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Spring 2014

Volume 16, Number 1

The Official Peer-Reviewed Publication of the Consortium of Multiple Sclerosis Centers

Measures of Cognitive Functioning Among People with MS Page 1

10 Factors Associated with Health-Related Quality of Life Among Older People with Multiple Sclerosis 20 Pelvic Floor Disorders and Multiple Sclerosis 26 Interest in Providing Multiple Sclerosis Care and Subspecializing in Multiple Sclerosis Among Neurology Residents 40 The TRUST (EvaluaTion of Bladder Function in RelapsingRemitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study 48 Comparing Two Conditions of Administering the Six-Minute Walk Test in People with Multiple Sclerosis 55 Nurses’ Perspective on Approaches to Limit Flu-Like Symptoms During Interferon Therapy for Multiple Sclerosis

ijmsc.org

Indication

~35,000 Patients Globally1

5,000+ 6 US Prescribers1

Months After FDA Approval

# Prescribed Oral Therapy for relapsing MS in the US2

When it’s time to treat relapsing MS, it’s time for Tecfidera. For more information, please visit TecfideraHCP.com

Tecfidera (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Important Safety Information Tecfidera may decrease lymphocyte counts; in clinical trials there was a mean decrease of ~30% in lymphocyte counts during the first year which then remained stable. Four weeks after stopping Tecfidera, mean lymphocyte counts increased but not to baseline. Six percent of Tecfidera patients and <1% of placebo patients had lymphocyte counts <0.5x109/L. Tecfidera has not been studied in patients with pre-existing low lymphocyte counts. The incidence of infections and serious infections was similar in patients treated with Tecfidera or placebo. Consider withholding treatment in patients with serious infections until resolved. A complete blood count is recommended within 6 months before initiating treatment, annually, and as clinically indicated. Tecfidera may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). 40% of patients taking Tecfidera reported flushing which was mostly mild to moderate in severity. Three percent of patients discontinued Tecfidera for flushing and <1% had serious flushing events that led to hospitalization. Taking Tecfidera with food may reduce flushing. Tecfidera may cause gastrointestinal (GI) events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). Four percent of Tecfidera patients and <1% placebo patients discontinued due to GI events. The incidence of serious GI events was 1%. The most common adverse reactions associated with Tecfidera versus placebo are flushing (40% vs 6%) and GI events: abdominal pain (18% vs 10%), diarrhea (14% vs 11%), nausea (12% vs 9%). Elevations in hepatic transaminases have been reported. A transient increase in mean eosinophil counts was seen during the first two months. Tecfidera should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage patients who become pregnant while taking Tecfidera to enroll in the Tecfidera pregnancy registry by calling 1-800-456-2255. For additional important safety information, please see Brief Summary of full Prescribing Information on the following pages. References: 1. Biogen Idec, Data on file. 2. Based on numbers of prescriptions from IMS NPA™ Weekly Data (September 27, 2013) and Biogen Idec, Data on file.

© 2013 Biogen Idec. All rights reserved. 01/14 TEC-1005014

TECFIDERA™ (dimethyl fumarate) delayed-release capsules, for oral use Brief Summary of Full Prescribing Information 1 INDICATIONS AND USAGE TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies (14)]. The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients. Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at ≥ 2% higher incidence than placebo

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Lymphopenia TECFIDERA may decrease lymphocyte counts [see Adverse Reactions (6.1)]. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L. Before initiating treatment with TECFIDERA, a recent CBC (i.e., within 6 months) should be available. A CBC is recommended annually, and as clinically indicated. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts. 5.2 Flushing TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/ or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing.

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in labeling: Lymphopenia, Flushing [see Warnings and Precautions (5.1, 5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea. Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness,

Blood and Lymphatic System Disorders Lymphopenia

Gastrointestinal Disorders Abdominal pain Diarrhea Nausea Vomiting Dyspepsia

Vascular Disorders Flushing

TECFIDERA N=769 %

Placebo N=771 %

2

<1

18 14 12 9 5

10 11 9 5 3

40

6

8 8 5

4 3 1

6 4

4 2

Skin and Subcutaneous Tissue Disorders Pruritus Rash Erythema

Investigations

Albumin urine present Aspartate aminotransferase increased

Gastrointestinal TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA. Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment and most patients with elevations had levels < 3 times the upper limits of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases ≥ 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo. Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Adverse Reactions in Placebo-Controlled and Uncontrolled Studies

17 PATIENT COUNSELING INFORMATION

In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 personyears. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.

See FDA-approved patient labeling (Patient Information)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD. Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD. Pregnancy Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-800-456-2255. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TECFIDERA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of TECFIDERA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

17.1 Dosage Inform patients that they will be provided two strengths of TECFIDERA when starting treatment: 120 mg capsules for the 7 day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow TECFIDERA capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that TECFIDERA can be taken with or without food [see Dosage and Administration (2.1)]. 17.2 Flushing and Gastrointestinal (GI) Reactions Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions, as taking TECFIDERA with food may help [see Adverse Reactions (6.1)]. 17.3 Pregnancy and Pregnancy Registry Instruct patients that if they are pregnant or plan to become pregnant while taking TECFIDERA they should inform their physician. Encourage patients to enroll in the TECFIDERA Pregnancy Registry if they become pregnant while taking TECFIDERA. Advise patients to call 1-800-456-2255 for more information [see Use in Specific Populations (8.1)]. 17.4 Lymphocyte Counts Inform patients that TECFIDERA may decrease lymphocyte counts. A recent blood test (i.e., within 6 months) should be available before they start therapy to identify patients with pre-existing low lymphocyte counts. Blood tests are also recommended annually, and as clinically indicated [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

41347-02 Manufactured by: Biogen Idec Inc. Cambridge, MA 02142 TECFIDERA is a trademark of Biogen Idec. © 2013 Biogen Idec 03/2013

Editorial Board

Spring 2014 • Vol. 16, No. 1

Editor in Chief Francois Bethoux, MD Cleveland Clinic Cleveland, Ohio, USA

Contents

Ex Officio June Halper, MSN, ANP, FAAN Hackensack, New Jersey, USA

vii

Editorial

1

Reliability and Validity of PROMIS Cognitive Abilities and Cognitive Concerns Scales Among People with Multiple Sclerosis



Heather Becker, Alexa Stuifbergen, HwaYoung Lee, Vicki Kullberg

10

Factors Associated with Health-Related Quality of Life Among Older People with Multiple Sclerosis



Marijean Buhse, Wendy M. Banker, Lynn M. Clement

20

Pelvic Floor Disorders and Multiple Sclerosis



Sangeeta T. Mahajan, Rebecca James, Heidi Frasure

26

Eduard Gappmaier, PT, PhD University of Utah Salt Lake City, Utah, USA

Interest in Providing Multiple Sclerosis Care and Subspecializing in Multiple Sclerosis Among Neurology Residents



Christoph Heesen, MD Institute of Neuroimmunology and Clinical MS Research University Medical Center Hamburg, Germany

Michael T. Halpern, Stephanie Teixeira-Poit, Heather L. Kane, Corey Frost, Michael Keating, Murrey Olmsted

40

The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study



Bhupendra O. Khatri, John F. Foley, Jennifer Fink, John F. Kramer, Choon Cha, Xiaojun You, John D. Warth, Pam Foulds

48

Comparing Two Conditions of Administering the Six-Minute Walk Test in People with Multiple Sclerosis



Brian M. Sandroff, Lara A. Pilutti, Deirdre Dlugonski, Yvonne C. Learmonth, John H. Pula, Robert W. Motl

55

Nurses’ Perspective on Approaches to Limit Flu-Like Symptoms During Interferon Therapy for Multiple Sclerosis



Mary L. Filipi, Jill Beavin, Raquel T. Brillante, Kathleen Costello, Gail C. Hartley, Kay Hartley, Marie Namey, Shirley O’Leary, Gina Remington

Project Manager Maria Stadtler, CCRP Cleveland Clinic Cleveland, Ohio, USA Board Members Ted Brown, MD, MPH Evergreen Neuroscience Institute and Medical Center Kirkland, Washington, USA Susan Coote, PT, PhD University of Limerick Limerick, Ireland Mary Filipi, PhD, ARNP University of Nebraska Medical Center Omaha, Nebraska, USA Marcia Finlayson, PhD, OT Reg (Ont), OTR Queen’s University Kingston, Ontario, Canada Frederick W. Foley, PhD Yeshiva University Bronx, New York, USA Holy Name Medical Center Teaneck, New Jersey, USA Kathleen Fuchs, PhD University of Virginia Health System Charlottesville,Virginia, USA

James Marriott, MD, FRCPC University of Manitoba Winnipeg, Manitoba, Canada Lori Mayer, MSN, DNP(s), MSCN, CCRP MS Clinic of Central Texas Round Rock, Texas, USA Sarah Morrow, MD, MSc, FRCPC University of Western Ontario London Health Sciences Centre London, Ontario, Canada Priscilla Russo, MS, RN, MSCN, CCRC Carolinas Medical Center Charlotte, North Carolina, USA Joanne Wagner, PT, PhD St. Louis University St. Louis, Missouri, USA Megan Weigel, DNP, ARNP-c Baptist Medical Center Jacksonville Beach, Florida, USA Mary Alissa Willis, MD Cleveland Clinic Cleveland, Ohio, USA Publishers Joseph J. D’Onofrio Frank M. Marino Delaware Media Group 66 S. Maple Ave., Ridgewood, NJ 07450 201-612-7676 [email protected] Managing Editor Annette Theuring Art Director James Ticchio

Cover photo credit: © Natalia Lukiyanova / Veer

International Journal of MS Care v

The Official Peer-Reviewed Publication of the Consortium of Multiple Sclerosis Centers

MISSION STATEMENT

The International Journal of MS Care (IJMSC) is the official peer-reviewed journal of the Consortium of Multiple Sclerosis Centers (CMSC). It is also the official publication of the International Organization of Multiple Sclerosis Nurses (IOMSN), the International Organization of Multiple Sclerosis Rehabilitation Therapists (IOMSRT), and Rehabilitation in Multiple Sclerosis (RIMS). The IJMSC publishes high-quality research, reviews, and consensus papers on a broad range of clinical topics of interest to MS health-care professionals, including neurological treatment, nursing care, rehabilitation, neuropsychological status, and psychiatric/psychosocial care. The mission of the journal is to promote multidisciplinary cooperation and communication among the global network of MS health-care profeswed Publication of the Consortium of of Mulitple Sclerosis sionals, with the goal maximizing the Centers, quality of life of people affected by MS. erosis, and the International Organization of Multiple Sclerosis Nurses REHABILITATION IN MULTIPLE SCLEROSIS European network for best practice and research

Information for Readers The International Journal of MS Care (IJMSC) (ISSN 1537-2073) is the official peer-reviewed publication of the Consortium of Multiple Sclerosis Centers (CMSC). It has also been adopted as the official publication of the International Organization of Multiple Sclerosis Nurses (IOMSN), the International Organization of Multiple Sclerosis Rehabilitation Therapists (IOMSRT), and Rehabilitation in Multiple Sclerosis (RIMS). It is published quarterly in Spring, Summer, Fall, and Winter by the Delaware Media Group, 66 S. Maple Ave., Ridgewood, NJ 07450. It contains peer-reviewed articles in areas of interest to multiple sclerosis health-care professionals.

Manuscripts and editorial correspondence should be submitted using the online submission system located at http:// ijmsc.msubmit.net. Editorial copy must conform to the guidelines contained in the IJMSC Information for Authors. General correspondence may be sent by e-mail to the Editorial Office at IJMSC@mscare. org, or by mail to Maria Stadtler, Mellen Center for MS Treatment and Research, U10, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44119. Telephone or fax inquiries may be directed to Maria Stadtler at 216-444-2330 or 800-223-2273, ext. 42330 (phone), or 216-445-0331 (fax).

SUBSCRIPTIONS

PEER REVIEW

IJMSC is a free publication. Please direct subscription inquiries and notice of change of address to: Joseph J. D’Onofrio, Delaware Media Group, 66 S. Maple Ave., Ridgewood, NJ 07450; telephone 201-6127676; fax 201-612-8282; e-mail [email protected].

ADVERTISING

Matters regarding commercial advertising should be directed to: Joseph J. D’Onofrio, Delaware Media Group, 66 S. Maple Ave., Ridgewood, NJ 07450; telephone 201-612-7676; fax 201-612-8282; e-mail [email protected]. IJMSC does not accept classified advertising. Acceptance and publication of an advertisement does not imply endorsement or approval of the company, product, or service by IJMSC or the CMSC.

INDEXING AND ABSTRACTING

IJMSC is indexed in the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Rehabilitation & Sports Medicine Source (EBSCO Publishing) and Scopus. All articles are archived in PubMed Central, with citations and abstracts retrievable in PubMed.

