PracticeUpdate Neurology June 2019

VOL. 4 • NO. 2 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4680

Validated Outcome of Treatment Changes According to International League Against Epilepsy Criteria in Adults With Drug-Resistant Focal Epilepsy

International Stroke Conference 2019

JOURNAL SCANS Brain State-Dependent Stimulation Boosts Functional Recovery Following Stroke

Magnetic Resonance Imaging or Computed Tomography Before Treatment in Acute Ischemic Stroke

Outbreaks of Acute Flaccid Myelitis? What Neurologists Need to Know

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MINIMUM PRODUCT INFORMATION AUBAGIO ® (teriflunomide). INDICATIONS: AUBAGIO is indicated for the treatment of patients with relapsing forms of Multiple Sclerosis to reduce the frequency of clinical relapses and to delay the progression of physical disability. DOSAGE AND ADMINISTRATION: AUBAGIO 14mg tablet orally once daily with or without food. CONTRAINDICATIONS: Hypersensitivity to leflunomide, teriflunomide or to any of the excipients; severe immunodeficiency states e.g. AIDS; significantly impaired bone marrow function or significant anaemia, leukopenia or thrombocytopenia; severe uncontrolled infections; severe impairment of liver function; pregnant women; women of childbearing potential who are not using reliable contraception (refer to full PI); when breastfeeding; severe hypoproteinaemia and patients who have or have had Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme. PRECAUTIONS: Elevations of liver enzymes; Blood pressure elevation; Infection; Haematological effects; Decrease in WBC count; Skin disorders; Respiratory (interstitial lung disease); Use in caution in patients showing signs of immunosuppression or renal impairment; Live viral vaccines; Peripheral neuropathy; switching to or from AUBAGIO. Rapid Elimination Procedure: Teriflunomide is eliminated slowly from the plasma. When desired, a rapid elimination procedure can be used. Monitoring: LFT (ALT/AST); FBC; Serious infections. Pregnancy Cat X (exclude pregnancy before starting treatment; effective contraception required during and post-treatment). INTERACTIONS: Potent CYP and transporter inducers such as rifampicin, carbamazepine, and St John’s Wort may decrease teriflunomide exposure; Caution with drugs metabolised by CYP2C8 such as repaglinide; CYP3A substrates such as midazolam; CYP1A2 such as duloxetine; Concomitant teriflunomide and warfarin resulted in a 25% decrease in peak INR; Teriflunomide may increase oral contraceptive levels; Use with caution when administered with OAT3 substrates such as penicillin G; BCRP/B1 and B3 substrates such as rosuvastatin. ADVERSE EFFECTS: Very common: Diarrhoea; nausea; alopecia; ALT increase. Common: Influenza; infections; neutropenia; paraesthesia; hypertension; abdominal pain upper; toothache; rash; musculoskeletal pain; myalgia; menorrhagia; GGT increase; AST increase; weight decrease; neutrophil count decrease; WBC count decrease; polyneuropathy; Refer to full PI. NAME OF SPONSOR: sanofi-aventis australia pty ltd ABN 31 008 558 807, 12–24 Talavera Road, Macquarie Park, NSW 2113. Based on Full PI with TGA date of approval of 14 November 2012 with most recent amendment on 23 December 2016. MS: multiple sclerosis; PBS: Pharmaceutical Benefits Scheme. References: 1. Pharmaceutical Benefits Scheme. Available at www.pbs.gov.au/medicine/item/2898M (accessed May 2018). 2. The Pharmaceutical Benefits Scheme. About the PBS. Available at: www.pbs.gov.au/info/about-the-pbs (accessed May 2019). 3. AUBAGIO (teriflunomide) Approved Product Information. December 2016. ©2019 Genzyme Corporation, a Sanofi company. All rights reserved. sanofi-aventis australia pty ltd ABN 31 008 558 807, 12–24 Talavera Road, Macquarie Park, NSW 2113. GZANZ.AUBA.19.04.0085b. May 2019. GEAB16412W. Ward6. Please review full Product Information before prescribing. Full Product Information is available at http://www.guildlink.com.au/gc/ws/sw/pi.cfm?product=swpaubag or 1800 818 806. Further information is available on request from Sanofi.

