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Beyond Mismatch, Perfusion Imaging Predicts Infarct Growth Before Revascularization.
Olivot, Jean Marc MD, PhD
doi : 10.1212/WNL.0000000000011271
pg. 41-42
What's Happening in Neurology(R) Neuroimmunology & Neuroinflammation.
doi : 10.1212/WNL.0000000000011260
pg. 57
Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.
Papp, Viktoria MD, PhD; Magyari, Melinda MD, PhD; Aktas, Orhan MD; Berger, Thomas MD; Broadley, Simon A. MD, PhD; Cabre, Philippe MD; Jacob, Anu MD; Kira, Jun-ichi MD, PhD; Leite, Maria Isabel MD, DPhil; Marignier, Romain MD, PhD; Miyamoto, Katsuichi MD, PhD; Palace, Jacqueline MD; Saiz, Albert MD, PhD; Sepulveda, Maria MD; Sveinsson, Olafur MD, PhD; Illes, Zsolt MD, PhD
doi : 10.1212/WNL.0000000000011153
pg. 59-77
AB Objective: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies. Methods: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence. Results: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time. Conclusion: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors. (C) 2021 American Academy of Neurology
Technical Difficulties in the Time of COVID.
Golomb, Meredith Rose MD, MSc
doi : 10.1212/WNL.0000000000011074
pg. 78
Child Neurology: Pheochromocytoma Unveiled by Reversible Cerebral Vasoconstriction Syndrome in a Child With Neurofibromatosis Type 1.
Lagace, Micheline MD; Graeber, Brendon MD, FAAP, DABR; Huh, Linda MD, FRCPC
doi : 10.1212/WNL.0000000000010801
pg. 79-82
Editors' Note: Neuro R2 Score: Predicting High-Risk Neurologic Readmissions Within 30 Days.
Lewis, Ariane MD; Galetta, Steven MD
doi : 10.1212/WNL.0000000000011262
pg. 83
Reader Response: Neuro R2 Score: Predicting High-Risk Neurologic Readmissions Within 30 Days.
Hunter, Rachel Maree
doi : 10.1212/WNL.0000000000011265
pg. 83-84
Reader Response: Neuro R2 Score: Predicting High-Risk Neurologic Readmissions Within 30 Days.
Majersik, Jennifer J.
doi : 10.1212/WNL.0000000000011267
pg. 84
Author Response: Neuro R2 Score: Predicting High-Risk Neurologic Readmissions Within 30 Days.
Freeman, William D.; Peacock, Sarah H.
doi : 10.1212/WNL.0000000000011266
pg. 84-85
Association of Collateral Status and Ischemic Core Growth in Patients With Acute Ischemic Stroke.
Lin, Longting PhD *; Yang, Jianhong MD *; Chen, Chushuang PhD; Tian, Huiqiao PhD; Bivard, Andrew PhD; Spratt, Neil J. MD; Levi, Christopher R. MD; Parsons, Mark W. PhD, MD; on behalf of the INSPIRE study group
doi : 10.1212/WNL.0000000000011258
pg. e161-e170
AB Objective: To test the hypothesis that patients with acute ischemic stroke with poorer collaterals would have faster ischemic core growth, we included 2 cohorts in the study: cohort 1 of 342 patients for derivation and cohort 2 of 414 patients for validation. Methods: Patients with acute ischemic stroke with large vessel occlusion were included. Core growth rate was calculated by the following equation: core growth rate = acute core volume on CT perfusion (CTP)/time from stroke onset to CTP. Collateral status was assessed by the ratio of severe hypoperfusion volume within the hypoperfusion region of CTP. The CTP collateral index was categorized in tertiles; for each tertile, core growth rate was summarized as median and interquartile range. Simple linear regressions were then performed to measure the predictive power of CTP collateral index in core growth rate. Results: For patients allocated to good collateral on CTP (tertile 1 of collateral index), moderate collateral (tertile 2), and poor collateral (tertile 3), the median core growth rate was 2.93 mL/h (1.10-7.94), 8.65 mL/h (4.53-18.13), and 25.41 mL/h (12.83-45.07), respectively. Increments in the collateral index by 1% resulted in an increase of core growth by 0.57 mL/h (coefficient 0.57, 95% confidence interval [0.46, 0.68], p < 0.001). The relationship of core growth and CTP collateral index was validated in cohort 2. An increment in collateral index by 1% resulted in an increase of core growth by 0.59 mL/h (coefficient 0.59 [0.48-0.71], p < 0.001) in cohort 2. Conclusion: Collateral status is a major determinant of ischemic core growth. (C) 2021 American Academy of Neurology
Blood Pressure During Endovascular Treatment Under Conscious Sedation or Local Anesthesia.
