PracticeUpdate: Neurology - Winter 2018

VOL. 3 • NO. 3 • WINTER 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4680

Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy

Australian & New Zealand Association of Neurologists Annual Scientific Meeting 2018 International Congress on Neuromuscular Diseases 2018

JOURNAL SCANS MRI-Guided Thrombolysis for Stroke With Unknown Time of Onset

Restarting Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage: Functional Outcomes

Functional Neurological Disorders in Parkinson Disease

restart the conversation. it’s time to prevent migraine. 1 Aimovig® is the 1st TGA approved therapy specifically designed for the prophylaxis of migraine in adults by targeting and blocking the CGRP* receptor. 1

Your migraine patients may be eligible for this new treatment through the AIMOVIG® PRODUCT FAMILIARISATION PROGRAM (PFP)

Find out more about Aimovig® and the PFP • To register for the Aimovig® PFP, visit myaimprogram.com.au • Or contact your Novartis Representative for more information • Patient enrolments will start in October

*Calcitonin gene-related peptide. Reference: 1 . Aimovig® Product Information, 2 July 2018. Novartis Pharmaceuticals Australia Pty Limited. ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park, NSW 2113. © 2018 Novartis Pharmaceuticals Australia Pty Limited. AU7109, August 2018. ZEST/NOVSY1213/0818 For the most up to date Product Information go to http://www.novartis.com.au/products_healthcare.html PBS information: This product is not listed on the PBS. See TGA approved Product Information before prescribing. TGA approved Product Information available on request. Aimovig (erenumab) Indication: Aimovig is indicated for prophylaxis of migraine in adults. Contraindications: Hypersensitivity to erenumab or to any of the excipients. Precautions: Traceability: In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product should be clearly recorded. Use in hepatic impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment. Use in renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Use in the elderly: Dose adjustments are not recommended due to insufficient data to determine whether geriatric patients respond differently from younger subjects. Paediatric use: The safety and effectiveness of Aimovig has not been studied in paediatric patients. Pregnancy: Safety has not been established. Aimovig should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lactation: It is not known whether erenumab is present in human milk. A decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the benefit-risk assessment for the mother and the infant. Females and males of reproductive potential: No human data are available. There were no adverse effects on surrogate markers of fertility in monkeys. Interactions: Erenumab is not metabolised by cytochrome P450 enzymes and is unlikely to cause marked changes in pro-inflammatory cytokines that may impact cytochrome P450 enzyme expression or activity. Interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Aimovig did not affect the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate and had no effect on the pharmacokinetics of sumatriptan. Concomitant administration of Aimovig with sumatriptan had no effect on resting blood pressure compared with sumatriptan alone. Dosage: The recommended dose of Aimovig is 70mg injected subcutaneously once every 4 weeks. Some patients may benefit from a dosage of 140 mg injected subcutaneously once every 4 weeks. Aimovig should be initiated under the guidance of a neurologist or specialist in the management of migraine. Treatment response should be evaluated by the prescriber after 8-12 weeks as recommended by the current Australian treatment guideline. Aimovig is intended for patient self-administration in the abdomen, thigh, or, if someone else is giving the injection, also into the outer area of the upper arm. Administration should be performed by an individual who has been trained to administer the product. The need for treatment continuation should be re-evaluated within regular intervals of 3-6 months as recommended by the current treatment guideline. The needle cover of Aimovig prefilled syringe and autoinjector/pen contain dry natural rubber, which may cause allergic reactions in individuals sensitive to latex. Adverse effects: Common: Injection site reactions, constipation, muscle spasm, pruritus. Description of selected adverse reactions: Injections site reactions include injection site pain, injection site erythema and injection site pruritus. A majority of injection site reactions were mild and transient. Immunogenicity: In pivotal studies the incidence of anti-erenumab antibody was 6.3% for the 70 mg dose (in-vitro neutralizing activity in 3 patients) and 2.6% for the 140 mg dose (no patients with in-vitro neutralizing activity). There was no impact of anti-erenumab antibody development on efficacy or safety of erenumab. (aim280618m) .

