PracticeUpdate Neurology Best of 2018

Best of 2018

VOL. 3 • NO. 4 • 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4680

TOP STORIES 2018 Gene Therapy is Here Neuromuscular Diseases: Hereditary Transthyretin Amyloidosis Stroke: The DEFUSE 3 Trial FDA Approval of Cannabidiol for Use in Lennox- Gastaut and Dravet Syndromes

JOURNAL SCANS Discontinuation of Disease- Modifying Therapy in Patients With Multiple Sclerosis Over Age 60

Adjunct Zonisamide to Levodopa for DLB Parkinsonism: A Randomized Double-Blind Phase 2 Study

Tenecteplase Versus Alteplase Before Thrombectomy for Ischemic Stroke

restart the conversation. it’s time to prevent migraine. 1 Aimovig® is the 1 st 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 1800 979 607 • Alternatively please contact your Novartis Representative for more information

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) . For the most up to date Product Information go to http://www.novartis.com.au/products_healthcare.html *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

CONTENTS 3

EDITOR’S PICKS 8 Discontinuation of Disease-Modifying Therapy in Patients With Multiple Sclerosis Over Age 60 Comment by Benjamin Segal MD 9 Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging Comment by Jean-Claude Baron MD, ScD, FMedSci 10 Zonisamide as an Adjunct to Levodopa for DLB Parkinsonism Comment by Mark Hallett MD 11 Differentiating Myelitis From Vascular and Other Causes of Myelopathy 11 Restarting Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage 12 Tenecteplase vs Alteplase Before Thrombectomy for Ischemic Stroke Comment by James C. Grotta MD 13 Complete Detoxification Is the Most Effective Treatment of Medication- Overuse Headache 14 Statin-Associated Muscle Disease 14 Emergency Department Neuroimaging for Epileptic Seizures 15 Effect of Modified Atkins Diet in Adults With Drug-Resistant Focal Epilepsy Comment by Amal Satte MD 16 Effect of Standard vs

TOP STORIES 2018 5 Gene Therapy is Here By Mark Hallett MD 6 Neuromuscular Diseases: Hereditary Transthyretin Amyloidosis By Marinos C. Dalakas MD 6 Stroke: The DEFUSE 3 Trial By Argye Elizabeth Hillis MD, MA 7 FDA Approval of Cannabidiol for Use in

Lennox-Gastaut and Dravet Syndromes By Nina F. Schor MD, PhD

Intensive Blood Pressure Control on Cerebral Blood Flow in Small-Vessel Disease Comment by Argye Elizabeth Hillis MD, MA

CONFERENCE

18 International Stroke Conference 2018 By the PracticeUpdate Editorial Team 17 Functional Neurological Disorders in Parkinson’s Disease 18 Training Emergency Medical Service Staff in Simple Test Helps Improve Identification of Posterior Stroke 19 Combination Medication Reduces Stroke by 44% in Patients With Only Moderate Risk Profile 20 COMPASS Study Identifies Massive Gaps in Stroke Rehabilitation Care

21 2018 Annual Meeting of the American Academy of Neurology By the PracticeUpdate Editorial Team 21 Eptinezumab Effective for Preventing Frequent Episodic Migraine 22 Cancer Commonly Comorbid With Stroke 22 New Method of Monitoring Multiple Sclerosis Effective and 10 Times Less Expensive Than Conventional MRI 23 Antiepileptic Treatment Maintains Seizure Freedom During Pregnancy and Postpartum Period

24 15th International Congress on Neuromuscular Diseases By the PracticeUpdate Editorial Team 24 Ultrasonography Valuable in Confirmation of Carpal Tunnel Syndrome 25 Some Neuromuscular Diseases Linked to Malignant Hyperthermia or Similar Reactions 26 Thymectomy Continues to Be Successful for Myasthenia Gravis

VOL. 3 • NO. 4 • 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. 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. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by itsmanufacturer.Theprintinganddistributionofthispublicationhasbeenmade possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate. com. All content 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 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: Medical cannabis/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 Deputy Director, National Institute of Neurological Disorders & Stroke, National Institutes of Health, Bethesda, MD; Senior Faculty Associate, University of Rochester, 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 EMNN121801

TOP STORIES 2018 5

Gene Therapy is Here By Mark Hallett MD

The promise of gene therapy is finally coming to fruition. Three articles that were stories of the week in 2018 feature two different types of gene therapy.