CONTENTS 5

RESEARCH Editor’s picks 7 Brain State-Dependent Stimulation Boosts Functional Recovery Following Stroke

COVER 9

Validated Outcome of Treatment Changes According to International League Against Epilepsy Criteria in Adults With Drug-Resistant Focal Epilepsy Comment by Sara Inati MD

8 Neural Basis of Induced Phantom Limb Pain Relief 8 Clinical Spectrum of Neuromuscular Complications After Immune Checkpoint Inhibition 9 Validated Outcome of Treatment Changes According to International League Against Epilepsy Criteria in Adults With Drug-Resistant Focal Epilepsy Comment by Sara Inati MD 10 Clinical Features of Sleep-Related Hypermotor Epilepsy in Relation to the Seizure-Onset Zone 11 Evidence-Based Management of Pediatric Myotonic Dystrophy Type 1 11 Outbreaks of Acute Flaccid Myelitis? What Neurologists Need to Know

CONFERENCE 18 International Stroke Conference 2019 By the PracticeUpdate Editorial Team

12 Subthalamic Stimulation, Apomorphine, and Levodopa Infusion Have Distinct Effect Profiles in Parkinson’s Disease 13 Treatment Approach to NREM Parasomnias 13 Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy 14 Atypical CIDP: Diagnostic Criteria, Progression, and Treatment Response 14 MRI or CT Before Treatment in Acute Ischemic Stroke 15 Risk and Predictors of Dementia and Parkinsonism in Idiopathic REM Sleep Behavior Disorder 16 Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis Comment by Erin Longbrake MD, PhD 17 Restoration of Brain Circulation and Cellular Functions Hours Post Mortem

18 Target: Stroke Phase II Improves Door-to-Needle Times in Acute Ischemic Stroke 19 Late Thrombectomy for Stroke Linked With Better Quality of Life Outcomes in DEFUSE 3 19 Some Stroke Patients May Benefit From Thrombolysis Beyond Standard 4.5-Hour Time Window 20 130/80 mmHg Identified as Likely Best Target for Repeat Stroke Prevention 21 SCENT Trial Reveals High Success Rates With Surpass Flow Diverter in Challenging Aneurysms 22 Minimally Invasive Surgery May be Option for Intracranial Hemorrhage

VOL. 4 • NO. 2 • 2019

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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

Kyle Binder MD Clinical Fellow, Neuroimmunology Clinic, National Institutes of Health, Bethesda, Maryland

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

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EDITOR’S PICKS 7

Brain State-Dependent Stimulation Boosts Functional Recovery Following Stroke Annals of Neurology Take-home message • The authors of this study sought to evaluate the efficacy of a novel brain-state dependent intervention when incorporated into the weekly rehabilitation program provided to subacute stroke patients. The authors divided 24 hospitalized subacute stroke patients between two intervention groups: the associative group received 30 pairings of a peripheral electrical nerve stimulus (ES) timed to correspond with the active phase of the motor cortex, whereas the control group received ES of an intensity too low to stimulate the nerve. The authors found that patients in the associative group experienced significantly improved functional recovery relative to those in the control group (P = .029). • The study authors note that these results provide the first evidence for clinical efficacy of a neuromodulatory intervention during the subacute phase of stroke. They suggest that a similar approach could be incorporated into daily routine stroke rehabilitation practice.

Abstract OBJECTIVE Adjuvant protocols devised to enhance motor recovery in subacute stroke patients have failed to show benefits with respect to classic therapeutic interventions. Here, we evaluate the efficacy of a novel brain state-dependent intervention based on known mechanisms of memory and learning that is integrated as part of the weekly rehabilitation program in subacute stroke patients. METHODS Twenty-four hospitalized subacute stroke patients were randomly assigned to 2 intervention groups: (1) the associative group received 30 pairings of a peripheral electrical nerve stimulus (ES) such that the generated afferent volley arrived precisely during the most active phase of the motor cortex as patients attempted to perform a movement; and (2) in the control group, the ES intensity was too low to generate a stimulation of the nerve. Functional

approach. The results indicate the potential of the proposed neuromodulation system in daily clinical routine for stroke rehabilitation. Brain State-Dependent Stimulation Boosts Functional Recovery Following Stroke. Ann Neurol 2019 Jan 01;85(1)84-95, N Mrachacz- Kersting, AJT Stevenson, HRM Jørgensen, et al. efficacy of a neuromodulatory intervention during the subacute phase of stroke. " " …these results provide the first evidence for clinical