CONTENTS 3

EDITOR’S PICKS 5 Emergency Department Neuroimaging for Red Flag Findings in Children With Headaches

COVER 9 Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy Comment by Amal Satte MD

EXPERT OPINION 12 Cerebral Blood Flow Changes After Radiation Therapy Identifies Pseudoprogression in Diffuse Intrinsic

6 MRI-Guided Thrombolysis for Stroke With Unknown Time of Onset 7 The Diagnostic Dilemma of Traumatic Lumbar Puncture 7 CNS-LCH: Common Hematopoietic Origin For LCH-Associated Neurodegeneration and Mass Lesions 8 α-Linolenic Acid is Associated With MRI Activity in Multiple Sclerosis 8 Restarting Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage 9 Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy Comment by Amal Satte MD 10 Functional Neurological Disorders in Parkinson’s Disease 10 Encephalitis With mGluR5 Antibodies

Pontine Gliomas By John Laterra MD 13

Ultrasound and MRI Both Detect Increased Intracranial Pressure to Complement Comprehensive Workup By Michael A. Williams MD

CONFERENCE 14 Australian & New Zealand Association of Neurologists Annual Scientific Meeting 2018 By the PracticeUpdate Editorial Team

20 International Congress on Neuromuscular Diseases 2018 By the PracticeUpdate Editorial Team

© TIRZA/www.tirza.at

14 CTA Spot Sign Fails to Predict Expansion of Spontaneous Intracerebral Hemorrhage 15 Better Screening for Atrial Fibrillation Needed in Patients Who Present With TIA/Stroke 16 Perampanel Demonstrates Sustained Long-Term Efficacy Against Secondarily Generalized Seizures and Safety in Idiopathic Generalized Epilepsy 18 Efficacy of Alemtuzumab for Active RRMS is Maintained for 7 Years, in the Absence of Continuous Treatment

20 Transcranial Magnetic Stimulation Can Help Diagnose and Prognose Children With Sequelae of Acute Transverse Myelitis 21 Ultrasonography Valuable in Confirmation of Carpal Tunnel Syndrome 22 Significant Progress Has Been Made in Immune-Mediated Neuropathies 23 Protein Biomarkers of Dysferlinopathy Identified 24 Next-Generation Sequencing Can Be Helpful in Diagnosing and Characterizing Limb Girdle Muscular Dystrophy 26 Immune Globulins Continue to Be the Most Effective Treatment for Multifocal Motor Neuropathy

VOL. 3 • NO. 3 • 2018

PRACTICEUPDATE NEUROLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Mark Hallett MD President, International Federation of Clinical Neurophysiology; Senior Investigator, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

PracticeUpdate® is a registered trademark of Elsevier Inc.

2018 Elsevier Inc. All rights reserved.

ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Neurology provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Neurology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Neurology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising fromor related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Althoughalladvertisingmaterial isexpectedtoconformtoethical (medical)stand- ards, inclusion in thispublicationdoesnotconstituteaguaranteeorendorsement of the quality or value of such product or of the claims made of it by its manufac- turer. The printing and distribution of this publication has been made possible throughpaidadvertising.Theeditorialcontentherein is independentlyproduced byElsevierwithno involvementby theadvertiser. Itcontainscontentpublished in accordancewiththeeditorialpoliciesofElsevier’sPracticeUpdate.com.Allcontent printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Fleur Gill fleur.gill@elsevier.com Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Concept brain activity/gettyimages.com PracticeUpdate Neurology is published by Elsevier Australia ISSN 2206-4680 (Print)

Associate Editors

Argye Hillis MD, MA Director, Cerebrovascular Division of Neurology; Professor of Neurology, Johns Hopkins University, Baltimore, Maryland

Avindra Nath MD Clinical Director, National Institute of Neurological Disorders and Stroke (NINDH); Chief, Section of Infections of the Nervous System, NIH, Bethesda, Maryland

Advisory Board

Marinos Dalakas MD Professor, Neurology; Director, Neuromuscular Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania

Nina Schor MD, PhD Chair, Department of Pediatrics; William H. Eilinger Professor of Pediatrics; Professor of Neurology; Professor of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry; Pediatrician-in-Chief, Golisano Children’s Hospital at Strong Memorial Hospital, Rochester, New York

Patrick Wen MD Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of Cancer Neurology, Department of Neurology, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School, Boston, Massachusetts

Editorial Contributors

Shila Azodi MD Clinical Fellow in Neurology, National Institutes of Health, Bethesda, Maryland

Codrin Lungu MD Chief, National Institutes of Health (NIH) Parkinson Clinic; Assistant Clinical Director, National Institute of Neurological Diseases and Stroke (NINDS); Clinic Director, Botulinum Toxin Clinic, NINDS, NIH, Bethesda, Maryland Elisabeth Marsh MD Assistant Professor of Neurology, Johns Hopkins School of Medicine; Director, Bayview Stroke Center, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Sarah Matteson Kranick MD NeuroHospitalist, MultiCare Health System, Tacoma, Washington