N usinersen, which had been demonstrated for early-onset spinal muscular atrophy (SMA), was shown in an article in The New England Journal of Medicine also to be of value in patients with later-onset disease. 1 SMA is caused by a loss of function of the SMN1 gene. There is an SMN2 gene that can produce the protein, but, ordinarily, it does not due to a splice-site variant that leads to the production of a dysfunctional protein. Nusinersen is an antisense oligonucleotide. It binds to a specific sequence in the SMN2 pre-messenger RNA, modifying its splicing, and promoting the expression of a full-length SMN protein. The CHERISH study was a double-blind, sham-con- trolled study with an endpoint at 15 months. Nusinersen was given intrathecally at days 1, 29, 85, and 274 in a 2:1 ratio, real to sham. The study was terminated at a prespecified interim analysis due to a large statistically significant difference between groups: real group with an average increase of 4.0 points on a functional scale and the sham group declining on average by 1.9 points. Two articles published together, also in The New England Journal of Medicine , showed that gene ther- apy could be useful for the treatment of hereditary transthyretin amyloidosis . This disorder is due to an autosomal dominant toxic gain-of-function mutation, wherein mutant transthyretin (TTR) gets deposited as amyloid in peripheral nerve, heart, kidney, and gastro- intestinal tract. The first paper used the technique of RNAi, RNA interference, which cleaves the messen- ger RNA that would lead to the production of TTR. 2 The APOLLO trial used the agent patisiran. The study was randomized and placebo-controlled in an adult population with polyneuropathy in a 2:1 ratio, real to

sham. Patients received the drug (or placebo) intra- venously once every 3 weeks until the endpoint at 18 months. The treated group improved on a neuropa- thy impairment scale by 6 points, while those on sham deteriorated by 28 points. There were also statistically significant improvements in secondary measures. The second article used an antisense oligonucleotide to inhibit the production of TTR. 3 The agent, inotersen, was used in a randomized, double-blind, placebo-con- trolled trial of patients with polyneuropathy over 15 months. Patients were assigned 2:1, real to placebo, to receive weekly subcutaneous injections of drug or placebo, with primary endpoints of a neuropathy impairment scale and quality-of-life scale. There was statistically significant benefit on both scales. However, it was of note that inotersen was associated with some patients developing glomerulonephritis or thrombocy- topenia, including 1 death from the latter complication. These articles are the leading edge of RNA-directed therapies, and already there are variations in the meth- ods. There is little doubt that we will be seeing much more work in this area. It is clear that such therapies will have to be monitored carefully for toxicity. Another issue will be their high cost, which will raise a variety of other problems. References 1. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 2018;378(7):625-635. 2. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379(1):11-21. 3. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31. www.practiceupdate.com/c/74280

" These articles are the leading edge of RNA-directed therapies, and already there are variations in the methods. There is little doubt that we will be seeing much more work in this area. "

VOL. 3 • NO. 4 • 2018

TOP STORIES 2018 6

Neuromuscular Diseases: Hereditary Transthyretin Amyloidosis By Marinos C. Dalakas MD H ereditary transthyretin (TTR) amyloid neuropathy is the first disease where oligonucleotide drugs, administered systemically, can improve symptoms or arrest disease progression.

