VBCN April 2014 Vol 1, No 1 by Value-Based Cancer Care

April 2014 • VOL 1 • NO 1

www.ValueBasedNeurology.com

Introduction

AAN Updated Its Guidelines for Value in Medicine: Welcome Stroke Prevention in Patients with to the Inaugural Issue of Nonvalvular Atrial Fibrillation Value-Based Care in Neurology Oral anticoagulants are scrutinized for benefits and risks

By Robert J. Adams, MS, MD Professor of Neuroscience, University Eminent Scholar Director, South Carolina Stroke Center of Economic Excellence Director, REACH MUSC Telemedicine Services, Charleston, SC

By Caroline Helwick

ecause atrial fibrillation is a major risk factor for ischemic stroke, there is a need for

I strategies to identify people at risk for stroke and prevent it at all ages. The American Academy of Neurolo-

Continued on page 5

Neurologists Propose New Algorithm for First-Line Natalizumab in Selected Patients with Multiple Sclerosis By Rosemary Frei, MSc

team of neurologists have proposed a new algorithm to help clinicians determine which patients with relapsing forms of multiple sclerosis (MS) may be suitable for first-line treatment with natalizumab

(Nicholas JA, et al. Ther Adv Chronic Dis. 2014;5:62-68). Natalizumab is associated with an increased risk for progressive multi focal leukoencephalopathy (PML), a rare infection in the brain. However, Continued on page 7

accepted the invitation to join the Editorial Board of Value-Based Care in Neurology with interest but also with some concern that I am not an expert in this area of “value.” I bring along my 30 years of experience in clinical medicine (a $2-billion cottage industry), albeit at academic medical centers (or as they used to be called, “sheltered workshops”), and some healthy skepticism about trends and buzzwords that have come and

Continued on page 4

Migraine Prevalence Rises with Decline in Income, but Remission Is Stable External stressors the culprit in headache etiology

By Charles Bankhead

igraine prevalence increased significantly as household income declined in a retrospective analysis of a large migraine database, supporting a social-causation hypothesis in the etiology of migraine,

investigators reported recently (Stewart WF, et al. Neurology. 2013;81:948-955). Migraine frequency increased in women and men as annual household income declined from ≥$60,000 to <$22,500. The association remained Continued on page 20

inside STROKE . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

EPILEPSY MANAGEMENT. . . . . 16

MULTIPLE SCLEROSIS. . . . . . . . . . .

PARKINSON’S DISEASE. . . . . . . 18

ALZHEIMER’S/DEMENTIA. . . . . .

HEALTH ECONOMICS . . . . . . . . . 20

Importance of rapid revascularization Novel algorithm for natalizumab Ofatumumab promising for MS

New quality measures for dementia Economic evaluation of Alzheimer’s

4 new drugs improve patient care

Role of nutrition identified Sex affects NMDA Ar-Abs encephalitis Glatiramer acetate cost-effective for preventing relapse in MS

Personalized Medicine in Neurology™ . . . . . . . . . . . . . . . . . . . . . 11 MIGRAINE MANAGEMENT.... 22 Biomarkers predict cognitive decline

Pregabalin safe, effective for seizures

Nonblinded treatment in clinical trials affects outcomes

Call for Papers Neurology Theme Issue American Health & Drug Benefits, in collaboration with Value-Based Care in Neurology, is publishing a theme issue on neurology in September 2014.

Take part of in the growing conversation on the human brain and the increased focus on brain research. The aging of the US population and the growing clinical and economic burdens associated with neurologic disorders have placed the field of neurology in the forefront of academic and clinical research. The growing prominence of personalized medicine and health economics will further impact neurologists and patients with neurologic disorders in the coming years, requiring new understandings of the role of genetics and the environment in central nervous system disorders, as well as how pharmacoeconomics and reimbursement issues are influencing patient care and clinical decisions. American Health & Drug Benefits is a peer-reviewed journal reaching providers, payers, and policy decision makers in the United States. All articles submitted for publication in this journal undergo the journal’s rigorous peer-review process and acceptance is dependent on that review. Readers of Value-Based Care in Neurology are invited to submit original research, case reports, or systematic reviews on any topic related to the field of neurology to further our understanding of the biology of the brain and neurologic conditions, and their role in the overall well-being of the American population.

Topics of particular interest include: ORIGINAL RESEARCH

REVIEW ARTICLES

• Case studies/case series

• Alzheimer’s disease: diagnosis, treatment

• Comparative effectiveness analyses

• Cost considerations in neurology

• Cost-effective analyses

• Dementia update

• Health economics research outcomes

• Developments in neurologic disorders

• Drug therapy related to a neurologic disorder

• Economic analyses in neurology

• New therapies for multiple sclerosis, seizures, or migraine

• Emerging therapies for neurologic disorders

• Patient-reported outcomes

• Migraine management

• Pharmacoeconomic analyses

• Multiple sclerosis management

• Quality-of-life issues in neurology

• Pain medicine

• Review articles on neurologic disorders

• Parkinson’s disease

• Survey results

• Practice guidelines

• Epilepsy: new developments

• Sleep disorders • Stroke/cerebrovascular disease

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In This Issue

Publishing Staff

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Melissa Lawlor

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881 Value-Based Care in Neurology, ISSN (applied), is published 3 times a year by Engage Healthcare Com munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Neurology is a trademark of Engage Health care Communi cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Neurology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Neurology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

VOL. 1

NO. 1

INTRODUCTION

IN THE LITERATURE

Value in medicine: welcome to the inaugural issue of Value-Based Care in Neurology

Elevated fatty acid levels increase recurrent stroke risk Pregabalin monotherapy safe, effective for partial-onset seizures More…

STROKE New AAN guidelines for stroke prevention in NVAF Importance of rapid revascularization after stroke

MULTIPLE SCLEROSIS Physical activities may be best medicine for patients with MS Ofatumumab a promising new therapy More…

ALZHEIMER’S DISEASE/DEMENTIA New dementia quality measures issued More…

Personalized Medicine in Neurology™

Understanding the genetics of epilepsy can improve the diagnosis Novel biomarker panel may predict cognitive impairment

EPILEPSY MANAGEMENT 4 new drugs approved by the FDA for patients with seizures

PARKINSON’S DISEASE Role of nutrition in Parkinson’s disease Vitamin D deficiency widespread in these patients More…

HEALTH ECONOMICS Economic analyses of ischemic stroke imaging Glatiramer acetate cost-effective for preventing relapse in MS More…

MIGRAINE MANAGEMENT Disclosing treatment type to patients affects clinical outcomes

Editorial Advisory Board Maria Lopes, MD, MS Chief Medical Officer CDMI Health Cresskill, NJ

Robert J. Adams, MS, MD Professor of Neuroscience University Eminent Scholar Director, South Carolina Stroke Center of Economic Excellence Director, REACH MUSC Telemedicine Services Charleston, SC

Daniel Kantor, MD Medical Director Neurologique President-Elect Duval County Medical Society Immediate Past President Florida Society of Neurology Ponte Vedra, FL

June Halper, MSN, APN-C, MSCN, FAAN CEO, Consortium of Multiple Sclerosis Centers Executive Director, IOMSN Hackensack, NJ

Patricia Kennedy, RN, CNP, MSCN Nurse Educator Can Do Multiple Sclerosis Avon, CO

Atheer A. Kaddis, PharmD Senior Vice President Diplomat Specialty Pharmacy Flint, MI

Matthew Mitchell, PharmD, MBA Director Pharmacy Services Murray, UT Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Charles Stemple, DO Corporate Medical Director, Policy Humana, OH

James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Mission Statement

Value-Based Care in Neurology provides a forum for payers, providers, and the entire neurology team to consider the cost-value issues particular to neurologic disease treatments. This unique focus is achieved through news coverage from major neurology meetings and the neurologic literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881. Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com. Address all editorial queries to: editorial@engagehc.com. Telephone: 732-992-1882 Fax: 732-992-1881. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Neurology, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

april 2014

www.ValueBasedNeurology.com

Introduction

Value in Medicine: Welcome to the Inaugural Issue of Value-Based Care in... Continued from page 1

gone. The emphasis on value in medicine, and in neurology in particular, will likely persist and persevere for some time. This focus on value, I hope, will improve the experience for all concerned stakeholders—patients, families, providers, payers, and hospitals. Perhaps a permanent realignment, or some would say initial alignment, of incentives will result from this approach. My limited experience in this arena includes a significant involvement in the design and implementation of the Joint Commission’s Primary Stroke Center Certification Program— one of the commission’s most successful disease-specific programs. In ad dition, I was Physician Cochair of the Measures and Outcomes Committee, as well as Chair of the American Stroke Association Advisory Committee, all of which may provide some basis to draw upon for this new focus on value in neurology. For physicians not only to survive this movement but also to contribute to it and “value” it, we have to look at this emphasis on “value-based medicine” as an opportunity to improve what we do, and how we do it. We have to move beyond seeing this approach as a metaphor for paying less to those of us who actually create the “work product” (ie, healthcare providers) for what we do, and paying more to those who watch the “work process” (ie, administrators, safety officers, quality managers, and so on). Instead, we have to see this effort as one of teamwork, in which we are all important players. Value in healthcare has been defined by Michael E. Porter, PhD, as “the health outcomes achieved per dollar spent.”1 As Dr Porter suggests, “Value should always be defined around the customer, and in a well-functioning health care system, the creation of value for patients should determine the rewards for all other actors in the system. Since value depends on results, not inputs, value in health care is measured by the outcomes achieved, not the volume of services delivered, and shifting focus from volume to value is a central challenge. Nor is value mea-

For physicians not only to survive this movement but also to contribute to it and “value” it, we have to look at this emphasis on “value-based medicine” as an opportunity to improve what we do, and how we do it. Robert J. Adams, MS, MD

sured by the process of care used; process measurement and improvement are important tactics but are no substitutes for measuring outcomes and costs.”1 In the evaluation of healthcare by an individual or a system, the following questions are often being asked: 1. What does the person or clinic/hospital have as resources (eg, training, certifications, equipment, staff)? 2. What does the person/entity do with what it has (the so-called process measurement—do they adhere to evidence-based guidelines)? 3. What happens to patients who are treated by/in this person/entity (ie, what are the actual outcomes)? The first 2 questions have been the easiest to evaluate, and the place where all this started. The emphasis on outcomes is relatively new, but value cannot be determined without relevant outcome assessment. This is where it gets very challenging. Outcomes in medicine are not passive results of process application, such as, for instance, car repair. Value in repair or rebuilding an automobile engine is easy to assess: it is an engine that works to specifications, divided by the cost. By contrast, our patients are active participants in many of the outcomes of medicine—in particular, those involving chronic diseases, such as stroke, movement disorders, or epilepsy. Caregivers become key in the later stages of degenerative diseases and stroke. This introduces an impor

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April 2014

tant fourth question: 4. Who did you perform the processes on that resulted in the outcomes of record? It is easy to understand that the same processes, correctly conceived

I hope that this new journal can help point the way to better care and outcomes for our patients, and at the same time, preserve what is good about clinical neurology and delivering good neurologic care, while helping to improve the medical care experience for everyone involved.