Mona Bahouth MD Assistant Professor of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland

Omar Khan MD Assistant Clinical Director, Medical Education, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMNN091801

EDITOR’S PICKS 5

Emergency Department Neuroimaging for Red Flag Findings in ChildrenWith Headaches Cephalalgia: An International Journal of Headache Take-home message • “Red flags” have been used as a justification for emergent neuroimaging for children with headaches when they present to the emergency department. However, little data exist regarding the prevalence and outcomes of these findings, or the prevalence of emergent intracranial abnormalities in this population. The authors report that, among the 224 patients prospectively enrolled in this observational study, 197 (87.9%) had at least one red flag finding on history and a third of the children reported several red flags, including headache waking from sleep (34.8%) and headache present or soon after waking (39.7%) or headaches increasing in frequency, duration, and severity (40%, 33.1%, and 46.3%). While 33% percent of children received emergency department neuroimaging, the prevalence of emergent intracranial abnormalities was only 1%. • For the practitioner, this is an interesting observation, suggesting that the prevalence of red flags in children is associated with emergency department neuroimaging while the risk of emergent intracranial abnormalities is low. Nonspecific red flag findings may lead to unnecessary neuroimaging in these children. Omar Khan MD

Abstract BACKGROUND Clinicians appear to obtain emergent neuroimaging for children with headaches based on the presence of red flag findings. However, little data exists regarding the prevalence of these findings in emergency department populations, and whether the iden- tification of red flag findings is associated with potentially unnecessary emergency department neuroimaging. OBJECTIVES We aimed to determine the preva- lence of red flag findings and their association with neuroimaging in otherwise healthy children presenting with headaches to the emergency department. Our secondary aim was to deter- mine the prevalence of emergent intracranial abnormalities in this population. METHODS A prospective cohort study of oth- erwise healthy children 2-17 years of age presenting to an urban pediatric emergency department with non-traumatic headaches was undertaken. Emergency department physicians completed a standardized form to document headache descriptors and characteristics, associated symptoms, and physical and neu- rological exam findings. Children who did not receive emergency department neuroimag- ing received 4-month telephone follow-up. Outcomes included emergency department neuroimaging and the presence of emergent intracranial abnormalities. RESULTS We enrolled 224 patients; 197 (87.9%) had at least one red flag finding on history. Sev- eral red flag findings were reported by more than a third of children, including: Headache waking from sleep (34.8%); headache present with or soon after waking (39.7%); or headaches " Nonspecific red flag findings may lead to unnecessary neuroimaging in these children. "

flag findings is associated with emergency department neuroimaging, although the risk of emergent intracranial abnormalities is low. Many children with headaches may be receiv- ing unnecessary neuroimaging due to the high prevalence of non-specific red flag findings. Red Flag Findings in Children With Headaches: Prevalence and Association With Emergency Department Neuroimaging. Cephalalgia 2018 Jun 06;[EPub Ahead of Print], DS Tsze, JB Ochs, AE Gonzalez, PS Dayan. www.practiceupdate.com/c/70300

increasing in frequency, duration and severity (40%, 33.1%, and 46.3%). Thirty-three percent of children received emergency department neuroimaging. The prevalence of emergent intracranial abnormalities was 1% (95% CI 0.1, 3.6). Abnormal neurological exam, extreme pain intensity of presenting headache, vomiting, and positional symptoms were independently associated with emergency department neuroimaging. CONCLUSIONS Red flag findings are common in children presenting with headaches to the emergency department. The presence of red

VOL. 3 • NO. 3 • 2018

EDITOR’S PICKS 6

MRI-Guided Thrombolysis for Stroke With Unknown Time of Onset The New England Journal of Medicine Take-home message • Treatment of acute stroke by intravenous thrombolysis is used under current guidelines only if the time since onset of symptoms is less than 4.5 hours. The authors of this study sought to determine whether stroke patients with an unknown time of onset would benefit from thrombolysis with the use of intravenous alteplase if the MRI suggested recent cerebral infarction. Patients with an unknown time of onset of stroke, but within approximately the previous 4.5 hours, were randomly assigned to receive either intravenous alteplase or placebo. Of the 503 patients enrolled, 254 received alteplase and 249 received placebo. A favorable outcome, as defined by a score of 0 or 1 on the modified Rankin Scale at 90 days, was reported in 53.3% of patients in the alteplase group and 41.8% in the placebo group (adjusted OR, 1.61; P = .02); the median score was 1 in the alteplase group and 2 in the placebo group (adjusted common OR, 1.62; P = .003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (OR, 3.38; P = .07). Symptomatic intracranial hemorrhage rate was 2% in the alteplase group and 0.4% in the placebo group (OR, 4.95; P = .15). • Among patients with acute stroke for whom the time of onset of symptoms is unknown but within approximately 4.5 hours, intra- venous thrombolysis with alteplase resulted in a better functional outcome, but with more intracranial hemorrhage, than placebo.