inhibits the production of TTR by the liver, 1 and an RNA interference therapeutic called patisiran, which inhibits the hepatic synthesis of TTR, 2 induce significant clinical benefits associated with a dose-de- pendent and sustained reduction of circulating TTR levels. Patisiran was used intravenously every 3 weeks in 225 patients, and inot- ersen was used subcutaneously in 172 patients once weekly for 64 weeks. Both drugs had a remarkable effect in suppressing the rate of neuropathy progression and significantly improved the main clini- cal manifestations, including autonomic symptoms, gait instability, and quality-of-lifemeasures. The serumconcentration of TTRwas reduced by 81% in the patisiran study and by 71% in the inotersen trial. Most importantly, over the 18-month therapy, 60%of the patients improved. These two independent large trials are remarkable because they convincingly show for the first time that oligonucleotide drugs admin- istered systemically can improve patients with hereditary amyloid peripheral neuropathy. The improvement or even reversal of the patients’ sensorimotor deficits and disabling autonomic symptoms is a breakthrough for such a devastating neuropathy that we could not previously treat. Both drugs have now gained FDA approval, the inotersen as Tegsedi and the patisiran as Onpattro. This is a his- toric approval, the first of its kind in human therapeutics, highlighting that drugs in the category of RNA interference or RNA targeting can help patients with a catastrophic hereditary disease. Although not yet tested, the results provide hope that these drugs may have the potential to prevent clinical manifestations in pre-symptomatic patients with mutations in the gene encoding TTR. References 1. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31. 2. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21. www.practiceupdate.com/c/75966

Hereditary TTR amyloid neuropathy is a pro- gressive, autosomal-dominant polyneuropathy

that leads to severe disability and death. The disease is caused by mutations in the gene encoding TTR, a protein synthesized in the liver. TTR is normally a tetrameric protein complex, but, in patients with TTR polyneuropathy, the mutations in the TTR gene destabilize its tetrameric structure, resulting in toxic monomers that aggregate as misfolded amyloid fibrils, which accumulate in multi- ple organs including peripheral nerves, ganglia, skeletal muscle, and heart, leading to a progressive sensorimotor and autonomic polyneuropathy often associated with cardiomyopathy. The dis- ease is incurable, with an average life expectancy of 3 to 15 years from symptom onset. Liver transplantation has been the standard of care, but continued deposition of wild-type TTR amyloid after transplantation limits its effectiveness. It has been proposed that the disease can be treated and perhaps prevented by approaches that reduce the availability of themisfolded TTR monomer. Two recently published phase III controlled studies in patients with TTR amyloid neuropathy have now shown that two agents, amodified antisense oligonucleotide called inotersen, which " …they convincingly show for the first time that oligonucleotide drugs administered systemically can improve patients with hereditary amyloid peripheral neuropathy. "

T his year’s story of the year in the field of stroke was the paper reporting the results of the DEFUSE 3 trial, 1 a mul- ticenter, randomized, open-label trial, with blinded outcome assessment, of thrombec- tomy in patients 6 to 16 hours after they were last known well whose imaging revealed ischemic brain tissue that was not yet infarcted. Participants in this trial all had proximal middle cerebral artery occlusion or internal carotid artery occlusion, an ini- tial core infarct volume under 70 cc, and a volume of ischemic (hypoperfused) tis- sue on perfusion imaging that was at least 1.8 times larger than the core infarct. The 182 participants were randomly assigned to endovascular therapy (ET) or standard medical therapy alone. The primary out- come was the modified Rankin Scale score (a measure of functional disability) at 90 days post stroke. The results revealed a favorable shift in the distribution of func- tional outcomes on the primary outcome

Stroke: The DEFUSE 3 Trial By Argye Elizabeth Hillis MD, MA

measure (OR, 2.77; P < .001) in those who received ET versus those who received medical therapy alone. Furthermore, more patients in the ET group were functionally independent, with a modified Rankin score of 0 to 2 (45% vs 17%; P < .001). Mortality at 90 days was marginally lower in the ET group (14% vs 26%; P = .05), and there was group difference in the frequency of symp- tomatic intracranial hemorrhage or serious adverse events. This study was published only a few weeks after the DAWN trial 2 also revealed marked better functional outcomes in patients with small core infarct but disproportionate neurological deficit – indicating a larger volume of ischemic hypoperfusion tissue than core infarct – treated 6 to 24 hours of last seen normal if they received ET versus medical treatment alone. Together, these studies provide complementary evi- dence that a subgroup of stroke patients can strongly benefit from ET at least up to