and competently applied, will have different outcomes when applied in midlife to an individual who has been fit, has received good lifelong medical care, and has adhered to good medical advice and lifestyle habits, than when applied to individuals with poorly controlled comorbidities, bad health self-regulation, and destructive lifestyle habits. Here is where my academic medical center experience tells me to be afraid, indeed very afraid, of value-based programs and compensation algorithms that do not correct for the health status of patients before assessing the “quality” of the treatments in question. For chronic disease outcomes, it is easy to see that well-funded community hospitals that are

largely serving insured patients will look a lot better on paper—based on patient outcomes—than inner-city academic medical centers with high indigent patient loads. If quality is hard to assess, then balancing and correcting for prevalent pretreatment health risk is even harder. Because neurology involves several high-volume and high-cost conditions of increasing importance to an aging population, such as the US population, neurologic care at all levels will come under increasing scrutiny in the coming years. Because the outcomes of interest take longer to become evident, it will be very important to derive and apply sensible measures that go far beyond the initial patient and caregiver satisfaction and short-term measures of “efficiency” of care. As a career-long clinical researcher, I look at this new emphasis on value and comparative effectiveness as modern affirmations of what has been clear to most of us all along; that is, that well-designed and executed studies that look at outcome as a function of process application (while minimizing bias), premorbid conditions, and compliance, as well as overall patient well-being, are the foundation for value-based medicine, without which these efforts cannot fully succeed. We need many more of these types of studies, and when we cannot have the desired data, we need to derive the best possible evidence from our experience, using administrative database approaches. Finally, as a so-called cognitive specialty, neurology may benefit from value-based approaches that could highlight the importance of nonprocedure and even nonpharmacologic interventions (extensive patient and caregiver counseling, for example) that now struggle to receive support in a payment system driven by procedures, volume, and myopic micromanagement (E and M coding, for example). I hope that this new journal can help point the way to better care and outcomes for our patients, and at the same time, preserve what is good about clinical neurology and delivering good neurologic care, while helping to improve the medical care experience for everyone involved. n Reference

1. Porter ME. What is value in health care? N Engl J Med. 2010;363:2477-2481.

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Stroke

AAN Updated Its Guidelines for Stroke Prevention in Patients with Nonvalvular... Continued from page 1

gy (AAN) has helped fill this gap with the release of new evidence-based guidelines (Culebras A, et al. Neurology. 2014;82:716-724). The Guideline Development Subcommittee of the AAN reviewed evidence published since 1998 with regard to the detection of nonvalvular atrial fibrillation (NVAF) in patients with a history of stroke, as well as new therapies for preventing stroke in this patient population. The new guidelines are focused on these 2 questions: 1. For patients with cryptogenic stroke (ie, no cause can be identified— How often can current technologies identify undiagnosed NVAF? 2. For patients with NVAF, which therapies reduce the risk for ischemic stroke with the least risk of hemorrhage? The main recommendation is to use cardiac rhythm monitoring in patients with cryptogenic stroke to identify those with occult NVAF, to routinely offer anticoagulation to patients with NVAF and a history of transient ischemic attack (TIA) or stroke, and to carefully counsel patients with NVAF (and no previous stroke) about the potential benefits of antithrombotic medications, as well as their potential risks. Lead author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, NY, told Value-

at a glance ➤ The new AAN guidelines encourage cardiac rhythm monitoring for cryptogenic stroke ➤ Consider anticoagulation for the elderly, people with moderate falls, and for mild dementia ➤ In patients with NVAF, dabigatran, rivaroxaban, and apixaban are at least as effective as warfarin in preventing stroke, with lower risk for intracranial hemorrhage ➤ Despite their higher cost, the new oral anticoagulants are safer, which could be costsavings in the long-term ➤ Triflusal-acenocoumarol combination is safer and likely more effective than acenocoumarol alone for stroke prevention, and is less costly than newer anticoagulants

VOL. 1

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Based Care in Neurology that this recommendation differs in some ways from previous guidelines.

lute stroke risk in patients with NVAF, the results of these tools vary widely. “Because it is difficult to determine

—Antonio Culebras, MD

“The new guidelines encourage the use of monitoring devices to identify atrial fibrillation in patients with cryptogenic stroke. The new guidelines also encourage physicians to consider anticoagulation in patients who are old, who sustain a moderate number of falls and who have mild dementia. These were traditional areas of exemption in the past,” Dr Culebras said. NVAF and Stroke Frequency In the studies evaluated, the proportion of patients identified with NVAF ranged from 0% to 23%, averaging a detection rate of 10.7%. Longer monitoring was significantly more likely to detect NVAF; therefore, the expert panel suggests that clinicians consider monitoring patients for at least 1 week, instead of the standard 24 hours, to increase the diagnostic yield. The analysis showed that within the population of patients with NVAF, the absolute risk for ischemic stroke varies widely, based on the presence of other stroke risk factors. The absolute stroke risk is highest among patients with NVAF who have a history of stroke and TIA, with an aggregated risk of approximately 10% annually. The panel recommends that clinicians consider not offering anticoagulation therapy to patients with NVAF who do not have additional risk factors, or consider prescribing aspirin. The panel further notes that although multiple risk stratification tools are available for estimating the abso-

with precision the absolute stroke risk in patients with NVAF, determining when the benefit from reduced stroke risk outweighs the harm of increased bleeding is likewise difficult,” the panel wrote. “In these circumstances, patient preferences and physician judgment become especially important.” Anticoagulants: What Are the Relative Efficacies and Risks? Specific patient considerations should inform the selection of the specific anticoagulant therapy in patients with NVAF who are judged to need anticoagulation therapy, the panel notes; they also offer information that should guide this decision-making. The effects of the antithrombotic regimens are being compared with dose-adjusted warfarin for the outcomes of stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and gastrointestinal bleeding from the best published studies. The panel concludes, based on their review of the evidence, that several anticoagulant medications decrease the risk for ischemic stroke in patients with NVAF, and these agents are “noninferior or superior” to warfarin, they note. “In most patients, the reduction in ischemic stroke risk outweighs the risk of bleeding complications,” the authors state. Specific Anticoagulant Therapies Regarding the individual agents, april 2014

the panel provides the following conclusions: • In patients with NVAF, the anticoagulants dabigatran, rivaroxaban, and apixaban are probably at least as effective as warfarin in preventing stroke and have a lower risk of intracranial hemorrhage • The combination of triflusal plus acenocoumarol is likely more effective than acenocoumarol alone in reducing stroke risk • Clopidogrel plus aspirin is probably less effective than warfarin in preventing stroke and has a lower risk of intracranial bleeding • Clopidogrel plus aspirin compared with aspirin alone probably reduces stroke risk but increases the risk of major hemorrhage • Apixaban is likely more effective than aspirin for decreasing stroke risk and has a bleeding risk similar to that of aspirin. Value-Based Considerations When asked whether any of the recommendations may be considered value-based—that is, consider cost versus benefit as part of the recommendations—Dr Culebras acknowledged,

“Because it is difficult to determine with precision the absolute stroke risk in patients with NVAF, determining when the benefit from reduced stroke risk outweighs the harm of increased bleeding is likewise difficult.” —Antonio Culebras, MD, and colleagues “The new oral anticoagulants are more costly in the pharmacy than warfarin. However, there could be long-term cost-saving in the improved safety inherent to a better bleeding profile.” “The combination of triflusal (a generic antiplatelet agent) and low-intensity acenocoumarol (a warfarin-like agent) for moderate-risk NVAF patients is safer than acenocoumarol [alone] and definitely less costly than the new oral anticoagulants,” he noted. “This combination could have great added value in developing countries, where triflusal is available but new oral anticoagulants are unavailable or unreachable,” Dr Culebras commented. n

www.ValueBasedNeurology.com

Stroke

Real-World Evidence Highlights Importance of Rapid Revascularization after Acute Ischemic Stroke Large, population-based study validates previous results By Rosemary Frei, MSc

large Spanish study conducted between January 2001 and December 2012 has provided real-world evidence confirming that revascularization is the strongest independent predictor of good outcomes after endovascular therapy (EVT) in patients who have had an acute ischemic stroke (Abilleira S, et al. Stroke. 2014 March 4. Epub ahead of print). The research also corroborates results from earlier studies showing that outcomes are better in younger patients aged less than 80 years than older than 80 years; those who have mild or moderate stroke; have atrial fibrillation; do not have hypertension; and have an onset-to-groin-puncture time of ≤6 hours. “All patients undergoing endovascular therapies in Catalonia throughout the study period were included in the study, since there is an external monitoring of completeness, and any undeclared case is included retrospectively,” Principal Investigator Sònia Abilleira, MD, PhD, a researcher for the Stroke Programme of the Catalan Health Department, told Value-Based Care in Neurology. “Thus, this is not a single-center study; this is an observational, population-based study, and therefore, quite robust.” Dr Abilleira and colleagues conducted this large study to evaluate clinical outcomes after EVT in real-

world conditions rather than in the confines of a clinical trial. They used information from an online registry

“All patients undergoing endovascular therapies in Catalonia throughout the study period were included in the study. Thus, this is not a single-center study; this is an observational, population-based study, and therefore, quite robust.” —Sònia Abilleira, MD, PhD

that was launched in January 2011 in the region of Catalonia, Spain, called

SONIIA. Their study is one of several using data from SONIIA that is exploring the benefits of EVT in patients with ischemic stroke, as part of the Endovascular Revascularization with Solitaire Device versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours (REVASCAT) trial. Many patients with acute ischemic stroke are left untreated because they either arrive late to the hospital or are receiving treatment but do not receive revascularization. There is a need to consider whether more patients should undergo this procedure. This study is part of an ongoing effort to determine the role of revascularization in this patient population based on real-world evidence. Study Details This new analysis included 536 patients who had an acute ischemic stroke and then had EVT at 1 of 7 comprehensive stroke centers in SONIIA. A total of 54.9% of the patients were men, the patients’ mean age was 67.5 years, and the median baseline National Institutes of Health Stroke Scale score was 17.5. The vast majority of patients—485 (90.5%)—had mechanical thrombectomy. Of the other patients, 40 (7.5%) had combined pharmacologic-mechanical procedures, and the other 11 (2%) patients had intra-arterial throm-

bolysis. Furthermore, 285 (53%) patients had received previous EVT. The median onset-to-groin-puncture time was 277 minutes, and the median EVT duration was 95 minutes. Overall, 73.9% of the EVT procedures successfully resulted in revascularization, whereas 5.6% were associated with symptomatic cerebral bleeds. The researchers performed a series of logistic regression analyses that revealed that revascularization was associated with an odds ratio of 8.12 for a favorable outcome, defined by a modified Rankin Scale score of 0, 1, or 2. It was also a strong independent predictor of reduced all-cause mortality (odds ratio, 0.21). Other protective factors were younger age, shorter onset-to-groinpuncture time, anterior circulation stroke, prestroke modified Rankin Scale score of 0 or 1, and the presence of atrial fibrillation. Earlier studies have uncovered all of these various components associated with this EVT-related picture, but none has been as large or comprehensive, pointed out Dr Abilleira. “It is also important to say that all tertiary hospitals in Catalonia are currently involved in the REVASCAT trial,” she said. “The coexistence of the registry and the trial will enhance knowledge on the real-world outcomes of neurointerventional treatment of stroke.” n

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value-based CARE in Neurology

April 2014

VOL. 1

NO. 1

Multiple Sclerosis

Neurologists Propose New Algorithm for First-Line Natalizumab in Selected Patients with... Continued from page 1

that risk is very small in patients with low levels of antibodies to the JC virus (JCV), the pathogen responsible for PML, and the clinical effectiveness of natalizumab outweighs its risks in many of those patients, according to the investigators. Jacqueline A. Nicholas, MD, MPH, Assistant Professor of Neurology, Division of Neuroimmunology, Ohio State University, Columbus, and her colleagues suggest that patients with newly diagnosed relapsing-remitting MS (RRMS) who are JCV-antibody– negative, or have not received immunosuppression and have a JCV antibody index of ≤1.5, are potential candidates for natalizumab treatment. Dr Nicholas and colleagues caution against the use of antibody titer to determine the exact risk of a patient for PML; however, they believe they are on safe ground with these general proposed guidelines. “This is the algorithm I have used to care for multiple sclerosis patients at the Ohio State University Multiple Sclerosis Center,” Dr Nicholas told Value-Based Care in Neurology. “It has been well-received by patients and by my colleagues.” At the same time, she noted, “we are absolutely monitoring patients’ outcomes and adverse events as this is the standard of care. I may report on this at a later date.” Dr Nicholas and colleagues are making the pitch for more first-line use of natalizumab, as a result of the impressive results of the clinical trials

AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing-Remitting Multiple Sclerosis).