(including the lower extremity Fugl-Meyer assessment [LE-FM; primary outcome meas- ure]) and neurophysiological (changes in motor evoked potentials [MEPs]) assessments were performed prior to and following the interven- tion period. RESULTS The associative group significantly improved functional recovery with respect to the control group (median [interquartile range] LE-FM improvement =6.5 [3.5-8.25] and 3 [0.75- 3], respectively; p=0.029). Significant increases in MEP amplitude were seen following all ses- sions in the associative group only (p≤0.006). INTERPRETATION This is the first evidence of a clin- ical effect of a neuromodulatory intervention in the subacute phase of stroke. This was evident with relatively few repetitions in comparison to available techniques, making it a clinically viable

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VOL. 4 • NO. 2 • 2019

EDITOR’S PICKS 8

Clinical Spectrum of Neuromuscular Complications After Immune Checkpoint Inhibition Neuromuscular Disorders

Neural Basis of Induced Phantom Limb

Pain Relief Annals of Neurology

Take-home message • The authors of this study sought to evaluate the use of task-concurrent noninvasive brain stim- ulation (NIBS) in the management of phantom limb pain (PLP). They used a within-participants, double-blind, sham-controlled design to eval- uate durable relief of PLP (lasting ≥1 week) following task-concurrent NIBS stimulation over the primary sensorimotor missing hand cortex (S1/M1). A single session of task-concurrent NIBS intervention significantly relieved PLP with effect durations lasting a week or more. Pain relief was associated with reduced activity in the S1/M1 missing hand cortex following NIBS. • The study authors conclude that these findings provide the foundation for development of novel PLP treatments. Abstract OBJECTIVE Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS- induced PLP relief is needed for future implementation of such treatment and generalization to related conditions. METHODS We used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal pro- cessing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation. RESULTS A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/ M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2). INTERPRETATION The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP inter- vention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. Neural Basis of Induced Phantom Limb Pain Relief. Ann Neurol 2019 Jan 01;85(1)59-73, S Kikkert, M Mezue, J O’Shea, et al. www.practiceupdate.com/c/80045

Take-home message • Immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, are finding increasing use in chemotherapy regimens, including first-line treatment for non-small cell lung cancer. These chemotherapeutic agents have been associated with neurological complications in up to 6% of patients, including the new onset of autoimmune neurological disorders. The authors of this review searched the literature for all reports of neuromuscular complications following immune checkpoint inhibition through February 2018. They identified 61 publications of 81 patients, with 30 patients who acquired myasthenia gravis, 29 with neuropathy, and 40 with muscle-related complications. Autoimmune myopathy was described in 10 patients. Overlap syndromes that do not usually occur were found in these patients, including myasthenia with myocarditis or polymyositis and myasthenia with hyperCK(creatine kinase)emia and neuropathy. The authors also present data regarding which treatments were effective in managing these complications; it is notable that some patients experienced recurrence of neuromuscular symptoms when they were rechallenged with these chemotherapeutic agents. • This review may be helpful for neurologists who provide consults in the hospital, especially involving cancer patients, as these therapies are likely to become more widely used. Sarah Matteson Kranick MD Abstract Cancer immunotherapy has transformed the field of oncology and enabled more effective management of previously refractory neoplasms by activation of the immune response. Upregulation of the immune response may also trigger autoimmune adverse events, including neuromuscular complications. We performed a systematic review of autoimmune neuromuscular complications following immune checkpoint block- ade. We searched PubMed database and identified 81 cases described, including 30 cases of myasthenia gravis (MG), 29 cases of neuropathy and 22 cases of myopathy. Most patients (89%) developed neuromuscular complications within 3 months from starting immune checkpoint blockade and 40% of all patients had elevated serum CK>1000 IU/L (typical normal <200). Guillain-Barre syndrome variants and overlaps of MG with myositis and/or myocarditis also occurred. One quarter of myasthenia patients presented with exacerbations of previously diagnosed myasthenia gravis, while neuropathy and myopathy typically presented with a new onset. Most patients improved with immunomodulatory treatment, but neuromuscular complications were sometimes refractory and associated with high mortality of 26% from cancer recur- rence, comorbidities, or treatment complications. Poor outcomes were more common with exacerbations of pre-existing myasthenia gravis and myocarditis overlap. Future prospective studies are needed to elucidate mechanisms and risk factors for auto- immune adverse events following immune checkpoint blockade. Clinical Spectrum of Neuromuscular Complications After Immune Checkpoint Inhibi- tion. Neuromuscul Disord 2019 Feb 01;29(2)127-133, A Puwanant, M Isfort, D Lacomis, SA Živković. www.practiceupdate.com/c/80615