PRACTICEUPDATE NEUROLOGY

TOP STORIES 2018 7

FDA Approval of Cannabidiol for Use in Lennox-Gastaut and Dravet Syndromes By Nina F. Schor MD, PhD

of hypoperfused tissue around the core infarct. Now, the triply revolutionized care of stroke involves rapid intervention (IV tPA and/or ET) given in well-organized, certi- fied stroke centers around the world. It is likely that the coming years will reveal that intervention can be effective even days after stroke in subsets of patients with persistent areas of hypoperfused tissue surrounding the ischemic core. But even the current management has resulted in higher functional outcomes for thousands of stroke patients each year. References 1. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378(8):708-718. 2. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med 2018; 378: 11-21. www.practiceupdate.com/c/73543 Unlike tetrahydrocannabinol or THC, can- nabidiol does not bind to CB1 receptors and therefore does not cause euphoria or intoxication. 2 The cumulative experience of individual-investigator, open-label studies of cannabidiol in 214 patients with Len- nox-Gastaut and Dravet syndromes and other causes of treatment-resistant epi- lepsy demonstrated a 36.5% decrease in seizure frequency. A state-sponsored T he approval by the FDA in June 2018 of Epidiolex (cannabidiol) as an anti-seizure drug in patients with Lennox-Gastaut and Dravet syndromes is remarkable in several ways. 1 First, Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana. The FDA will doubtless need to withstand the public stigma of endorsing the use of a marijuana derivative as a med- ication. Second, Epidiolex is the first drug approved by the FDA for Dravet syndrome. The FDA is to be greatly commended for taking action on behalf of children with intractable seizures and intellectual disa- bility. Third, this drug of stigmatized origin to be used in a stigmatized pair of condi- tions is aimed at improving the lives and function of a frequently marginalized pop- ulation – young children.

study of adults and children with treat- ment-resistant epilepsy demonstrated significant reduction in seizure frequency that exceeded 50% in half of the patients. One study in children with tuberous sclero- sis demonstrated a durable 50% reduction in seizure frequency. 3 GW Pharmaceuticals, the manufacturer of Epidiolex, has sponsored four rand- omized, controlled trials of that drug in patients with treatment-resistant epilepsy syndromes, including Lennox-Gastaut and Dravet syndromes and tuberous sclerosis. Dose-dependent reductions in seizure frequency were as high as 42%. Adverse effects were largely mild or mod- erate, often transient, and most commonly included somnolence and diarrhea. 3 The availability of a potentially efficacious drug for treatment-resistant epilepsy is an advance in and of itself. But the most significant impact of the FDA’s approval of Epidiolex for patients with syndromes marked by treatment-resistant epilepsy may be the demarginalization of these patients and the destigmatization of their disease. References 1. US Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Silver Spring, MD. US Depart of Health and Human Services; 2018. 2. Nahler G, Grotenhermen F, Zuardi AW, Crippa JAS. A conversion of oral cannabidiol to delta9-tetrahydrocannabinol seems not to occur in humans. Cannabis Cannabinoid Res 2017;2(1):81-86. 3. O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav 2017;70(Pt B):341-348. www.practiceupdate.com/c/74531