Samuels, Noor MD; van de Graaf, Rob A. MD; van den Berg, Carlijn A.L. BSc; Nieboer, Daan MSc; Eralp, Ismail MD, PhD; Treurniet, Kilian M. MD; Emmer, Bart J. MD, PhD; Immink, Rogier V. MD, PhD; Majoie, Charles B.L.M. MD, PhD; van Zwam, Wim H. MD, PhD; Bokkers, Reinoud P.H. MD, PhD; Uyttenboogaart, Maarten MD, PhD; van Hasselt, Boudewijn A.A.M. MD; Muhling, Jorg MD, PhD; Burke, James F. MD; Roozenbeek, Bob MD, PhD; van der Lugt, Aad MD, PhD; Dippel, Diederik W.J. MD, PhD; Lingsma, Hester F. PhD; van Es, Adriaan C.G.M. MD, PhD
doi : 10.1212/WNL.0000000000011006
pg. e171-e181
AB Objective: To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT). Methods: Patients treated in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry centers with CS or LA as preferred anesthetic approach during EVT for ischemic stroke were analyzed. First, we evaluated the effect of CS on area under the threshold (AUT), relative difference between baseline and lowest procedural mean arterial pressure ([INCREMENT]LMAP), and procedural BP trend, compared to LA. Second, we assessed the association between BP and functional outcome (modified Rankin Scale [mRS]) with multivariable regression. Lastly, we evaluated whether BP explained the effect of CS on mRS. Results: In 440 patients with available BP data, patients treated under CS (n = 262) had larger AUTs (median 228 vs 23 mm Hg*min), larger [INCREMENT]LMAP (median 16% vs 6%), and a more negative BP trend (-0.22 vs -0.08 mm Hg/min) compared to LA (n = 178). Larger [INCREMENT]LMAP and AUTs were associated with worse mRS (adjusted common odds ratio [acOR] per 10% drop 0.87, 95% confidence interval [CI] 0.78-0.97, and acOR per 300 mm Hg*min 0.89, 95% CI 0.82-0.97). Patients treated under CS had worse mRS compared to LA (acOR 0.59, 95% CI 0.40-0.87) and this association remained when adjusting for [INCREMENT]LMAP and AUT (acOR 0.62, 95% CI 0.42-0.92). Conclusions: Large BP drops are associated with worse functional outcome. However, BP drops do not explain the worse outcomes in the CS group. (C) 2021 American Academy of Neurology
Association of Cerebral Small Vessel Disease and Cognitive Decline After Intracerebral Hemorrhage.