—Jacqueline A. Nicholas, MD, MPH

had a 64% drop in 24-week sustained disability progression at 2 years, as was shown in a 2009 study. And a post hoc analysis of the AFFIRM results showed that 64% of patients receiving natalizumab were without clinical disease activity throughout the 2 years of the study, while 58% were free of radiographic disease activity, and 37% had neither clinical nor radiographic disease activity. In addition, results of a more recent study confirm that natalizumab may be particularly effective as first-line therapy and also suggest that aggressive phenotypes of MS in African Americans respond well to the medication. However, PML can occur in patients with MS who are being treated with natalizumab, possibly because of reduced immune surveillance in the brain that, in turn, allows previously quiescent viruses to multiply. As of February 4, 2014—the latest data that are available according to the manufacturer of the drug—437 patients with MS from around the world who are receiving natalizumab had contracted PML. The overall natalizumab-associated PML incidence was 3.5/1000 people, and the mortality rate was 23% (https://medinfo.biogenidec.com).

For example, patients in the AFFIRM trial who were treatment-naïve (ie, received natalizumab as first-line therapy) and had highly active RRMS

The New Proposed Guidelines Because of the strong efficacy data, Dr Nicholas’s group posited that nat alizumab “should be considered in patients with aggressive MS disease courses at least for the first 12-24

“This is the algorithm I have used to care for multiple sclerosis patients at the Ohio State University Multiple Sclerosis Center. It has been well-received by patients and by my colleagues.”

months regardless of JCV serum antibody status.” For other patients, the treatment decision depends on the JCV-antibody status. The investigators suggest that: • JCV-antibody–negative patients who have a <1/10,000 risk for developing PML may be considered for first-line natalizumab • JCV-antibody–positive patients who have had immunosuppression events should not receive first-line natalizumab • JCV-antibody–positive patients who have not had immunosuppression and have a JCV antibody index of up to 15—which is associated with a 1:10,000 risk for PML in the first 24 months of treatment, and up to 1.3:1000 at 49 to 72 months of treatment—are potential candidates for first-line natalizumab; these patients should undergo a limited cerebral magnetic resonance imaging to monitor for PML lesions every 3 to 4 months, and their JCV antibody index should be remeasured every 3 to 6 months • JCV-antibody–positive individuals who have not had immunosuppression events and have a JCV antibody index of more than 1.5 should be considered for 12 to 24 months of firstline natalizumab only if they have aggressive MS; the PML risk with a JCV antibody index of more than 1.5 is 1:1000 for the first 24 months, 8.1:1000 from 25 to 48 months, and 8.5:1000 for months 49 to 72. n

For Patients with Multiple Sclerosis, Increasing Physical Activities May Be the Best Medicine By Rosemary Frei, MSc

ifestyle physical activity should be as central to the health-promoting habits of patients with multiple sclerosis (MS) as exercise training, according to one expert (Motl RW. Mult Scler. 2014 March 6. Epub ahead of print). Dr Motl cites many studies—including some he was a coinvestigator in—to show that increasing self-selected physical activities can significantly improve the health of patients with MS. “The time is ripe that researchers and clinicians might consider the paradigm shift away from solely supervised and prescriptive exercise training and toward embracing lifestyle physical activity as another therapeu-

VOL. 1

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“The time is ripe that researchers and clinicians might consider the paradigm shift away from solely supervised and prescriptive exercise training and toward embracing lifestyle physical activity as another therapeutic strategy in the comprehensive care of MS.” —Robert Motl, PhD

tic strategy in the comprehensive care of MS,” wrote Robert Motl, PhD, Associate Professor, Department of Kinesiology and Community Health, College of Applied Health Sciences, University of Illinois at Urbana-Champaign. “Excitedly, the author is interested to see if the MS community will embrace ‘the new kid on the MS block,’” he wrote. A Paradigm Shift in MS Is Crucial The central problem is, Dr Motl suggests, that patients with MS do not do much physical activity, despite the well-established benefits to individuals’ overall health and quality of life. Supervised exercise training can have april 2014

significant benefits for this patient population, but approximately 80% of patients with MS do not meet the recommended levels of physical activity, he emphasizes. A paradigm shift toward daily physical activities is necessary, similar to what has taken place in the general population. Lifestyle physical activity is personalized and self-managed, and rather than focusing on physical fitness, which does not appeal to many people, is geared to overall health promotion, observed Dr Motl. It also fits in much more seamlessly with patients’ lives since it can take place as part of everyday life and these activities are “accumulated in Continued on page 8

www.ValueBasedNeurology.com

Multiple Sclerosis

Ofatumumab Shows Promise in the Treatment of Patients with Multiple Sclerosis By Alice Goodman

ew evidence from a phase 2 clinical trial suggests that ofatumumab—a monoclonal antibody used to treat B-cell–related hematologic malignancies—may be beneficial for the treatment of patients with relapsing forms of multiple sclerosis (MS). In this new study, ofatumumab, given twice by infusion 2 weeks apart, was safe and well tolerated in patients with relapsing-remitting MS (RRMS) and reduced the number of new magnetic resonance imaging (MRI) lesions characteristic of the disease (Sorensen PS, et al. Neurology. 2014;82:573-581). “The phase 2A study showed a profound effect of ofatumumab in a wide range of doses administered intravenously,” lead investigator Per Soelberg Sorensen, MD, DMSc, FAAN, Director, Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Denmark, told Value-Based Care in Neurology. This study used MRI imaging of the brain to measure the activity of ofatumumab; it was not designed to assess the long-term safety of this medication or detect less common adverse events. Relapsing forms of MS is the most common type of MS, occurring in approximately 85% of newly diagnosed patients. This form of disease is characterized by episodes of worsening neurologic function (relapse) followed by periods of remission. Currently, 10 treatments are approved by the US Food and Drug Administration (FDA) for the treatment of patients with RRMS, and all of them decrease the frequency and severity of relapse, and reduce the number of gadolinium-enhancing (GDE)

lesions characteristic of the disease. Ofatumumab is a humanized mono clonal anti-CD20 antibody that induces B-cell depletion. Rituximab and

MS judged from the relapse rate and MRI findings at diagnosis. The efficacy of anti-CD20 B-cell depletion monoclonal antibodies is very pro-

“In addition to second-line therapy, ofatumumab would be an ideal drug as third-line therapy in patients with aggressive MS judged from the relapse rate and MRI findings at diagnosis. The efficacy of anti-CD20 B-cell depletion monoclonal antibodies is very profound, and these drugs should be used as single therapy, not as add-on therapy.” —Per Soelberg Sorensen, MD, DMSc, FAAN ocrelizumab—both B-cell–depleting therapies—have also achieved reductions in the number of GDE lesions on MRI versus placebo in phase 2 trials. Ofatumumab is presumed to be less immunogenic than rituximab, because it is humanized. “In my opinion, B-cell–depleting drugs could be used as second-line therapy in patients who failed treatment with first-line therapies. We have experience with rituximab and ofatumumab in patients who fail nat alizumab and have seen very good results with rituximab/ofatumumab in these patients,” said Dr Sorensen when asked how ofatumumab might fit into current treatment algorithms for patients with RRMS. “In addition to second-line therapy, ofatumumab would be an ideal drug as third-line therapy in patients with aggressive

found, and these drugs should be used as single therapy, not as add-on therapy.” Study Details At the time of enrollment, patients with RRMS included in the study were stable and were not being treated with any FDA-approved medications for their MS. The investigators randomized 38 patients in a 2:1 ratio to treatment with 2 infusions of ofatumumab, using 100 mg, 300 mg, or 700 mg, versus placebo; at week 24, patients were switched to the other treatment arm to ensure that all patients had an active therapy. Overall, 36 patients completed the study; 2 patients receiving the 300-mg dose withdrew from the study because of adverse events. Ofatumumab was safe and well

at a glance ➤ New evidence indicates that ofatumumab, a monoclonal antibody indicated for B-cell– related malignancies, is beneficial for the treatment of patients with relapsing MS ➤ This study showed an impressive effect of ofatumumab on patients with MS, using a wide range of doses ➤ Ofatumumab was associated with profound B-cell depletion and was well tolerated ➤ All doses of ofatumumab suppressed new brain lesion activity by 99% in the first 24 weeks of treatment ➤ The investigators suggest that B-cell–depleting agents should be used for these patients as a single rather than an add-on therapy tolerated, with the most common adverse event of infusion-related reactions confined to day 1 of the infusion. Ofatumumab demonstrated little immunogenicity, with no patient developing antihuman antibodies. As measured by CD19 reduction, ofatumumab was associated with profound B-cell depletion. On MRI, all doses of ofatumumab suppressed new brain lesion activity by 99% in the first 24 weeks of treatment; significant reductions (P <.001) were observed with ofatumumab in new T1-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions versus placebo. n

For Patients with Multiple Sclerosis, Increasing Physical Activities... Continued from page 7 short bouts over the day as part of one’s life rather than one long, continuous bout [of structured exercise].… Accordingly, lifestyle physical activity would seem ideal for those with MS, considering [this population‘s] rates of sedentary behavioral and physical inactivity.” Dr Motl describes the difference between structured exercise and lifestyle physical activities, discussing the importance of this paradigm shift and why it is so important, and outlining behavioral intervention that may help to increase physical activities.

This approach has been shown to improve everything from walking mobility to pain in people with MS, Dr Motl emphasizes. Furthermore, it has already been embraced in the general population, and can be implemented cost-effectively and on a large scale for people with MS and other chronic conditions, according to Dr Motl. Online Education He and several coinvestigators have conducted a randomized controlled trial, for example, demonstrating that Internet-delivered encouragement of

value-based CARE in Neurology

April 2014

at a glance ➤ Encourage patients with MS to incorporate physical activities into their daily lives ➤ Research has shown the significant benefit of this approach, but the majority of patients are not physically active ➤ It is easier to fit this into patients’ daily lives much more than episodes of structured exercise

increased lifestyle physical activity among people with MS reduces their fatigue severity and its physical impacts, and also reduces depression and anxiety (Pilutti L, et al. Mult Scler. 2013 Sept 5. Epub ahead of print). In addition, the intervention— which involves a website demonstrating the benefits of lifestyle physical activity and one-on-one video coaching by exercise professionals— also improved cognition and performance on the 6-minute walk test (Sandroff BM, et al. J Neurol. 2014;261: 363-372). n VOL. 1

NO. 1

Alzheimer’s Disease/Dementia

New Dementia Quality Measures Issued by 5 Professional Organizations Calling on payers to use quality as a basis for reimbursement By Caroline Helwick

n interdisciplinary group of 5 professional organizations, the Dementia Measures Work Group (DWG), recently published a set of quality measures that could improve the care of patients with dementia (Odenheimer G, et al. Neurology. 2013;81:1545-1549). The effort was led by the American Academy of Neurology, the American Geriatrics Society, the American Medical Directors Association, the American Psychiatric Association, and the American Medical Association–convened Physician Consortium for Performance Improvement. “The idea was to establish the absolute minimum standard of good quality care that could be easily performed and measured,” said lead investigator Germaine L. Odenheimer, MD, Associate Professor, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr Odenheimer and colleagues acknowledged that other efforts have been made to set dementia quality care standards; however, these have not been fully embraced by providers, healthcare systems, or by health insurers. The new set of quality measurements incorporates some of the con-

at a glance ➤ A new set of quality measures in dementia was issued by the American Academy of Neurology, in collaboration with 4 other medical societies ➤ The new measures recognize the enormous challenge dementia presents to patients, caregivers, providers, public health, and insurers ➤ These measures have the potential to dramatically affect practice and improve care quality for patients with dementia ➤ These measures seem obvious to those involved in dementia care, but they are not being met by the medical community ➤ Payers may need to consider quality measures in their reimbursement policies

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cepts previously put forth, but expands on them. This new set of measures:

quality improvement initiatives must be explicit and practical.

