PracticeUpdate Neurology February 2019

VOL. 4 • NO. 1 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4680

Timing of Anticoagulation After Recent Ischemic Stroke in Patients With Atrial Fibrillation

Expert Opinion Provocative Induction of Psychogenic Nonepileptic Seizures by Barbara Ann Dworetzky MD Young-Onset Multiple System Atrophy by Sonja W. Scholz MD, PhD

JOURNAL SCANS Diagnostic Sensitivity of Electrophysiology and Ultrasonography in Ulnar Neuropathies of Different Severity

Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid- Lowering Agents in the Elderly

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-Analysis

MAVENCLAD ® cladribine tablets

PBS LISTED IN RRMS 1 1st January 2019

† 2-5

† In RRMS, MAVENCLAD ® is an oral therapy with a ‘Tailored Dosing Regimen’ (Weight-based, short-course treatment, with a maximum of 20 days treatment over 2 years) . PBS, Pharmaceutical Benefits Scheme. RRMS, relapsing-remitting multiple sclerosis.

PBS information: Authority Required. Refer to PBS Schedule for full authority information.

Before prescribing, please review the Full Product Information available from Merck Australia (1800 633 463)

MAVENCLAD ® Minimum Product Information: Indications: MAVENCLAD is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical relapses and to delay the progression of physical disability. Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 4. Re-initiation of therapy after year 4 has not been studied. Contraindications: Patients with hypersensitivity to cladribine or to any of the tablet excipients, infected with the human immunodeficiency virus (HIV), active chronic infections (tuberculosis, hepatitis), immunocompromised patients, including patients receiving immunosuppressive or myelosuppressive therapy, moderate or severe renal impairment (creatinine clearance < 60 mL/min), during pregnancy and breastfeeding. Precautions: Haematological monitoring is required prior to and during therapy. Lymphopenia; Infections; Malignancies; Switching to and from MAVENCLAD treatment; Renal impairment; Hepatic impairment; Fructose intolerance; Effects on fertility (incl. male patients), Use in pregnancy (Category D) and lactation; Use in Paediatric or Elderly; Carcinogenicity, Genotoxicity. Interactions: 3 hours interval required for administration of other oral medicines. Concomitant treatment with immunosuppressive or myelosuppressive agents is contraindicated; must not be initiated within 4 to 6 weeks after vaccination with live/live-attenuated vaccines. Recommendations to avoid co-administration with potent ENT1, CNT3 and ABCG2 transporter inhibitors. Adverse reactions: Very Common: Lymphopenia (may be severe, Grade 3 or 4). Common: Rash, alopecia, oral herpes, dermatomal herpes zoster, decrease in neutrophil count. Dosage and administration: Haematological and infections screening criteria for starting and continuing therapy have to be met before initiating MAVENCLAD therapy or administering any subsequent treatment course. The recommended cumulative dose of MAVENCLAD is 3.5 mg/kg body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight. Patients should receive no more than 2 treatment courses over two consecutive years. The recommended dose should not be exceeded. Following completion of the 2 treatment courses, no further cladribine treatment is required in year 3 and year 4. Re-initiation of therapy after year 4 has not been studied. Based on approved PI dated 5 December 2017. Sponsor: Merck Serono Australia Pty Ltd, 3-4/25 Frenchs Forest Rd East, Frenchs Forest NSW 2086. ®Registered Trade Mark. References: 1. Schedule of Pharmaceutical Benefits, January 2019. 2. MAVENCLAD ® Product Information, Date of most recent amendment 5 December 2017. 3. Giovannoni G et al. N Engl J Med 2010;362:416–26. 4. Giovannoni G et al. N Engl J Med 2010;362:416–26 (supplementary information). 5. Giovannoni G et al. Multiple Sclerosis Journal 2017; Online, first published 5 Sept 2017:1–11.