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EDITOR’S PICKS 9

Validated Outcome of Treatment Changes According to International League Against Epilepsy Criteria in Adults With Drug-Resistant Focal Epilepsy Epilepsia Take-home message • After a 2010 ad hoc task force report of the International League Against Epilepsy (ILAE) proposed a new definition of drug- resistant epilepsy, treatment providers have employed new working concepts in caring for patients with epilepsy. The definitions provided included two hierarchical levels of anti-epileptic drug response as well as the term “pseudo-drug resistance,” as well as a formal definition of seizure freedom. Extending this previous report, the authors present a multicenter study of 1052 patients with presumed drug-resistant focal epilepsy with the aim of investigating the validity of these definitions in clinical practice. Assessing the patients at multiple 6-month intervals for up to 34 months, investigators rated drug resistance status and treatment outcomes according to the ILAE criteria; at least 2 independent members of an external expert panel provided review. While the results supported the validity of the outcome criteria, the authors also made note of some interesting findings. Seizure freedom after two failed drugs was 11.8%, and this fell to 2.6% after six failures. In addition, almost 20% of patients were deemed pseudo-drug resistant. • This is an interesting study. It validates the 2010 ILAE criteria of drug-resistant epilepsy as well as terms used for seizure freedom. In addition, it identifies less chance of success with more drug trials. Interestingly, there is a significant contrast in the perception of seizure freedom among practitioners. Omar Iqbal Khan MD

Abstract OBJECTIVE Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. METHODS This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investi- gators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). RESULTS A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as hav- ing a “treatment failure” as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as “undetermined outcome” (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP. SIGNIFICANCE This study validates the use of ILAE treatment outcome crite- ria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases. Validated Outcome of Treatment Changes According to International League Against Epilepsy Criteria in Adults With Drug-Resistant Focal Epilepsy. Epilepsia 2019 Mar 13;[EPub Ahead of Print], M Mula, G Zaccara, CA Galimberti, et al. www.practiceupdate.com/c/81307

COMMENT By Sara Inati MD T his prospective, multicenter study provides validated estimates of seizure outcomes in 1053 adults with drug- resistant focal epilepsy (DRE), followed for up to 34 months after the introduction of an additional antiepileptic drug (AED) into their treatment regimen. Utilizing the International League Against Epilepsy (ILAE) 2010 criteria for drug resistance and treatment outcomes, the researchers found that, overall, fewer than 10% of patients achieved seizure freedom (from 11.8% after two failed AEDs to 2.6% with more than six failed AEDs). These outcome data will be valuable when counseling patients about the risks and benefits of additional trials of AEDs in comparison with invasive procedures, such as surgery. This study additionally highlights the ongoing difficulty in identifying which patients have DRE, a distinction with important clinical implications such as consideration of referral to an epilepsy center. In this study, outcomes were assessed independently by study investigators and an expert panel. Overall agreement was 70.4%, with the panel labeling significantly fewer patients as treatment failures and more as having “undetermined outcomes.” These patients with “pseudo drug resistance” may respond differently to new treatment interventions, and this designation may also explain some of the variability in responses to interventions seen during clinical trials in epilepsy. Dr. Inati is Chief of the EEG Section and Director of the Epilepsy Service of the Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