“For those of us who specialize in dementia care, these measures seemed so obvious, but they are not being met by the medical community. We hope that as insurers base payment on quality measures, that these will become routine and standard of care.” —Germaine L. Odenheimer, MD

• Includes all stages of dementia in a single measurement set • Calls for the use of functional staging in planning care • Prompts the use of validated in struments in patient and caregiver assessment and in patient interventions • Highlights the relevance of using palliative care concepts • Recommends instruments for tracking patient-centered outcomes. “For those of us who specialize in dementia care, these measures seemed so obvious, but they are not being met by the medical community. We hope that as insurers base payment on quality measures, that these will become routine and standard of care,” Dr Odenheimer said in an interview with Value-Based Care in Neurology. Dr Odenheimer and colleagues emphasize that there are many opportunities for improvement in the area of dementia care and its assessment, based on the following considerations: • Healthcare for persons with dementia is inconsistent, often suboptimal, and largely unplanned • Ethnic and socioeconomic disparities are important influences on the quality of dementia care • Partnership with caregivers is integral to improving care • The well-being and behavioral stability of patients with dementia is strongly influenced by the well-being of their caregivers • Comprehensive integrated care and

What Quality Measures Are Appropriate in Dementia Management? Clinical performance measures ideally include patient-level outcomes, as well as processes of care, but because of the nature of this disease, patient- reported measures are often unreliable. In their place, the assessment of dementia care must rely on measuring care processes that have been associated with positive outcomes in a rapidly evolving evidence base, the investigators indicated. Dr Odenheimer and colleagues constructed the following measurement set of auditable quality measures that can be applied to the care of patients already diagnosed with dementia. It asks healthcare providers to determine the percentage of patients, regardless of age (and in some cases, caregivers), who underwent the following care modalities within a 12month period: • Staging of dementia as mild, moderate, or severe • Cognitive, functional, and neuropsychiatric symptom assessments • Management of neuropsychiatric symptoms, if present, or recommendation for such • Screening for depressive symptoms • Counseling regarding safety concerns and risks of driving • Palliative care counseling and advance care planning • Caregiver education and support, including referral to additional resources. april 2014

Practical Implications “The DWG measures have the potential to dramatically affect practice and improve the quality of care provided to patients with dementia,” Dr Odenheimer and colleagues predicted. They noted that almost all measures were selected for the most recent Physician Quality Reporting System lists, and 1 measure (cognitive assessment) was included in the clinical quality measure list for the Centers for Medicare & Medicaid Services’ meaningful use. “The emphasis on dementia management in this measurement set recognizes the enormous challenge dementia presents to individual patients and their caregivers, health care providers, public health, and government and private insurers,” Dr Odenheimer and colleagues suggested. “While patients, caregivers, and health professionals await more effective disease-modifying treatments for patients with dementia, adherence to the measures outlined here will improve the quality of life for patients and caregivers with dementing illnesses.” n

By the numbers

In 2010, the worldwide costs associated with all dementias were estimated at $604 billion (US dollars), which was approximately 1% of the global gross domestic product

The costs of dementia mainly comprise resources used to cope with the consequences of the disease; only a small fraction of resources are spent on preventing or delaying disease onset/progression

Since the 1990s, acetylcholine esterase inhibitors and memantine have been available for the symptomatic treatment of AD, but no cure or preventive therapies are available

The discovery of novel biomarkers may lead to the development of improved therapies for AD (see page 12) Source: Wimo A, et al. J Intern Med. 2014;275:304-316.

www.ValueBasedNeurology.com

Alzheimer’s Disease/Dementia

New Framework Proposed for Economic Evaluation of Alzheimer’s Treatment Cost-effective analyses should be considered for clinical decisions

See also page 9

By Rosemary Frei, MSc

newly released study has found a set of 10 lipids from peripheral blood that can predict a neurodegenerative process that may be linked to Alzheimer’s disease (AD) or other types of cognitive impairment using a blood test to identify these biomarkers (Mapstone M, et al. Nat Med. 2014;20:415-418). This led the media around the globe to declare this a potential game-changing breakthrough in early detection of the disease. Closer examination, however, indicates that this is only one step in the long process of creating an accurate blood test for predicting the development of cognitive impairment. The study was conducted by lead author Mark E. Mapstone, PhD, MA, Associate Professor of Neurology, University of Rochester Medical Center, NY, and colleagues from Georgetown University, Washington, DC. “We posit that this ten-phospho lipid biomarker panel…reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI [amnestic mild cognitive impairment] or AD and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” Dr Mapstone and colleagues wrote.

“This ten-phospholipid biomarker panel…reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI or AD and may mark the transition between preclinical states...to subtle cognitive changes.” —Mark E. Mapstone, PhD, MA, and colleagues The team sifted through plasma samples of 451 people aged ≥70 years who were cognitively normal, and 74 who had aMCI or AD. The objective of the study was to find an amino-acid and phospholipid profile that is unique to people who will go on to develop aMCI or AD.

“The more immediate questions we have related to this work are, ‘Can this blood test be used to screen a larger and more diverse population?’ and ‘Can it be used to screen younger people to predict onset of disease?’” —Mark E. Mapstone, PhD, MA

Dr Mapstone and colleagues iden tified a set of 8 phosphatidylcholine molecules and 2 acylcarnitines that were less abundant in the plasma of people who had transitioned over a 2- to 3-year span from being cognitively normal to the aMCI state or to AD than in the blood of those who remained cognitively normal. The 10-metabolic lipids panel had a sensitivity and specificity of 90% for being able to discriminate between individuals who switched from being cognitively normal to having cognitive impairment and those who remained cognitively normal. “The more immediate questions we have related to this work are, ‘Can this blood test be used to screen a larger and more diverse population?’ and ‘Can it be used to screen younger people to predict onset of disease?’” Dr Mapstone told Value- Based Care in Neurology. Study Details A total of 525 community-dwelling individuals aged ≥70 years were enrolled in the study; of these, 46 had aMCI or mild AD at baseline, and another 28 developed one of these conditions in an average of 2.1 years. In the third year of the 5-year

value-based CARE in Neurology

April 2014

study, the investigators selected 53 participants with aMCI or mild AD, including 18 patients who had developed one of the conditions during the study, for serum analysis for possible metabolomic and lipidomic biomarkers; the investigators also selected 53 matched cognitively normal participants to act as controls. In addition, the researchers created an internal cross-validation subset that included the remaining 10 patients who had developed aMCI or mild AD during the study, and 11 of the participants who had aMCI or AD at baseline, together with 20 matched controls. The initial search for biomarkers yielded a set of 10 metabolites that comprised 8 phosphatidylcholine molecules and 2 acylcarnitines; a targeted biomarker analysis in a sepa-

rate group of 40 participants that served as an independent, blinded, cross-validation, revealed similar levels of the 10 biomarkers to the initial search. Statistical analyses showed that the 10-metabolite panel had a 90% sensitivity and a 90% specificity in classifying which individuals would develop aMCI or mild AD, and which individuals would not. The investigators repeated the analyses with the addition of apolipoprotein E to the metabolite panel—because apolipoprotein E is implicated in the development of AD—and found that this did not increase the accuracy of the test. The authors cautioned that the panel needs to be validated by other researchers before it can be refined and put into clinical use. n

REST Regulates Neuronal Genes in the Aging Brain, Is Absent in AD

new study by a team of researchers led by Bruce A. Yankner, MD, PhD, Professor of Genetics and Neurology, Harvard Medical School, Director of the Harvard Neurodegeneration Training Program, and Codirector of the Paul F. Glenn Laboratories for the Molecular Biology of Aging, has found that a gene regulating protein known as REST (repressor element 1-silencing transcription factor) is involved in protecting the aging brain by reducing oxidative stress, but its absence in old age signals brain disorders, especially Alzheimer’s disease (AD) and potentially other types of dementia (Lu T, et al. Nature. 2014;507:448-454). The team found that REST confers neuroprotective qualities during aging: it is active during fetal development and then is reactivated during the aging process, reducing oxidative stress and protecting neurons in the brain from stresses, including the various proteins that have been implicated in AD. Furthermore, REST is diminished in early AD and is absent in the brain of patients with full-fledged AD. REST has been known as a “repressor of neuronal genes during embryonic development that is downregulated once terminal neuronal differentiation has occurred,” the authors wrote. What this new study

shows is that “REST is induced in the ageing human brain and regulates a network of genes that mediate cell death, stress resistance and AD pathology. This gene network becomes dysregulated at early stages of AD pathology.” Furthermore, REST “plays a role as a neuroprotective modulator, in part by repressing genes that promote cell death and the pathology of AD,” they note. REST activates genes that promote neuronal response to stress, a natural mechanism developed to preserve brain function and brain well-being. However, according to Dr Yankner and colleagues, “REST is induced in the ageing brain and declines in AD. Transcriptional profiling has demonstrated significant changes in the expression of neuronal genes in the prefrontal cortex of the ageing humans.” Therefore, testing people for the level of REST in their brain could determine who is likely to develop AD. “One very positive, optimistic note from this study is that it suggests that dementia can be resisted by some people, and it provides the first molecular inkling of how that might occur, “ Dr Yankner said in an interview with the Boston Globe. Developing a test that shows who has low levels of REST may be the first step to developing preventive therapies for AD. n

VOL. 1

NO. 1

In the Literature Elevated Fatty Acid Levels Increase Risk for Recurrent Stroke in Patients with Cardioembolic Stroke

Plasma free fatty acids (FFAs) are related to lipid metabolism, and elevated levels of FFA have been associated with risk factors for atherosclerosis, such as abdominal obesity, arterial hypertension, and insulin resistance.

The potential link between FFAs and ischemic stroke has been previously suggested, but no causal relationship has been established. A new study set out to investigate whether elevated FFAs constitute a risk factor for recurrent events in patients with cardioembolic stroke (Choi JY, et al. Neurology. 2014;82:1142-1148). Using a hospital-based stroke reg-

AUBAGIO® (teriﬂunomide) tablets for oral administration

istry in Korea, the investigators recruited patients between January 2008 and May 2010. The patients were enrolled in the study within 7 days of the onset of an acute ischemic stroke. Of the 864 patients with acute ischemic stroke who met the study inclusion criteria, 20 died during the initial hospitalization, 79 did not have Live7” measurements baseline FFA level

Rx Only

Brief Summary of Prescribing Information

WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Risk of Teratogenicity Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment [see Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.1)].

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patients on placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months. One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. Teriflunomideinduced liver injury in this patient could not be ruled out. Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue teriflunomide and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered. 5.2 Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)]. Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)]. Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk. [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)] 5.3 Procedure for Accelerated Elimination of Teriflunomide Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures: • Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used. • Administration of 50 g oral activated charcoal powder every 12 hours for 11 days. If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly. At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations. Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment. 5.4 Bone Marrow Effects/Immunosuppression Potential/Infections White Blood Cell (WBC) count decrease A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 10% and 15% of patients on AUBAGIO 7 mg and 14 mg , respectively, compared with 5% of patients on placebo; lymphocyte count <0.8×109/L was observed in 7% and 10% of patients on AUBAGIO 7 mg and 14 mg, respectively, compared with 5% of patients on placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression. Risk of Infection / Tuberculosis Screening Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician. AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections. In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with teriflunomide 7 mg (1.4%) or 14 mg (2.2%) compared to placebo (2.1%).