Merck Serono Australia Pty Ltd | ABN 72 006 900 830. Unit 3–4, 25 Frenchs Forest Road East, Frenchs Forest NSW 2086 Australia. Phone (02) 8977 4100 | Fax (02) 9975 1516. ® = Registered Trademark. MAV033 | Date of preparation: January 2019 | AUS/CLA/1218/0195

CONTENTS 3

RESEARCH Editor’s picks 5 Timing of Anticoagulation After Recent Ischemic Stroke in Patients With Atrial Fibrillation 6 Effect of Nonmyeloablative HSCT vs Continued Disease-Modifying Therapy on Disease Progression in Relapsing– Remitting MS Comment by Erin Longbrake MD

COVER 5

12 Lasmiditan: An Effective Acute Treatment for Migraine 12 Adherence With Psychotherapy and Treatment Outcomes in Patients With Psychogenic Nonepileptic Seizures 13 Diagnostic Sensitivity of Electrophysiology and Ultrasonography in Ulnar Neuropathies of Different Severity Comment by Simon Podnar MD, DSc

Timing of Anticoagulation After Recent Ischemic Stroke in Patients With Atrial Fibrillation

EXPERT OPINION 20 Provocative Induction of Psychogenic

7 Abortion Induces Reactivation of Inflammation in Relapsing–Remitting MS 8 Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid-Lowering Agents in the Elderly Comment by William H. Theodore MD 9 Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Clinical Trials of Alzheimer’s Disease Comment by Irene Mace Hamrick MD, FAAFP, AGSF 10 Stiripentol Decreases Seizure Frequency in Dravet Syndrome

Nonepileptic Seizures By Barbara Ann Dworetzky MD

14 Generalized Polyspike Train as EEG Biomarker of Drug-Resistant Idiopathic Generalized Epilepsy 15 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antiepileptic Drugs 15 Management of Antiplatelet Therapy in Patients Undergoing Neuroendovascular Procedures 16 Treatment Effect in Cerebrotendinous Xanthomatosis Depends on Age at Start of Treatment Comment by Shuke Nie MD, PhD 17 Novel Method to Distinguish Convulsive Epileptic and Psychogenic Nonepileptic Seizures

22 Young-Onset Multiple System Atrophy By Sonja W. Scholz MD, PhD

11 Stroke Outcomes and Anticoagulation Strategies 11 Statin-Associated Muscle Disease

VOL. 4 • NO. 1 • 2019

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.

2019 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

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

Cover: Blood clot in brain medical concept/gettyimages.com PracticeUpdate Neurology is published by Elsevier Australia ISSN 2206-4680 (Print)

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMNN021901

EDITOR’S PICKS 5

Timing of Anticoagulation After Recent Ischemic Stroke in Patients With Atrial Fibrillation The Lancet Neurology Take-home message • The timing of initiation of anticoagulation after an acute ischemic stroke related to atrial fibrillation (AF) remains a difficult decision in practice. This is particularly an issue with the newer direct oral anticoagulants (DOACs), where fewer data are historically available for patients with recent ischemic stroke. The authors review the prospective observational studies and two small randomized trials assessing the risks and benefits of early DOAC initiation in mild to moderate AF-associated ischemic stroke. The data suggest that the risk of intracranial hemorrhage with early DOAC initiation is low, whereas delaying the treatment past 7 days is associated with an increased risk of recurrent stroke. • Rigorous prospective trials comparing early and later anticoagulation are needed and four such trials are underway, with results expected in the next 2 years. Condrin Lungu MD Abstract

dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and sec- ondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation. RECENT DEVELOPMENTS Prospective observa- tional studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3-5 days) in mild-to-moder- ate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treat- ment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was asso- ciated with an increased frequency of recurrent ischaemic stroke. WHERE NEXT?: Adequately powered randomised controlled trials com- paring early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the accept- able safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff time- points for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the opti- mal timing to initiate DOAC administration after recent ischaemic stroke and whether the tim- ing should differ according to stroke severity. RESULTS of these trials are expected from 2021. Timing of Anticoagulation After Recent Ischaemic Stroke in Patients With Atrial Fibril- lation. Lancet Neurol 2019 Jan 01;18(1)117-126, DJ Seiffge, DJ Werring, M Paciaroni, et al. www.practiceupdate.com/c/78233

harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, hepari- noids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised con- trolled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban,

BACKGROUND About 13-26% of all acute ischae- mic strokes are related to non-valvular atrial fibrillation, the most common cardiac arrhyth- mia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially

VOL. 4 • NO. 1 • 2019

EDITOR’S PICKS 6

Effect of Nonmyeloablative HSCT vs Continued Disease-Modifying Therapy on Disease Progression in Relapsing–Remitting MS JAMA: The Journal of the American Medical Association Take-home message • The authors of this small trial randomized 110 patients with relapsing–remitting mul- tiple sclerosis (MS) who had two or more relapses while receiving disease-modifying therapy (DMT) in the prior year to receive either nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus cyclophosphamide and antithymocyte globulin or DMT of higher efficacy or a different class than previously taken. After a median follow-up of 2 years, disease had progressed in 3 patients in the HSCT group and 34 patients in the DMT group. Furthermore, in the first year, disability scores improved in the HSCT group but worsened in the DMT group. • In patients with relapsing–remitting MS, nonmyeloablative HSCT appears to be more effective for slowing disease progression than DMT.