Abstract BACKGROUND Under current guidelines, intrave- nous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and fea- tures suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would bene- fit from thrombolysis with the use of intravenous alteplase. METHODS In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffu- sion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previ- ous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. " …intravenous thrombolysis with alteplase resulted in a better functional outcome, but with more intracranial hemorrhage, than placebo. "

(odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffu- sion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intrac- ranial hemorrhages than placebo at 90 days. MRI-Guided Thrombolysis for Stroke With Unknown Time of Onset. N Engl J Med 2018 May 16;[EPub Ahead of Print], G Thomalla,

A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symp- tomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group

CZ Simonsen, F Boutitie, et al. www.practiceupdate.com/c/68203

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 7

The Diagnostic Dilemma of Traumatic Lumbar

CNS-LCH: Common Hematopoietic Origin For LCH-Associated Neurodegeneration and Mass Lesions Take-home message • Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm associated with BRAFV600E mutation. CNS involvement (CNS-LCH) presents as intraparenchymal brain lesions or a poorly understood neurodegenera- tive disorder (LCH-ND). Here, McClain and colleagues identify osteopontin as a disease-specific CSF biomarker of CNS-LCH. BRAFV6003 detection in peripheral blood mononuclear cells was associated with an increased risk of LCH-ND (sensitivity 0.59; specificity 0.86). Of 4 CNS-LCH patients treated with BRAFV600E inhibitors, 3 had a complete or partial clinical response. • The data suggest a direct role of BRAFV600E-mutated myeloid neoplastic cells in LCH-ND, rather than paraneo- plasia, and suggest that BRAFV600E inhibition may result in clinical improvement in patients with CNS-LCH. Abstract BACKGROUND Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neu- rodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define themechanisms of pathogenesis that drive CNS-LCH. METHODS Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhib- itor was evaluated in 4 patients with progressive disease. RESULTS Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infil- tration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION In LCH-ND patients, BRAFV600E+ cells in PBMCs and infil- trating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoi- etic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK sig- naling may be effective for LCH-ND. CNS Langerhans Cell Histiocytosis: Common Hematopoietic Origin For LCH-Associated Neurodegeneration and Mass Lesions. Cancer 2018 Jun 15;124(12)2607-2620, KL McClain, J Picarsic, R Chakraborty, et al. www.practiceupdate.com/c/70898 Cancer

Puncture Journal of Child Neurology

Take-home message • Meningitis is more common in the first months of life than at any other age, and thus lumbar puncture is an important part of the evaluation of the febrile infant. As many as one-third of infants can have traumatic taps, which limits the diagnostic certainty of CSF interpretation. Studies in adults have sought to use biomarkers such as CSF procalcitonin and lactate to help evaluate for meningitis in complicated scenarios such as post neurosurgery. The authors of this prospective cohort study evaluated these biomarkers in 252 infants aged 3 to 90 days old with meningitis and a traumatic tap seen in their ER over a 4-year period. CSF procalcitonin, lactate, and CSF:serum lactate ratio were more efficient at diagnosing meningitis than uncorrected or corrected CSF WBC count. • These data may be very helpful in a practical way for pedi- atric neurologists. Sarah Matteson Kranick MD Abstract OBJECTIVE To assess the diagnostic efficiency of cerebrospinal fluid mark- ers of procalcitonin, lactate, and cerebrospinal fluid/serum lactate ratio for detecting bacterial meningitis during traumatic lumbar puncture, and to compare these markers with routinely used uncorrected and corrected leukocyte measurements. METHODS Infants aged ≤90 days with traumatic lumbar puncture were pro- spectively studied. The diagnostic characteristics of cerebrospinal fluid assays of uncorrected and corrected leukocyte count, procalcitonin, lac- tate, and lactate ratio were described and compared. RESULTS Considering the area under the curve (95% CI) analysis and stand- ard cutoff values, the lactate-ratio (0.985 [0.964-0.989] at cutoff 1.2) had the best test indexes for identifying meningitis, followed by lactate (0.964 [0.945-0.984] at cutoff 2.2 mmol/L) and procalcitonin (0.939 [0.891-0.986] at cutoff 0.33 ng/mL) measurement, whereas the corrected total leukocyte count assay (0.906 [0.850-0.962] at cutoff 350 cells/mm 3 ) had diagnos- tic properties moderately superior to uncorrected total leukocyte count measurement (0.870 [0.798-0.943] at cutoff 430 cells/mm 3 ). CONCLUSION Cerebrospinal fluid levels of procalcitonin, lactate, and lactate-ratio are reliable markers to diagnose bacterial meningitis in blood-contaminated cerebrospinal fluid. The Diagnostic Dilemma of Traumatic Lumbar Puncture: Current Stand- ing of Cerebrospinal Fluid Leukocyte Corrections and Our Experience With Cerebrospinal Fluid Biomarkers. J Child Neurol 2018 Jun 01;33(7)441- 448, M Nazir, WA Wani, K Kawoosa, et al. www.practiceupdate.com/c/69190 " CSF procalcitonin, lactate, and CSF:serum lactate ratio were more efficient at diagnosing meningitis than uncorrected or corrected CSFWBC count. "

