16 (2021)
       
  • Editors' Note: Intravenous Immunoglobulin Therapy in Patients With Painful
           Idiopathic Small Fiber Neuropathy

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      Authors: Lewis, A; Galetta, S.
      Pages: 791 - 791
      Abstract: In "Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy," Geerts et al. report no significant difference in Pain Intensity Numerical Rating Scale score for patients with idiopathic small fiber neuropathy (I-SFN) 12 weeks after randomized administration of IVIG or placebo.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012707
      Issue No: Vol. 97, No. 16 (2021)
       
  • Reader Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

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      Authors: Song, P; Xu, X.
      Pages: 791 - 792
      Abstract: We read with great interest the recent article by Margot Geerts et al.1 The authors evaluated the efficacy of IV immunoglobulin (IVIG) in patients with idiopathic small fiber neuropathy (I-SFN). Immunologic mechanisms may be involved in the pathophysiology of some I-SFN.2 Previous studies showed that IVIG treatment is effective against immune-mediated SFN3-5; however, they found that IVIG treatment was not effective in 30 patients with I-SFN. Previous studies on SFN used IVIG for at least 5 consecutive days, and the pain was evaluated immediately after treatment.3-5 Alternatively, IVIG was administrated in this study for 2 consecutive days with a 3-week interval for 4 rounds based on a regimen for chronic inflammatory demyelinating polyneuropathy but not for SFN. The pain was evaluated at weeks 1 and 12 and month 6 after the first dose.1 Therefore, if the authors followed the protocols for SFN as in previous studies,3-5 they may have different conclusions on IVIG efficacy. The authors should compare the efficacy of 2 regimens about IVIG usage.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012711
      Issue No: Vol. 97, No. 16 (2021)
       
  • Author Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

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      Authors: Geerts, M; de Greef, B. T. A, Sopacua, M, van Kuijk, S. M. J, Hoeijmakers, J. G. J, Faber, C. G, Merkies, I. S. J.
      Pages: 792 - 792
      Abstract: We would like to respond to the comments made by Pu Song and Xingshun Xu about the chosen administration of IV immunoglobulin (IVIG), which is based on a regimen for chronic inflammatory demyelinating polyneuropathy (CIPD). These authors also expressed doubts about our conclusion that IVIG was not effective in patients with painful with idiopathic small fiber neuropathy (I-SFN).
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012712
      Issue No: Vol. 97, No. 16 (2021)
       
  • Reader Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

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      Authors: Gemignani; F.
      Pages: 793 - 793
      Abstract: Geerts et al.1 showed, in a randomized controlled trial, that intravenous immunoglobulin (IVIg) has no significant effect on pain in patients with painful idiopathic small fiber neuropathy (SFN). A potential exception is represented by patients with idiopathic SFN with a nonlength-dependent (NLD) phenotype, as they were excluded by the design of the study.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012709
      Issue No: Vol. 97, No. 16 (2021)
       
  • Author Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

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      Authors: Geerts, M; de Greef, B. T. A, Sopacua, M, van Kuijk, S. M. J, Hoeijmakers, J. G. J, Faber, C. G, Merkies, I. S. J.
      Pages: 793 - 794
      Abstract: We would like to respond to the comments made by Mr. Franco Gemignani on our article1 regarding the nonlength-dependent small fiber neuropathy (NLD-SFN) phenotype as a potential condition that could benefit from intravenous immunoglobulin therapy (IVIg). We fully agree that future studies in NLD-SFN would be needed to determine whether IVIg would have a therapeutic role in these conditions. There are some open-label clinical studies suggesting a potential therapeutic role,1,2 as well as distal SFN case-studies showing a positive effect of IVIg, whereas the results of our RCT showed that IVIg treatment had no significant effect on pain in patients with painful idiopathic SFN. This underlines the pitfalls of case reports or open case studies and the importance of double-blind randomized trials.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012710
      Issue No: Vol. 97, No. 16 (2021)
       
  • Reader Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

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      Authors: Wilder-Smith, E; Spoendlin, J.
      Pages: 794 - 794
      Abstract: We read with interest the results of the first RCT evaluating the efficacy of intravenous immunoglobulin therapy (IVIg) in patients with idiopathic small fiber neuropathy (I-SFN) and congratulate the authors for this important trial.1
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012713
      Issue No: Vol. 97, No. 16 (2021)
       
  • Author Response: Intravenous Immunoglobulin Therapy in Patients With
           Painful Idiopathic Small Fiber Neuropathy

    • Free pre-print version: Loading...

      Authors: Geerts, M; de Greef, B. T. A, Sopacua, M, van Kuijk, S. M. J, Hoeijmakers, J. G. J, Faber, C. G, Merkies, I. S. J.
      Pages: 794 - 795
      Abstract: We would like to respond to the comments made by Drs. Wilder-Smith and Spoendlin on our study1 related to the heterogeneous group of patients with idiopathic small fiber neuropathy (I-SFN), who might benefit from intravenous immunoglobulin (IVIg) therapy. Before study entry, all patients had a diagnostic SFN workup, which includes tests for several associated conditions, as mentioned in the inclusion criteria.1 Of 257 patients, there were 193 patients who did not meet the inclusion criteria, 41 of which (16%) were excluded because of known autoimmune conditions, which is in line with previous findings.2 Future studies are needed to definitely determine whether IVIg may have a therapeutic role in the treatment of autoimmune conditions that cause SFN. There are some open-label clinical studies suggesting a potential therapeutic role,3,4 but stronger evidence from a randomized study is needed. Our RCT showed that IVIg treatment had no significant effect on pain in patients with painful I-SFN and should therefore be discouraged.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012714
      Issue No: Vol. 97, No. 16 (2021)
       
  • Prospective Quantification of CSF Biomarkers in Antibody-Mediated
           Encephalitis

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      Pages: 795 - 795
      Abstract: In the article "Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis" by Day et al.,1 the second author's name should be listed as "Melanie L. Yarbrough." The authors regret the error.
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012472
      Issue No: Vol. 97, No. 16 (2021)
       
  • Cross-Sectional Profile of Most Bothersome Problems as Reported Directly
           by Individuals With Parkinson's Disease (2697)

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      Pages: 795 - 795
      PubDate: 2021-10-18T12:45:26-07:00
      DOI: 10.1212/WNL.0000000000012412
      Issue No: Vol. 97, No. 16 (2021)
       
 
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