COMMENT By Erin Longbrake MD N onmyeloablative hematopoietic stem cell therapy (HSCT) has been emerging as an effective therapy for aggressive, relapsing multiple scle- rosis (MS). Several case series and a phase II clinical trial reported decreases in relapses and improvement in neuro- logic disability after HSCT, 1,2 but questions about safety and relative efficacy com- pared with standard immunomodulatory treatments remained. In this article, Burt and colleagues pro- vide initial findings for the MS International Stem cell Transplant (MIST) trial. In this open-label trial, patients with highly active, relapsing MS were randomized to either HSCT or standard immunomodulatory medications. A variety of immunomodu- lators were utilized, including natalizumab as well as injectable and oral medications. Most experts will agree that these immu- nomodulators have wide-ranging efficacy for MS, with natalizumab typically recog- nized as more efficacious. Among the 55 patients randomized to pharmacologic immunomodulation, 21 were prescribed natalizumab. HSCT was performed using autologous hematopoietic stem cells after immunoablation with pulse cyclophospha- mide and antithymocyte globulin. Patients receiving HSCT had significantly longer times to disability progression and relapse

than patients receiving standard immu- nomodulation, with a large effect size (eg, 9.7% of HSCT patients had disease progression at 5 years compared with 75.3% of patients on standard immuno- modulation). This was true even when natalizumab-treated patients were con- sidered separately in a subgroup analysis. There were no deaths, and infectious complications occurred in both treatment groups. Larger studies will be needed to assess the relative risk of HSCT compared with traditional immunomodulation. It is important to note that patients in the HSCT arm received pulse cyclo- phosphamide as immunoablation. Pulse cyclophosphamide has been long rec- ognized as an effective treatment for MS, although it is not widely used due to long-term safety concerns (eg, late malignancies). 3 Longer follow-up data will be necessary to determine whether malignancy is increased in MS patients receiving HSCT. It will also be important to compare HSCT with best-available immunotherapy, as the variable effica- cies and mechanisms of action for the immunomodulators utilized in this trial limit interpretability. A clinical trial compar- ing HSCT with alemtuzumab is recruiting (Clinicaltrials.gov NCT03477500) and will provide more definitive data about the

relative efficacy of HSCT versus other highly effective treatments. Available data suggest that HSCT is effective for relapsing, but not progressive MS, limit- ing its scope of use. HSCT also remains experimental, used at limited MS centers or in the context of clinical trials. Finally, it should be noted that HSCT is synony- mous with bone marrow transplantation and does not equate with using stem cells to replace nerves and/or myelin that have been previously destroyed by MS, a dis- tinction that is sometimes not appreciated by the public. References 1. Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 2015;313(3):275-284. 2. Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing- remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol 2015;72(2):159-169. 3. Weiner HL, Hauser SL, Hafler DA, et al. The use of cyclophosphamide in the treatment of multiple sclerosis. Ann N Y Acad Sci 1984;436(1):373-381. Dr. Longbrake is an Assistant Professor in the Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut.

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 7

Abortion Induces Reactivation of Inflammation in Relapsing–RemittingMS Journal of Neurology, Neurosurgery, and Psychiatry Take-home message • Several studies have addressed the interaction between pregnancy and the course of multiple sclerosis (MS), but similar information is lacking with respect to abor- tion. This is a retrospective, multicenter, observational study assessing the course of relapsing–remitting MS in women undergoing spontaneous or elective abortions. The mean annualized relapse rate increased from 0.50 in the preconception year to 0.63 post abortion, and the mean number of gadolinium-enhancing lesions grew from 0.39 to 0.77. The main predictors of relapse were elective abortion (OR, 1.77), continuation of disease-modifying therapy at conception (OR, 0.71; meaning that treatment continuation reduced the risk), and higher preconception annualized relapse rate (OR, 1.32). • These data offer useful information for women with MS and the risks associated with abortion in this population. Codrin Lungu MD Abstract OBJECTIVE To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS An independent, multicentre retrospective study was con- ducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covar- iance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treat- ment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, dis- continuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly. Abortion Induces Reactivation of Inflammation in Relapsing-Remitting Multiple Sclerosis. J Neurol Neurosurg Psychiatr 2018 Dec 01;89(12)1272-1278, D Landi,