24 hours after stroke. These results sub- stantially increased the window of time for effective treatment and led to the third major revolution in the treatment of acute ischemic stroke. The first revolution in stroke care, more than 2 decades ago, occurred when a large randomized clini- cal trial showed that IV tPA given ≤3 hours post onset in patients with hemorrhage or early evidence of large infarct resulted in better functional outcomes compared with placebo. The second revolution occurred when several randomized clinical trials showed the benefit of ET (with or without IV tPA) up to 6 hours post onset in patients with large-vessel occlusion and small core infarct compared with IV tPA alone. Less than 25 years ago, there was essentially no medical intervention to limit expansion of the infarct in the early stages of stroke, despite evidence from animal studies obtained decades earlier that infarcts expanded into the larger area " …thisdrugof stigmatizedorigin to be used in a stigmatized pair of conditions is aimed at improving the lives and function of a frequently marginalized population – young children. "

VOL. 3 • NO. 4 • 2018

EDITOR’S PICKS 8

Discontinuation of Disease-Modifying Therapy in Patients With Multiple Sclerosis Over Age 60 Multiple Sclerosis

" …the current study supports the option of DMT discontinuation in older

Take-home message • There are no guidelines for discontinuation of disease-modifying therapy (DMT) in multiple sclerosis patients. This retrospective observational study reviewed cases at three American multiple sclerosis centers to characterize anyone over the age of 60 who discontinued DMT. Of 600 patients identified, 178 discontinued DMT at the average age of 65, 68% discontinuations being provider initiated due to side effects (49%), stable disease (28%), age (22.5%), lack of benefit (21%), and secondary progressive disease (20%), comorbidities (15%), and cost (10%). In patients who re-initiated DMT (n=19; 10.7%) the reasons were patient preference (n=8), MRI changes (n=3), clinical progression (n=4), entering a trial (n=1), and provider preference (n=3). There was one relapse documented in those who discontinued DMT. Although studies of younger patients discontinuing DMT show increases in relapses and disease progression, these increases were not observed in the older patients in this study. • Age should be a factor when considering discontinuation of DMT in patients with multiple sclerosis. Shila Azodi MD O ver the past 20 years, unprecedented advances have been made in the treat- ment of multiple sclerosis (MS). As of April 2018, 15 disease-modifying therapies (DMT) have received regulatory approval for the management of relapsing MS. The majority of these therapeutic agents were designed to reduce the development of MS inflammatory lesions and associated clinical exacerbations by modulating path- ogenic immune cells in the periphery. However, it is unclear when, if ever, DMT should be discontinued in patients following years of disease quiescence and/or following transition into a secondary progressive stage (during which gradual disability accumu- lation occurs independent of new gadolinium-enhancing lesions and/or relapses). This issue is particularly pertinent to MS patients in late middle age or older because the frequency of enhancing lesions and clinical relapses naturally declines over time and several of the approved DMTs were found to be ineffective in progressive MS trials. The current manuscript describes a retrospective, observational “real-world” study of DMT discontinuation in MS patients over 60 years of age who had been treated with DMT for at least 2 years. Of the 600 individuals included, 178 (29.7%) discontinued DMT. There was only 1 clinical relapse among the discontinuers, the vast majority of whom remained off DMT. The reinitiation rate was approximately 10% and primarily driven by patient preference as opposed to MRI changes or clinical progression. Although more definitive data on this topic will await the outcome of an ongoing prospective rand- omized controlled trial, the current study supports the option of DMT discontinuation in older MS patients with a stable or progressive clinical course and no recent evidence of neuroinflammatory activity. COMMENT By Benjamin Segal MD