Pasi, Marco MD *; Sugita, Lansing BS *; Xiong, Li MD, PhD; Charidimou, Andreas MD, PhD; Boulouis, Gregoire MD, MSc; Pongpitakmetha, Thanakit MD; Singh, Sanjula BS; Kourkoulis, Christina BS; Schwab, Kristin BA; Greenberg, Steven M. MD, PhD; Anderson, Christopher D. MD, MMSc; Gurol, M. Edip MD, MSc; Rosand, Jonathan MD, MSc; Viswanathan, Anand MD, PhD; Biffi, Alessandro MD
doi : 10.1212/WNL.0000000000011050
pg. e182-e192
AB Objective: To determine whether MRI-based cerebral small vessel disease (CSVD) burden assessment, in addition to clinical and CT data, improved prediction of cognitive impairment after spontaneous intracerebral hemorrhage (ICH). Methods: We analyzed data from ICH survivors enrolled in a single-center prospective study. We employed 3 validated CSVD burden scores: global, cerebral amyloid angiopathy (CAA)-specific, and hypertensive arteriopathy (HTNA)-specific. We quantified cognitive performance by administering the modified Telephone Interview for Cognitive Status test. We utilized linear mixed models to model cognitive decline rates, and survival models for new-onset dementia. We calculated CSVD scores' cutoffs to maximize predictive performance for dementia diagnosis. Results: We enrolled 612 ICH survivors, and followed them for a median of 46.3 months (interquartile range 35.5-58.7). A total of 214/612 (35%) participants developed dementia. Higher global CSVD scores at baseline were associated with faster cognitive decline (coefficient -0.25, standard error [SE] 0.02) and dementia risk (sub-hazard ratio 1.35, 95% confidence interval 1.10-1.65). The global score outperformed the CAA and HTNA scores in predicting post-ICH dementia (all p < 0.05). Compared to a model including readily available clinical and CT data, inclusion of the global CSVD score resulted in improved prediction of post-ICH dementia (area under the curve [AUC] 0.89, SE 0.02 vs AUC 0.81, SE 0.03, p = 0.008 for comparison). Global CSVD scores >=2 had highest sensitivity (83%) and specificity (91%) for dementia diagnosis. Conclusions: A validated MRI-based CSVD score is associated with cognitive performance after ICH and improved diagnostic accuracy for predicting new onset of dementia. (C) 2021 American Academy of Neurology
Association of Enlarged Perivascular Spaces and Measures of Small Vessel and Alzheimer Disease.
Gertje, Eske Christiane MD *; van Westen, Danielle MD, PhD *; Panizo, Clara MD; Mattsson-Carlgren, Niklas MD, PhD +; Hansson, Oskar MD, PhD +
doi : 10.1212/WNL.0000000000011046
pg. e193-e202
AB Objective: To investigate the relationship between enlarged perivascular spaces (EPVS) and measures of Alzheimer disease (AD), small vessel disease (SVD), cognition, vascular risk factors, and neuroinflammation, we tested associations between EPVS and different relevant neuroimaging, biochemical, and cognitive variables in 778 study participants. Methods: Four hundred ninety-nine cognitively unimpaired (CU) individuals, 240 patients with mild cognitive impairment, and 39 patients with AD from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study were included. EPVS with diameter >1 mm in centrum semiovale (CSO), basal ganglia (BG), and hippocampus (HP); hippocampal volume; white matter lesions (WML); and other SVD markers were determined from MRI. CSF levels of [beta]-amyloid42 (A[beta]42), phosphorylated tau, total tau, and neuroinflammatory markers; amyloid accumulation determined with [18F]-flutemetamol PET; and vascular risk factors and results from cognitive tests were determined and collected. Results: EPVS in CSO, BG, and HP were associated with WML volume and Fazekas score in individuals without dementia. No associations were found between EPVS and CSF A[beta]42, total tau and phosphorylated tau, neuroinflammatory markers, vascular risk factors, and cognitive tests. EPVS in HP were associated with hippocampal atrophy. In a matched group of individuals with AD and CU, EPVS in HP were associated with AD diagnosis. Conclusions: EPVS are related to SVD, also in early disease stages, but the lack of correlation with cognition suggests that their importance is limited. Our data do not support a role for EPVS in early AD pathogenesis. (C) 2021 American Academy of Neurology
Efficacy of High-Intensity Aerobic Exercise on Brain MRI Measures in Multiple Sclerosis.