Abstract IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). OBJECTIVE To compare the effect of nonmyeloablative HSCT vs dis- ease-modifying therapy (DMT) on disease progression. DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disabil- ity Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South Amer- ican centers. Final follow-up occurred in January 2018 and database lock in February 2018. INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n=55) or DMT of higher efficacy or a different class than DMT taken dur- ing the previous year (n=55). MAIN OUTCOMES AND MEASURES The primary end point was disease pro- gression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evalua- tions 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evalu- ated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95%CI, 0.02-0.24; P<.001). Dur- ing the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P<.001). There were no deaths and no patients who received HSCT developed non- hematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA 2019 Jan 15;321(2)165-174, RK Burt, R Balabanov, J Burman, et al. www.practiceupdate.com/c/78658

P Ragonese, L Prosperini, et al. www.practiceupdate.com/c/76841

VOL. 4 • NO. 1 • 2019

EDITOR’S PICKS 8

Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid-Lowering Agents in the Elderly Epilepsia

Take-home message • Through this study, the authors wanted to examine the change in effectiveness of statins caused by carbamazepine interaction. Among the 194 participants of the STEP-ONE trial, the authors examined lipid fractions, lipoprotein (a), and C-reactive protein (CRP) and found that, in patients not taking statins, those treated with carbamazepine had a higher level of total cholesterol than those treated with levetiracetam (+16.6 mg/dL; P = .053), and lipoprotein(a) was significantly lower in patients taking lamotrigine than in the patients taking carbamazepine and leveti- racetam, with CRP higher in patients on carbamazepine than in other patients. • The authors concluded that carbamazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Contrary to what has been reported by some previous studies, they also noted that other lipid markers yielded drug– gender interactions without a consistent pattern. Omar Khan MD COMMENT By William H. Theodore MD M intzer et al analyzed a data subset from a clinical trial of antiepileptic drugs (AEDs) in the elderly. 1 Patients not taking statins treated with carbamazepine (CBZ) had higher total cholesterol than those treated with levetiracetam (LEV). Lipoprotein(a) was significantly lower in patients taking lamotrigine (LTG) than CBZ or LEV. C-reactive protein was higher in people on CBZ. When differences in lipid levels between patients taking statins or not were compared, lipid-lowering effects seemed to be reduced in patients on CBZ. Interpretation of the results needs to consider difficulties of post hoc subset analysis. Only 194 of 361 patients randomized in the underlying study, not designed to meas- ure effects on lipids, were included and not all had full data available. The original randomization did not take lipids or C-reactive protein into account. Baseline BMI was significantly higher in the CBZ group. The study was supported by UCB, maker of levetiracetam. Previous studies suggested hepatic enzyme-inducing AEDs may alter lipid profiles, even in patients not taking statins. In addition, because these drugs are metabolized via cytochrome P450, it is reasonable that CBZ, a hepatic enzyme inducer, might vitiate their effects. Interactions of hepatic enzyme-inducing AEDs with many other therapeutic drugs are well-known. Some data suggest that CBZ may be more effective for seizure control, but less well-tolerated than LTG or LEV. Both CBZ and LTG have mood-stabilizing properties, whereas LEV can have adverse psychiatric effects. Choosing the best AED requires careful balancing of antiseizure and adverse effects, and depends on a full evalua- tion of each patient, particularly including concurrent systemic disease. Reference 1. Werhahn KJ, Trinka E, Dobesberger J, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56(3):450-459.