Abstract BACKGROUND The risk-benefit ratio of continuing immunomodulating disease-modifying therapy (DMT) in older multiple sclerosis (MS) patients is unknown. OBJECTIVE To evaluate clinical and patient-re- ported outcomes after stopping DMT in older MS patients. METHODS Retrospective, observational study identifying patients from our MS clinics who were aged over 60 and on DMT > 2 years. Cause-specific Cox proportional hazards regres- sion modeled time to discontinuation and time to reinitiation of therapy. Pre- and post-discon- tinuation comparisons of Performance Scales (PS), Timed 25-Foot Walk, and Patient Health Questionnaire-9 (PHQ9) were analyzed using linear mixed models. RESULTS A total of 600 patients were included, with 178 (29.7%) discontinuing. Discontinuers were 2.2years older, had 3.2years longer dis- ease duration, and 1.6 years lesser treatment exposure. Providers initiated discontinuation more than patients (68.0%). Only one clinical relapse occurred in discontinuers. A proportion (10.7%) reinitiated DMT. Provider-initiated discon- tinuers restarted less often (hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.12-0.9). In discontinuers, relapsing-remitting patients had lower PS on average than primary progres- sive. Provider-initiated discontinuation was associated with lower PS than patient- initiated discontinuation. PHQ9 scores appeared higher in those stopping intravenous (IV) therapies than interferons. Lower PS and PHQ9 indicate bet- ter outcomes. CONCLUSION Most patients over age 60, who dis- continued DMT, remained off DMT. This study provides real-world data that may guide clini- cians considering discontinuing DMT. Discontinuation of Disease-Modifying Therapy in Patients With Multiple Sclerosis Over Age 60. Mult Scler 2018 Mar 20;[EPub Ahead of Print], LH Hua, TH Fan, D Conway, et al. www.practiceupdate.com/c/65862 MS patients with a stable or progressive clinical course and no recent evidence of neuroinflammatory activity. "

Dr. Segal is Holtom-Garrett Professor of Neurology and Director of the Multiple Sclerosis Center at the University of Michigan Medical School in Ann Arbor, Michigan.

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EDITOR’S PICKS 9

Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging The New England Journal of Medicine

Take-home message • The authors of this randomized open-label trial with blinded assessment evaluated the effectiveness of endovascular thrombectomy plus standard medical therapy vs standard medical therapy alone for the treatment of ischemic stroke in patients who had MCA or ICA occlusion, were 6 to 16 hours from last known normal, and had ischemic tissue on perfusion imaging. Compared with the standard care alone group, the thrombectomy group had significantly better 90-day functional outcomes on the modified Rankin scale and lower 90-day mortality. There was no difference in serious adverse events between the groups. • Endovascular therapy plus standard treatment was more effective than standard treatment alone in patients with ischemic stroke who were 6 to 16 hours from last known normal and who had ischemic, but not infarcted, tissue on perfusion imaging. Abstract

middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard med- ical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90.

BACKGROUND Thrombectomy is currently rec- ommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. METHODS We conducted a multicenter, rand- omized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal COMMENT By Jean-Claude Baron MD, ScD, FMedSci T he DEFUSE 3 randomized controlled trial documents that patients with large-vessel occlusion (LVO) andclear mismatch between at-risk but salvageable tissue and already irreversibly damaged tis- sue (ie, penumbra and core, respectively) treated with mechanical thrombectomy (MT) 6 to 16 hours from last-time-seen-well (LTSW; ie, including wake-up and unknown time-of-onset strokes) enjoyed markedly improved functional outcomes relative to best medical therapy. Only a few weeks ago, the DAWN trial reported similar results in patients with small-core but dispropor- tionate neurological deficit – suggestive of mismatch – treated 6 to 24 hours from LTSW. Showing that a subgroup of patients can strongly benefit fromMT up to 24 hours after stroke is the third major revolution in acute stroke management, occurring only 3 years after the second revolution demon- strating that MT added on to intravenous thrombolysis (IVT) using tPA up to 6 hours post onset in patients with LVO and small- core infarct improved outcome over IVT alone. And it occurred 22 years after the

RESULTS The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular ther- apy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were function- ally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemor- rhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respec- tively; P=0.18). CONCLUSIONS Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical ther- apy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or inter- nal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging. N Engl J Med 2018 Jan 24;[EPub Ahead of Print], GW Albers, MP Marks, S Kemp, et al. www.practiceupdate.com/c/63459

first, which showed that tPA ≤3 hours (sub- sequently extended to ≤4.5 hours) afforded better outcomes than placebo. Both trials being highly positive, the AHA/ ASA guidelines changed the same day, recommending MT alone in imaging- based selected patients up to 24 hours post onset – a fourfold extension relative to previous guidelines published only 3 years ago! Although this breakthrough will increase the overall number of patients benefitting from MT, exerting pressure on the care systems given the relative scarcity of MT-capable centers, the emphasis that the earlier recanalization is achieved, the better the outcome (ie, that “time is brain”) remains unchanged.