Langeskov-Christensen, Martin PhD; Grondahl Hvid, Lars PhD; Nygaard, Mikkel Karl Emil MSc; Ringgaard, Steffen PhD; Boye Jensen, Henrik MD, PhD; Hvilsted Nielsen, Helle MD, PhD; Petersen, Thor MD, DMSc; Stenager, Egon MD; Fristed Eskildsen, Simon PhD; Dalgas, Ulrik PhD
doi : 10.1212/WNL.0000000000011241
pg. e203-e213
AB Objective: To determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS). Methods: We conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired patients with MS aged 18-65 years were randomized (1:1). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle. Results: Eighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% confidence interval [CI] -0.27 to 0.51, p = 0.55). In contrast, cardiorespiratory fitness (+3.5 mL O2/min/kg, 2.0 to 5.1, p < 0.01) and annualized relapse rate (0.00, 0.00-0.07 vs +0.45, 0.28 to 0.61, p < 0.01) improved in the exercise group. Conclusion: These findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS and it did not lead to a statistically significant difference in gray matter parenchymal fraction. PAE led to improvements in cardiorespiratory fitness and a lower relapse rate. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted. Clinicaltrials.gov identifier: NCT02661555. Classification of evidence: This study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate. (C) 2021 American Academy of Neurology
Treatment Response Score to Glatiramer Acetate or Interferon Beta-1a.
Bovis, Francesca PhD; Kalincik, Tomas MD; Lublin, Fred MD; Cutter, Gary PhD; Malpas, Charles PhD; Horakova, Dana MD; Havrdova, Eva Kubala MD; Trojano, Maria MD; Prat, Alexandre MD; Girard, Marc MD; Duquette, Pierre MD; Onofrj, Marco MD; Lugaresi, Alessandra MD; Izquierdo, Guillermo MD; Eichau, Sara MD; Patti, Francesco MD; Terzi, Murat MD; Grammond, Pierre MD; Bergamaschi, Roberto MD; Sola, Patrizia MD; Ferraro, Diana MD; Ozakbas, Serkan MD; Iuliano, Gerardo MD; Boz, Cavit MD; Hupperts, Raymond MD; Grand'Maison, Francois MD; Oreja-Guevara, Celia MD; van Pesch, Vincent MD; Cartechini, Elisabetta MD; Petersen, Thor MD; Altintas, Ayse MD; Soysal, Aysun MD; Ramo-Tello, Cristina MD; McCombe, Pamela MD; Turkoglu, Recai MD; Butzkueven, Helmut MBBS; Wolinsky, Jerry S. MD; Solaro, Claudio MD; Sormani, Maria Pia PhD
doi : 10.1212/WNL.0000000000010991
pg. e214-e227
AB Objective: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-[beta]-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-[beta]-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. Results: The overall ARR ratio of GA to IFN-[beta]-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-[beta]-1a: in the trial, patients with the largest benefit from GA vs IFN-[beta]-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001). Conclusions: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-[beta]-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice. (C) 2021 American Academy of Neurology
Mexiletine in Myotonic Dystrophy Type 1: A Randomized, Double-Blind, Placebo-Controlled Trial.
Heatwole, Chad MD, MS-CI; Luebbe, Elizabeth MS; Rosero, Spencer MD; Eichinger, Katy PhD, DPT, NCS; Martens, William BA; Hilbert, James MS; Dekdebrun, Jeanne MS; Dilek, Nuran MS; Zizzi, Christine BA; Johnson, Nicholas MD; Puwanant, Araya MD; Tawil, Rabi MD; Schifitto, Giovanni MD, MS; Beck, Christopher A. PhD; Richeson, J. Franklin MD; Zareba, Wojciech MD, PhD; Thornton, Charles MD; McDermott, Michael P. PhD; Moxley, Richard III MD
doi : 10.1212/WNL.0000000000011002
pg. e228-e240
AB Objective: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). Methods: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months. Results: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants. Conclusions: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period. Classification of Evidence: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months. (C) 2021 American Academy of Neurology
Sleep-Disordered Breathing in Adult Patients With Mitochondrial Diseases: A Cohort Study.