Abstract OBJECTIVE To examine serologic markers of vas- cular risk under treatment with commonly used antiepileptic drugs (AEDs) in the elderly in a randomized setting, and to determine whether the reduced exposure to hydroxymethylglutar- yl-CoA reductase inhibitors (“statins”) caused by carbamazepine reduces the effectiveness of the drugs as lipid-lowering agents. METHODS Standard lipid fractions, lipoprotein(a), and C-reactive protein (CRP) were examined in a subset of those participating in the STEP- ONE trial, in which elderly patients with new epilepsy were randomized to treatment with carbamazepine, lamotrigine, or levetiracetam. Separate comparisons were made by individ- ual AED, among those treated with statins, and, for CRP, among those treated with anti-inflam- matory drugs. RESULTS One hundred ninety-four patients had the aforementioned serologic measurements. In patients not taking statins, those treated with carbamazepine had higher total cholesterol than those treated with levetiracetam (+16.6 mg/dL, P = 0.053), with values from patients on lamotrig- ine intermediate, whereas cholesterol fractions were subject to drug-gender interactions which did not show a consistent pattern. Lipoprotein(a) was significantly lower in lamotrigine patients than in the carbamazepine and levetiracetam groups. After accounting for the effects of ster- oids, CRP was higher in carbamazepine patients than in other patients. Patients taking a statin had lower lipid levels than those not taking a statin regardless of AED, but the differences between statin-treated and non-statin-treated patients were much larger (50%-100% or more) in the lamotrigine and levetiracetam groups than in the carbamazepine group (P = 0.035 for interaction effect of statin use and AED on total cholesterol). SIGNIFICANCE Here, we demonstrate that carba- mazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Native AED effects on lipids were inconsistent and sub- ject to drug-gender interaction, in contrast with other studies; further investigation is necessary to determine if these latter findings are genu- ine or spurious. Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid-Lowering Agents in the Elderly. Epilepsia 2018 Oct 01;59(10)1899-1907, S Mintzer, E Trinka, G Kraemer, et al. www.practiceupdate.com/c/74819

Dr. Theodore is Chief of the Clinical Epilepsy Section at the National Institute of Neurological Disorders and Stroke, National Institutes of Health in Bethesda, Maryland.

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 9

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Clinical Trials of Alzheimer’s Disease JAMA Network Open

Take-home message • This study explored whether the concomitant use of cholinesterase inhibitors (ChEIs) and memantine among participants in clinical trials of Alzheimer’s disease impacted the trials’ cognitive outcomes. The researchers conducted a meta-analysis of 18 studies and estimated an annual rate of decline on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Their analysis showed that study participants who received ChEls and/or memantine had a significantly greater annual rate of decline than participants receiving neither medication. Those taking memantine, with or without ChEIs, experienced a faster rate of decline than those taking only ChEIs or taking nei- ther medication. Notably, in later studies, just about all of the participants were taking ChEIs at study entry, and the majority were also taking memantine. • The concomitant use of medications for Alzheimer’s dis- ease among trial participants is associated with a rate of cognitive decline that can exceed the hypothesized effect of the interventions being investigated in a given clinical trial, and, unless that use is accounted for in trial design and in interpretation of trial results, it may be confounded with outcomes on the ADAS-cog. Moshe Ornstein MD

COMMENT By Irene Mace Hamrick MD, FAAFP, AGSF T his study examined nine randomized clinical trials and one observational study, with a total of 2714 participants with Alzheimer’s dementia (AD), who were enrolled in studies of new AD medications. In these studies, most patients were allowed to continue on their previous stable-dose demen- tia medications, and one-third was taking acetylcholinesterase inhibitors (AchEI), 5.4% memantine, one-third both, and 27.4% were taking neither. The ADAS-cog, a 70-point scale was the primary outcome, and showed a 1.5-point worsening of cogni- tion with the concomitant use of AchEI, and a 2-point worsening with the use of memantine compared with patients who were on neither. Although a 2-point difference is often used to define a significant therapeutic effect in AD clinical trials, one study showed that a 10% difference (7 points) is needed to for a clin- ically meaningful difference. 1 These medications have shown a statistical difference, leading to FDA approval, but very rarely have I seen clinical improve- ment in my patients. More recent studies support my clinical experience, and one Bayesian network meta-analysis of 142 studies, after an exhaustive review of the literature, demon- strated that cognitive enhancers in general have minimal effects on cognition. 2 The current study adds to our knowledge that more (demen- tia medicine) is not better. We should monitor our patients started on these dementia medications for side effects, includ- ing bradycardia, diarrhea, and weight loss. I usually stop these medications after a trial of 3 to 6 months and monitor for wors- ening of cognition. Rarely do my patients’ families or I see worsening, and then I restart them, monitoring for improvement. What may be equally important, is to stop medications that contribute to dementia, an effect that seems to be cumulative throughout life: benzodiazepines and anticholinergic meds. 3,4 References 1. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician 2011;83(12):1403-1412. 2. Tricco AC, Ashoor HM, Soobiah C, et al. Comparative effectiveness and safety of cognitive enhancers for treating Alzheimer’s disease: systematic review and network metaanalysis. J Am Geriatr Soc 2018;66(1):170-178. 3. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 2014;349:g5205. 4. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015;175(3):401-407.