Dr. Baron is Director of Research and Deputy- Director of the Inserm/Paris Descartes University Research Centre for Psychiatry and Neuroscience, and Honorary Neurology Consultant at

Sainte-Anne Hospital in Paris, France.

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Zonisamide as an Adjunct to Levodopa for DLB Parkinsonism Neurology

Take-home message • Parkinsonism is an important component of the dementia with Lewy bodies (DLB) phenotype. It is difficult to treat because the dopaminergic drugs effective against these symptoms tend to exacerbate the psychiatric features of the disease. Zonis- amide is an anti-epileptic drug that has shown efficacy as an adjunct therapeutic agent for motor symptoms of Parkinson’s through several proposed mechanisms. This is a phase II, placebo-controlled randomized double-blind study assessing the role of zonisamide as an adjunct to levodopa in DLB therapy. The reductions in the UPDRS part III (motor) scores at week 12 were (least squares mean) 2.1 points in the placebo group, 4.4 points in the zonisamide 25-mg dose group, and 6.2 in the zonisamide 50-mg dose group, both active arms meeting significance thresholds. The most common drug-related adverse events were weight loss, reduced appetite, and rash. There was no difference in severe adverse events between the groups. There was no worsening of cognition or psychiatric symptoms. • Overall, zonisamide appeared to be well-tolerated and effective in treating parkinsonism in DLB. Codrin Lungu MD

COMMENT By Mark Hallett MD Z onisamide was first noted to be helpful for motor symptoms in Parkinson’s disease when it was given to a patient to control epilepsy. Subsequently, it has been studied in a number of patients and the utility has been confirmed, particularly with a reduction in wearing off. More recently, it has become clear that zonisamide is also helpful for non-motor features of Parkinson’s disease such as impulse control disorders. The current article shows that, although there are a vari- ety of mild side effects with zonisamide, there is no worsening of cognitive function or psychiatric manifestations in patients with Lewy Body Dementia parkinsonism. It certainly seems that it should be considered as an adjunct in the treatment of patients with Parkin- son’s disease. It is not clear how zonisamide is helpful, but there are many theories, largely based on animal models. Monoamine oxidase is inhibited and dopamine turnover is reduced. Increased dopamine release has been found. Levodopa-induced quinone formation is reduced, mitochondria are protected, and alpha-synuclein neurotoxicity is blocked. Zonisamide reduces endoplasmic reticulum stress and may be neuroprotective of dopaminergic neu r on s . Ano t he r po s s i b l e neuroprotective mechanism is an increase in brain-derived neurotrophic factor (BDNF) signaling. The mechanism of action of zonisamide in epilepsy is also unknown, but the most likely mechanism is blockade of sodium and T-type calcium channels. Thus, the most straightforward explanation of how it might work in Parkinson’s disease is by blocking the T-type calcium channel in the subthalamic nucleus, reducing its firing rate, and favorably modulating the overactive basal ganglia circuit.

" It certainly seems that it should be considered as an adjunct in the treatment of patients with Parkinson’s disease. "

Abstract OBJECTIVE To investigate the efficacy and safety of zonisamide as an adjunct to levodopa ther- apy for parkinsonism in patients with dementia with Lewy bodies (DLB). METHODS This phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (pla- cebo or zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from base- line in Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symp- toms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed. RESULTS Overall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was signif- icantly greater in the zonisamide 50 mg group compared with placebo (between-group differ- ence -4.1; 95% confidence interval -6.8 to -1.4;p=