VOL. 4 • NO. 2 • 2019

EDITOR’S PICKS 10

Clinical Features of Sleep-Related Hypermotor Epilepsy in Relation to the Seizure-Onset Zone Epilepsia Take-home message • Even though sleep-related seizures are thought to be related to what was previously known as nocturnal frontal lobe epilepsy and is now called sleep-related hypermotor epilepsy (SHE), seizures with a frontal lobe-like semiology can also arise outside the frontal lobe in a third of cases. The authors argue that distinguishing a frontal from an extrafrontal onset is thus challenging based on currently known studies. A study that would describe the clinical features of both frontal- and extrafrontal-onset SHE would be helpful in surgical planning for refractory patients. From 91 frontal SHE and 44 extrafrontal SHE patients, the authors classified seizure semiology according to four semiology patterns (SPs): elementary motor signs (SP1); unnatural hypermotor movements (SP2); integrated hypermotor movements (SP3); and gestural behaviors with high emotional content (SP4). Frontal and extrafrontal SHE shared many features (such as young age at onset, high seizure-frequency rate, high rate of scalp electroencephalography and magnetic resonance imaging abnormalities, similar histopathologic substrates, and good postsurgical outcomes) in temporal SHE, elementary motor signs (SP1) were rare, and gestural behaviors with high emotional manifestations (SP4) were common, whereas, in operculo-insular and posterior SHE, SP4 was absent. • Postictal confusion is significantly more common in temporal SHE. Early non-motor manifestations were common (eg, cephalic, sensory, pain) and may play a role in localizing the seizure-onset zone. Omar Iqbal Khan MD Abstract

four semiology patterns (SPs): elementary motor signs (SP1), unnatural hypermotor movements (SP2), integrated hypermotor movements (SP3), and gestural behaviors with high emotional con- tent (SP4). Early nonmotor manifestations were also assessed. " Postictal confusion is significantly more common in temporal SHE. " RESULTS Our case series consisted of 91 frontal SHE and 44 extrafrontal SHE cases. Frontal and extrafrontal SHE shared many features such as young age at onset, high seizure-frequency rate, high rate of scalp electroencephalography (EEG) and magnetic resonance imaging (MRI) abnor- malities, similar histopathologic substrates, and good postsurgical outcome. Within the frontal lobe, SPs were organized in a posteroanterior gradient (SP1-4) with respect to the SOZ. In tem- poral SHE, SP1 was rare and SP3-4 frequent, whereas in operculoinsular and posterior SHE, SP4 was absent. Nonmotor manifestations were frequent (70%) and some could provide valuable localizing information. SIGNIFICANCE Our study shows that the presence of certain SP and nonmotor manifestations may provide helpful information to localize seizure onset in patients with SHE. Clinical Features of Sleep-Related Hypermotor Epilepsy in Relation to the Seizure-Onset Zone: A Review of 135 Surgically Treated Cases. Epilepsia 2019 Apr 01;60(4)707-717, SA Gibbs,

of both frontal and extrafrontal SHE, focusing on ictal semiologic patterns in order to increase diagnostic accuracy. METHODS We retrospectively analyzed the clini- cal features of patients with drug-resistant SHE seen in our center for epilepsy surgery. Patients were divided into frontal and extrafrontal SHE (temporal, operculoinsular, and posterior SHE). We classified seizure semiology according to

OBJECTIVES Sleep-related hypermotor epilepsy (SHE), formerly nocturnal frontal lobe epilepsy, is characterized by abrupt and typically sleep-re- lated seizures with motor patterns of variable complexity and duration. They seizures arise more frequently in the frontal lobe than in the extrafrontal regions but identifying the seizure onset-zone (SOZ) may be challenging. In this study, we aimed to describe the clinical features

P Proserpio, S Francione, et al. www.practiceupdate.com/c/81308

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EDITOR’S PICKS 11

Evidence-Based Management of Pediatric Myotonic Dystrophy Type 1 Neurology Take-home message • This is a cross-sectional registry study providing genotypic and phenotypic characterization of pediatric myotonic dys- trophy type 1 (DM1). As expected, there was a relationship between the length of CTG expansion and severity, although short repeats with severe manifestations and vice versa are possible. There was a high prevalence of cognitive dysfunction, most commonly slowness (83% of the entire sample). Orthopedic and musculoskeletal manifestations were also common, with facial dysmorphism present in 71% of the sample. Cardiorespiratory impairment was rare, but tended to be life-threatening when present. • This comprehensive characterization of the condition can be a very useful resource in practice and research contexts. Codrin Lungu MD Abstract OBJECTIVE To genotypically and phenotypically characterize a large pedi- atric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. METHODS Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehen- sive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. RESULTS We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cog- nitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spec- trum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. CONCLUSIONS The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (includ- ing transition into adulthood) and health policy planning. A Large Multicenter Study of Pediatric Myotonic Dystrophy Type 1 for Evidence-Based Management. Neurology 2019 Feb 19;92(8)e852-e865, E Lagrue, C Dogan, M De Antonio, et al. www.practiceupdate.com/c/80099 " This comprehensive characterization of the condition can be a very useful resource in practice and research contexts. "