EDITORIAL CONTENT AND SUBMISSION PROCEDURE

Statements and opinions in this publication are solely those of the authors and contributors and do not necessarily reflect the views of the Editorial Board, the CMSC, the publisher, or sponsors.

Submissions are sent for peer review to content experts in the particular area of the submitted manuscript. Members of the Editorial Board may participate in the peer-review process. Conflict-of-interest disclosures of the Editorial Board members are on file in the Editorial Office.

IJMSC WEBSITE

IJMSC is available free online at http://ijmsc.org. The website includes current and past issues, published supplements, information for authors and reviewers, and a listing of Editorial Board members.

COPYRIGHT AND PERMISSIONS

Copyright ©2014 by the Consortium of Multiple Sclerosis Centers. All rights reserved. None of the contents of this publication may be reproduced without written permission of the publisher. Permission requests to reproduce material from IJMSC should be sent to the publisher. Letters requesting permission should include the issue and page number on which the material appears and the name of the publication in which the material will be reproduced.

PRINTING INFORMATION

Printed in the United States of America at Quad/Graphics, 1700 James Savage Rd., Midland, MI 48642.

EDITORIAL

A

s the new editor in chief of the IJMSC, I am pleased to introduce the Spring 2014 issue. I am excited to take on this role at a time of continued growth of the journal, which strives to bring to its readers the evidence and expert knowledge needed to promote multidisciplinary MS care. It is a humbling experience to follow in the steps of Dr. Lael Stone, who, with the help of an outstanding editorial team and editorial board, has created a momentum of growth and maturation that will continue to bear fruit in the years to come. Thanks to Dr. Stone’s careful planning, I have had the opportunity to work with the editorial team, the editorial board, our publisher, and the leadership of the Consortium of Multiple Sclerosis Centers (CMSC) during the months leading to the official transition. Following a very productive strategic planning meeting in Cleveland, Ohio, in December 2013, we are implementing new initiatives that will benefit our readers and authors, and will help further the mission of the journal. The contents of this issue of the IJMSC reflect its multidisciplinary nature. Dr. Mary Filipi and colleagues developed a consensus statement regarding the management of flu-like symptoms associated with interferon therapy in MS. Side effects from medications jeopardize treatment adherence, which is primordial in a chronic condition requiring long-term treatment such as MS. Even though the number of available disease-modifying therapies (DMTs) has increased, it still holds true that treatment efficacy cannot be fully assessed if side effects compromise adherence. The authors’ recommendations, based on published evidence and opinion from experts in MS nursing care, give clear and practical guidance that can be applied in day-to-day clinical practice. While there is a strong research focus on the early stages of MS, with the goal of initiating comprehensive management early to lessen the long-term impact of the disease, the challenges faced by our patients as they age with a chronic progressive disease should not be forgotten. Dr. Marijean Buhse and colleagues remind us that caregivers should pay attention to factors affecting health-related quality of life in older individuals with MS. Detecting and managing problems such as depression and cognitive limitations could have a positive impact on these patients’ lives.

Two articles cover issues related to pelvic floor dysfunction in MS. Although it has been established that bladder function is frequently affected by MS, and that urinary symptoms (particularly incontinence) reduce patients’ quality of life, there is a lack of evidence regarding the impact of DMTs on bladder function. The article from Dr. Bhupendra Khatri and colleagues provides evidence of improved patient-reported quality of life related to incontinence, using validated symptom-specific questionnaires, 6 months after initiation of treatment with natalizumab. Even though no definitive conclusions can be drawn from an open-label uncontrolled study, their findings are encouraging and will be helpful in designing future studies. Dr. Sangeeta Mahajan and colleagues administered a survey on pelvic floor disorders to a large sample (over 9000 respondents) of participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry, a nonprofit project of the CMSC. They found that, for each area of pelvic dysfunction (bladder, bowel, sexual), moderate to severe symptoms were reported by one-third or more of respondents. The fact that most respondents had been asked about, and were satisfied with, the care they received for bladder and bowel dysfunction suggests that comprehensive MS care is a reality. However, the authors identified a gap with regard to sexual dysfunction. This finding should prompt clinicians to pay more attention to this frequent consequence of MS, which has significant repercussions for patients and their families yet may improve with adequate management. Easy-to-use and validated instruments are essential for clinicians and researchers to evaluate and monitor various aspects of neurologic dysfunction resulting from MS. This need has been highlighted recently by an increased demand for quantified measurement of the outcomes of care, in order to optimize the delivery of health care. Two articles discuss assessments of distinct consequences of MS, cognitive impairment and walking limitations, which were shown in other publications to affect each other. Dr. Heather Becker and colleagues report on the psychometric properties of two short selfreport assessments of perceived cognitive function, the PROMIS Cognitive Abilities and Cognitive Concerns Scales. These eight-item questionnaires are derived from a broad National Institutes of Health initiative, the

International Journal of MS Care vii

Editorial

Patient Reported Outcomes Measurement Information System (PROMIS). Mr. Brian Sandroff and colleagues compare two modes of administration of one of the most validated tests of walking endurance in MS, the 6-Minute Walk. The use of walking performance tests is sometimes limited by practical constraints, particularly space limitations. As most performance tests were initially validated under specific conditions, well-designed comparisons offer clinicians and researchers additional options that will help generalize their use. Finally, the article by Dr. Michael Halpern and colleagues sheds light on interest in MS among neurology residents. It is important that individuals with MS have access to health-care professionals who specialize in the disease, given the complexity of needs and treatment decisions. Considering a predicted shortage of MSspecialized neurologists, it is somewhat reassuring that two-thirds of the survey respondents were interested in providing some MS care, and one-third were interested in MS subspecialization. The survey results provide insight into potential strategies to increase the interest of neurology residents in treating MS patients.

In her editorial published in the Winter 2013 issue, Dr. Stone announced the signing of a participation agreement between the CMSC and PubMed Central (PMC), the US National Library of Medicine’s archive of freely accessible literature in the life sciences, to include the journal’s full-text articles in its database. All articles published in IJMSC since 2011 are now accessible in PMC, with citations and abstracts retrievable through searches in PubMed. We believe that this increase in the journal’s visibility will help advance research in MS care, and ultimately benefit our patients. In closing, we hope that you plan to attend the 2014 annual meeting of the CMSC, which will be held in Dallas, Texas, from May 28 to 31. This will be the sixth cooperative meeting of the CMSC and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), and we look forward to the opportunity for in-person discussions of important topics related to comprehensive care for our MS patients. Enjoy reading the articles in this issue, and see you in Dallas! —Francois Bethoux, MD Editor in Chief

IJMSC Now in PubMed Central and PubMed The International Journal of MS Care (IJMSC) now participates in PubMed Central (PMC), a free electronic archive of full-text biomedical and life sciences journal literature at the US National Institutes of Health’s National Library of Medicine (NLM). Newly published articles can be accessed in PMC soon after publication, along with older articles going back to 2011. Citations and abstracts of these articles are retrievable in PubMed, the NLM’s journal abstract database (which includes the MEDLINE subset), through various types of searches. PMC, which launched in 2000, serves as a digital counterpart to the NLM’s print journal collection. It is a repository for journal literature deposited by participating publishers, as well as for author manuscripts that have been submitted in compliance with the NIH Public Access Policy and similar policies of other research funding agencies. Currently, nearly 3 million articles from over 4000 journals are archived in PMC. The availability of IJMSC content in PMC and PubMed will make it more discoverable to researchers, health professionals, and the public. Each IJMSC search result in PubMed contains a link to the full-text article in PMC. This increased visibility and accessibility should lead to wider citation of IJMSC articles, helping to advance research and clinical practice in multiple sclerosis. Copyright to IJMSC material deposited in PMC remains with the Consortium of Multiple Sclerosis Centers, which is clearly indicated to PMC users. In addition to being available in PMC and PubMed, IJMSC is indexed in the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Rehabilitation & Sports Medicine Source (EBSCO Publishing), as well as Scopus.

International Journal of MS Care viii

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Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

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2014 CMSC ACTRIMS COOPERATIVE MEETING Growing your MS knowledge

ª Hear from prestigious physicians and researchers including Dr. Stephen D. Miller, Dr. Patricia K. Coyle, Dr. Mark S. Freedman, Dr. Richard A. Rudick, Dr. Elliott Frohman, and many more! ª Enjoy ample networking opportunities, organized meals, awards ceremonies, evening entertainment featuring country music star Clay Walker, poster sessions, platform presentations, research interest groups, and exhibits with the latest products and services- all included in your conference registration fee! ª Earn continuing education credit from our fully accredited program that includes credit for physicians, nurses, pharmacists, social workers and psychologists. ª Become a Multiple Sclerosis Certified Nurse! Exam and pre-registration required.

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ª Get the most up-to-date information on multiple sclerosis to positively impact patient care and research.

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May 28-31, 2014 Hilton Anatole Hotel Dallas, Texas www.cmsc-actrims.org

Reliability and Validity of PROMIS Cognitive Abilities and Cognitive Concerns Scales Among People with Multiple Sclerosis Heather Becker, PhD; Alexa Stuifbergen, PhD, RN, FAAN; HwaYoung Lee, PhD; Vicki Kullberg, MA Background: Cognitive impairment is among the most debilitating outcomes of multiple sclerosis (MS). Although several neuropsychological tests and self-report cognitive measures have been used to assess cognitive impairment, they may not be sensitive to change over time, or may not be feasible to administer in a clinical setting. The purpose of this study was to assess the reliability and validity of the 8-item PROMIS Cognitive Abilities and Cognitive Concerns Scales in a large community-based sample of people with MS. The PROMIS Cognitive Abilities and Cognitive Concerns Scales derive from the National Institutes of Health–funded Patient Reported Outcomes Measurement Information System (PROMIS), an item repository that capitalizes on recent psychometric advances to produce short, psychometrically sound health measures. Methods: Mailed survey data were collected from 322 individuals recruited from two National Multiple Sclerosis Society chapters in a southwestern state. Results: Both cognitive scales demonstrated high internal consistency reliability and were moderately correlated with self-reported depressive symptoms, self-efficacy, barriers to health promotion, health, and functional status (all correlation coefficients >0.35). In hierarchical regression analysis, the PROMIS Cognitive Concerns score added significant unique variance to the prediction of MS Incapacity Status after controlling for self-reported depressive symptoms, exercise, spiritual growth, and global health. Those who were unemployed owing to their disabilities had significantly lower PROMIS Cognitive Abilities scores and higher Cognitive Concerns scores than those who were working or those who were retired or not working for other reasons. Conclusions: The PROMIS Cognitive Abilities and Cognitive Concerns Scales are short, psychometrically sound measures that assess an important dimension of functioning and health for people with MS. Int J MS Care. 2014;16:1–8.

C

problem,8 and clinicians need more effective methods to screen quickly for cognitive impairment and monitor cognitive functioning over time. Previous research has found a relationship between cognitive functioning and other constructs such as depression,5,9-11 social participation, 1,12 and coping11 among those with MS. In particular, Arnett and colleagues13 reported that the relationship between cognitive impairment and depression was higher among those who were not using active coping strategies. To the extent that health-promotion activities might be considered an active coping mechanism for people with MS, we might expect a positive relationship between

ognitive impairment is a major source of concern for people with multiple sclerosis (MS); its impact on major areas of life functioning, including employment, can be profound.1-7 Cognitive impairment has been observed early in the MS trajectory, making timely clinical assessment key to effective disease management. However, underdiagnosis is a

From the School of Nursing, University of Texas at Austin, Austin, TX, USA. Correspondence: Heather Becker, PhD, School of Nursing, University of Texas at Austin, 1710 Red River, Austin, TX 78701; e-mail: [email protected]. DOI: 10.7224/1537-2073.2012-047 © 2014 Consortium of Multiple Sclerosis Centers.

International Journal of MS Care 1

Becker et al.