0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups. CONCLUSION Zonisamide (adjunctive to levo- dopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms. CLINICAL TRIAL REGISTRATION JapicCTI-122040. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB. Adjunct Zonisamide to Levodopa for DLB Parkinsonism: A Randomized Double-Blind Phase 2 Study. Neurology 2018 Feb 20;90(8) e664-e672, MMurata, T Odawara, K Hasegawa, et al. www.practiceupdate.com/c/64546

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 11

Differentiating Myelitis FromVascular and Other Causes of Myelopathy Neurology Take-home message • Transverse myelitis (TM) is a diagnostic challenge, with impor- tant implications given the balance between effectiveness and risk of available therapies. This is a retrospective analysis of patients with presumptive TM, using logistic regression to determine characteristics that can help establish the diagnosis. The final diagnosis distribution included 54% inflammatory TM, 20% vascular myelopathy, 8% spondylotic, and 18%other mye- lopathy. The best individual classifier for diagnostic category was the temporal profile of symptoms, with a correct classifi- cation rate of 77%. When adding temporal profile, initial motor examination, andMRI lesion distribution toCSF pleocytosis and MRI gadolinium enhancement, the multinomial AUC was 0.67. • The results suggest that using this multifactorial algorithm, weighted toward the clinical presentation characteristics, can improve TM diagnostic accuracy. Codrin Lungu MD Abstract OBJECTIVE To assess the predictive value of the initial clinical and para- clinical features in the differentiation of inflammatory myelopathies from other causes of myelopathy in patients with initial diagnosis of transverse myelitis (TM). METHODS We analyzed the clinical presentation, spinal cord MRI, and CSF features in a cohort of 457 patients referred to a specialized myelopathy center with the presumptive diagnosis of TM. After evaluation, the mye- lopathies were classified as inflammatory, ischemic/stroke, arteriovenous malformations/fistulas, spondylotic, or other. A multivariable logistic regres- sion model was used to determine characteristics associated with the final diagnosis and predictors that would improve classification accuracy. RESULTS Out of 457 patients referred as TM, only 247 (54%) were con- firmed as inflammatory; the remaining 46% were diagnosed as vascular (20%), spondylotic (8%), or other myelopathy (18%). Our predictive model identified the temporal profile of symptom presentation (hyperacute <6 hours, acute 6-48 hours, subacute 48 hours-21 days, chronic >21 days), initial motor examination, and MRI lesion distribution as characteristics that improve the correct classification rate of myelopathies from 67% to 87% (multinomial area under the curve increased from 0.32 to 0.67), compared to only considering CSF pleocytosis and MRI gadolinium enhancement. Of all predictors, the temporal profile of symptoms contributed the most to the increased discriminatory power. CONCLUSIONS The temporal profile of symptoms serves as a clinical bio- marker in the differential diagnosis of TM. The establishment of a definite diagnosis in TM requires a critical analysis of the MRI and CSF character- istics to rule out non-inflammatory causes of myelopathy. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that for patients presenting with myelopathy, temporal profile of symptoms, ini- tial motor examination, and MRI lesion distribution distinguish those with inflammatory myelopathies from those with other causes of myelopathy. Clinical Biomarkers Differentiate Myelitis From Vascular and Other Causes of Myelopathy. Neurology 2018 Jan 02;90(1)e12-e21, P Barreras,

Restarting Antiplatelet TherapyAfter Spontaneous Intracerebral Hemorrhage 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 outcome measures 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 functional outcomes. Codrin Lungu MD Abstract OBJECTIVE To compare the functional outcomes and health-related quality 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 functional 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 dif- ference in primary outcome was observed between restarting vs not restarting APT (35.5% vs 43.9%; p = 0.105). There were also no differ- ences 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 Hemorrhage: Functional Outcomes. Neurology 2018 Jul 03;91(1)e26- e36, CJ Chen, D Ding, TJ Buell, et al. www.practiceupdate.com/c/70538 Neurology

KC Fitzgerald, MA Mealy, et al. www.practiceupdate.com/c/62703

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