Primiano, Guido MD; Brunetti, Valerio MD; Vollono, Catello MD, PhD; Losurdo, Anna MD; Moroni, Rossana PhD; Della Marca, Giacomo MD; Servidei, Serenella MD
doi : 10.1212/WNL.0000000000011005
pg. e241-e249
AB Objective: To describe the prevalence and characteristics of sleep-disordered breathing (SDB) in a large cohort of patients with genetically confirmed mitochondrial diseases. Methods: This is a prospective observational study performed at the Neurophysiopatology Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS. All participants had a defined mitochondrial disease and were investigated by full-night polysomnography. Results: One hundred three consecutive patients were enrolled. SDB was demonstrated in 49 patients (47.6%). Regarding phenotypes, we found differences in distribution between the groups: patients affected by progressive external ophthalmoplegia with single or multiple mtDNA deletions frequently had obstructive apneas (50% and 43.8%) or REM-related hypoventilation when associated with m.3243A>G mutations (75%). Furthermore, a high percentage of participants with maternally inherited diabetes and deafness and myoclonic epilepsy with ragged-red fibers syndromes were characterized by obstructive sleep apnea and REM-related hypoventilation, respectively. In contrast to what has been described in previous studies, central sleep apnea was rarely reported in our cohort. Conclusions: SDB has a higher prevalence in mitochondrial diseases compared to general population-based data. Overall, these results suggest that patients characterized by a specific phenotype-genotype combination are most at risk of developing a specific subgroup of SDB. The early identification of this disorder is crucial in the management of these fragile patients. (C) 2021 American Academy of Neurology
REM Sleep Behavior Disorder in Children With Type 1 Narcolepsy Treated With Sodium Oxybate.
Antelmi, Elena MD, PhD; Filardi, Marco PsyD, PhD; Pizza, Fabio MD, PhD; Vandi, Stefano RPSGT; Moresco, Monica MSc, PhD; Franceschini, Christian PsyD, PhD; Tinazzi, Michele MD, PhD; Ferri, Raffaele MD, PhD; Plazzi, Giuseppe MD, PhD
doi : 10.1212/WNL.0000000000011157
pg. e250-e254
AB Objective: To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1). Methods: Nineteen children and adolescents with NT1 (9 female, mean age 12.5 +/- 2.7 years, mean disease duration 3.4 +/- 1.6 years) underwent neurologic investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. v-PSG was independently analyzed by 2 sleep experts to rate RBD episodes. RSWA was automatically computed by means of the validated REM sleep atonia index (RAI). Results: Compared to baseline, RAI significantly improved (p < 0.05) and complex movements during REM sleep were remarkably reduced after stable treatment with SO. Compared to baseline, children also reported improvement in clinical complaints and showed a different nighttime sleep-stage architecture. Conclusions: RBD and RSWA improved after treatment with SO, pointing to a direct role of the drug in modulating motor control during REM sleep. Classification of Evidence: This study offers Class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in children with NT1 because of the absence of a control group. (C) 2021 American Academy of Neurology
Association of Age at Onset and First Symptoms With Disease Progression in Patients With Metachromatic Leukodystrophy.
Kehrer, Christiane MD *; Elgun, Saskia *; Raabe, Christa; Bohringer, Judith PhD; Beck-Wodl, Stefanie PhD; Bevot, Andrea MD; Kaiser, Nadja MD; Schols, Ludger MD, PhD; Krageloh-Mann, Ingeborg MD, PhD; Groeschel, Samuel MD, PhD
doi : 10.1212/WNL.0000000000011047
pg. e255-e266
AB Objective: To compare disease progression between different onset forms of metachromatic leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression. Methods: Clinical, genetic, and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI; onset age <=2.5 years), early-juvenile (EJ; onset age 2.6 to <6 years), late-juvenile (LJ; onset age 6 to <16 years), and adult (onset age >=16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding. Results: Ninety-seven patients with MLD were enrolled. Patients with LI (n = 35) and EJ (n = 18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n = 38) and adult-onset (n = 6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independently of their age at onset. A certain genotype-phenotype correlation was observed. Conclusions: In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counseling and therapy. Classification of Evidence: This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression. (C) 2021 American Academy of Neurology
Immunomodulation With Azathioprine Therapy in Rasmussen Syndrome: A Multimodal Evaluation.