What is the evidence for construct and criterion validity of the PROMIS cognitive scales as measures of perceived cognitive functioning in people with MS?

frequency of reported health-promotion behaviors and cognitive abilities, and a negative relationship with cognitive concerns. Perceived barriers to health-promoting behaviors might in turn relate positively to cognitive concerns, but negatively to cognitive abilities. Because people with MS have indicated that cognitive limitations made them feel less competent and less confident when performing tasks,4 the construct of self-efficacy might also be hypothesized to relate in a positive direction to cognitive abilities and in a negative direction to cognitive concerns. Finally, cognitive abilities might be expected to relate positively to global perceptions of health status, while perceived health status might relate negatively to cognitive concerns. Both neuropsychological tests and self-report measures have been used to quantify the degree of cognitive impairment experienced by people with MS.1,8 While neurocognitive measures are considered the most precise way of diagnosing impairment, self-report measures add key information about the impact of cognitive functioning on the individual’s daily life. Some measures, designed primarily for research purposes, may be less applicable to clinical situations and have not been shown to be sensitive to change over time following exposure to interventions designed to build cognitive skills. Moreover, many of these studies have been conducted in small samples recruited from one clinical setting.8,14 In an earlier study, we observed that the short forms of the PROMIS Cognitive Abilities and Cognitive Concerns Scales demonstrated good internal consistency reliability and were sensitive to change following a cognitive skills–building intervention in a small sample of 29 individuals with MS.15 These measures were derived from the Patient Reported Outcomes Measurement Information System (PROMIS), an initiative of the National Institutes of Health (NIH) designed to provide an item repository of commonly assessed physical and mental functioning outcomes.16 The aim of the current study was to examine the reliability and validity of the PROMIS cognitive scales in a larger community-based sample of people with MS, all of whom had been diagnosed more than 15 years earlier. The specific research questions were as follows: What is the reliability of the PROMIS cognitive scales in a large community-based sample of individuals with MS?

Methods Data-Collection Procedures The data for these analyses are from the 16th year of data collection in an ongoing longitudinal study of people with MS recruited for a study of healthpromoting behaviors. Following receipt of institutional review board approval from the authors’ university, the sample was originally recruited from a large mailing to the members of two National Multiple Sclerosis Society chapters in a southwestern state (Texas). Some of those participating in year 16 mailings have since moved to 23 other states, and the sample is now more diverse in location even though a majority still live in Texas. Recruitment procedures for the original sample are documented elsewhere.17,18 The mailing to individuals in the 2012 spring cohort of the longitudinal study (N = 375) included a letter introducing the survey, which was also enclosed, and a postage-paid return envelope. Completed surveys were checked for omissions, and a letter with any missing responses was sent back to the respondents. This helped control the amount of missing information. Respondents were thanked for their participation, and a small gift of $30 was offered for their time.

Instruments The PROMIS version 1.0 short-form subscales of Cognitive Abilities and Cognitive Concerns each contain 8 items. The Cognitive Abilities items target positive self-assessments of cognitive functioning such as “My memory has been as good as usual” and “I have been able to concentrate.” The Cognitive Concerns items are worded negatively and express concerns in the same areas. Two examples are “My thinking has been slow” and “I have had trouble shifting back and forth between different activities that require thinking.” Items on both subscales use a 5-point rating from “not at all” to “very much.” Items are summed to create a total score for each subscale. These relatively short scales were derived from an intensive item analysis using Item Response Theory and qualitative analysis to produce short but reliable measures.16 In the previous study,15 Cronbach α coefficients of 0.94 were reported for both scales. The test-retest correlation coefficients over a

International Journal of MS Care 2

PROMIS Among People with MS

2-month period were 0.83 for Cognitive Concerns and 0.80 for Cognitive Abilities. The 16-item Incapacity Status Scale (ISS)19 measures functional limitations related to MS in the areas of personal activity and care, such as mobility, bowel and bladder function, sensory or cognitive impairments, emotional distress, bathing, dressing, and feeding. The predominantly physical functioning items were endorsed by the International Federation of Multiple Sclerosis Societies for use in MS research, and Kurtzke19 has presented data to support the scale’s validity. Items are rated on a 5-point scale, with higher scores indicating greater inability to perform activities. Total scores can range from 0 to 64. The Cronbach α coefficient for the ISS in this study was 0.90. The Center for Epidemiological Studies Depression Scale–10 (CESD-10) was used to measure depressive symptoms.20 Respondents rated how frequently they have experienced ten depressive symptoms, each on a 4-point scale. The CESD-10 has demonstrated good reliability and validity with various populations, including people with chronic and disabling conditions.21,22 For this study, the Cronbach α coefficient of the CESD10 was 0.85. Health-promoting behavior was measured by the Health-Promoting Lifestyle Profile II (HPLP-II).23 Self-reported frequency of behavior on the 52-item HPLP-II yields scores on six subscales (Physical Activity, Health Responsibility, Spiritual Growth, Interpersonal Relations, Nutrition, and Stress Management). Reliability and validity of the HPLP-II have been supported in multiple studies.24,25 For this study, the Cronbach α coefficient for HPLP-II subscales ranged from 0.81 to 0.90. The Global Health Self-Rating is a single question that asks for an overall health rating “at the present time.” The four response categories range from excellent (4) to poor (1). The developers have demonstrated its reliability and validity in previous research.26 The Barriers to Health Promoting Activities scale for people who are disabled27 is designed to address intrapersonal (eg, not interested), interpersonal (eg, difficulty with communication), and environmental barriers (eg, bad weather). It includes 18 items rated on a 4-point scale (from never to routinely). Higher total scores indicate greater perceived barriers. Its reliability and validity have been documented in previous research. 25 The Cronbach α reliability coefficient was 0.88 in this study.

The Sherer et al.28 measure of General Self-Efficacy was used as a measure of general self-confidence to affect outcomes in various situations. Respondents rated 17 items on a 5-point scale from “disagree strongly” to “agree strongly,” with a choice of “neither agree nor disagree” offered. Those responses were summed to create a general self-efficacy score. Higher General Self-Efficacy scores indicate greater self-confidence in one’s abilities. Sherer et al. reported a Cronbach α coefficient of 0.86.28 Construct validity is evidenced by the confirmation of predicted correlations with other psychological constructs, as well as success in vocational, educational, and military settings. Previous studies by Stuifbergen and Becker29 and Stuifbergen30 reported Cronbach α coefficients of 0.87 and 0.86, respectively, and moderate correlation coefficients with the HPLP-II. The Cronbach α reliability coefficient in this study was 0.90.

Data-Analysis Plan All analyses were performed using IBM SPSS Statistics, version 19. Cronbach α coefficients were computed to assess internal consistency reliability (Research Question 1). Descriptive statistics were computed to profile the sample and to provide means and standard deviations for all major study variables. Bivariate correlation analysis was performed to explore the relationships between PROMIS Cognitive Abilities and PROMIS Cognitive Concerns Scales and other health-related measures. To further understand the unique contribution of PROMIS scores to the prediction of functional impairment, a hierarchical regression was performed to determine how much variance in the prediction of Incapacity Status was explained by PROMIS Cognitive Concerns scores after taking into account other health measures. The advantage of hierarchical regression analysis is that it allows researchers to examine the change in R2 when key variables are added to a model, once the effects of other related variables have been held constant. Before conducting multiple regression analysis, multiple regression assumptions such as multicollinearity and outliers were checked. To avoid problems with issues of multicollinearity and suppression,31 only one of the PROMIS scales (Cognitive Concerns) and two subscales of the HPLP-II were chosen as predictors. Thus, the predictors used in the first step of the regression analysis were restricted to the 1-item Global Health Self-Rating, the CESD-10 measure of depressive symptoms, and two subscales of the HPLPII: Physical Activity and Spiritual Growth (representing

International Journal of MS Care 3

Becker et al. Table 1. Study sample background characteristics (N = 322)

the physical and emotional aspects of health promotion most highly correlated with the ISS). The PROMIS Cognitive Concerns Scale was then entered on the second step of the analysis to predict Incapacity Status scores. The R2 for change was examined to determine whether there was a significant change in the amount of variance accounted for in the model when the PROMIS Cognitive Concerns Scale was added. To assess criterion validity using known groups, the sample was divided into three groups: those employed full time or part time (n = 62), those who indicated that they were unemployed owing to their disability (n = 100), and those unemployed for other reasons, primarily retirement (n = 160). One-way analysis of variance (ANOVA) with post hoc analysis was then performed to determine whether those who reported being unemployed owing to disability had significantly different PROMIS scores than the other two groups (at P < .05).

Characteristic

Value

Gender, No. (%)    Male    Female

44 (13.66) 278 (86.35)

Race, No. (%)    Black    White    Multiple    Missing

14 (4.34) 270 (83.85) 11 (3.42) 27 (8.39)

Education, No. (%)    No degree or less than high school    High school/GED    College    Missing

38 (11.80) 100 (31.06) 159 (49.38) 25 (7.76)

Employment, No. (%)    Part/full time    Unemployed owing to disability    Unemployed owing to age, having been laid      off, fired, or retired

Results

Marital status, No. (%)    Married    Divorced/separated/widowed    Never married

The data were entered into SPSS for the 322 completed surveys, which represented an 86% response rate. A sample of 17% of the single-entered cases were double-checked against the actual survey responses by research staff not involved in the initial data entry. The error rate was less than 0.5%. Almost all respondents answered all the items that they were asked. When a couple of items were missed on a scale, mean substitution was used. If a participant missed more than 15% of items for a scale, however, the participant’s responses were deleted.

Age, y    Mean (SD)   Range Time since diagnosis with MS, y    Mean (SD)   Range

62 (19.25) 100 (31.06) 160 (49.69) 212 (65.84) 89 (27.64) 21 (6.52) 62 (9.45) 34–88 25.62 (6.51) 16–55

Abbreviations: GED, General Educational Development; MS, multiple sclerosis.

scores are shown for the PROMIS Cognitive Abilities and Cognitive Concerns average scores. The calibration sample is described by the PROMIS assessment center as “generally enriched for chronic illness.” The T scores for this MS sample are slightly below the T score average (44 and 47 for Cognitive Concerns and Cognitive Abilities, respectively).

Sample Description As shown in Table 1, participants’ ages ranged from 34 to 88 years, with an average age of 62 (SD 9.45). The average time since diagnosis was 25.62 years (SD 6.51), and 72% had taken at least two courses of steroids. The sample was predominantly married non-Hispanic white females. About half of them had a college degree. Only 19% were employed for pay (either full time or part time), and 31% (n = 100) reported being unemployed owing to their disability. The average quality of life rating on a 10-point scale (1 = very poor; 10 = very good) was 7.25 (SD 2.14). Forty percent rated their health as fair or poor.

Internal Consistency Reliability The PROMIS Cognitive Abilities and Cognitive Concerns Scales demonstrated high internal consistency reliability, with Cronbach α coefficients of 0.97 for both.

Construct Validation Correlations with Related Construct The PROMIS scales were strongly correlated with each other (r = −0.85) and moderately correlated with a number of health-related measures (Table 3). As

Descriptive Information About the PROMIS Scales Means, standard deviations, and score ranges for all scale scores are shown in Table 2. Corresponding T

International Journal of MS Care 4

PROMIS Among People with MS Table 3. Correlation coefficients among PROMIS Cognitive Abilities Scale, PROMIS Cognitive Concerns Scale, Incapacity Status Scale, and Other Health Measures (N = 322)

Table 2. Descriptive statistics for PROMIS cognitive scales and other health-related measures (N = 322) Variable

Mean

SD

Min

Max

HPLP-Responsibility

24.62

5.44

10

36

HPLP-Physical Activity

16.17

6.05

8

32

HPLP-Nutrition

25.12

5.47

9

36

HPLP-Spiritual Growth

27.95

5.72

9

36

HPLP-Interpersonal Relations

28.60

5.15

12

36

HPLP-Stress Management

23.36

4.77

10

T value (SE)

PROMIS PROMIS IncapacCognitive Cognitive ity Status Abilities Concerns Scale PROMIS Cognitive Abilities

32

1

−0.853a

−0.357a

PROMIS Cognitive Concerns

−0.853a

1

Incapacity Status Scale

−0.357a

0.365a

HPLP-Responsibility

0.170

−0.140

−0.085

HPLP-Physical Activity

0.237

a

−0.190

−0.509a

HPLP-Nutrition

0.328a

−0.275a

−0.187a

HPLP-Spiritual Growth

0.370a

−0.243a

−0.335a

HPLP-Interpersonal Relations

0.366a

−0.274a

−0.262a

HPLP-Stress Management

0.333a

−0.209a

−0.218a

CESD-10

−0.513a

0.541a

0.422a

−0.503a

0.500a

0.506a

a

a

0.365a b

1

9.54

6.21

 0

26

Barriers to Health Promoting Activities Scale

30.39

8.46

18

54

Incapacity Status Scale

18.98 10.96



55

PROMIS Cognitive Abilities

27.60

8.86

8

40

47 (1.5)

Barriers to Health Promoting Activities scale

PROMIS Cognitive Concerns

19.65

9.19

8

40

44 (1.8)

General Self-Efficacy

0.483a

−0.464a

−0.435a

General Self-Efficacy

65.15 12.07

Global Health Self-Rating

0.420a

−0.382a

−0.557a

CESD-10

Global Health SelfRating

2.68

0.83

31

85

1

4

Abbreviations: CESD-10, Center for Epidemiological Studies Depression Scale–10; HPLP, Health-Promoting Lifestyle Profile II; MS, multiple sclerosis; PROMIS, Patient Reported Outcomes Measurement Information System. a P < .01. b P < .05.