VOL. 3 • NO. 3 • 2018

EDITOR’S PICKS 8

Restarting Antiplatelet Therapy After Spontaneous

α-Linolenic Acid is Associated With MRI Activity in Multiple

Intracerebral Hemorrhage Neurology

Sclerosis Multiple Sclerosis

Take-home message • The authors of this randomized, placebo-controlled study of omega-3 fatty acids in multiple sclerosis report on the relationship between serum levels of the plant-based omega-3 fatty acid α-linolenic acid (ALA) and MRI and clinical outcome measures over 2 years. For the first 6 months, the patients were randomized to use omega-3 fatty acids in monotherapy or placebo. None of the patients used any disease-modifying drugs during this period. After 6 months, all patients started with subcuta- neous injections of 44 μg of interferon beta-1a three times weekly. ALA was measured in serum phospholipids at baseline and at 6, 12, and 24 months of follow-up. Higher levels of ALA were associated with lower odds of new T2 lesions and T1 gadolinium-enhancing lesions, disability progression, and new relapses during follow-up, but these effect estimates were not statistically significant. • This study is most notable for the introduction of the idea and suggestion for further investigation of the role of ALA and plant-based fatty acids (vs marine sources) in multiple sclerosis pathways. Shila Azodi MD Abstract BACKGROUND The plant-based ω-3 fatty acid α-linolenic acid (ALA) has been associated with lower MS risk. It is currently unknown whether ALA affects disease activity. OBJECTIVE To investigate the association between ALA levels and dis- ease activity. METHODS We conducted a cohort study including 87 multiple sclerosis (MS)-patients who originally participated in a randomized trial of ω-3 fatty acids (the OFAMS study). We measured serum levels of ALA dur- ing follow-up and used random intercept logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association between ALA levels, new magnetic resonance imaging (MRI) lesions, Expanded Disability Status Scale (EDSS) progression and new relapses adjusting for age at inclusion, sex, and use of interferon beta-1a. RESULTS In continuous (per 1-SD increase) multivariable-adjusted analy- ses, higher ALA levels were significantly associated with lower odds of new T2-lesions (OR: 0.59, 95% CI: 0.37-0.95) during follow-up. The effect estimates were similar for new T1Gd+ lesions (OR: 0.73, 95% CI: 0.48- 1.11), EDSS-progression (OR: 0.62, 95% CI: 0.34-1.16) and new relapses (OR: 0.49, 95% CI: 0.22-1.10), but these estimates did not reach statisti- cal significance. Further adjustment for vitamin D and tobacco use did not materially change the results. CONCLUSION We found that higher levels of ALA were associated with lower disease activity in MS-patients. α -Linolenic Acid Is Associated With MRI Activity in a Prospective Cohort of Multiple Sclerosis Patients. Mult Scler 2018 May 01;[EPub Ahead of Print], K Bjornevik, KM Myhr, A Beiske, et al. www.practiceupdate.com/c/69742