Pellegrin, Serena MD; Baldeweg, Torsten MD; Pujar, Suresh MD; D'Arco, Felice MD; Cantalupo, Gaetano MD; Varadkar, Sophia MD, PhD *; Cross, J. Helen MB, ChB, PhD *
doi : 10.1212/WNL.0000000000011004
pg. e267-e279
AB Objective: To verify safety and efficacy of the corticosteroid-sparing drug azathioprine (AZA) in Rasmussen syndrome (RS), we retrospectively analyzed a cohort of patients with RS recruited in a single pediatric neuroscience center. Methods: We compared outcomes in 30 patients with RS who received AZA with 23 patients who were not treated with this drug. We used a multimodal approach to correlate therapy with clinical features (seizures, epilepsia partialis continua [EPC], hemiparesis) and neuroimaging markers of progressive brain atrophy. Results: AZA was well tolerated; only 1 patient discontinued treatment due to pancytopenia. In 27 of 30 patients receiving AZA, all of whom were corticosteroid responders, corticosteroid therapy could be weaned or reduced without worsening of seizures in 89%. Patients receiving AZA had a lower prevalence of EPC (42% vs 67% in controls) and hemiparesis (64% vs 92%, respectively). Cox regression showed for the AZA group compared to controls a delayed time to (1) EPC ([almost equal to]2 years, exp[B] = 0.295, 95% confidence interval [CI] 0.108-0.807; p = 0.017), (2) hemiparesis ([almost equal to]1 year, exp[B] = 0.315, 95% CI 0.137-0.724; p = 0.007), and (3) surgery ([almost equal to]2 years, exp[B] = 2.068, 95% CI 1.012-4.227; p = 0.046). However, there were no group differences in cognitive decline over time (IQ change per year) or in hemispheric gray matter atrophy on serial MRI scans. Conclusion: AZA treatment appears to slow clinical progression of RS in steroid responders; this will give the greatest advantage in patients in the early stages of the disease in whom surgical decision-making may require further time. Classification of Evidence: This study provides Class III evidence that for pediatric patients with RS AZA is well tolerated and slows hemiparesis and appearance of EPC. (C) 2021 American Academy of Neurology
The Ictal Signature of Thalamus and Basal Ganglia in Focal Epilepsy: A SEEG Study.
Pizzo, Francesca MD, PhD; Roehri, Nicolas PhD; Giusiano, Bernard MD, PhD; Lagarde, Stanislas MD, PhD; Carron, Romain MD, PhD; Scavarda, Didier MD, PhD; McGonigal, Aileen MD, PhD; Filipescu, Cristina MD; Lambert, Isabelle MD, PhD; Bonini, Francesca MD, PhD; Trebuchon, Agnes MD, PhD; Benar, Christian-George PhD *; Bartolomei, Fabrice MD, PhD *
doi : 10.1212/WNL.0000000000011003
pg. e280-e293
AB Objective: To determine the involvement of subcortical regions in human epilepsy by analyzing direct recordings from these regions during epileptic seizures using stereo-EEG (SEEG). Methods: We studied the SEEG recordings of a large series of patients (74 patients, 157 seizures) with an electrode sampling the thalamus and in some cases also the basal ganglia (caudate nucleus, 22 patients; and putamen, 4 patients). We applied visual analysis and signal quantification methods (Epileptogenicity Index [EI]) to their ictal recordings and compared electrophysiologic with clinical data. Results: We found that in 86% of patients, thalamus was involved during seizures (visual analysis) and 20% showed high values of epileptogenicity (EI >0.3). Basal ganglia may also disclose high values of epileptogenicity (9% in caudate nucleus) but to a lesser degree than thalamus (p < 0.01). We observed different seizure onset patterns including low voltage high frequency activities. We found high values of thalamic epileptogenicity in different epilepsy localizations, including opercular and motor epilepsies. We found no difference between epilepsy etiologies (cryptogenic vs malformation of cortical development, p = 0.77). Thalamic epileptogenicity was correlated with the extension of epileptogenic networks (p = 0.02, [rho] 0.32). We found a significant effect (p < 0.05) of thalamic epileptogenicity regarding the postsurgical outcome (higher thalamic EI corresponding to higher probability of surgical failure). Conclusions: Thalamic involvement during seizures is common in different seizure types. The degree of thalamic epileptogenicity is a possible marker of the epileptogenic network extension and of postsurgical prognosis. (C) 2021 American Academy of Neurology
CSF Biomarkers in Patients With COVID-19 and Neurologic Symptoms: A Case Series.