Dr. Hamrick is Associate Professor of Clinical Health Sciences in the Department of Family Medicine, University of Wisconsin, and Director of Geriatrics Services, Department of Family Medicine at the University of Wisconsin in Madison, Wisconsin.

Association of Concomitant Use of Cholinesterase Inhibitors or Meman- tine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-Analysis. JAMA Netw Open 2018 Nov 02;1(7)e184080, RE Kennedy, GR Cutter, ME Fowler, LS Schneider www.practiceupdate.com/c/75573

VOL. 4 • NO. 1 • 2019

EDITOR’S PICKS 10

Stiripentol Decreases Seizure Frequency in Dravet Syndrome Journal of Child Neurology Take-home message • In Dravet syndrome, an epileptic encephalopathy of infancy, the neurocognitive outcomes of these patients are related to early control of seizures and status epilepticus. Although there are approved therapies, not all patients respond to the treatments available. Stiripentol is a new anti-epileptic medication with a novel mechanism of action (allosteric modulator of GABA-A receptor), which has shown efficacy in treating seizures in patients with Dravet syndrome in placebo-controlled trials. In this study, the authors retrospectively reviewed their results of adding stiripentol to the anti-epileptic regimens in 21 patients with Dravet syndrome between 2016 and 2017. The mean duration of stiripentol use in this cohort was 41 months. Seizure frequency decreased by more than 50% in more than half of the patients, and 2 patients became seizure-free. Adverse effects included sedation, tremor, and ataxia; 1 patient stopped stiripentol due to increased seizure frequency. • These data, collected over a longer duration of use than what has previously been reported in clinical trials of stiripentol, support the efficacy and relative tolerability of a new adjunctive treatment for Dravet syndrome. Sarah Matteson Kranick MD

Abstract Dravet syndrome is a rare and progressive epileptic encephalopathy of infancy. Stiripen- tol reduces the seizure frequency in patients with Dravet syndrome. We evaluated the clin- ical characteristics of patients with Dravet syndrome and their response to stiripentol. We retrospectively collected the data of 21 patients (11 females; mean age, 8.2 years, range: 5.4-15 years) with Dravet syndrome who were treated with stiripentol in our outpatient clinic between June 2016 and June 2017. Patients with seizure reduction ≥50% were considered responders. Most of our patients had severe (47%) or moder- ate (33%) cognitive disabilities, although 14% had mild cognitive disability. There was a significant difference in both status epilepticus and age between the groups with normal/mild versus severe/moderate neurocognitive prognoses. Of the patients, 85.7% were using stiripentol. The mean duration of stiripentol use was 41.2 months (range: 24-64 months). In 12 patients (57%), the seizure frequency decreased by more than 50%, and 2 of them were seizure-free. Status epilepticus was not recorded after stiripentol treatment in 8 of 11 patients with status epilepti- cus. Despite the small sample size, our results suggest that stiripentol has a favorable efficacy. In addition, considering the absence of status epilepticus after treatment and the negative effects of status epilepticus on cognitive devel- opment, early treatment should be initiated in SD patients, for whom disease control is difficult. Efficacy of Stiripentol and the Clinical Outcome in Dravet Syndrome. J Child Neurol. 2018 Oct 26;[EPub Ahead of Print], E Pembegul Yıldız, " These data… support the efficacy and relative tolerability of a new adjunctive treatment for Dravet syndrome. "