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1. INDICATIONS AND USAGE AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis [see Clinical Studies (14) in the full prescribing information]. 2. DOSAGE AND ADMINISTRATION The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food. Monitoring to assess safety • Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. • Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)]. • Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test [see Warnings and Precautions (5.4)]. • Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.9)]. 4. CONTRAINDICATIONS 4.1. Severe Hepatic Impairment Patients with severe hepatic impairment [see Warnings and Precautions (5.1)]. 4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception AUBAGIO may cause fetal harm when administered to a pregnant woman. In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)]. AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)]. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling. [see Warnings and Precautions and Use in Specific Populations (5.2, 8.1)] 4.3. Current treatment with leflunomide Co-administration of teriflunomide with leflunomide is contraindicated. 5. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. In placebo-controlled trials, ALT greater than three times the ULN occurred in 14/429 (3%) and 21/415 (5%) of patients on teriflunomide 7 mg and 14 mg, respectively, and 17/421 (4%) of

(which disqualified them for the study), and 96 were lost to follow-up. A total of 669 patients were included in the study analysis. Of the 669 patients, 429 were male, and the average age was 65.13 years. The patients were divided into 2 groups—those with noncardioembolic stroke (N = 564), who served as the control group, and patients with

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cardiometabolic stroke (N = 105). Of those with cardioembolic stroke, 79 patients had atrial fibrillation, 13 had patent foramen ovale or atrial septal defects, 10 had valvular heart disease, 9 had acute or recent myocardial infarction, and 1 had congestive heart failure. The results showed that plasma FFA concentration was approximate-

ly 1.5-fold higher in patients with cardioembolic stroke than in those with ischemic stroke unrelated to cardioembolic disease (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.43; P <.001). During the 25.4-month follow-up period, 56 (8.4%) of all the patients had recurrent stroke, but the recurrence rate was not significantly

different between the 2 groups—10.5% among patients with cardioembolic stroke and 8% in those with noncardio embolic stroke (P = .396). However, a significant difference between the 2 groups was found in the association between stroke recurrence and plasma FFA concentration: in the patients with cardioembolic

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AUBAGIO® (teriflunomide) tablets for oral administration and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.11 Concomitant Use with Immunosuppressive or Immunomodulating Therapies Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established. In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment [see Warnings and Precautions (5.3)]. 6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: • Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)] • Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)] • Peripheral Neuropathy [see Warnings and Precautions (5.5)] • Acute Renal Failure [see Warnings and Precautions (5.6)] • Hyperkalemia [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.8)] • Blood Pressure Effects [see Warnings and Precautions (5.9)] • Respiratory Effects [see Warnings and Precautions (5.10) The most frequent adverse reactions for AUBAGIO (incidence ≥10% and ≥2% greater than placebo) in the placebo-controlled studies were ALT increased, alopecia, diarrhea, influenza, nausea, and paresthesia. Alopecia was the most common cause of discontinuation because of adverse events in controlled clinical studies as compared to placebo (0.5% and 1.4% of patients on AUBAGIO 7 mg and 14 mg, respectively, and 0% on placebo). If desired, teriflunomide can be rapidly cleared from the body by the use of an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 6.1 Clinical Trial Experience A total of 844 patients on teriflunomide (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of MS (RMS). Approximately 72% of patients were female and the mean age was 38 years. Study 1 was a 108-week placebo-controlled clinical study in 1086 RMS patients treated with teriflunomide 7 mg (n=368), teriflunomide 14 mg (n=358), or placebo (n=360). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriflunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) Teriflunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) INFECTIONS AND INFESTATIONS Influenza 12% 9% 10% Upper respiratory tract infection 9% 9% 7% Bronchitis 8% 5% 6% Sinusitis 6% 4% 4% Cystitis 4% 2% 1% Gastroenteritis viral 4% 2% 1% Oral herpes 4% 2% 2% BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 4% 2% 0.3% Leukopenia 1% 2% 0.3% IMMUNE SYSTEM DISORDERS Seasonal allergy 3% 2% 1% PSYCHIATRIC DISORDERS Anxiety 4% 3% 2% NERVOUS SYSTEM DISORDERS Headache 19% 22% 18% Paraesthesia 10% 9% 8% Sciatica 3% 1% 1% Burning sensation 3% 2% 1% Carpal tunnel syndrome 3% 1% 0.3% EYE DISORDERS Vision blurred 3% 3% 1% Conjunctivitis 1% 3% 1% CARDIAC DISORDERS Palpitations 2% 3% 1%

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However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting, in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed. In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO. Vaccination No clinical data are available on the efficacy and safety of vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is, however, not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO. Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO. 5.5 Peripheral Neuropathy In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking AUBAGIO than in patients taking placebo. In one 108-week placebo-controlled study in 1086 patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.2% (4 patients) and 1.9% (6 patients) on 7 mg and 14 mg of AUBAGIO, respectively, compared with 0% on placebo. Treatment was discontinued in 2 patients with polyneuropathy, one on each dose; one of them recovered following treatment discontinuation. The other cases of peripheral neuropathy did not resolve with continued treatment. There have also been reports of peripheral neuropathy in patients receiving leflunomide. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.6 Acute Renal Failure In placebo-controlled trials, 10 of 844 (1.2%) of AUBAGIO-treated subjects had transient acute renal failure with a creatinine measurement increased by 100% or more of their baseline serum creatinine value, compared to 0 of 421 placebo-treated subjects. Seven of the 10 subjects had a nadir creatinine clearance less than 30 cc/minute. In each of the 10 subjects, the serum creatinine level was normal on the next reported measurement (6–48 days from the increase in creatinine) with continued teriflunomide use. These increased creatinine measurements occurred between 12 weeks and 2 years after first dose of teriflunomide. Of the 6 subjects with available serum potassium measurements, 3 (50%) had hyperkalemia (measurements of 6.7, >7.3, and >7.3 mmol/L). No associated symptoms were documented. AUBAGIO causes increases in renal uric acid clearance with mean decreases in serum uric acid of 20–30%. Acute uric acid nephropathy is a likely explanation for the cases of transient acute renal failure seen with teriflunomide. Although symptoms associated with acute uric acid nephropathy, such as loin pain or flank pain, were not reported, this information was not systematically collected. No inciting factors, such as dehydration, exercise, or increase in physical activity in the 30 days prior to the adverse event were reported, but this information was not systematically collected. 5.7 Hyperkalemia In placebo-controlled trials, treatment-emergent hyperkalemia >7.0 mmol/L occurred in 8/829 (1.0%) of teriflunomide-treated subjects, compared to 1/414 (0.2%) of placebo-treated subjects. Two teriflunomide-treated subjects had hyperkalemia >7.0 mmol/L with acute renal failure. Possible causes in other cases were not documented. Check serum potassium level in AUBAGIO-treated patients with symptoms of hyperkalemia or with acute renal failure. 5.8 Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.9 Blood Pressure Increase In placebo-controlled studies, mean change from baseline in systolic blood pressure was 2.9 mmHg and 2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -1.3 mmHg for placebo. The change from baseline in diastolic blood pressure was 1.4 mmHg and 1.3 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.9 mmHg for placebo. Hypertension was reported as an adverse reaction in 4% of patients treated with 7 mg or 14 mg of AUBAGIO, compared with 2% on placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO. 5.10 Respiratory Effects Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy

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stroke, an elevated baseline FFA concentration was independently linked to stroke recurrence (HR, 2.7; CI, 1-6.9). By contrast, no such association was found in the patients with noncardioembolic stroke. These results indicate that an elevated FFA level is a marker for stroke in patients with cardioembolism. Fur-

In the Literature thermore, an elevated FFA concentration may predict stroke recurrence in patients with stroke caused by cardioembolic disease. “Although FFA could be involved in CE [cardioembolic] stroke by several mechanisms, each mechanism may play some part in common pathophysiologic cascades,” the investigators concluded.

Pregabalin Monotherapy Safe and Effective in Patients with Partial-Onset Seizures

The antiepileptic drug (AED) pregabalin (Lyrica) is approved in many countries—but not in the United States—for the adjunctive treatment of patients with partial-onset seizures in adults. The US Food and Drug AdLive7”

Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriﬂunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) (continued) Teriﬂunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) VASCULAR DISORDERS Hypertension 4% 4% 2% GASTROINTESTINAL DISORDERS Diarrhoea 18% 15% 9% Nausea 14% 9% 7% Abdominal pain upper 6% 5% 4% Toothache 4% 4% 2% Abdominal distension 1% 2% 0.3% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia 13% 10% 3% Acne 3% 1% 1% Pruritus 3% 4% 2% MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Musculoskeletal pain 4% 5% 3% Myalgia 3% 4% 2% INVESTIGATIONS Alanine aminotransferase 14% 12% 7% increased 3% 5% 1% Gamma-glutamyltransferase increased Aspartate aminotransferase 3% 2% 1% increased Weight decreased 2% 3% 1% Neutrophil count decreased 2% 3% 0.3% White blood cell count decreased 1% 3% 0%

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AUBAGIO® (teriflunomide) tablets for oral administration Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Use in Males AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)]. Pregnancy Registry Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447, option 2. 8.3 Nursing Mothers Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of AUBAGIO did not include patients over 65 years old. 8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. Teriflunomide is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1) and Warnings and Precautions (5.1)]. 8.7 Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. 10. OVERDOSAGE There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects. In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination [see Warnings and Precautions (5.3)]. Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 A SANOFI COMPANY September 2012a TER-BPLR-SA-SEP12

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onset seizures (French J, et al. Neurology. 2014;82:590-597). This study is the second to publish results based on a historical-controlled trial design in patients with epilepsy related to monotherapy; the first study was reported with lamotrigine extended release (Lamictal XR). The current study was a 20week, double-blind, randomized, historical-controlled study conducted at 54 international centers, including 44 centers in the United States. Overall, the study included an 8-week baseline phase maintaining the previous AED regimen, then a 20week double-blind monotherapy with pregabalin, and a 1-week open-label initiation for patients who were to enter the 6-month extension phase. Patients were randomized to receive pregabalin 600 mg or 150 mg daily in a 4:1 ratio. The 150-mg dosing group was not powered for efficacy and was only included for blinding. The primary end point was the proportion of patients receiving pre gabalin 600 mg who met ≥1 of the predefined seizure-related efficacy criteria. All patients had received ≥1 AEDs before enrollment in the pregab alin study. The mean time since the diagnosis of epilepsy in both groups was 14 years. Overall, 161 patients were randomized to receive ≥1 dose of pregabalin. Patients were enrolled between September 2007 and June 2011. During the 8-week baseline phase, the most common seizure types were simple and complex partial-onset seizures. In total, 129 (54.3%) patients in the pregabalin 600-mg group and 15 (46.9%) in the 150-mg group completed 20 weeks of double-blind treatment with this drug. The trial was stopped early after positive efficacy findings were reported by an interim analysis in 125 patients during the pregabalin monotherapy phase. Of the 102 patients in the interim analysis who received pregabalin 600 mg daily, 28.4% met at least 1 exit criterion. Of the 120 patients in the full study population, 25% met at least 1 exit criterion. Of the total patient population, the exit rate for patients receiving pregabalin 600 mg daily was 27.5% (95% CI, 17.8%-37.2%). Because the upper limit of the CI was less than the 74% reported with the historical- control threshold (as well as the more rigorous CI threshold of 68%), these results were declared as appropriate efficacy for monotherapy with pregabalin 600 mg daily. The safety profile of pregabalin was consistent with its previously established safety profile as adjunctive therapy in patients with partial-onset seizures. n

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Cardiovascular deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between teriflunomide and cardiovascular death has not been established. Hypophosphatemia In clinical trials, 18% of teriflunomide-treated subjects had mild hypophosphatemia (≥ 0.6 mmol/L and < lower limit of normal), compared to 9% of placebo-treated subjects; 5% of teriflunomide-treated subjects had moderate hypophosphatemia (≥0.3 mmol/L and <0.6 mmol/ L), compared to 1% of placebo-treated subjects. No subject in either treatment group had a serum phosphorus <0.3 mmol/L. 7. DRUG INTERACTIONS Effect of teriflunomide on CYP2C8 substrates There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone is recommended as they may have higher exposure. Effect of teriflunomide on warfarin A 25% decrease in peak international normalized ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is recommended. Effect of teriflunomide on oral contraceptives There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide. Consideration should be given to the type or dose of oral contraceptives used in combination with teriflunomide. Effect of teriflunomide on CYP1A2 substrates Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55% respectively, suggesting that teriflunomide may be in vivo a weak inducer of CYP1A2. Therefore, patients should be monitored when teriflunomide is coadministered with drugs metabolized by CYP1A2 (such as duloxetine, alosetron, theophylline, and tizanidine), as the efficacy of such drugs could be reduced. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4.2) and Warnings and Precautions (5.2)] When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).