Abbreviations: CESD-10, Center for Epidemiological Studies Depression Scale–10; HPLP, Health-Promoting Lifestyle Profile II; PROMIS, Patient Reported Outcomes Measurement Information System. Note: T values provided by PROMIS staff (assessmentcenterhelp@ northwester.edu). A score of 50 represents the average of the calibration sample that was generally more enriched for chronic illness.

To avoid problems with issues of multicollinearity and suppression,24 the predictors used in the first step of the regression analysis were restricted to the 1-item Global Health Self-Rating, the CESD measure of depressive symptoms, and two subscales of the HPLP-II: Physical Activity and Spiritual Growth (representing the physical and emotional aspects of health promotion most highly correlated with the ISS). The PROMIS Cognitive Concerns Scale was then entered on the second step of the analysis to predict Incapacity Status scores. The unstandardized regression coefficients (b) and intercept, the standardized regression coefficients (β), and confidence intervals for the full model are reported in Table 4. The results of step 1 indicated that the variance accounted for (R2) with the first four independent variables (HPLP two subscales, Global Health Self-Rating, CESD) was 0.44 (adjusted R2 = 0.43) and it was significantly different from zero (F4,315 = 60.53, P < .001). In the first step, the HPLP Physical Activity Scale, the CESD, and the Global Health Self-Rating were sig-

expected, both cognitive scales were moderately to highly correlated in opposite directions with the CESD measure of depressive symptoms, Sherer’s self-efficacy measure, and the Barriers to Health Promoting Activities scale (all correlation coefficients >0.40). In addition, the Cognitive Abilities score had a moderate relationship with the Global Health Self-Rating item, but only low to moderate correlations with the subscales of the HPLP-II. Both scales were moderately correlated with the ISS (r = 0.37 for Cognitive Concerns and −0.36 for Cognitive Abilities). Hierarchical Regression Analysis To further explore the construct validity of the PROMIS Cognitive Concerns scale, a hierarchical regression was performed to determine how much variance in the prediction of Incapacity Status, a measure of functional impairment, was explained by PROMIS Cognitive Concerns after taking into account other health measures.

International Journal of MS Care 5

Becker et al. Table 4. Multiple hierarchical regression analysis to predict incapacity status (n = 319) Variable

b (SE)

b

t value

P value

95% CI

Intercept

33.49 (3.82)

 

8.76

<.01

25.97 to 41.02

HPLP-Physical Activity

−0.60 (0.09)

−0.33

−7.00

<.01

−0.77 to −0.43

HPLP-Spiritual Growth

0.09 (0.11)

0.05

0.81

.422

−0.12 to 0.29

CESD-10

0.22 (0.11)

0.13

2.01

.046

0.00 to 0.44

−4.50 (0.71)

−0.34

−6.31

<.01

−5.90 to −3.10

0.14 (0.06)

0.12

2.24

0.026

0.02 to 0.26

Global Health Self-Rating PROMIS Cognitive Concerns

Abbreviations: CESD-10, Center for Epidemiological Studies Depression Scale–10; CI, confidence interval; HPLP, Health-Promoting Lifestyle Profile II; PROMIS, Patient Reported Outcomes Measurement Information System.

opment process undertaken by the PROMIS research team. As expected, scores on the two PROMIS scales were highly related in opposite directions (r = −0.85). The moderate to strong correlation coefficients between PROMIS cognitive scales and the other health measures examined here suggest that for people with MS, their perceptions of their cognitive functioning are highly related to their perceptions of depressive symptoms, selfefficacy, barriers to health promotion, and functional impairment and perceived health status. These findings support the construct validity of the PROMIS scales among people with MS. While the relationships were less strong with the various dimensions of health promotion measured by the HPLP-II, the moderate-strength correlations between PROMIS Cognitive Abilities and four of the six HPLP-II subscales suggest that future research should explore the impact of cognitive function on health promotion. The pattern of results reveals that Cognitive Concerns scores, which present negatively stated items, were more strongly correlated with other negatively oriented scales (Incapacity Status, depressive symptoms), while Cognitive Abilities scores had higher numeric correlation coefficients with other measures that focus on abilities rather than limitations or deficits. This pattern of results may reflect the influence of cognitive response set on the measurement of the construct under investigation and suggests that the answers obtained are related not only to the questions asked but also to their positive or negative valence. Among the set of predictors in the hierarchical regression, the self-reported exercise behaviors and global health self-rating were the strongest predictors of functional limitations as reflected in the ISS. However, cognitive concerns contributed significant unique variance to the prediction of functional limitations, after mea-

nificant predictors of Incapacity Status scores (Physical Activity, b = −0.60, P < .001; CESD-10, b = 0.22, P < .01; health self-rating, b = −4.50, P < .01). In step 2, the PROMIS Cognitive Concerns score was entered into the regression equation. The change in variance accounted for (ΔR2) was equal to 0.01, which was associated with significant change (F for change1,314 = 5.03, P < .05). That is, the PROMIS Cognitive Concerns score added significant variance to the prediction of functional impairment, after controlling for all other health variables. Incapacity Status scores increase, on average, by 0.14 point for each 1-point Cognitive Concerns score increase, holding constant health-promoting behavior subscales (Physical Activity, Spiritual Growth), depressive symptoms, and self-rated health status. The adjusted R2 for the final model was 0.44. Known Group Validation with Employment Status There were statistically significant differences in PROMIS Cognitive Abilities (F2,319 = 6.38, P < .01) and PROMIS Cognitive Concerns scores by employment status (F2,319 = 5.70, P < .01). Post hoc analyses indicated that those unemployed owing to their disability reported significantly poorer cognitive abilities and more cognitive concerns than those who were working or those who were unemployed for other reasons.

Discussion To our knowledge, this is the first exploration of the PROMIS cognitive scales in a large sample of individuals with MS. The PROMIS Cognitive Abilities and Cognitive Concerns Scales not only capitalize on recent advances in psychometric theory, but also facilitate comparisons of cognitive functioning among people with other chronic conditions. The Cronbach α coefficients suggest that the internal consistency reliabilities are impressive for 8-item scales and reflect the careful devel-

International Journal of MS Care 6

PROMIS Among People with MS

sures of physical activity, spirituality, depressive symptoms, and general health self-rating were controlled for. This finding suggests that self-perceived cognitive limitations, as measured by the PROMIS Cognitive Concerns scale, are associated with perceived functional incapacity independent of the relationship functional incapacity has to other health factors. Consistent with previous research, 1,2,4,6 PROMIS cognitive scale scores differed by employment status. Because there were many retired individuals in our older sample (average age, 62 years), we divided the unemployed group into those who reported being employed owing to disability and those unemployed for other reasons. The fact that we found that those who were unemployed owing to disability reported poorer cognitive functioning than either those who were working or those who were unemployed for other reasons suggests that future researchers should consider differentiating those who are unemployed owing to disability from those who are unemployed for other reasons. As expected, those who were unemployed for various reasons other than disability were older than the other two groups. Those unemployed owing to disability were more similar in age to those who were working, so the observed differences in perceived cognitive function between these two groups do not appear to be due to age differences. As has been observed in other studies,5,9-11,32,33 cognitive scores were moderately correlated with a measure of depressive symptoms. Whether cognitive impairment leads to depression or both result directly from the brain deterioration caused by MS, the results of the hierarchi-

cal regression analysis performed here suggest that both contribute independently to perceived MS functional limitations, as measured by the ISS. These data are subject to the biases commonly found with self-report measures such as social desirability and response set. Because the analyses presented here are cross-sectional in nature, causal inferences cannot be made. Moreover, the findings are based on a convenience sample of individuals originally recruited through the MS society in one state, although a number have now moved to other states. The results may not generalize to people with MS who are not members of this MS society—or chose not to participate in this study. Future studies should be undertaken with more diverse samples recruited using other sampling strategies. In addition, it should be noted that the ISS is heavily weighted toward mobility impairment. Future studies should investigate the relationship of the PROMIS Cognitive Abilities and Cognitive Concerns scores to other measures of functional status. The findings do suggest that the PROMIS Cognitive Abilities and Cognitive Concerns scales can provide clinicians with short yet psychometrically sound measures of self-reported cognitive functioning. Because each scale contains only eight items, they reduce patient burden relative to longer cognitive measures. Future studies should be undertaken in clinical sites to test their utility in those settings. o Financial Disclosures: The authors have no conflicts of interest to disclose. Funding/Support: This project was supported by a grant from the National Institute of Nursing Research (Grant 5 R01 NR00319511A1), Alexa Stuifbergen, Principal Investigator.

PracticePoints

References  1. Rao SM, Leo GJ, Ellington L, et al. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology. 1991;41:692–696.  2. Amato MP, Ponziani G, Rossi F, et al. Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Mult Scler. 2001;7:340–344.  3. Benedict RH, Cookfair D, Gavett R, et al. Validity of the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006;12:549–558.  4. Shevil E, Finlayson M. Perceptions of persons with multiple sclerosis on cognitive changes and their impact on daily life. Disabil Rehabil. 2006;28:779–788.  5. Figved N, Benedict R, Klevan G, et al. Relationship of cognitive impairment to psychiatric symptoms in multiple sclerosis. Mult Scler. 2008;14:1084–1090.  6. Messmer Uccelli M, Specchia C, Battaglia A, Miller DM. Factors that influence the employment status of people with multiple sclerosis: a multi-national study. J Neurol. 2009;256:1989–1996.   7. Stuifbergen AK, Becker H, Perez F, et al. A randomized controlled trial of a cognitive rehabilitation intervention for persons with multiple sclerosis. Clin Rehabil. 2012;26:882–893.  8. Benedict RH, Munschauer F, Linn R, et al. Screening for multiple sclerosis cognitive impairment using a self-administered 15-item question-

• Patients with MS and their health-care providers would benefit from short, psychometrically sound measures of cognitive functioning that are feasible to administer in clinical settings. • The 8-item PROMIS Cognitive Abilities and Cognitive Concerns Scales demonstrated good internal consistency reliability in a sample of 322 people with MS. • Scores on the PROMIS Cognitive Abilities and Cognitive Concerns Scales were strongly related to scores on self-reported measures of self-efficacy, depressive symptoms, barriers to health promotion, health, and functional status, including employment.

International Journal of MS Care 7

Becker et al. naire. Mult Scler. 2003;9:95–101.  9. Stuifbergen AK, Phillips LJ. The influence of metamemory on the quality of life of persons with multiple sclerosis. J Neurosci Nurs. 2006;38:428–434. 10. Julian L, Merluzzi NM, Mohr DC. The relationship among depression, subjective cognitive impairment, and neuropsychological performance in multiple sclerosis. Mult Scler. 2007;13:81–86. 11. Goretti B, Portaccio E, Zipoli V, et al. Coping strategies, cognitive impairment, psychological variables and their relationship with quality of life in multiple sclerosis. Neurol Sci. 2010;31:S227–230. 12. Pierson SH, Griffith N. Treatment of cognitive impairment in multiple sclerosis. Behav Neurol. 2006;17:53–67. 13. Arnett PA, Higginson CI, Voss WD, Randolph JJ, Grandey AA. Relationship between coping, cognitive dysfunction and depression in multiple sclerosis. Clin Neuropsychol. 2002;16:341–355. 14. Amato MP, Zipoli V. Clinical management of cognitive impairment in multiple sclerosis: a review of current evidence. Int MS J. 2003;10: 72–83. 15. Becker H, Stuifbergen AK, Morrison J. Promising new approaches to assess cognitive functioning in people with multiple sclerosis. Int J MS Care. 2012;14:71–76. 16. Cella D, Riley W, Stone A, et al. Initial item banks and first wave testing of the Patient-Reported Outcomes Measurement Information System (PROMIS) network: 2005–2008. J Clin Epidemiol. 2010;63: 1179–1194. 17. Stuifbergen AK, Roberts G. Health promotion practices of women with multiple sclerosis. Arch Phys Med Rehabil. 1997;78(suppl 5):S3–S9. 18. Harrison T, Stuifbergen A, Adachi E, et al. Marriage, impairment, and acceptance in persons with multiple sclerosis. West J Nurs Res. 2004;26:266–285. 19. Kurtzke JF. A proposal for a uniform minimal record of disability in multiple sclerosis. Acta Neurol Scand. 1981;64(suppl 87):110–129. 20. Andresen EM, Malmgren JA, Carter WB, et al. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. IJMSC_ad.ai 2/14/13 10:43:17 PM 1994;10:77–84.

21. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401. 22. Stuifbergen AK, Seraphine A, Roberts G. An explanatory model of health promotion and quality of life in chronic disabling conditions. Nurs Res. 2000;49:122–129. 23. Walker SN, Sechrist KR, Pender NJ. The Health Promoting Lifestyle Profile: development and psychometric characteristics. Nurs Res. 1987;36:76–81. 24. Berger AM, Walker SN. An explanatory model of fatigue in women receiving adjuvant breast cancer chemotherapy. Nurs Res. 2001;50:43–54. 25. Stuifbergen AK, Becker H, Blozis S, et al. A randomized clinical trial of a wellness intervention for women with multiple sclerosis. Arch Phys Med Rehabil. 2003;84:467–476. 26. Lawton MP, Moss M, Fucomer M, et al. A research and service oriented multilevel assessment instrument. J Gerontol. 1982;37:91–99. 27. Becker H, Stuifbergen AK, Sands D. Development of a scale to measure barriers to health promotion activities among persons with disabilities. Am J Health Promot. 1991;5:449–454. 28. Sherer M, Maddux J, Mercandante B, et al. The self-efficacy scale: construction and validation. Psychol Rep. 1982;51:663–671. 29. Stuifbergen AK, Becker H. Predictors of health-promoting lifestyles in persons with disabilities. Res Nurs Health. 1994;17:3–13. 30. Stuifbergen AK. Health-promoting behaviors and quality of life among individuals with multiple sclerosis. Sch Inq Nurs Pract. 1995;9:31–50. 31. Bobko P. Correlation and Regression: Applications for Industrial Organizational Psychology and Management. Thousand Oaks, CA: Sage Publications; 2001. 32. Arnett PA, Barwick FH, Beeney JE. Depression in multiple sclerosis: review and theoretical proposal. J Int Neuropsychol Soc. 2008;14:691–724. 33. Barwick FH, Arnett PA. Relationship between global cognitive decline and depressive symptoms in multiple sclerosis. Clin Neuropsychol. 2011;25:193–209.

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International Journal of MS Care 8

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AUBAGIO® (teriflunomide) tablets for oral administration

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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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

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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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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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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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).

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)].

Factors Associated with Health-Related Quality of Life Among Older People with Multiple Sclerosis Marijean Buhse, PhD, RN, NP; Wendy M. Banker, MPA; Lynn M. Clement, MPH Background: This study was conducted to determine which factors (clinical and demographic) are associated with mental and physical health-related quality of life (HRQOL) among people with multiple sclerosis (MS) aged 60 years and older. Methods: Data were collected at four MS centers on Long Island, New York, from a total of 211 patients. Three surveys were administered that collected demographic information and included validated questionnaires measuring quality of life (QOL), cognition, depression, and disability. Multivariate linear regression analyses examined the relationship between patient demographics and scores on standardized scales measuring mental and physical HRQOL (Multiple Sclerosis Quality of Life–54). Variables included in the regression models were selected on the basis of the Andersen Healthcare Utilization model. This framework encompasses the multiple influences on health status, including predisposing characteristics, enabling resources, need, and health behavior. Results: We found that mental HRQOL was negatively associated with having a high school education or less, risk of neurologic impairment, physical disability, and depression. No variables were positively associated with mental HRQOL. Physical HRQOL was negatively associated with risk of neurologic impairment, physical disability, depression, and the comorbidity of thyroid disease. However, patient employment and, surprisingly, being widowed were positively associated with physical HRQOL. These findings are consistent with those of similar studies among younger patients in which lower HRQOL was associated with increased disability, depression, risk of neurologic impairment, and lower levels of education. Conclusions: The findings that patient employment and being widowed were associated with better physical HRQOL suggest that older patients have the ability to adapt and adjust to the challenges of MS over time. Clinicians should regularly screen for HRQOL in older patients with MS. Int J MS Care. 2014;16:10–19.

M

ultiple sclerosis (MS) is a progressive neurologic disease usually diagnosed between the ages of 20 and 50 years.1 Although the life­span of those with MS has been shown to be shorter than that of age- and sex-matched populations, many people will still age with MS.2 Daily life is challenging for many MS patients because of physical and psychoFrom SUNY Stony Brook School of Nursing, Stony Brook, NY, USA (MB); and KJT Group, Honeoye Falls, NY, USA (WMB, LMC). Correspondence: Marijean Buhse, PhD, RN, NP, SUNY Stony Brook School of Nursing, HSC, Level 2, Room 199, Stony Brook, NY 11794-8240; e-mail: [email protected]. DOI: 10.7224/1537-2073.2012-046 © 2014 Consortium of Multiple Sclerosis Centers.

logical impairments. Physically, MS patients may experience fatigue, pain, visual impairments, weakness, mobility impairment, and bladder and bowel dysfunction.3-9 Psychologically, they may have impaired cognition, depression, reduced social interaction, and increased reliance on others.4,5,10,11 MS symptoms are burdensome and negatively affect health-related quality of life (HRQOL). In MS, HRQOL is a multidimensional construct that refers to an individual’s physical functioning, ability to perform daily activities, sense of well-being, satisfaction with life, perception of psychological status, and social functioning.12 Past research suggests that HRQOL has both physical and psychological components that interact

International Journal of MS Care 10

HRQOL Among Older People with MS

with each other.12-14 Specifically, HRQOL has been found to be affected by disability, fatigue, and depression in young and middle-aged people with MS. 14 Furthermore, middle-aged patients with a secondary progressive disease course are known to have poorer HRQOL.3 Few studies have focused on HRQOL among elderly MS patients. DiLorenzo and colleagues 15 compared quality of life (QOL) and mental health challenges in older (mean age 66.1 years) and younger (mean age 47.3 years) individuals with MS (n = 60). Although older patients had greater physical limitations, QOL and mental health were similar in the two groups. Garcia and Finlayson16 found that older people with MS (n = 725) reported fewer mental health challenges than younger ones. Minden et al.17 reported that disability was significantly greater in patients over age 65 compared with a younger group; however, cognitive and emotional problems were significantly lower in the older population. One-third of the group over age 65 reported fair to poor health. Yet Klewer and colleagues7 found that 58% of older adults with MS (n = 53) have frequent depressed feelings and that 30% report having contemplated suicide. Older adults with MS also have to cope with feelings of helplessness, loss of control, and disability-related losses that can affect quality of life.1 Adherence to medications has been shown to affect HRQOL in younger populations of MS patients but remains unexplored in older patients. Cerghet et al.18 found that those patients with MS (average age 54 years) who adhered to their treatment had better mental health and were more likely to be employed and have less disability. Adherence to medications in the elderly with MS has not been described. Lastly, as people with MS age, they may be prone to the same comorbidities as other aging individuals. Marrie et al.19 reported that the incidences of the most commonly reported comorbidities of MS patients— hypercholesteremia, hypertension, and arthritis—were the same as in the general population. The average age in that study was 53 years. It is important to explore how comorbidities affect the HRQOL of the older person with MS. These diverse studies highlight the need for further exploration of factors associated with HRQOL in older adults with MS. The present study used the Andersen Healthcare Utilization model to investigate factors associated with mental and physical HRQOL among the aging population with MS. A secondary aim of the study was to character-

ize the older MS population in terms of demographics, MS clinical features, and HRQOL.

Methods Participants MS patients aged 60 years and older were recruited through four MS centers on Long Island, New York. Health-care practitioners at each center explained the research to age-appropriate patients. Inclusion criteria were age 60 years or older and the ability to understand and sign consent forms and complete the surveys. If a patient was physically unable to complete the surveys but had the cognitive ability to do so, he or she could be included in the study if someone else was available to write down the answers. This cognitive ability was determined by the health-care practitioner at each site. Patients with severe cognitive impairment as determined by the health-care practitioner at each site were excluded from the study. A self-selected, convenience sample of patients who expressed an interest in participating were recruited into the study. At the time of recruitment, the patient completed a consent form and an oral Symbol Digit Modalities Test (SDMT) while the health-care practitioner completed a short intake form.20 Patients were also given the option of completing the first survey with the health-care practitioner at this visit.

Data-Collection Procedures Three different cross-sectional, paper-based surveys, each intended to take 15 minutes to complete, were designed to identify the issues that MS patients aged 60 years and older cope with regularly. Recruitment began in August 2010, and the last completed survey was received in July 2011. As the surveys were lengthy, only the first one was routinely administered during a visit with the health-care provider, with the two subsequent surveys mailed sequentially to the participant’s home immediately after the previous one was returned. If a patient did not return a survey within 2 weeks of its mailing, the investigator made a reminder telephone call. Because of this method of survey administration, the time it took for participants to complete and return all surveys varied. If the participant chose to complete the first survey at another time, he or she was given a self-addressed, postage-paid envelope to mail it back to the investigators. Upon return of this first survey, the patient was immediately mailed the second survey along with a $20 gift card (which was also sent to those who completed the first survey at the visit) and a postage-paid return envelope. This process was repeated for the third survey, with a

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Buhse et al.

norms for the SDMT have been validated for use in people aged 60 to 87 years.21 Medication adherence was measured using the Morisky Medication Adherence Scale. 22 This scale consists of eight survey items that measure several medication-taking behaviors. The first seven items are yes/ no dichotomous responses, whereas the last item is measured using a 5-point Likert scale (“never/rarely” to “all the time”). Scores for this scale range from 0 to 8, with Measures 0 indicating high adherence, 1 to 2 indicating medium The measures included in each survey as well as the adherence, and greater than 2 indicating low adherence. number of completed interviews for each one are shown This scale is widely used in the elderly population to in Figure 1. The first survey included demographic ques- measure adherence.23 tions, the Morisky Medication Adherence Scale, and the Risk for neuropsychological impairment was measured Patient Multiple Sclerosis Neuropsychological Screening using the P-MSNQ.24,25 This scale consists of 15 items Questionnaire (P-MSNQ). The second survey included rated on a 5-point scale of 0 (never, does not occur) to the Multiple Sclerosis Quality of Life–54 (MSQOL- 4 (very often, very disruptive) that are used to assess fre54), and the final survey included the Beck Depression quency and disruption level of several problems patients Inventory (BDI-II) and the self-reported Expanded Dismay experience. Scores range from 0 to 60, with higher ability Status Scale (EDSS). scores indicating higher risk for neuropsychological Cognitive function was measured using the oral impairment. Although there are no age guidelines for SDMT.20 This was completed at the time of recruitthis questionnaire, it has been correlated with a higher ment with the assistance of the health-care practitioner. risk of neuropsychological impairment in many different Respondents were provided with a worksheet containing 26,27 rows of blank squares, each of which was associated with populations. Health-related quality of life was measured using a symbol. The worksheet also contained a key matchthe MSQOL-54.27 The scale consists of 54 items: 18 ing each symbol with a corresponding number. Using the symbol key, respondents were given 90 seconds to MS-specific items and 36 general health items, which verbalize as many numbers as possible. The more cor- are from the 36-item Short Form Health Status Surrect numbers verbalized, the higher the score, indicating vey (SF-36). The scale is divided into 12 subscales and better cognitive function. The published international has two summary scores: the physical health composite summary and the mental health composite summary. In Survey 1 (n = 211) each of the subscales, a higher score indicates better health. Patient Multiple Sclerosis Morisky Medication Adherence Scale Neuropsychological Screening The MSQOL-54 has not been Questionnaire (P-MSNQ) validated in the elderly MS population, but it has been ▼ validated in the general MS Survey 2 (n = 188) population. 28,29 Additionally, the SF-36 has been shown to be Multiple Sclerosis Quality of Life–54 (MSQOL-54) reliable and valid in the general elderly population.30 ▼ Disability was measured Survey 3 (n = 179) using the self-reported version of the EDSS.31 This scale Expanded Disability Status Scale (EDSS) Beck Depression Inventory (BDI-II) includes 19 self-rated items related to walking ability, Figure 1. Survey details strength, coordination, sensa$25 gift card. When the patient returned the third survey, a final gift card of $30 was sent in appreciation for completing the study. With the objective of identifying issues that this population faces regularly, sociodemographic data, clinical data, and several validated scales were used to assess a set of health-related measures. SUNY Stony Brook and North Shore University Medical Center provided institutional review board approval for this research.

International Journal of MS Care 12

HRQOL Among Older People with MS

tion, bladder function, vision, swallowing, thinking, and MS disease activity. Scores range from 0 to 10, with higher scores indicating more advanced disease. This scale was validated in a sample of MS patients aged 18 to 78 years.31 The presence and severity of symptoms of depression were assessed using the BDI-II.32 This 21-item instrument includes several symptoms of depression, which are rated on a 4-point scale ranging from 0 to 3, and has a maximum score of 63. Patients with a score of 0 to 13 are considered to have minimal depression; 14 to 19, mild depression; 20 to 28, moderate depression; and 29 to 63, severe depression.