MU Ozkan, TA Uzunhan, et al. www.practiceupdate.com/c/77662

PRACTICEUPDATE NEUROLOGY

EDITOR’S PICKS 11

Stroke Outcomes and Anticoagulation Strategies Circulation Take-home message • This is an analysis of data from the COMPASS trial that looked at stroke outcomes in 27,395 patients with peripheral artery disease or stable coronary artery disease. The COMPASS participants were randomized to one of three anticoagulation strategies; follow-up was a mean of 23 months. The treatment groups were: aspirin 100 mg daily; rivaroxaban 5 mg twice daily; or low-dose rivaroxaban 2.5 mg twice daily and aspirin. Patients who received rivaroxaban and aspirin had significantly fewer strokes than those who received aspirin alone. The number of ischemic strokes was also significantly reduced. The number of strokes was similar in the rivaroxaban-only and aspirin-only groups. Prior stroke, systolic blood pressure at baseline, hypertension, diabetes, age, and Asian ethnicity were all independent predictors of stroke. • These findings support the use of rivaroxaban plus aspirin to reduce stroke risk in patients with stable vascular disease.

Abstract BACKGROUND Strokes were significantly reduced by the combination of rivaroxaban plus aspirin compared with aspirin in the COMPASS Trial. We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. METHODS Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117) or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients requiring anticoagulation, stroke within 1 month, previous lacunar stroke or intracerebral hemorrhage were excluded. RESULTS During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 Take-home message • This review discusses the recent evidence in the diagnosis and man- agement of statin-associated muscle symptoms (SAMS). • The authors concluded that better management of SAMS may increase the number of patients able to ben- efit from statin therapy. Future trials are warranted to more accurately assess SAMS via a rigorous dechal- lenge–rechallenge protocol or a double-blind, placebo-controlled statin run-in study.

[0.9% per year] vs. 142 [1.6% per year], HR 0.58, 95% CI 0.44-0.76, p<0.0001). Ischemic/uncer- tain strokes were reduced by nearly half (68 [0.7% per year] vs. 132 [1.4% per year] HR 0.51, 95% CI 0.38-0.68, p<0.0001) by the combination compared with aspirin. No significant difference was noted in the occurrence of stroke in the rivaroxaban alone group compared with aspi- rin: annualized rate of 0.7% (HR 0.82, 95% CI 0.65-1.05). The occurrence of fatal and disabling stroke (mRS 3-6) was decreased by the combi- nation (32 [0.3% per year] vs. 55 [0.6% per year], HR 0.58, 95% CI 0.37-0.89, p=0.01). Independent predictors of stroke were prior stroke, hyper- tension, systolic blood pressure at baseline, age, diabetes, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke Abstract Since the first approval of lovastatin in 1987, hydroxy-methyl-glutaryl CoA (HMG CoA) reduc- tase inhibitors, or statins, have been effective and widely popular cholesterol-lowering agents with substantial benefits for the prevention and treat- ment of cardiovascular disease. Not all patients can tolerate these drugs, however, and statin intolerance is most frequently associated with a range of side effects directed toward skeletal muscle, termed statin-associated muscle symp- toms or SAMS. SAMS are particularly difficult to treat because there are no validated biomark- ers or tests that can be used to confirm patient self-reports of SAMS, and a number of patients who report SAMS have non-specific muscle pain not attributable to statin therapy. This review sum- marizes the most recent evidence related to diagnosis and management of SAMS. First, the range of skeletal muscle side effects associated

(HR 3.63, 95% CI 2.65-4.97, p<0.0001) and was associated with a 3.4% per year rate of stroke recurrence on aspirin. The effect of the com- bination compared with aspirin was consistent across subgroups with high stroke risk, includ- ing those with prior stroke. CONCLUSIONS Low-dose rivaroxaban plus aspi- rin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis. Stroke Outcomes in the Cardiovascular Out- coMes for People Using Anticoagulation StrategieS (COMPASS) Trial. Circulation 2019 Jan 22;[EPub Ahead of Print], M Sharma, RG Hart, SJ Connolly, et al. www.practiceupdate.com/c/79091

Statin-Associated Muscle Disease Neurotherapeutics

with statin therapy is described. Second, data regarding the incidence and prevalence of SAMS, the most frequently experienced muscle side effect, are presented. Third, themost promis- ing new techniques to confirmdiagnosis of SAMS are explored. Finally, themost effective strategies for the clinical management of SAMS are summa- rized. Better diagnostic and treatment strategies for SAMS will increase the number of patients using these life-saving statins, thereby increas- ing statin adherence and reducing the costs of avoidable cardiovascular events. Statin-Associated Muscle Disease: Advances in Diagnosis and Management. Neurotherapeutics 2018 Sep 24;[EPub Ahead of Print], BA Taylor, PD Thompson. www.practiceupdate.com/c/74615