ministration (FDA) has requested evidence from individual monotherapy trials for AEDs before an AED could be considered for FDA approval as monotherapy for seizures in the United States. A recent study, therefore, investigated the safety and efficacy of pregabalin monotherapy for patients with inadequately controlled partial-

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Epilepsy Management

Patient Management Improves with the Recent FDA Approval of 4 New Drugs for Seizures

recent spate of US Food and Drug Administration (FDA) approvals for epilepsy medications—4 in all—has fortified the armamentarium of drugs available for the treatment of seizure disorders. These new treatment options—1 is a new molecular entity, and the other 3 are new, long-acting versions of drugs previously approved by the FDA for the treatment of seizures—represent a much needed, if incremental, improvement in patient care. Welcoming the news, Phillip M. Gattone, MEd, President and CEO, Epilepsy Foundation, Landover, MD, stated, “It is imperative that we continue to explore new ways to help those living with epilepsy….With less than 40 anti epilepsy medications currently available to help—and much fewer for severe syndromes like Lennox-Gastaut—it is imperative that pharmaceutical companies continue to innovate and improve upon treatments.”1

A Long History Indeed, there is not much new about unmet need when it comes to seizure-related disorders. The first historical mention of epilepsy dates back to the fifth millennium bc, with ancient medical texts describing “the falling disease.” Alexander the Great and Julius Caesar suffered from seizures, and Hippocrates, writing in 400 bc, was the first to recognize the condition as a dysfunction of the brain and not a supernatural event. Although seizures have been identified as a medical condition for the past 2400 years, a certain air of mystery surrounding the condition persists. For example, in many patients, the onset of seizures cannot be explained by events that are generally associated with the disorder, such as a recent stroke, a brain tumor, an infection of the central nervous system, or head injury. Types of Seizures In general, the condition is characterized by recurrent seizures. The types of seizures are as variable as the patients having them, ranging from momentary disruptions of the senses, to convulsions, to unconsciousness. Seizures are divided into 3 general types— generalized, partial, and others.2

Generalized Seizures

Absence seizures. Onset occurs be-

tween the ages of 4 and 12 years, and these seizures are characterized by brief impairments of consciousness usually lasting no more than a few seconds. Atonic seizures. These seizures produce an abrupt loss of muscle tone. Tonic-clonic. The most common type of generalized seizure, tonic-clonic seizures Electroencephalography of tonic-clonic seizure. begin with stiffening of the limbs, followed by jerking of the Other Seizures Gelastic/dacrystic. These seizures limbs and face. Myoclonic. Myoclonic seizures are are sometimes called “laughing seirapid, brief contractions of bodily zures,” because they resemble unconmuscles that usually occur on both trolled laughter or giggling. In some children, the vocalization has a crying sides of the body simultaneously. quality and is called a dacrystic Partial Seizures seizure. Simple. Individuals with simple Nonepileptic seizures. These are epipartial seizures do not lose conscious- sodic, paroxysmal events unrelated to ness; however, movement, emotions, abnormal electrical activity in the sensations, and feelings can be affect- brain. Seizures of this type are consided. Some patients cannot speak or ered to be of psychologic rather than move until the seizure is over. physical origin. Status epilepticus. Status epilepticus seizures are nonstop and require hospitalization.

“It is imperative that we continue to explore new ways to help those living with epilepsy….With less than 40 antiepilepsy medications currently available to help—and much fewer for severe syndromes like LennoxGastaut—it is imperative that pharmaceutical companies continue to innovate and improve upon treatments.”

—Phillip M. Gattone, MEd

Complex. Complex partial seizures are more severe than simple partial seizures, especially because they affect consciousness. During a seizure of this type, individuals are not in control of their movements, speech, or actions, and they have no memory of what happened during the seizure.

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Disease Prevalence and Associated Costs In the United States, there are approximately 2.3 million adults and nearly half a million children aged <18 years with epilepsy, and >150,000 new cases of the disorder are diagnosed annually.3-5 According to the Institute of Medicine, “Epilepsy is the nation’s fourth most common neurological disorder, after migraine, stroke, and Alzheimer’s disease….Epilepsy is a complex spectrum of disorders—sometimes called the epilepsies—that affects millions of people in a variety of ways and is characterized by unpredictable seizures that differ in type, cause, and severity.”5 Such a large caseload incurs an equally large expense. The estimated costs of treating epilepsy and the associated reduced earnings/productivity of patients with epilepsy are estimated to exceed $15.5 billion annually.6 Although it is reported that antiepileptic drugs provide complete symptom control for more than 50% of patients with seizure disorders and

By Neil Canavan reduce the frequency of seizures in another 20% to 30% of patients, approximately 20% of patients do not respond to the currently available medications.7 For such patients, surgery may be the only option.7 With a growing patient population, including millions of individuals who experience a suboptimal response or no response at all to current treatments, it is no wonder that the estimated future expenditures loom so large. A recent analysis by the market research firm, GBI Research, predicts that the current annual therapeutic costs of $1.9 billion in the United States will swell to $2.6 billion by 2019.8 In the same time frame, the global costs of epilepsy are expected to exceed $4.5 billion.8 Four Recently Approved Treatment Options The need for new drugs to treat epilepsy is ongoing; the causes of the disorder and the associated sequelae vary widely from patient to patient. Therefore, different therapeutic approaches are often required.

Aptiom

On November 8, 2013, the FDA approved the new molecular entity eslicarbazepine acetate (Aptiom; Sunovion Pharmaceuticals), an oral drug that is the S(+) enantiomer of licarbazepine, and as such is designed to avoid the production of active metabolites that are thought to be responsible for certain side effects, as well as drug– drug interactions.9 Eslicarbazepine acetate is specifically indicated as an adjunctive treatment for partial-onset seizures. Although the precise mechanism by which eslicarbazepine acetate quells convulsive activity is unclear, the drug is a known voltage-gated sodium channel blocker.10 The recommended initial dose of eslicarbazepine acetate is 400 mg once daily. After 1 week, the dosage should be increased to 800 mg once daily, which is the recommended maintenance dosage.10 The FDA approval of eslicarbazepine acetate was based on the results of 3 randomized, double-blind, placebo-controlled, multicenter trials in 794 adults with partial-onset seizures. Patients received 800 mg or 1200 mg daily of eslicarbazepine acetate or placebo for 12 weeks.10 VOL. 1

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Epilepsy Management The pooled results of these studies showed that although a striking 21.5% of patients in the placebo arm had at least a 50% reduction in seizure frequency, 36.5% of patients receiving 800 mg and 43.5% of those receiving 1200 mg daily of eslicarbazepine acetate had a 50% reduction in seizure frequency (P <.001).11 The most common adverse events observed for active treatment were dizziness, sleepiness, nausea, headache, vomiting, blurred vision, and shakiness.11 Eslicarbazepine acetate is in FDA pregnancy category C, which means that patients should not start or stop taking eslicarbazepine acetate during pregnancy without their doctor’s advice. “Some patients with epilepsy do not achieve satisfactory seizure control from existing treatments,” stated Eric Bastings, MD, Acting Director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, after the approval of eslicarbazepine acetate. “It is impor tant we continue to make new treatment options available to patients.”9

cy of –38.2% (P = .078) with oxcarbazepine 1200 mg daily and, –42.9% (P = .003) with oxcarbazepine 2400 mg daily compared with –28.7% with placebo.13 The most common adverse events were dizziness, somnolence, headache, balance disorder, tremor, vomiting, double vision, asthenia, and fatigue.13 The label warnings for this medication include the potential for hypo natremia, anaphylactic reactions and angioedema, serious dermatologic reactions, and events related to the withdrawal of oxcarbazepine.13

Oxtellar XR

Trokendi XR

A new, extended-release form of oxcarbazepine (Oxtellar XR; Supernus Pharmaceuticals) was approved by the FDA in October 2012 and became available in February 2013. This is a once-daily extended-release formulation of the previously available antiepileptic drug oxcarbazepine (Trileptal).12 Oxcarbazepine is believed to block voltage-sensitive sodium channels, resulting in diminution of the propagation of synaptic impulses, thereby reducing the spread of the seizure signal.13 The extended-release agent is specifically indicated as an adjunctive therapy for partial seizures in adults and in children aged 6 to 17 years.13 The pivotal trial leading to the FDA approval of the extended-release formulation of oxcarbazepine involved 366 adult patients with refractory partial epilepsy who were randomized to extended-release oxcarbazepine 1200 mg daily, 2400 mg daily, or to placebo in a multicenter, double-blind, placebo-controlled, 3-arm, parallel-group study with a duration of 12 weeks.13 All patients were receiving treatment with at least 1, and as many as 3, antiepileptic drugs before and during the trial, and were stable with treatment for a minimum of 4 weeks before entering the trial.13 The primary end point was the median percentage change from baseline in seizure frequency in 28 days during the treatment period.13 The results showed seizure frequenVOL. 1

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“Some patients with epilepsy do not achieve satisfactory seizure control from existing treatments. It is important we continue to make new treatment options available to patients.”

—Eric Bastings, MD

On August 16, 2013, the FDA approved an extended-release formu lation of topiramate (Trokendi XR; Supernus Pharmaceuticals), an oral, once-daily epilepsy drug.14 Extended-release topiramate is indicated for initial monotherapy in patients aged ≥10 years with partial-onset or primary generalized tonic-clonic seizures, for adjunctive therapy in patients aged ≥6 years with partial- onset or primary generalized tonic- clonic seizures, and for adjunctive therapy in patients aged ≥6 years with seizures associated with Lennox- Gastaut syndrome.15 The FDA approval of Trokendi XR was based on the same studies used to approve the earlier, immediate-release formulation of topiramate and on the later demonstration of the pharmacokinetic equivalence of topiramate to immediate-release topiramate. In brief, the initial immediate-release studies were adjunctive therapy. In all adjunctive topiramate trials, the reduction in seizure rate from baseline (fraction of patients with at least a 50% reduction) ranged from 9% to 24%, depending on the patient population and dose.15 The most frequently observed adverse events in these trials were paresthesia, anorexia, fatigue, dizziness, somnolence, nervousness, difficulty with memory/concentration, cognitive problems, fever, infection, and flushing.15 The labeling for topiramate con-

tains several warnings, including the potential for elevated ocular pressure, suicidal behavior and ideation (common to many antiepileptic drugs), cognitive issues, and fetal toxicity.15 It is further strongly advised that topiramate not be taken after being crushed. If patients cannot swallow topiramate capsules whole, they should tell their healthcare provider, because they may need a different medicine.15

Qudexy XR

On March 11, 2014, the FDA approved yet another extended-release version of topiramate (Qudexy XR; Upsher-Smith Laboratories) for the initial monotherapy of patients aged ≥10 years with partial-onset or primary generalized tonic-clonic seizures, as an adjunctive therapy in patients aged ≥2 years with partial-onset or primary generalized tonic-clonic seizures, and as an adjunctive therapy in patients aged ≥2 years with seizures associated with Lennox-Gastaut syndrome.16,17 Qudexy XR, an oral once-daily anti epileptic drug, addresses one issue of the noncrushable nature of Trokendi XR: because of the pharmacokinetic profile of its formulation, Qudexy XR of any strength may be swallowed whole or administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of soft food.17 As stated by the manufacturer, “This makes it the only approved extended- release topiramate product for patients who experience challenges swallowing whole capsules or tablets.”16 Qudexy XR was approved by the FDA on the strength of the results from the PREVAIL trial, a randomized, multicenter, double-blind, placebo-controlled, parallel-group study that enrolled 249 adult patients with refractory partial-onset seizures.17 The results from PREVAIL demonstrated that after 11 weeks of treatment, topiramate was associated with a significantly greater median percent reduction from baseline in the frequency of partial-onset seizures compared with placebo (39.5% vs 21.7%, respectively; P <.001).17 The most common side effects observed with topiramate extended release were paresthesia, irregular movements of the eyes, loss of appetite, nausea or indigestion, diarrhea, weight loss, nervousness, and upper respiratory tract infection.17 Labeled warnings for topiramate include the potential for secondary angle closure glaucoma, visual field effects, oligohydrosis and hyperthermia, metabolic acidosis, cognitive impairment, fetal toxicity, and kidney stones.17 april 2014