Eden, Arvid MD, PhD *; Kanberg, Nelly MD *; Gostner, Johanna PhD; Fuchs, Dietmar PhD; Hagberg, Lars MD, PhD; Andersson, Lars-Magnus MD, PhD; Lindh, Magnus MD, PhD; Price, Richard W. MD; Zetterberg, Henrik MD, PhD; Gisslen, Magnus MD, PhD
doi : 10.1212/WNL.0000000000010977
pg. e294-e300
AB Objective: To explore whether hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neurologic symptoms have evidence of CNS infection, inflammation, and injury using CSF biomarker measurements. Methods: We assessed CSF SARS-CoV-2 RNA along with CSF biomarkers of intrathecal inflammation (CSF white blood cell count, neopterin, [beta]2-microglobulin, and immunoglobulin G index), blood-brain barrier integrity (albumin ratio), and axonal injury (CSF neurofilament light chain protein [NfL]) in 6 patients with moderate to severe coronavirus disease 2019 (COVID-19) and neurologic symptoms who had undergone a diagnostic lumbar puncture. Neurologic symptoms and signs included features of encephalopathies (4 of 6), suspected meningitis (1 of 6), and dysgeusia (1 of 6). SARS-CoV-2 infection was confirmed by real-time PCR analysis of nasopharyngeal swabs. Results: SARS-CoV-2 RNA was detected in the plasma of 2 patients (cycle threshold [Ct] value 35.0-37.0) and in CSF at low levels (Ct 37.2, 38.0, 39.0) in 3 patients in 1 but not in a second real-time PCR assay. CSF neopterin (median 43.0 nmol/L) and [beta]2-microglobulin (median 3.1 mg/L) were increased in all. Median immunoglobulin G index (0.39), albumin ratio (5.35), and CSF white blood cell count (<3 cells/[micro]L) were normal in all, while CSF NfL was elevated in 2 patients. Conclusion: Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection. (C) 2021 American Academy of Neurology
Clinical Reasoning: A 6-Year-Old Boy With Muscle Twitching.
Lewis, Hannah Smashey MD; Srinivasa Sekaran, Balaji Subramanian MBBS; Stefans, Vikki MD; Veerapandiyan, Aravindhan MD
doi : 10.1212/WNL.0000000000010746
pg. e301-e304
Teaching NeuroImages: Central Serous Chorioretinopathy After Corticosteroid Treatment for Optic Neuritis.
Ling, Jennifer MSc; Micieli, Jonathan A. MD, CM
doi : 10.1212/WNL.0000000000010807
pg. e305-e306
Teaching Neuroimages: COVID-19-Associated Acute Disseminated Encephalomyelitis With Corpus Callosal Hemorrhage.
Green, Christopher FRCR *; Morrison, Hamish MRCP *; Smith, Paul FRCR; Golestani, Farhad FRCP, MD; Rice, Claire FRCP, PhD; Coulthard, Elizabeth FRCP, PhD; Searle, Julie FRCR; Lyburn, Iain FRCR
doi : 10.1212/WNL.0000000000011001
pg. e307-e308