Data Analysis Statistical analysis was performed using Stata, version 10 (StataCorp, College Station, TX). Because of a large quantity of missing data at the sexual function series of questions for the MSQOL-54, we used the second scoring version of the physical health summary, which does not incorporate the sexual function subscale. Standard scoring algorithms were used for all other health-related measures. The Andersen Healthcare Utilization model 33 domains were adapted to select and categorize variables from the surveys for multivariate regression models. These domains and the variables within each are displayed in Table 1. We used this model because it encompasses the multiple influences on health status, including predisposing characteristics, enabling resources, need, and health behavior. Thus it provides a comprehensive view of the potential influences on HRQOL. Each regression analysis (variables associated with mental HRQOL [Table 2] and variables associated with physical HRQOL [Table 3]) had two components. The first models (models 1–4 and models 6–9) were constructed using the variables within each Andersen Healthcare Utilization model domain (Predisposing Character-

istics, Enabling Resources, Need, and Health Behavior) to determine the association between each of the outcome measures (physical and mental HRQOL from the MSQOL-54) in separate analyses. The final model for each outcome measure (physical [model 10] and mental [model 5] HRQOL) used the independently significant predictors found in the first models (mental HRQOL [models 1–4] and physical HRQOL [models 6–9]). The regression coefficients in the models represent the extent to which the mean MSQOL physical and mental scores (dependent variable) are expected to decrease (if the coefficient is negative) when specific factors (independent variables) are present, keeping other independent variables constant. Sample sizes varied by regression model (n = 157 to n = 188), as some variables had missing data. Statistical significance was measured using the likelihood ratio test and was defined as P < .05 or P < .01.

Results Respondent Demographic Characteristics A total of 211 patients participated in the study between August 2010 and July 2011. Specifically, 211 patients returned the first survey, 188 the second, and 179 the third. The overall attrition rate was 15% from the first to the third survey. Because of the uniqueness of the study, we cannot provide a comparable attrition rate for this type of research. In addition, because the surveys were paper-based, response rates varied by question, as patients could leave an individual question blank. The 95% confidence interval (CI) for the sample at the final stage of n = 179 is ±0.073249. The reliability of the study sample is estimated with a 95% CI of ±0.073. Respondent demographics were self-reported and are displayed in Table 4. On average, respondents were 65.5 (SD 5.6) years old. The majority were female (80%), and nearly all were white (95%). Two-thirds were

Table 1. Factors included in regression model by Andersen categories Predisposing Characteristics

Enabling Resources

Need

Health Behavior

• Gender • Age • Education level • Employment status • Race • Marital status • Household income level

• Caregiver present • Living situation (lives with others or alone)

• MS disease course • Comorbid conditions • Years since MS diagnosis • P-MSNQ • SDMT • EDSS • BDI a

• Specialty of health-care provider who treats MS • Current MS medication use (injection vs. noninjection) • Morisky Medication Adherence Scale

Abbreviations: BDI, Beck Depression Inventory; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; P-MSNQ, Patient Multiple Sclerosis Neuropsychological Screening Questionnaire; SDMT, Symbol Digit Modalities Test. a MS disease course is type of MS (clinically isolated syndrome, relapsing-remitting MS, primary progressive MS, secondary progressive MS, progressive relapsing MS, or not sure/can’t recall).

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Buhse et al. Table 2. Multivariate linear regression model: estimated change in mental HRQOL (95% CI) in various models by patient variable

 Variable

Model 1 Predisposing Characteristics (n = 188)

Patient has a high school education or less

−8.7a

Patient is employed

10.0a

Patient has a caregiver

Model 2 Enabling Resources (n = 188)

Model 3 Need (n = 157)

Model 4 Health Behavior (n = 188)

Model 5 Final Model (n = 157) −5.4b

−10.8a

P-MSNQ

−0.5a

−0.5a

EDSS

−2.7a

−2.4a

BDI-II

−1.5a

−1.5a

Abbreviations: BDI-II, Beck Depression Inventory; CI, confidence interval; EDSS, Expanded Disability Status Scale; HRQOL, health-related quality of life; P-MSNQ, Patient Multiple Sclerosis Neuropsychological Screening Questionnaire. a P < .01. b P < .05.

Table 3. Multivariate linear regression model: estimated change in physical HRQOL (95% CI) in various models by patient variable

 Variable

Model 6 Predisposing Characteristics (n = 188)

Model 7 Enabling Resources (n = 188)

Model 8 Need (n = 157)

Model 9 Health Behavior (n = 188)

Model 10 Final Model (n = 157)

Patient is employed (full time, part time, or self-)

18.0a

6.3b

Patient is a widow

12.7a

9.6b

Patient household income is ≥$50,000 Patient has a caregiver

5.9b −12.3a

P-MSNQ

−0.4a

−0.4a

EDSS

−5.3a

−4.8a

BDI-II

−1.2a

−1.1a

Patient diagnosed with thyroid disease

−6.4b

−6.0b

Patient uses injectable MS medication

6.7b

Abbreviations: BDI-II, Beck Depression Inventory; CI, confidence interval; EDSS, Expanded Disability Status Scale; HRQOL, health-related quality of life; MS, multiple sclerosis; P-MSNQ, Patient Multiple Sclerosis Neuropsychological Screening Questionnaire. a P < .01. b P < .05.

married (67%), one-eighth were widowed (13%), and nearly three-quarters were retired (72%). Respondents were more likely to be currently living with their spouse (65%) than alone (18%) or with their children (17%). Sixty-five percent of respondents had a caregiver who assisted them with their everyday activities. Of those, 83% reported that their caregiver lived with them. Care-

givers were most frequently the patient’s spouse (70%), a paid caregiver (12%), or a child (6%). The most common comorbidities reported by respondents were high cholesterol (46%), hypertension (45%), arthritis (33%), depression (31%), and thyroid disease (20%). All but one respondent (99.5%) reported that they were covered by health insurance, and 98% of those

International Journal of MS Care 14

HRQOL Among Older People with MS Table 4. Respondent demographics Value (n = 211)

Characteristic Gender,a %   Female

80

  Male

20

Age, mean (SD),b y

65.5 (5.6)

Age, range, y

60–87

Marital status, %

1a (23%), glatiramer acetate (21%), interferon beta-1b (13%), or natalizumab (7%). On the Morisky Medication Adherence Scale, the majority (62%) were classified as medium adherers to their injectable MS medication. Further, 20% were low adherers and 18% were high adherers. The most frequent adherence issues among patients using an injectable MS medication were feeling hassled about the treatment plan (17%), not taking the last dose (15%), and sometimes forgetting to take the medication (13%).

  Married

67

  Divorced

15

Health-Related Measures

  Widowed

13

  Never married

4

  Separated

1

Table 5 presents the mean scores, standard deviations, and ranges for the P-MSNQ, oral SDMT, EDSS, BDIII, and MSQOL-54 physical and mental health composite scores. The mean P-MSNQ score among all patients was 27.7 (SD 9.0), indicating that the average respondent had a moderate risk of neuropsychological impairment. In addition, 56% of respondents’ self-reported scores classified them as being cognitively impaired (score of higher than 24).4 According to the SDMT’s classifications, the patients in our sample were cognitively impaired. On average, they scored 32.6 (SD 10.9) on the oral SDMT, which is lower than the average for healthy volunteers aged 55 to 75 (SDMT mean range, 46.2–48.4).34 The mean EDSS score among respondents was 5.4 (SD 1.7). Eighteen percent of respondents were fully ambulatory without aid and self-sufficient for up to 12 hours a day (EDSS 0 to <4). Just over half (56%) were able to walk at least 20 yards without resting (EDSS 4 to <7), and 26% were largely confined to a wheelchair (EDSS ≥7). On average, respondents

Race,c %   White

95

  Black

2

   Other/decline to answer

3

Education level,a %    High school or less

31

   Some college but no degree

24

   College degree (associate’s or bachelor’s)

21

   At least some graduate school

23

Employment status, % d

  Retired

72

   Employed full or part time

16

  Homemaker

9

   Not employed or student

9

  Self-employed

2

2009 annual income, % c

  <$25,000

11

   $25,000 to <$50,000

12

  ≥$50,000

34

Table 5. Descriptive statistics for outcome measures

   Decline to answer

43

Measure

a

P-MSNQ

b

Oral SDMT

Data missing for 1 respondent. Data missing for 3 respondents. c Data missing for 2 respondents. d Multiple responses permitted.

a b

EDSSc

Mean

SD

Range

27.7

9.0

13–51

32.6

10.9

1–65

5.4

1.7

0–9

indicated that their health plan provided prescription drug coverage.

8.8

7.9

0–41

MSQOL-54 physical health composite scoree

49.6

20.3

6–97

MS Clinical Characteristics

MSQOL-54 mental health composite scoree

64.5

20.9

6–97

BDI-IId

On average, patients reported that they had been diagnosed with MS 19.7 (SD 12.3) years previously. Thirtyeight percent of respondents reported that they had relapsing-remitting MS, 26% had secondary progressive MS, and 14% had primary progressive MS. In terms of treatments for their disease, respondents were most likely to be currently taking interferon beta-

Abbreviations: BDI-II, Beck Depression Inventory; EDSS, Expanded Disability Status Scale; MSQOL-54, Multiple Sclerosis Quality of Life–54; P-MSNQ, Patient Multiple Sclerosis Neuropsychological Screening Questionnaire; SDMT, Symbol Digit Modalities Test. a n = 211. b n = 203. c n = 159. d n = 179. e n = 188.

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Buhse et al.

had a BDI-II score of 8.8 (SD 7.9), indicating minimal depression. Using the standard BDI-II categories, 76% of respondents were minimally depressed (score of 0–13), 10% were mildly depressed (score of 14–19), 13% were moderately depressed (score of 20–28), and 1% were severely depressed (score of 29–63). According to the MSQOL-54, respondents were in better mental health (mean 64.5, SD 20.9) than physical health (mean 49.6, SD 20.3).

Association Between Patient Health Factors and Quality of Life Table 2 presents the multivariate associations observed between the Predisposing Characteristics, Enabling Resources, Need, and Health Behavior variables as well as the final combined model and patient mental HRQOL (MSQOL-54 mental health composite score). The following variables were significantly associated with a decreased mental HRQOL in the final model: education level (high school or less) (Predisposing Characteristic), risk of neuropsychological impairment (P-MSNQ score) (Need), disability status (EDSS score) (Need), and level of depression (BDI-II score) (Need). None of the variables were found to be associated with an increased mental HRQOL. Table 3 presents the multivariate associations between the Predisposing Characteristics, Enabling Resources, Need, and Health Behavior variables as well as the final combined model and patient physical HRQOL (MSQOL-54 physical health composite score). The following variables were significantly associated with a decreased physical HRQOL in the final model: risk of neuropsychological impairment (P-MSNQ score) (Need), disability status (EDSS score) (Need), level of depression (BDI-II score) (Need), and presence of a comorbid condition (diagnosed by a health-care provider with thyroid disease) (Need). On the other hand, the following variables were found to be significantly associated with increased physical HRQOL in the final model: employment status (employed) and marital status (widowed) (Predisposing Characteristics).