Outbreaks of Acute Flaccid Myelitis? What Neurologists Need to Know

The Lancet Neurology Take-home message

• In this short report, the author discusses the recent outbreaks of acute flaccid myelitis (AFM) in the US. The condition affects the grey matter of the spinal cord, and its acute onset often follows a respiratory illness. • It is worth reminding physicians to remain alert to the possibility of AFM, and to be aware of any guidelines or announcements that are forthcoming. Codrin Lungu MD Abstract After a third apparent spike in cases of acute flaccid myelitis across the USA, the US Centers for Disease Control and Prevention is on alert. Neurologists worldwide should be aware of what might be an emerging disease. Adrian Burton reports. Outbreaks of Acute Flaccid Myelitis? What Neurologists Need to Know. Lancet Neurol 2019 Mar 01;18(3)234-235, A Burton. www.practiceupdate.com/c/80347

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Subthalamic Stimulation, Apomorphine, and Levodopa Infusion Have Distinct Effect Profiles in Parkinson’s Disease Movement Disorders Take-home message • The authors of this prospective, nonrandomized, observational, multicenter, international, real-life cohort study with a 6-month follow-up period evaluated the effectiveness of undergoing one of three procedures: deep-brain stimulation of the subthalamic nucleus (STN-DBS) or other targets; intrajejunal levodopa infusion (IJLI); and apomorphine infusion (APO) in patients with Parkinson’s disease (PD). They found that PDQuestionnaire-8, UPDRS-IV, and Non-Motor Symptoms Scale (NMSS) total scores improved significantly at follow-up in all groups. The levodopa equivalent daily dose was reduced by 52% in the DBS group, but not in the other two groups. No differences were found in the motor scores. Treatments had different profiles in terms of effect on NMSS scores: DBS improved urinary/sexual function, mood/cognition, and sleep/fatigue; IJLI improved mood/cognition, sleep/fatigue, and gastrointestinal symptoms; and APO improved mood/cognition, perceptual problems/hallucinations, and attention/memory. Serious adverse events occurred in 6.9% of STN patients, 12.1% of IJLI patients, and 10.3% of APO patients. In the immediate postoperative period, nonserious adverse events, in particular abdominal pain and gastrointestinal symptoms, were found more frequently in the IJLI group. • DBS, IJLI, and APO appear to have distinct effects on motor and non-motor symptoms in patients with PD, and patients would benefit from personalized assessment to determine which treatment is best for them. Codrin Lungu MD Abstract

Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demo- graphic and clinical characteristics. RESULTS In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equiva- lent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/ fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointes- tinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/ memory, and the miscellaneous domain. Over- all, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neu- ropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome. CONCLUSIONS This is the first comparison of qual- ity of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to person- alize treatment choices. EuroInf 2: Subthalamic Stimulation, Apomor- phine, and Levodopa Infusion in Parkinson’s Disease. Mov Disord 2019 Mar 01;34(3)353-365, HS Dafsari, P Martinez-Martin, A Rizos, et al. www.practiceupdate.com/c/81368

international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were fol- lowed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention.

OBJECTIVE Real-life observational report of clin- ical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson’s disease (PD). METHODS In this prospective, multicenter,