VOL. 4 • NO. 1 • 2019

EDITOR’S PICKS 12

Lasmiditan: An Effective Acute Treatment for Migraine Neurology

Adherence With Psychotherapy and Treatment Outcomes in Patients With Psychogenic Nonepileptic Seizures Neurology Take-home message • This prospective cohort study evaluated the association between adherence with psychotherapy and outcomes in 105 patients with psychogenic nonepileptic seizures (PNES). Adherence was associated with decreased sei- zure frequency, better quality of life, and fewer emergency department visits. • Minority patients and patients with a history of childhood abuse were less likely to adhere to psychotherapy. Abstract OBJECTIVE We conducted a prospective cohort study of patients with psychogenic nonepileptic seizures (PNES) to examine the association between adherence with psychotherapy and outcomes, including signif- icant (≥50%) reduction in PNES frequency, PNES freedom, improvement in quality of life, and reduction in emergency department (ED) utilization. METHODS A total of 105 participants were referred to receive psychother- apy either at Brigham and Women’s Hospital or with a local therapist. We called participants at 12-24 months follow-up and obtained detailed follow-up data from 93 participants (89%). Participants were considered adherent with psychotherapy if they attended at least 8 sessions within a 16-week period starting at the time of referral. RESULTS Adherence with psychotherapy was associated with reduction in seizure frequency (84% in adherent group vs 61% in nonadherent, p = 0.021), improvement in quality of life (p = 0.044), and reduction in ED uti- lization (p = 0.040), with medium effect sizes; there was no difference in PNES freedom. The association between adherence and ≥50% reduction in PNES frequency persisted when controlling for potential confounders in a multivariate model. Psychotherapy nonadherence was associated with baseline characteristics of self-identified minority status (odds ratio 7.47, p = 0.019) and history of childhood abuse (odds ratio 3.30, p = 0.023).

Take-home message • The authors of this phase III placebo-controlled trial ran- domized adults with migraine to 100 mg or 200 mg of lasmiditan, a high-affinity, highly selective 5-HT1F receptor agonist, or placebo to treat their next migraine attack. More patients on active treatment were free of headache pain at 2 hours after dosing (32% with 200 mg, 28.2% with 100 mg, and 15.3% with placebo). Improvements in favor of the active arms were also seen in global impression of change and disability levels. No serious treatment-emer- gent adverse events were reported, and most common adverse events were dizziness and paresthesia. • The results indicate the safety and efficacy for lasmiditan in the acute treatment of migraine attacks in adults, many of whom had at least one cardiovascular risk factor. Codrin Lungu MD " Improvements in favor of the active arms were also seen in global impression of change and disability levels. " Abstract OBJECTIVE To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. METHODS Adult patients with migraine were randomized (1:1:1) to a dou- ble-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). RESULTS Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardi- ovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0-3.6, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6-3.0, p< 0.001). Further- more, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3-2.1, p< 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3-2.2, p< 0.001) were free of their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity. CONCLUSIONS Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors. Lasmiditan Is an Effective Acute Treatment for Migraine: A Phase 3 Randomized Study. Neurology 2018 Nov 16;[EPub Ahead of Print], B Kuca, SD Silberstein, L Wietecha, et al. www.practiceupdate.com/c/77394

" Minority patients and patients with a history of childhood abuse were less likely to adhere to psychotherapy. "

CONCLUSIONS Our study is limited in that it cannot establish a causal rela- tionship between adherence with psychotherapy and outcomes, and the results may not generalize beyond the single quaternary care center study site. Among participants with documented PNES, adherence with psycho- therapy was associated with reduction in PNES frequency, improvement in quality of life, and decrease in ED visits. Adherence With Psychotherapy and Treatment Outcomes With Psy- chogenic Nonepileptic Seizures. Neurology 2019 Jan 04;[EPub Ahead of Print], B Tolchin, BA Dworetzky, S Martino, et al. www.practiceupdate.com/c/78679

PRACTICEUPDATE NEUROLOGY