Discussion In this study of older patients with MS, we found that Predisposing Characteristics—specifically, being widowed, remaining employed, and education level— were the strongest predictors of better QOL. Physical HRQOL was positively associated with the patient being widowed and being employed, while mental HRQOL was negatively associated with having a high school education or less. Need characteristics were the

strongest predictors of a decrease in QOL. Patient disability status (EDSS) was found to be negatively associated with both physical and mental HRQOL. Elderly individuals who are widowed have often been reported to have lower QOL as a result of the effects of social isolation and loneliness.35 However, Carr and Utz36 found that elderly widows adjust to loss very differently and may not be as grief-stricken as their younger counterparts. The widow must take on responsibilities that had been shared by both spouses and modify routines, daily decisions, and household duties. The ability to complete these tasks daily despite having MS may increase physical HRQOL. Elderly individuals with MS have reported their ability to adapt and adjust to MS over many years, and being independent and remaining at home is highly valued.37 These results are similar to the findings from the Sonya Slifka Longitudinal Multiple Sclerosis Study, in which it was shown that patients over age 65 years often lived alone but viewed their health status positively, thus appearing to adapt over time despite the progression of disease.17 This sample of patients was slightly different from the overall MS population, as women made up 80% of this study, compared with approximately 66% of the overall MS population. Also, 95% were white, which is also dissimilar to the overall MS population; however, this may be attributed to the recruitment area, a suburb of New York City. Although our sample consisted of people aged 60 and older, 16% worked either full or part time. Being employed was positively associated with physical HRQOL. These results are similar to those found in the larger MS population: past research has found that MS patients who are employed have higher HRQOL than those who are unemployed.38,39 Such findings suggest that remaining employed is very important in maintaining the QOL of the MS patient. Strober et al.40 found that employed MS patients have a higher level of persistence, defined as the degree to which someone is hardworking, industrious, and stable despite frustration and fatigue. Other studies on employment in MS have shown that those patients who remain employed have better self-reported quality of life.40,41 Thus older MS patients should be encouraged to stay employed as long as possible. The education level of the older MS patients in our study was found to be associated with mental HRQOL. Specifically, less education (high school or less, compared with at least some college) was negatively associated with mental HRQOL. Previous research among

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HRQOL Among Older People with MS

younger MS patients has also found less education to be associated with lower mental HRQOL.38,39 Patti et al.38 concluded that mental HRQOL is significantly influenced by level of education in MS patients and that higher level of education may result in better awareness of the disease as well as an increased ability to cope with its challenges. Aging patients with lower educational levels may need more time with their health-care providers to understand the impact, management, and treatment of MS. Patients can also be directed to the National Multiple Sclerosis Society website (http://www.nationalmssociety.org) for details on support groups and further information about MS. Previous research has found patient physical disability to be associated with poorer overall HRQOL.42-45 Patient physical disability has also been found to be associated with mental health challenges as well as reduced physical HRQOL.5,16,42 Older adults with MS may be more isolated, be less able to leave their homes, and have less social support than younger individuals with MS. Lack of social support, disabling symptoms, and social isolation have been reported as negative aspects of aging with MS.46 Encouraging the use of rehabilitation services and participation in MS support groups may help increase elderly patients’ HRQOL by helping them cope with their physical disability. Both mental and physical HRQOL were negatively associated with patient depression (BDI-II). Depression has been found to be a significant predictor of low HRQOL in past research.12,42 Specifically, depression affects both the mental and physical domains of HRQOL, as it impairs motivation and interest and limits physical progress.12 Depression is common in elderly patients with chronic diseases who live in the community, with more than one-quarter experiencing symptoms.47 Older adults with MS may face different problems than younger people with MS, which can predispose them to depression. These include limited social support, role transitions, changes in relationships, and decreased accessibility of the environment.11 For some older adults, depression may lead to suicide.48 Thus screening for and treating depression in older adults with MS is essential. In our study, mental and physical HRQOL were found to be negatively associated with patient risk of cognitive impairment (P-MSNQ), and most patients were cognitively impaired according to the SDMT. While patient cognition as measured using the P-MSNQ was significantly associated with both mental and physical HRQOL, the SDMT score was not. Conversely,

prior research found that among younger individuals with MS, lower SDMT scores were significantly associated with poorer HRQOL.13,49 However, two recent studies involving younger MS patients revealed weak correlations between HRQOL and cognitive impairment.50,51 Elderly people with MS appear to be similar to other older people with cognitive impairment. Among elderly people with dementia, QOL is associated with mood, engagement in pleasant activities, and the ability to perform activities of daily life (ADLs), whereas for a younger person with MS, cognitive impairment is associated with poor QOL in relation to working, interpersonal relationships, and leisure activities.12,52 This may be related to the older person being able to adapt and adjust his or her lifestyle to MS over time. Interventions such as cognitive stimulation and rehabilitation services should be used for elderly MS patients with cognitive impairment. Although according to the SDMT the sample in this study was cognitively impaired, this should not affect their self-report. Gold et al.53 studied cognitively impaired MS patients and their ability to accurately self-report and found that QOL and affective symptomatology can be reliably assessed in MS patients with cognitive impairment. Sprangers et al.54 compared QOL in young, middle-aged, and older people with numerous chronic diseases and found that patients who were older, had a lower level of education, and had at least one comorbid condition had the lowest QOL. In our study, one comorbid condition, thyroid disease, was negatively associated with physical HRQOL. The influence of comorbidity on HRQOL is important. In the general population, patients with comorbid conditions reported the lowest levels of physical and mental HRQOL.55 As individuals with MS age, they are likely to have the same comorbidities as the general population, including hypertension, heart conditions, diabetes, and even thyroid disease.37 These comorbidities may also lead to other related illnesses. Ploughman et al.37 reported that older people with MS are very concerned about comorbid conditions and the effects on their lifestyle. Aging individuals with MS must have a primary health-care provider who will manage comorbid conditions appropriately. Encouraging them to obtain age-related screenings and management of disease may reduce the impact of the comorbidity. While significant progress has been made in the clinical management of common chronic diseases, much less is known about the impact of comorbidity—including both physical and mental health comorbidities—on disease management and clinical outcomes.55

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Buhse et al.

Finally, adherence to injectable medications had no impact on HRQOL in this sample of older MS patients. The majority of patients (62%) were medium adherers, meaning that they took their injectable medication as prescribed most of the time (the most common therapy was interferon beta-1a). In studies of QOL in younger MS patients on interferon medications, findings were similar, with no impact of the medication on HRQOL.56,57

Limitations Although this study involved a very large sample of older patients with MS, the findings must be interpreted within the context of limitations. First, the study participants were drawn from a convenience sample from four MS centers on Long Island, New York. Two centers were in academic health centers, and two were private practices. Participation was voluntary; therefore, this nonrandom sample may result in self-selection bias. Second, the self-report design of the study is a potential limitation because people might provide answers that they think they should provide rather than those that are true.58 Self-report can also leave room for response bias; however, this may be the only way for a researcher to obtain this type of information about the patient. Third, this study did not include the many individuals with MS who do not go to MS centers for their health care or who reside in nursing homes. This may also bias the study toward patients who are able to be home (with or without a caregiver) and those who seek specialized MS care. Moreover, the study sample was from a suburban area outside of New York City. There may be differences in the care patients receive in other areas of the country or outside of the United States; the results cannot be gen-

PracticePoints • Clinicians should regularly screen older patients with MS for health-related quality of life (HRQOL). • Depression and cognitive impairment should be assessed regularly in such patients because of their influence on both physical and mental HRQOL. • Aging MS patients should have a primary-care provider who manages comorbid conditions appropriately. Age-related screenings and disease management may reduce the impact of comorbidities on overall HRQOL.

eralized to the entire population of elderly MS patients. Finally, we used the BDI-II, which was not specifically designed for use among elderly people. There are geriatric depression scales that may be more useful in future studies when determining risk for depression in this population.

Conclusion Our study demonstrates the various influences on HRQOL in an aging population of MS patients. Specifically, HRQOL was found to be significantly associated with physical disability, depression, cognition, being employed, being a widow, having been diagnosed with thyroid disease, and level of education. These findings support the regular screening and monitoring of older MS patients for physical disability, depression, and cognitive impairment. Early detection and intervention may help improve patients’ physical and mental HRQOL. In addition, as lower level of education is negatively associated with mental HRQOL, health-care providers may want to spend more time with these patients to help them better understand their disease and cope with its impact on their lives. In the United States, each state has an Office for the Aging that can provide specific information about local support services for the elderly. Health-care practitioners should have information available to give to any patient who may benefit from these services. o Financial Disclosures: The authors have no conflicts of interest to disclose. Funding/Support: Funding for this research was provided by Bayer Healthcare Pharmaceuticals.

References  1. Finlayson M. Concerns about the future among older adults with multiple sclerosis. Am J Occup Ther. 2004;58:54–63.  2. Redelings MD, McCoy L, Sorvillo F. Multiple sclerosis mortality and patterns of comorbidity in the United States from 1990 to 2001. Neuroepidemiology. 2006;26:102–107.   3. Beiske A, Naess H, Aarseth J, et al. Health-related quality of life in secondary progressive multiple sclerosis. Mult Scler. 2007;13:386–392.  4. Benedict RH. Integrating cognitive function screening and assessment into the routine care of multiple sclerosis patients. CNS Spectr. 2005;10:384–391.   5. Goretti B, Portaccio E, Zipoli V, et al. Coping strategies, psychological variables and their relationship with quality of life in multiple sclerosis. Neurol Sci. 2009;30:15–20.  6. Douglas C, Wollin JA, Windsor C. The impact of pain on the quality of life of people with multiple sclerosis. Int J MS Care. 2009;11: 127–136.  7. Klewer J, Pohlau D, Haas J, Kugler J. Problems reported by elderly patients with multiple sclerosis. J Neurosci Nurs. 2001;33:167–171.  8. Pawar VS, Pawar G, Miller LA, et al. Impact of visual impairment on health-related quality of life in multiple sclerosis. Int J MS Care. 2010;12:83–91.   9. Finlayson M. Health and social profile of older adults with MS: findings from three studies. Int J MS Care. 2002;4:139–151.

International Journal of MS Care 18

HRQOL Among Older People with MS 34. Cetofani C. Selected Somatosensory and Cognitive Test Performances as a Function of Age and Education in Normal and Neurologically Impaired Adults [dissertation]. University of Michigan; 1975. 35. Coyle C, Dugan E. Social isolation, loneliness and health among older adults. J Aging Health. 2012;24:1346–1363. 36. Carr D, Utz R. Late-life widowhood in the United States: new directions in research and theory. Ageing Int. 2002;27:65–88. 37. Ploughman M, Austin MW, Murdoch M, et al. Factors influencing healthy aging with multiple sclerosis: a qualitative study. Disabil Rehabil. 2012:34:26–33. 38. Patti F, Montanari E, Pappalardo A, et al. Effects of education level and employment status on HRQoL in early relapsing-remitting multiple sclerosis. Mult Scler. 2007;13:783–791. 39. Miller A, Dishon S. Health-related quality of life in multiple sclerosis: the impact of disability, gender and employment status. Qual Life Res. 2006;15:259–271. 40. Strober LB, Christodoulou C, Benedict RH, et al. Unemployment in multiple sclerosis; the contribution of personality and disease. Mult Scler. 2012;18:647–653. 41. Krokavcova M, Nagyova I, Rosenberger J, et al. Employment status and perceived health status in younger and older people with multiple sclerosis. Int J Rehabil Res. 2012;35:40–47. 42. Karatepe AG, Kaya T, Gunaydin R, Demirhan A, Ce P, Gedizlioglu M. Quality of life in patients with multiple sclerosis: the impact of depression, fatigue, and disability. Int J Rehabil Res. 2011;34:290–298. 43. Twork S, Wiesmeth S, Spindler M, et al. Disability status and quality of life in multiple sclerosis: non-linearity of the Expanded Disability Status Scale (EDSS). Health Qual Life Outcomes. 2010;8:5–11. 44. Nortvedt MW, Riise T, Myhr KM, Nyland HI. Quality of life as a predictor for change in disability in MS. Neurology. 2000;55:51–54. 45. Zwibel HL. Contribution of impaired mobility and general symptoms to the burden of multiple sclerosis. Adv Ther. 2009;26:1043–1057. 46. Finlayson M, Van Denend T, DalMonte J. Older adults’ perspectives on the positive and negative aspects of living with multiple sclerosis. Br J Occup Ther. 2005;68:117–124. 47. Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population. Arch Gen Psychiatry. 2000;57:601–607. 48. Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci. 2003;58:249–265. 49. Mitchell AJ, Kemp S, Benito-Leon J, Reuber M. The influence of cognitive impairment on health-related quality of life in neurological disease. Acta Neuropsychiatrica. 2010;22:2–23. 50. Glanz BI, Healy BC, Rintell DJ, Jaffin SK, Bakshi R, Weiner HL. The association between cognitive impairment and quality of life in patients with early multiple sclerosis. J Neurol Sci. 2010;290:75–79. 51. Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross sectional study. BMC Neurol. 2011;11:17. 52. Logsdon RG, McCurry SM, Teri L. Evidence-based interventions to improve quality of life for individuals with dementia. Alzheimers Care Today. 2007;8:309–318. 53. Gold SM, Schulz H, Mönch A, Schulz KH, Heesen C. Cognitive impairment in multiple sclerosis does not affect reliability and validity of self-report health measures. Mult Scler. 2003;9:404–410. 54. Sprangers MAG, de Regt EB, Andries F, et al. Which chronic conditions are associated with better or poorer quality of life? J Clin Epidemiol. 2000;53:895–907. 55. Bierman A, Spector W, Atkins D. Improving the Health and Health Care of Older Americans. US Department of Health and Human Services, Agency for Healthcare Research and Quality. http://www.ahrq. gov/research/olderam/oldam1.htm. Accessed 2012. 56. Abolfazli R, Hosseini A, Gholami K, Torkamandi H, Emami S. Quality of life assessment in patients with multiple sclerosis receiving interferon beta-1a: a comparative longitudinal study of Avonex and its biosimilar CinnoVex. ISRN Neurol. 2012;2012:786526. 57. Vermersch P, De Seze J, Delisse B, Lemaire S, Stojkovic T. Quality of life in multiple sclerosis: influence of interferon-beta 1a (Avonex) treatment. Mult Scler. 2002;8:377–381. 58. McDonald J. Measuring personality constructs: the advantages and disadvantages of self-reports, informant reports and behavioural assessments. Enquire. 2008;1:1–18.