Conclusion According to the Institute of Medicine, living with epilepsy is not only about seizures. For patients with epilepsy, the disorder often means dealing with “challenges in school, uncertainties about social situations and employment, limitations on driving, and questions about independent living.”5 The recent addition of 4 new treatments—including the new molecular entity eslicarbazepine acetate and the 3 new extended-release formulations, 1 for oxcarbazepine and 2 for topiramate—to the market may improve outcomes for the growing number of patients with this old and common condition. The different types and etiologies of seizures require a multitude of treatment options to address the variety of mechanisms involved in this debilitating “spectrum of disorders,”5 as evidenced by the large percentage of patients who are not controlled with current therapeutic options.7 n References

1. Epilepsy Foundation. New antiepilepsy drug receives final FDA approval. August 28, 2013. www.epilepsy foundation.org/news/Trokendi-XR-Approved.cfm. Accessed March 19, 2014. 2. Epilepsy Foundation. Seizures: types of seizures. www. epilepsyfoundation.org/aboutepilepsy/seizures/index. cfm. Accessed March 16, 2014. 3. Centers for Disease Control and Prevention (CDC). Epilepsy in adults and access to care—United States, 2010. MMWR Morb Mortal Wkly Rep. 2012;61:909-913. 4. Child and Adolescent Health Measurement Initiative. 2009/10 national survey of children with special health care needs. Data query. www.childhealthdata. org/browse/survey/results?q=2076. Accessed March 16, 2014. 5. Institute of Medicine (US) Committee on the Public Health Dimensions of the Epilepsies. England MJ, Liverman CT, Schultz AM, Strawbridge LM, eds. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: National Academies Press; 2012. 6. Epilepsy Foundation. Epilepsy and seizure statistics. http://old.epilepsyfoundation.org/about/statistics.cfm. Accessed April 2, 2014. 7. Eadie MJ. Shortcomings in the current treatment of epilepsy. Expert Rev Neurother. 2012;12:1419-1427. 8. GBI Research. Global epilepsy market value to reach $4.5 billion by 2019 thanks to recent drug approvals. Press release. March 12, 2014. www.gbiresearch.com/ pressreleasedetails.aspx?title=Pharmaceuticals_and_ Healthcare&prid=285. Accessed March 19, 2014. 9. US Food and Drug Administration. FDA approves Aptiom to treat seizures in adults. Press release. November 8, 2013. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm374358.htm. Accessed March 19, 2014. 10. CenterWatch. Aptiom (eslicarbazepine acetate). www. centerwatch.com/drug-information/fda-approveddrugs/drug/1293/aptiom-eslicarbazepine-acetate/ ?mp=empty. Accessed March 18, 2014. 11. Gever J. New seizure drug wins FDA approval. November 8, 2013. www.medpagetoday.com/Neurol ogy/Seizures/42820. Accessed April 2, 2014. 12. Supernus Pharmaceuticals. Supernus receives FDA approval for Oxtellar XR in epilepsy. Press release. October 22, 2012. http://ir.supernus.com/releasedetail. cfm?releaseid=714986. Accessed April 2, 2014. 13. Oxtellar XR (oxcarbazepine) extended-release tablets [prescribing information]. Rockville, MD: Supernus Pharmaceuticals, Inc; October 2012. 14. Supernus Pharmaceuticals. Supernus Announces Final FDA Approval and Upcoming Launch of Tro kendi XR. Press release. August 19, 2013. http://ir. supernus.com/releasedetail.cfm?ReleaseID=785927. Accessed April 2, 2014. 15. Trokendi XR (topiramate) extended-release capsules [prescribing information]. Rockville, MD: Supernus Pharmaceuticals, Inc; August 2013. 16. CenterWatch. Upsher-Smith receives FDA approval for Qudexy XR (topiramate). March 13, 2014. www. centerwatch.com/news-online/article/6042/upshersmith-receives-fda-approval-for-qudexy-xr-topira mate. Accessed March 19, 2014. 17. Qudexy XR (topiramate) extended-release capsules [prescribing information]. Maple Grove, MN: UpsherSmith Laboratories, Inc; March 2014.

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Parkinson’s Disease

Role of Nutrition in Parkinson’s Disease: Neuroprotective Effects Identified, but Definitive Evidence Still Lacking By Charles Bankhead

efinitive answers about the role of nutrition in Parkinson’s disease (PD) remain elusive. Epidemiologic data have suggested a beneficial role for nutrition-related factors, including omega-3 fatty acids, tea, caffeine, and wine. Other studies have pointed to potential deleterious effects of certain nutrients, such as milk and other dairy products, according to a new review (Seidl SE, et al. Front Aging Neurosci. 2014;6:36). “In spite of promising effectiveness of these nutrients in PD, we lack definitive evidence-based answers as a result of limited large prospective randomized controlled studies designed to address these issues,” coauthor Judith A. Potashkin, PhD, MS, Professor of Pharmacology and Molecular Biology, Rosalind Franklin University of Medicine and Science, and colleagues, noted in their review. Epidemiologic studies cannot account for issues such as changing dietary habits and the potential for confounding by nonmotor symptoms of PD, such as dysphagia, constipation, and hyposmia, that can affect nutrition status. “These factors may remain undetected and therefore not properly reported,” the investigators noted. “Incorporation of these critical factors into clinical practice and epidemiological studies will greatly improve the reliability of studies assessing the role of nutrients in PD.” Current Evidence Phytochemicals. The review of potentially beneficial nutrients in PD started with phytochemicals, substances in fruits and vegetables associated with a slowing of age-related functional decline. Several epidemiologic studies have shown inverse associations between PD and the consumption of fruits, vegetables, and fish. Many fruits and vegetables contain large amounts of antioxidants, another nutrient class associated with a reduced risk for PD. A word of caution came from the investigators of a preclinical study showing that pomegranate juice (a source of antioxidants) exacerbated oxidative stress and neurodegeneration in a PD model (Tapias V, et al. Neurobiol Aging. 2014;35:1162-1176). B vitamins. Mixed results have also come from studies of riboflavin, because some evidence has suggested beneficial antioxidant effects, whereas others suggested deleterious effects, such as glutathione depletion, mito-

chondrial DNA mutations, and abnormal iron metabolism. “Larger placebo controlled blinded studies done over a longer period of time would be beneficial for determining if riboflavin or other related B vitamins are useful supplements for PD patients,” the investigators concluded. Omega-3 fatty acids. Substantial experimental evidence points to neuroprotective effects of omega-3 polyunsaturated fatty acids and some of their constituents, such as DHA. DHA and its precursor, eicosapentaenoic acid, have demonstrated neuroprotective effects in experimental models of PD. However, the only clinical evidence has come from a study showing that omega-3 supplementation was associated with a reduced prevalence of depression in patients with PD.

“As the disease advances, it is necessary to have frequent nutritional and swallowing assessments done.” —Judith A. Potashkin, PhD, MS

Isoflavone genistein. Studies of preclinical models of PD have demonstrated neuroprotective effects of the soy-derived isoflavone genistein. Several reports have documented favorable effects on dopaminergic- mediated activities associated with neuroprotection. Caffeine. Animal models have provided a wealth of evidence pointing to neuroprotective effects of caffeine, including inhibition of dopaminergic neuron degradation, dopaminergic- mediated motor dysfunction, and dopaminergic toxicity. Estrogen may counter the neuroprotective effects of caffeine, according to epidemiologic evidence that postmenopausal women receiving estrogen replacement therapy are at an increased risk for PD compared with women not using such therapy. Tea. Observational and preclinical studies have produced results consistent with a neuroprotective effect of tea, including green and black tea. Both types of tea are rich in polyphenols, which have antioxidant properties and have demonstrated neuroprotective properties in laboratory experiments. “Tea consumption seems to be a promising lifestyle choice that may

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April 2014

slow age-related deficits and neurodegenerative diseases,” the authors said. “Given the evidence from preclinical studies, green tea polyphenols are currently being tested as a treatment for de novo PD patients.” Alcohol. Data are mixed for the putative neuroprotection afforded by alcohol. Case-control and cohort studies have suggested an inverse association between alcohol consumption and PD, although evidence suggests a deleterious effect of heavy alcohol intake. Other epidemiologic studies have found no association between alcohol and PD. Conflicting data aside, the red wine constituents resveratrol and quercetin have accumulated preclinical evidence of neuroprotective effects that could reduce the risk for PD. Other nutrients. A number of other nutrients have questionable or controversial associations with PD, according to the investigators, including dietary fat; meat; carbohydrates; and vitamins C, D, and E. Negative effects. The list of nutrients associated with adverse implications for PD is limited mostly to milk and other dairy products. The consumption of milk and other dairy products has been linked to an increased risk for PD. The association is stronger in men than in women. Dopaminergic neurotoxins have been postulated as the milk and dairy constituents most likely to initiate or increase neurodegeneration. However, new evidence shows the neuroprotec-

tive role of vitamin D, which is often added to milk (see article, page 19). Practical Implications Despite the unsettled role of nutrition in PD, clinical guidance includes recommendations involving diet and nutrition, Dr Potashkin and colleague Hope T. Bilyk, MS, RD, LDN, Assistant Professor of Nutrition, Rosalind Franklin University of Medicine and Science, told Value-Based Care in Neurology. Patients with PD are advised to maintain ideal body weight by consuming adequate energy from nutrient-rich foods, have periodic assessments of nutrition and swallowing, ensure adequate intake of essential macro- and micronutrients, consume fiber-rich foods to reduce constipation, maintain adequate fluid intake for hydration, and adhere to nutrition recommendations related to interactions with medications. “As the disease advances, it is necessary to have frequent nutritional and swallowing assessments done,” said Dr Potashkin. “Many factors, such as depression, cognitive issues, malnutrition, sarcopenia, and impaired immune function, can play a major adverse role in the nutritional status and overall health of the patient, resulting in a geriatric failure to thrive.” Patients who avoid milk but consume yogurt or other dairy products should make sure that these are fortified with vitamin D, which does not occur naturally in dairy products, Dr Potashkin and Ms Bilyk added. n

Vitamin D Deficiency May Be Widespread in Patients with Parkinson’s Disease By Frederique H. Evans, MBS

recent study conducted as part of the Harvard Biomarker Study, a longitudinal case-control study to assess molecular diagnostics that track or predict the progression of early-stage Parkinson’s disease (PD), suggests that vitamin D deficiency plays a significant role in patients with PD (Ding H, et al. Neurology. 2013;81:1531-1537). “Our study shows that as much as 17.6% of patients with PD may be de-

See also page 11 ficient in vitamin D,” coauthor Clemens R. Scherzer, MD, Director, Neurogenomics Laboratory, Brigham and Women’s Hospital, Boston, told Value- Based Care in Neurology. “Considering that there are 1 million patients with PD in North America, and many more in the rest of the world, this is a very large number.” The investigators became interested in vitamin D deficiency after seeing the results of a genome-wide VOL. 1

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Parkinson’s Disease

Men with NMDA Ar-Abs Encephalitis Have Different Presentation than Women By Alice Goodman

en with N-methyl-D-aspartate (NMDA) receptor antibodies (NMDAr-Abs) encephalitis present different from women, according to a recent study (Viaccoz A, et al. Neurology. 2014;82:556563). Adult men are more likely to present with seizures, whereas women rarely present with seizures and are much more likely to present with behavioral and psychiatric features as their first symptom. Males and females have a similar course of global progression and similar recovery. “Our take-home message is that the first symptoms of NMDAr-Abs encephalitis in adult males are different than in females. As in children with this disease, the first symptoms in adult males are frequently partial seizures rather than abnormal behavior and psychiatric presentations,” explained senior investigator Jérôme Honnorat, MD, PhD, Professor, Service de Neuro-Oncologie, Hôpital Neurologique, Bron, France, in an interview with the Valued-Based Care in Neurology. “This is important for neurologists to know, because they must be aware that adult male patients with partial seizure, normal MRI [magnetic resonance imaging], and inflammation of the cerebral spinal fluid may have an NMDAr-Abs encephalitis.” Although relatively rare, NMDArAbs encephalitis could represent between 2% and 40% of the cases of suspected viral encephalitis, Dr Honnorat said.