Take-home message • The decision to restart antiplatelet therapy (APT) after an intracranial hemorrhage (ICH) and balancing the risks of ischemic vascular events with those of ICH recurrence are difficult and frequent dilemmas for the neurologist. This multicenter, retrospective, matched cohort study compared functional outcomes and health-related quality of life (HRQoL) associated with restarting vs not restarting APT in patients with ICH. After propensity matching, a modified Rankin Scale score (mRS) of 0–2 was achieved in 35.5% of patients resuming APT and 43.9% of patients not resuming APT, not reaching statistical significance. The other outcomemeasures were also non-significantly different between the groups. • The results suggest that, in patients already on APT before presenting with spontaneous ICH, restarting the APT after the acute hospitalization is not associated with worse func- tional outcomes. Codrin Lungu MD Abstract OBJECTIVE To compare the functional outcomes and health-related qual- ity of life metrics of restarting vs not restarting antiplatelet therapy (APT) in patients presenting with intracerebral hemorrhage (ICH) in the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study. METHODS Adult patients aged 18 years and older who were on APT before ICH and were alive at hospital discharge were included. Patients were dichotomized based on whether or not APT was restarted after hospital discharge. The primary outcome was a modified Rankin Scale score of 0-2 at 90 days. Secondary outcomes were excellent outcome (modified Rankin Scale score 0-1), mortality, Barthel Index, and health status (EuroQol-5 dimensions [EQ-5D] and EQ-5D visual analog scale scores) at 90 days. RESULTS The APT and no APT cohorts comprised 127 and 732 patients, respectively. Restarting APT was associated with lower rates of good func- tional outcome (36.5% vs 40.8%; p = 0.021) and lower Barthel Index scores at 90 days (p = 0.041). The 2 cohorts were then matched in a 1:1 ratio, and the matched cohorts each comprised 107 patients. No difference in pri- mary outcome was observed between restarting vs not restarting APT (35.5% vs 43.9%; p = 0.105). There were also no differences between the secondary outcomes of the 2 cohorts. CONCLUSION Restarting APT in patients with ICH of mild to moderate severity after acute hospitalization is not associated with worse func- tional outcomes or health-related quality of life at 90 days. In patients with significant cardiovascular risk factors who experience an ICH, restarting APT remains the decision of the treating practitioner. Restarting Antiplatelet Therapy After Spontaneous Intracerebral Hem- orrhage: Functional Outcomes. Neurology 2018 Jul 03;91(1)e26-e36, CJ

Chen, D Ding, TJ Buell, et al. www.practiceupdate.com/c/70538

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 9

Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy Epilepsia

Take-home message • High-fat, low-carbohydrate diets are gaining attention. The authors argue that, while these diets have shown a seizure-reducing effect in children, there is a lack of strong evidence for a similar effect in adults. In this randomized controlled trial of a modified Atkins diet after a period of 12 weeks, using a cutoff of 25% seizure frequency reduction, but not 50%, there was a significant reduction in seizures in the 24 patients who completed the diet. While there were no serious adverse events, 3 of the 28 patients who were on the diet for at least 1 week terminated the diet early due to increased seizure frequency; problems including reduced exercise capacity and reduced energy were reported. • This is good information for the practicing provider, advocating for a possible benefit of a modified Atkins diet in patients with refractory epilepsy. However, interestingly, the authors do note that the seizure response varied considerably among individuals and was perhaps negatively influenced by a drop in serum concentrations of antiepileptic drugs, raising caution to the provider that it may be necessary to measure drug levels carefully while patients are on these diets. Omar Khan MD Abstract

" As the diet was effective in some patients, it might be worth trying in adult focal epilepsy. "

was 4.5 (IQR -4.8-33.5). The median difference between the groups was -7.0 (95% confidence interval [CI] -37.0-3.0; P = .21). In the intention-to- treat analysis, the relative risk (RR) for achieving >50% seizure reduction was 1.8 (95% CI 0.3-10.2; P = .65), while for achieving >25% seizure reduc- tion RR was 2.43 (95% CI 0.94-6.28; P = .06). We observed no serious adverse events. SIGNIFICANCE In this RCT investigating the effect of an adjunctive modified Atkins diet on seizure frequency in adults with difficult-to-treat focal epilepsy, we found a significant reduction in sei- zure frequency in the diet group compared to the controls, but only for moderate benefit (>25% seizure reduction) among those who completed the intervention. However, seizure response var- ied considerably between individuals, perhaps negatively influenced by a drop in serum con- centrations of antiepileptic drugs. Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy: A Randomized Clinical Trial. Epilepsia 2018 Jun 14;[EPub Ahead of Print], M Kverneland, E Molteberg, PO Iversen, et al. www.practiceupdate.com/c/70012