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Treatment Approach to NREM Parasomnias Sleep Medicine Take-home message • Non-REM parasomnias, including sleepwalking and sleep terrors, are not uncommon complaints in the general population, and yet there are no large studies addressing optimal management. The authors of this study retrospectively identified 512 adult patients from their sleep laboratory database with videoPSG data who were treated for NREM parasomnias over 7.5 years with a median of 8 months of follow-up time. Their clinic’s approach is to use nonpharmacologic strategies as a first-line treatment and to discontinue any medications possibly contributing to the parasomnia. They found that these first- line strategies resulted in acceptable symptom control or resolution in 32% of patients, and 60% of patients were treated with medication, regardless of parasomnia type. The most common medication used was clonazepam (40%), and 72% of those treated with clonazepam had a good response. A total of 19% received antidepressants, most commonly fluoxetine, and 37% responded well. Fewer patients received z-drugs or sustained-release melatonin, but with generally good results, suggesting that zopiclone and melatonin may also be considered in the treatment of these patients. • This large study has helpful implications for those neurologists and sleep specialists who manage NREM parasomnias. Sarah Matteson Kranick MD Abstract BACKGROUND Non-REM parasomnias are not uncommon conditions in the general population. Current treatment options are based on small case series and reports. In this study, we aimed to present the clinical experience from a large cohort of patients. PATIENTS Five hundred and twelve patients with Non-REM parasomnia or parasom- nia overlap disorder (POD), who had undergone a video polysomnography and were exposed to treatment, were retrospectively identified. Treatment outcome was assessed based on patients’ reports, and treatment approach on a locally accepted hierarchy of interventions. RESULTS Forty percent of patients were diagnosed with sleepwalking, 23.8% with mixed-phenotype and 10% with POD. Ultimately, 97.2% reported adequate control of their symptoms. Moreover, 60.1% were treated with pharmacotherapy and 32.0% without, consistent across all phenotypes (p = 0.09). Benzodiazepines were the most common drugs prescribed (47.1%, p < 0.05). In the end, 37.7% of our patients were receiving a benzodiazepine as part of their successful treatment, 11.7% an antidepressant, 9.2% a z-drug, and 10.7% melatonin. Finally, 13.2%, 12.1%, and 5.8% of our patients reported good control of their symptoms with sleep hygiene, man- agement of sleep-disordered breathing, and psychological interventions (cognitive behavioral therapy [CBT] or mindfulness-based stress reduction [MBSR]), as mon- otherapy, respectively. CONCLUSION The treatment approach to effective treatment of the patients with Non-REM parasomnias or POD offering first sleep hygiene advice, next treatment of concurrent sleep disorders and management of other priming factors like stress and anxiety, and lastly pharmacotherapy for Non-REM parasomnia is supported by our results. Non pharmacological interventions were effective in one third of our patients, and CBT/MBSR and melatonin appeared promising new treatments. NREM Parasomnias: A Treatment Approach Based Upon a Retrospective Case Series of 512 Patients. Sleep Med 2019 Jan 01;53(xx)181-188, P Drakatos, L Marples, R Muza, et al. www.practiceupdate.com/c/79703

Pembrolizumab Treatment for

Progressive Multifocal Leukoencephalopathy The New England Journal of Medicine Take-home message • A cohort of 8 patients with progressive multi- focal leukoencephalopathy (PML) received one to three doses of pembrolizumab. In all patients, pembrolizumab induced down-regulation of PD-1 expression on lymphocytes both in the blood and the cerebrospinal fluid (CSF). Clinical improvement was observed in 5 patients, with an accompanying reduction in the JC viral load in the CSF and an increase in CD4+ and CD8+ anti–JC virus activity. No change in viral load or antiviral cellular immune response was seen in the remaining 3 patients. • Pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus in select patients with PML. Further research is warranted to evaluate the use of PD-1 inhibitors in the treatment of PML. Abstract BACKGROUND Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a nega- tive regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti–JC virus immune activity in patients with PML was unknown. METHODS We administered pembrolizumab at a dose of 2 mg per kilogram of body weight every 4 to 6 weeks to eight adults with PML, each with a different underlying predispos- ing condition. Each patient received at least one dose but no more than three doses. RESULTS Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cer- ebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti–JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement. CONCLUSIONS Our findings are consistent with the hypothe- sis that in some patients with PML, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus; clinical improvement or stabilization occurred in five of the eight patients who received pembrolizumab. Further study of immune checkpoint inhibitors in the treat- ment of PML is warranted. Pembrolizumab Treatment for Progressive Multifocal Leu- koencephalopathy. N Engl J Med 2019 Apr 10;[EPub Ahead of Print], I Cortese, P Muranski, Y Enose-Akahata, et al. www.practiceupdate.com/c/82180