Viaccoz and colleagues pointed out that most reports of this disease (which was first described in (Dalmau J, et al. Ann Neurol. 2007;61:25-36) include both females and males. However, unlike in females, the clinical course of the disease has been less clear in male patients.

“Our takehome message is that the first symptoms of NMDAr-Abs encephalitis in adult males are different than in females” —Jérôme Honnorat, MD, PhD

The present study included 13 adult male patients diagnosed with NMDAr-Abs encephalitis using 2 different tests to confirm the results and to avoid false-positives. According to the presenting symptoms, males can be categorized as seizure, psychiatric and behavioral disorders, or cognitive dysfunction. Seizures were the first presenting signs in 8 of the 13 patients in the study; 4 of them had partial seizures, and within 12 days, partial seizures were followed by psychiatric symptoms (ie, hallucinations, psychosis, agitation with hypersexuality,

psychosis, and fluctuating levels of consciousness) or cognitive symptoms (ie, confusion associated with speech disturbances). Of the male patients who did not present initially with seizures, 23% had cognitive dysfunction and 7.7% had psychiatric symptoms. Of the 13 adult males, 12 received immunotherapy with corticosteroids and/or intravenous immunoglobulin; 8 patients received second immunomodulatory treatment with rituximab or cyclophosphamide. Severe disease occurred in 9 patients, and 9 patients were admitted to the hospital. Favorable outcomes were reported in 10 patients, and 6 patients achieved complete recovery. Relapse occurred in 3 patients. Dr Honnorat stated that early recognition of the disease is important, because “we suppose that early immunomodulatory treatment could improve the rate of total recovery and could accelerate healing.” The investigators compared the 13 male patients with 58 female patients identified in their database. Tumors were present in 24 (23 ovarian teratomas and 1 breast cancer) females versus only 1 (schwannoma) tumor in adult males. The first symptoms in males differed from females: 67% of females had behavioral and psychiatric symptoms at initial presentation versus 7.7% of the males (P >.01). Seizure at onset was observed in 8 (13.8%) of the 58 female patients and in 8 (61.5%) of

13 male patients (P <.001). Subsequent neurologic symptoms are observed earlier in female patients than in males with seizure at disease onset (median of 2 days for females vs 13 days for males; P <.01). However, all symptoms were equally present in both sexes at different time points. Expert Commentary In an accompanying editorial in the same issue of Neurology, Titulaer and Dalmau wrote that the study provided the novel observation that adult males present with seizures more often than females (who usually initially present with abnormal behavior and psychiatric symptoms). In a previous series of 577 patients, Titulaer and Dalmau confirmed that seizures were more often the initial symptom in adult males (27% vs 11% of females), but they also found that psychiatric symptoms remained the most common initial symptoms (54% of men vs 67% of women). They suggest that women with acute psychiatric symptoms are more often suspected to have this disorder than men with a similar presentation. “In men antibody testing and other ancillary investigations may not be considered until they develop seizures.” It is possible that regardless of the presenting symptoms, in men the diagnosis is delayed rather than missed. “The astute observation of Viaccoz et al should help improve diagnosis in adult men, prompting early therapy and possibly better outcomes,” they noted. n

Vitamin D Deficiency May Be Widespread in... Continued from page 18 screening that showed an increase in the expression of the vitamin D receptor gene VDR in the blood of patients with PD. In the current study, the investigators used liquid chromatography/tandem mass spectrometry to evaluate the plasma levels of the transcriptionally active 25-hydroxy-vitamin D3 (25[OH]D3) in 388 patients with PD and in 283 controls. Lower plasma 25[OH]D3 levels were significantly associated with the presence of PD compared with the controls in a univariate analysis (P <.0034) and a multivariate analysis (P <.047). Overall, 17.6% of patients with PD were vitamin D deficient (25[OH]D level <20 ng/mL) compared with 9.3% of the controls. In addition, 47.2% of patients with PD VOL. 1

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were vitamin D insufficient (25[OH] D level <30 ng/mL) compared with 39.9% of the controls. Low 25[OH]D3 and total 25[OH]D levels were associated with increased total Unified Parkinson’s Disease Rating Scale scores, which is indicative of more advanced disease severity. “The data from our Harvard Biomarker study suggest that patients with Parkinson’s disease should be included among the categories of individuals at high risk for vitamin D deficiency that warrant vitamin D biomarker measurement and vitamin D treatment,” Dr Scherzer explained. Furthermore, the investigators posited that vitamin D management should become part of a personalized medicine approach for patients with PD.

“Our study shows that as much as 17.6% of patients with PD may be deficient in vitamin D.” —Clemens R. Scherzer, MD

Taking a closer look at the mechanism of action, the investigators suggested that vitamin D supplementation before PD diagnosis may protect the substantia nigra from dopamine depletion. A study with 6-hydroxydopamine–lesioned rats that were preapril 2014

treated with 1,25[OH]D3 demonstrated partial restoration of tyrosine hydroxylase expression. “Correcting vitamin D deficiency in patients with PD is directly relevant for patients. Parkinson’s patients are already at an increased risk of falling and fractures, because of their Parkinson’s-related progressive loss of balance and gait impairment. Vitamin D supplementation (at doses higher than 400 IU/day) is known to reduce fractures in individuals older than age 65,” Dr Scherzer said. “Therefore, supplementing vitamin D in Parkinson’s patients with deficiency in vitamin D could potentially have an important impact for patients, public health, and healthcare cost-savings.” n

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Health Economics

Migraine Prevalence Rises with Decline in Income, but Remission Is... See also Migraine, page 22 Continued from page 1

significant in both sexes after accounting for race and other confounders. However, the likelihood of migraine remission was unaffected by household income, as poorer and more affluent patients had similar remission rates. “What the study of socioeconomic status shows for the first time is that [migraine] incidence is related to household income,” Walter F. Stewart, PhD, Vice President and Chief Research and Development Officer for Sutter Health in Walnut Creek, CA, told Value-Based Care in Neurology. “One way that we think of this is that income level represents a basket of possible exposures to stressors. In general, the higher the income, up to a certain point, the lower the level of exposure to stressors. So, this study demonstrates that the reason why prevalence is related to household income is because new migraine cases occur at a faster rate in lower-income groups. This suggests that the onset of migraine is probably strongly related to external exposures.” The finding of the lack of association between income and remission is new and unexpected. “This may suggest that endogenous factors—such as genetics or psychological and physiologic response to pain—mediate how quickly migraine remits in individuals,” said Dr Stewart. “Individuals in different income groups remit at the same rate. So, endogenous factors that mediate remission are not influenced by stressors that differ by income.”

at a glance ➤ Migraine frequency increased as annual household income declined from ≥$60,000 to <$22,500 ➤ The association remained significant in both sexes after accounting for confounders ➤ However, the likelihood of migraine remission was unaffected by household income ➤ Migraine prevalence peaked between age 38 and 40 years ➤ These results suggest that the onset of migraine is strongly influenced by external stressors, such as income

As is the case in many diseases, socioeconomic status is linked to overall health and well-being. That the preva-

“What the study of socioeconomic status shows for the first time is that [migraine] incidence is related to household income. In general, the higher the income, up to a certain point, the lower the level of exposure to stressors.” —Walter F. Stewart, PhD

lence of migraine increases as socioeconomic status declines may not be new, but the explanation for the association has remained unclear. Two general hypotheses have evolved: social selection and social causation. The social-selection hypothesis posits that a disabling disease can cause a decline in social status because of adverse effects on an individual’s performance. The social-causation hypothesis holds that low socioeconomic status is associated with stress or other disease factors that affect the incidence or duration of a condition. Study Details Dr Stewart and colleagues performed a retrospective cohort study to test the 2 migraine hypotheses. If the association between socioeconomic status and migraine reflected social selection, no observable effect on migraine incidence or remission would be expected. If the association were explained by social causation, the data would be expected to show higher incidence and lower remission rate or longer duration of the condition in

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April 2014

migraine patients with low socioeconomic status. The analysis involved data from the American Migraine Prevalence and Prevention Study, which had a population sample comprising 132,674 females and 124,665 males aged ≥12 years. About 60% of the participants (85,373 women and 77,332 men) responded to an information request Dr Stewart and colleagues sent to them. Migraine incidence and remission rates were estimated for men and women within 3 annual household income levels: • <$22,500 • $22,500 to $59,999 • ≥$60,000. The lowest income tertile included 23.1% of females and 16.9% of males. Overall, 17.1% of females reported current or active migraine, including 27.3% in the lowest income tertile. Men had a migraine prevalence of 5.6%, including 26.7% who had an annual household income <$22,500. In both sexes, patients in the lowest-income group tended to have extremely severe pain and Grade IV MIDAS (Migraine Disability Assessment) questionnaire impact, were less likely to have infrequent headache days, and were more likely to have a history of prescription migraine medication use in the past year.

“This study demonstrates that the reason why prevalence is related to household income is because new migraine cases occur at a faster rate in lower-income groups. This suggests that the onset of migraine is probably strongly related to external exposures.” —Walter F. Stewart, PhD

Migraine prevalence peaked at age 38 years in women and at age 40 years in men. In both sexes, age-specific prevalence was higher in the lowest- household-income group. Unexpectedly, age-specific remission rates did not differ by household income in either sex. “We know from other work on re-

mission that most individuals who get migraine remit, and most of the remission occurs within 5 years of when migraine first started,” said Dr Stewart. “That is the good news,” he emphasized. “Unfortunately, some people may lack factors that are critical to remission, and they continue to have migraines over many years. Fortunately, for these individuals we have a large array of treatment options. Hopefully, in the future, we can better understand how remission occurs and design treatments that foster remission in those who are at risk of having migraine for decades,” he concluded. n

By the numbers

Approximately 2.5 million people worldwide are affected by multiple sclerosis (MS), with the highest prevalence in North American and Europe

In the United States, the number of patients with MS is approximately 400,000

The economic impact of MS includes direct medical costs (including medications, inpatient/ outpatient care, and more), and indirect costs related to disability and productivity loss

In the United States in 1998, the total costs of MS were $6.8 billion-$11.9 billion annually, which averages approximately $34,000 per patient annually

Based on a 2004 US survey of patients with MS using diseasemodifying therapy, the estimated total average cost per patient was $47,000 annually

In Europe, the current estimated mean annual cost per person with MS is €27,000

On average, approximately 66% of the total costs for MS are direct costs and 33% are indirect costs

Patients with MS who had a relapse have higher costs than patients without relapse

Furthermore, several studies have shown that total costs rise with increasing disability Source: Castrop F, et al. Neuropsychiatr Dis Treat. 2013;9:1339-1349.

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Health Economics

Economic Analyses of Acute Ischemic Stroke Imaging Modalities Missing Important Data High-quality methodology but flawed radiologic information