Atkins diet (diet group) or habitual diet (control group). Primary endpoint was a change in sei- zure frequency from baseline to the intervention period, comparing those on diet with controls. RESULTS We assigned 37 patients to the diet group and 38 to the control group. Nine of the patients in the diet group and 4 controls were excluded. Of those who completed the dietary intervention (n = 24), median seizure change was -1.0 (interquartile range [IQR] -13.7-8.8), while in the control group (n = 32) the median change

OBJECTIVE Ketogenic diets reduce seizures in children with drug-resistant epilepsy. Whether adults benefit from similar treatment has not been clarified. We therefore examined the effi- cacy of the modified Atkins diet in adults with drug-resistant focal epilepsy. METHODS We performed a randomized clinical trial (RCT) with patients >16 years who had at least 3 seizures per month despite having tried at least 3 antiepileptic drugs. They were ran- domized to either 12 weeks on the modified

COMMENT By Amal Satte MD T he Atkins diet is widely used to treat drug-resistant epi- lepsy in children. However, there are few studies on the effect of this diet on refractory epilepsy in adults. On the other hand, most of these studies don’t specify the response to the diet with respect to epilepsy type. The objective of this trial was to evaluate the impact of adjunctive Atkins diet on refractory focal epilepsy in adults. One of the strengths of this study is that it was a randomized clinical trial with two arms: a diet group and a control group. But, because of slow recruitment, the number of participants was relatively low: 24 patients in the diet group versus 32 patients in the control group. This may be the reason why there was no significant seizure-reducing effect seen with the diet, although the individual variation in seizure response was important. In practice: • As the diet was effective in some patients, it might be worth trying in adult focal epilepsy. • A close follow-up and support may improve adherence to the diet. In this trial, there were few dropouts compared with other studies. This may be explained by a shorter trial period, but also the close follow-up (information, training, recipes, etc).

• Efficacy in some patients in this study was seen after 2 to 3 months, which may suggest the need to prolong the diet duration. • Some patients on the Atkins diet may experience an increased seizure frequency. This effect can be transient and is some- times related to a drop-in serum concentration of antiepileptic drugs (AED). Thus, it can be important to monitor AED serum levels in patients on the Atkins diet. • In this study, there were no serious adverse events. • Finally, there’s a need for further studies with a larger number of participants and long follow-up, which would also take into account other factors such as seizure history, the effect on different types of seizures, quality of life, interactions between specific AEDs and the diet, AED serum concentration, any protective and triggering factors (especially stressful events linked or not to the diet). Dr. Satte is from the Neurophysiology Department of Mohammed V Teaching Military Hospital Mohammed V University in Rabat, Morocco.

VOL. 3 • NO. 3 • 2018

EDITOR’S PICKS 10

Functional Neurological Disorders in Parkinson’s Disease Journal of Neurology, Neurosurgery, and Psychiatry Take-home message • Functional neurologic disorders (FNDs) are common and underrecog- nized. They frequently occur together with a different, organic disorder, posing diagnostic and therapeutic challenges. This is a multicenter case–control study in several countries, assessing the clinical and demographic features of FNDs in patients with Parkinson’s disease (PD). Functional symptoms preceded PD onset or occurred at the same time in 34% of cases and were typically seen on themost affected side. Patients with coexisting FNDs had longer delay to PD diagnosis and received a DAT scan to assist diagnosis more frequently. Psychiatric disorders and family history of PD were more common when FNDs were associated. PD-FND patients had higher mean scores on the Beck Depression Inventory (34 vs 17) and the Beck Anxiety Inventory (21 vs 14). Healthcare utilization was higher, including more hospitaliza- tions (mean, 1.2 vs 0.9). The most common functional symptoms were gait/balance dysfunction and tremor. • This article draws attention to the prevalence of FNDs in PD and offers useful information on clinical details. Codrin Lungu MD Abstract

Encephalitis WithmGluR5 Antibodies Neurology

Take-home message • This case series outlines the features and evo- lution of metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis. Clin- ically, the condition is associated with a complex neuropsychiatric syndrome, with psychiatric and cognitive features present in most patients. Sev- eral patients had prodromal features consisting most often of weight loss or headache. Of the 11 patients, 6 had an associated cancer, most commonly Hodgkin’s lymphoma. Response to immunotherapy appears to be typical (with ster- oids often the first-line treatment), but relapse was seen, both with and without an associated tumor. • This report is a useful reference for this rare condition. Codrin Lungu MD Abstract OBJECTIVE To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associ- ated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. METHODS Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell- based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. RESULTS From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the dis- ease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunother- apy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients’ IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95. CONCLUSIONS Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5. Encephalitis With mGluR5 Antibodies: Symptoms and Anti- body Effects. Neurology 2018 May 29;90(22)e1964-e1972, M Spatola, L Sabater, J Planagumà, et al. www.practiceupdate.com/c/68853