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Atypical CIDP: Diagnostic Criteria, Progression, and Treatment Response Journal of Neurology, Neurosurgery, and Psychiatry Take-home message • There are atypical variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) that lack well-established diagnostic criteria and sufficient data on natural history and response to therapy. The authors propose a set of diagnostic criteria for atypical CIDP, which include distal acquired demyelinating symmetric neuropathy (DADS), purely motor or sensory CIDP, Lew- is-Sumner syndrome (LSS), and focal CIDP. In the Italian database utilized, 18% of patients had an atypical form of CIDP. Patients with DADS and LSS tended to have a lower rate of response to therapy (64% and 67%, respectively) compared with patients who have typical CIDP (87%). • DADS and LSS may have a different underlying mech- anism than typical CIDP since they respond less well to IVIG therapy. Codrin Lungu MD Abstract OBJECTIVES A few variants of chronic inflammatory demyelinating polyra- diculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typ- ical CIDP, and treatment response. METHODS We applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typ- ical CIDP. RESULTS At the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with dis- tal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symp- toms and signs present at onset and for at least 1year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immuno- globulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response. CONCLUSIONS The proportion of patients with atypical CIDP varies dur- ing the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism. Atypical CIDP: Diagnostic Criteria, Progression and Treatment Response. Data From the Italian CIDP Database. J Neurol Neurosurg Psychiatr 2019 Feb 01;90(2)125-132, PE Doneddu, D Cocito, F Manga- nelli, et al. www.practiceupdate.com/c/79218

MRI or CT Before Treatment in Acute Ischemic Stroke Stroke: A Journal of Cerebral Circulation Take-home message • The authors of this study evaluated data from ischemic stroke patients recruited to the THRACE randomized trial of mechan- ical thrombectomy after intravenous tPA. Patients were adults presenting within 4.5 hours of stroke symptom onset, NIHSS score of 10 to 25, with a proximal cerebral artery occlusion identified on imaging. Site investigators could choose their imaging screening modality of CT or MRI. The authors sought to compare workflow, times to treatment, and functional out- come between modalities. Of the randomized patients, 401 were included in the analysis; 299 in the MRI group and 102 in the CT group. Median scan duration in the MRI and CT groups were 13 minutes and 9 minutes, respectively. Despite longer scanning time in the MRI group, the time from scan to tPA was slightly less in the MRI cohort. • Functional outcomes were no different between image groups. The use of MRI should be promoted given its imaging advantages over CT. Mona Bahouth MD Abstract BACKGROUND AND PURPOSE The acute management of stroke patients requires a fast and efficient screening imaging modality. We compared workflow and functional outcome in acute ischemic stroke patients screened by magnetic resonance imaging (MRI) or computed tomogra- phy (CT) before treatment in the THRACE trial (Thrombectomie des Artères Cérébrales), with the emphasis on the duration of the imaging step. METHODS The THRACE randomized trial (June 2010 to February 2015) evaluated the efficacy of mechanical thrombectomy after intravenous tPA (tissue-type plasminogen activator) in ischemic stroke patients with proxi- mal occlusion. The choice of screening imaging modality was left to each enrolling center. Differences between MRI and CT groups were assessed using univariable analysis and the impact of imaging modality on favora- ble 3-month functional outcome (modified Rankin Scale score of ≤2) was tested using multivariable logistic regression. RESULTS Four hundred one patients were included (25 centers), compris- ing 299 MRI-selected and 102 CT-selected patients. Median baseline National Institutes of Health Stroke Scale score was 18 in both groups. MRI scan duration (median [interquartile range]) was longer than CT (MRI: 13 minutes [10-16]; CT: 9 minutes [7-12]; P<0.001). Stroke-onset-to-imaging time (MRI: median 114 minutes [interquartile range, 89-138]; CT: 107 minutes [88-139]; P=0.19), onset-to-intravenous tPA time (MRI: 150 minutes [124-179]; CT: 150 minutes [123-180]; P=0.38) and onset-to-angiography-suite time (MRI: 200 minutes [170-250]; CT: 213 minutes [180-246]; P=0.57) did not differ between groups. Imaging modality was not significantly associated with functional outcome in the multivariable analysis. CONCLUSIONS Although MRI scan duration is slightly longer than CT, MRI- based selection for acute ischemic stroke patients is accomplished within a timeframe similar to CT-based selection, without delaying treatment or impacting functional outcome. This should help to promote wider use of MRI, which has inherent imaging advantages over CT. Magnetic Resonance Imaging or Computed Tomography Before Treat- ment in Acute Ischemic Stroke. Stroke 2019 Mar 01;50(3)659-664, C Provost, M Soudant, L Legrand, et al. www.practiceupdate.com/c/80606

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