OBJECTIVE To ascertain demographic and clinical features of Parkinson dis- ease (PD) associated with functional neurological features. METHODS A standardised form was used to extract data from electronic records of 53 PD patients with associated func- tional neurological disorders (PD-FND) across eight movement disorders cen- tres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect. RESULTS Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were pre- dominantly female (68%), had longer delay to PD diagnosis, greater prev- alence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxi- ety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater health- care resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psy- chiatric disorder (P=0.008) and family history of PD (P=0.036).

CONCLUSIONS A subtype of PD with func- tional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor dis- ability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients. Functional Neurological Disorders in Parkinson Disease. J Neurol Neurosurg Psychiatr 2018 Jun 01;89(6)566-571, BD Wissel, AK Dwivedi, A Merola, et al. www.practiceupdate.com/c/68819

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EXPERT OPINION 12

Cerebral Blood Flow Changes After Radiation Therapy Identifies Pseudoprogression in Diffuse Intrinsic Pontine Gliomas By John Laterra MD Dr. Laterra is a Professor of Neurology, Oncology and Neuroscience and co-Director of the Brain Cancer Program at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

B rain MRI serves as a bedrock for monitor- ing patients with brain cancer and evaluating responses to radiation and chemotherapy. MRI is very sensitive but often lacks sufficient specificity when evaluating brain cancer responses to radiation or combination radiation/chemotherapy. This retrospec- tive analysis of multimodality MRI and clinical outcomes in children with diffuse intrinsic pontine gliomas (DIPGs) by Calmon et al 1 highlights this obstacle to evaluat- ing treatment responses, specifically distinguishing true tumor progression from treatment-induced “pseu- doprogression” in brain cancer patients. The ability to make appropriate treatment decisions, prognosti- cate, and effectively evaluate experimental treatments hangs in the balance. This is a critical challenge for adults and children with malignant gliomas. Adult patients most often have hemispheric tumors that allow repeat excisional biopsy or surgical resection to update pathological processes following therapy – options not readily applicable to DIPGs and other deep infiltrating malignancies of childhood. This current study describes changes in arterial spin labeling cerebral blood flow (ASL-CBF) as a potential noninvasive biomarker of early pseudoprogression in patients with aggressive pontine glioma. Strengths of this study are that all patients had biopsies confirming similar aggressive, high-grade, infiltrative glioma before starting treatment; all patients received standard radi- ation therapy, and, while chemotherapies varied to some degree, this apparently did not differ significantly between the pseudoprogression and true tumor pro- gression groups. A key limitation is the absence of any post-treatment pathology (the gold standard for distin- guishing true progression from pseudoprogression) to validate the ASL-CBF biomarker.

Certain unexpected findings warrant pause and further study. The finding that pseudoprogression was asso- ciated with increased ASL-CBF, speculated to result from a vascular normalization mechanism, is somewhat counterintuitive because pseudoprogression following the treatment of supratentorial tumors, a much more extensively studied process, is characterized by vas- cular dysfunction with reductions in cerebral blood volume and cerebral blood flow. One might also expect patients with pseudoprogression to survive longer than those with true tumor progression because the for- mer reflects a more robust anti-tumor response and is often self-limiting. That no differences in survival were observed between the two groups raises ques- tions regarding the clinical/radiographic criteria used to partition patients into the true progression and pseu- doprogression groups. These unexpected findings might very well reflect the very distinct biology of DIPGs, regional differences in cerebrovascular responses to radiation-based thera- pies, and the greater life-threatening consequences of progressive pontine injury whether from true tumor progression or pseudoprogression. The potential utility of ASL-CBF in evaluating treatment responses in DIPG is intriguing and potentially promising. The absence of either histopathology confirmation or clinically distinct biomarker-associated patient outcomes highlights the need to better understand the biological and clinical significance of ASL-CBF in DIPG. Reference 1. R Calmon, S Puget, P Varlet, et al. Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas. Neuro-oncology 2018;20(7):994-1002. www.practiceupdate.com/c/70299

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