10. Patti F, Amato M, Trojano M, et al. Quality of life, depression, and fatigue in mildly disabled patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: 3-year results from the COGIMUS study. Mult Scler J. 2011;17:991–1001. 11. Fong T, Finlayson M, Peacock N. The social experience of aging with a chronic illness: perspectives of older adults with multiple sclerosis. Disabil Rehabil. 2006;28:695–705. 12. Mitchell AJ, Benito-Leon J, Morales Gonzalez JM, Rivera-Navarro J. Quality of life and its assessment in multiple sclerosis: integrating physical and psychological components of wellbeing. Lancet Neurol. 2005;4:556–566. 13. Hoogs M, Kaur S, Smerbeck A, Biana WG, Benedict RHB. Cognition and physical disability in predicting health-related quality of life in multiple sclerosis. Int J MS Care. 2011;13:57–63. 14. Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci. 2002;205:51–58. 15. DiLorenzo T, Terry D, Halper J, Picone MA. Comparison of older and younger individuals with multiple sclerosis: a preliminary investigation. Rehabil Psychol. 2004;49:123–125. 16. Garcia J, Finlayson M. Mental health and mental health service use among people aged 45+ with multiple sclerosis. Can J Commun Ment Health. 2005;24:9–22. 17. Minden S, Frankel D, Hadden L, Srinath K, Perloff J. Disability in elderly people with multiple sclerosis: an analysis of baseline data from the Sonya Slifka Longitudinal Multiple Sclerosis Study. NeuroRehabilitation. 2004;19:55–67. 18. Cerghet M, Dobie E, Lafata J, et al. Adherence to disease-modifying agents and association with quality of life among patients with relapsing-remitting multiple sclerosis. Int J MS Care. 2010;12:51–58. 19. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity, socioeconomic status and multiple sclerosis. Mult Scler. 2008;14:1091–1098. 20. Smith A. The Symbol Digit Modalities Test: A Neuropsychologic Test of Learning and Other Cerebral Disorders. Seattle, WA: Special Child Publications; 1968. 21. Vogel A, Stokholm J, Jorgensen K. Performances on Symbol Digit Modalities Test, Color Trails Test and modified Stroop test in a healthy, elderly Danish sample. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2013;20:370–382. 22. Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens. 2008;10:348–354. 23. Krousel-Wood M, Muntner P, Islam T, Morisky D, Webber L. Barriers to and determinants of medication adherence in hypertension management: perspective of the Cohort Study of Medication Adherence Among Older Adults. Med Clin North Am. 2009;93:753–769. 24. Benedict RH, Munschauer F, Linn R, et al. Screening for multiple sclerosis cognitive impairment using a self administered 15-item questionnaire. Mult Scler. 2003;9:95–101. 25. Benedict R, Cox D, Thompson L, Foley F, Weinstock-Guttman B, Munschauer F. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10:675–678. 26. Sonder J, Mokkink L, van der Linden G, Polman C, Uitdehaag B. Validation and interpretation of the Dutch version of the Multiple Sclerosis Neuropsychological Screening Questionnaire. J Neurol Sci. 2012;320:91–96. 27. Vickrey B, Hays R, Harooni R, Myers L, Ellison G. A healthrelated quality of life measure for multiple sclerosis. Qual Life Res. 1995;4:187–206. 28. Ackbar N, Honarmand K, Kou N, Levine B, Rector N, Feinstein A. Validity of an internet version of the Multiple Sclerosis Neuropsychological Screening Questionnaire. Mult Scler. 2010;16:1500–1506. 29. Heiskanen S, Merilainen P, Pietila A. Health-related quality of life testing the reliability of the mSQOL-54 instrument among MS patients. Scand J Caring Sci. 2007;21:199–206. 30. Lyons R, Perry I, Littlepage B. Evidence for the validity of the shortform 36 questionnaire (SF-36) in an elderly population. Age Aging. 1994;23:182–184. 31. Bowen J, Gibbons L, Gianes A, Kraft GH. Self administered Expanded Disability Status Scale with functional system scores correlates well with a physician-administered test. Mult Scler. 2001;7:201–206. 32. Beck AT, Steer RA, Brown GK. Beck Depression Inventory-II Manual. San Antonio, TX: Psychological Corporation; 1996. 33. Andersen RM. Revisiting the behavioral model and access to medical care: does it matter? J Health Soc Behav. 1995;36:1–10.

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Pelvic Floor Disorders and Multiple Sclerosis Are Patients Satisfied with Their Care? Sangeeta T. Mahajan, MD; Rebecca James, MD; Heidi Frasure, MS Background: Despite recent efforts to educate multiple sclerosis (MS) health-care providers about the importance of pelvic floor disorders (urinary, bowel, and sexual dysfunction), no data are currently available to assess outcomes of these efforts in terms of patient satisfaction. Methods: As part of the fall 2010 North American Research Committee on Multiple Sclerosis survey, we conducted a prospective, survey-based cohort study (N = 14,268) to evaluate patient satisfaction with the current evaluation and treatment of pelvic floor disorders. Patients were queried about 1) bother from bladder, bowel, or sexual symptoms; 2) whether they had been evaluated by a health-care provider for pelvic floor issues in the last 12 months; and 3) satisfaction with the evaluation and treatment they received, on a 5-point Likert scale. Patients were also asked whether these treatments had affected their quality of life (7-point Likert scale). Results: A total of 9397 responses were received (response rate of 65.9%); respondents were primarily white (89%) and female (77.4%). Moderate-to-severe pelvic floor symptoms were reported by one-third of patients (bladder, 41%; bowel, 30%; sexual, 42%). Most respondents had been asked about bladder (61%) or bowel (50%) issues by their health-care providers, but only 20% had been queried about sexual dysfunction. Most respondents were moderately to very satisfied with the management of their bladder and bowel disorders but significantly less satisfied with that of sexual dysfunction. Conclusions: While MS patients are generally satisfied with current management of bladder and bowel dysfunction, improvement is needed in that of sexual dysfunction. Int J MS Care. 2014;16:20–25.

M

ultiple sclerosis (MS) is well known to have significant detrimental effects on bowel, bladder, and sexual function. In recent years, several organizations have attempted to educate health-care providers on the importance of pelvic floor disorders in order to improve patient care. In 1999, the Multiple Sclerosis Council for Clinical Practice Guidelines drafted recommendations for the management of urinary dysfunction in patients with MS, setting the first standards for the management of these problems.1 More

From the Department of Obstetrics and Gynecology (STM, RJ, HF) and Urology (STM), Case Western Reserve University, Cleveland, OH, USA. Correspondence: Sangeeta T. Mahajan, MD, Division of Female Pelvic Medicine and Reconstructive Surgery, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH; e-mail: [email protected]. DOI: 10.7224/1537-2073.2012-052 © 2014 Consortium of Multiple Sclerosis Centers.

recently, the Consortium of Multiple Sclerosis Centers (CMSC) published consensus guidelines for the management of bowel and urinary symptoms, which included treatment algorithms to guide patients, families, and health-care providers and reflected advances in patient care in a variety of related fields.2 A previous study demonstrated the significant undertreatment of overactive bladder (OAB) symptoms among patients with MS.3 Sixty-five percent of respondents to the fall 2005 North American Research Committee on Multiple Sclerosis (NARCOMS) questionnaire reported at least one moderate-to-severe urinary symptom, including urinary frequency, urgency, leakage of any kind, and nocturia. Among respondents with moderate-to-severe OAB symptoms, only 55% had ever undergone urologic evaluation for these complaints, and only 51% had ever been treated with an anticholinergic medication. Among those who had been treated, the treatments used tended to be older (characterized as

International Journal of MS Care 20

Pelvic Floor Disorders and MS

being less well tolerated and having greater side effects compared with newer medications) and not in line with those used in the general population. Longer disease duration was significantly correlated with worsening OAB symptoms, as represented by a higher urinary symptom score (r = 0.135, P < .001). Given the inadequate treatment and evaluation of bladder-related dysfunction demonstrated in previous research, we sought to determine the experience of MS patients with pelvic floor disorders in general, including bladder, bowel, and sexual problems. Although significant effort has been put forth to educate both patients and health-care providers on the importance of evaluating and treating these problems, pelvic floor disorders remain embarrassing and difficult to discuss, resulting in their frequent neglect in the course of routine patient care. Furthermore, patient-based outcomes reflecting the impact of these educational efforts have not been assessed to date. The goal of this study was to assess patient satisfaction with the care received for pelvic floor disorders— including bowel, bladder, and sexual dysfunction symptoms—using a large database of community-dwelling patients with MS. Patient history of evaluation and treatment and association with degree of physical disability were also assessed.

Methods The NARCOMS Registry, a project of the CMSC (www.mscare.org), is the largest registry in North America of patients with MS. Consisting of MS patients who volunteered to participate in research-related activities, it captures self-reported demographic and clinical information from MS patients at enrollment in the registry and semiannually thereafter through questionnaires administered either online or by mail, in accordance with participant preference. The registry is the largest self-report database of patients with MS worldwide, with more than 14,000 active participants, and is approved by the Western Institutional Review Board (IRB) and the IRB at the University of Alabama at Birmingham. We obtained an exemption from the University Hospitals Case Medical Center IRB for this study. De-identified data from the fall 2010 questionnaire were supplied for analysis by NARCOMS in the form of an Excel (Microsoft, Redmond, WA) spreadsheet with a data dictionary. At enrollment in NARCOMS, participants provide demographic information and clinical information, including age at MS onset. Each semiannual NARCOMS questionnaire includes an assessment of disabil-

ity status and quality of life (QOL). The Patient-Determined Disease Steps (PDDS) measures disability based on self-report and has been validated in large MS populations against the physician-scored Expanded Disability Status Scale (EDSS).4-6 It is scored from 0 to 8, with 0 defined as no disability and 8 as bed-bound.7 Respondents are also evaluated for bladder and spasticity-related disability using standardized questionnaires. In the fall of 2010, we collaborated with the NARCOMS staff to create a two-page questionnaire on pelvic floor disorders for inclusion in the fall 2010 survey. Specifically, patients were asked to report their degree of bother from bladder, bowel, and sexual problems on a 4-point scale (1 = not at all bothered, 4 = severely bothered). Respondents were given a choice of “not applicable” for each of the pelvic floor disorder types if they did not have these symptoms. Patients were asked whether their health-care providers had inquired about each type of pelvic floor disorder in the last 12 months (yes or no). Patients were also asked to rate on a 5-point Likert scale (1 = not at all, 5 = completely) their degree of satisfaction with the care they received for each problem. Finally, they were asked whether their QOL had changed with treatment (7-point Likert scale; 1 = much better, 7 = much worse). Medication use, evaluation by a urologist, and correlation with disability as measured by PDDS score were also evaluated. Data analysis used descriptive statistics, χ2 tests for comparisons between genders, calculation of correlation coefficients, and 95% confidence intervals (CIs). Data analysis was performed with SAS, version 9.2 (SAS Institute Inc, Cary, NC).

Results In the fall of 2010, the biannual NARCOMS questionnaire was delivered to 14,268 participants; a total of 9397 questionnaires were returned, for a response rate of 65.9%. Respondents were primarily white (89%) and female (77.4%), with an average (SD) age of 55 (10.5) years. Significant disability, defined as a PDDS score of at least 3 (representing gait disability or worse), was reported by 6070 respondents (64.6%; 95% CI, 63.665.5). Moderate-to-severe bladder disability scores were reported by 2743 respondents (29.2%; 95% CI, 28.330.1), with 281 (3%; 95% CI, 2.7-3.4) reporting total loss of bowel and bladder control. Moderate-to-severe pelvic floor symptoms, defined as a Likert scale score of 3 or higher, were reported by a large number of respondents (Table 1). Moderate-tosevere bother from bladder symptoms was reported by

International Journal of MS Care 21

Mahajan et al. Table 1. Degree of bother from pelvic floor symptoms reported by respondents (N = 9397) Degree of symptom bother

Bladder

Bowel

Sexual

Female

Male

Total

Female

Male

Total

Female

Male

Total

Not at all

1579 (21.7)

374 (17.69)

1953 (20.8)

2388 (32.8)

626 (29.4)

3014 (32.1)

2730 (37.5)

435 (20.5)

3165 (33.7)

Mildly bothered

2789 (38.4)

772 (36.3)

3561 (37.9)

2689 (37.0)

811 (38.1)

3500 (37.2)

1464 (20.1)

406 (19.1)

1870 (19.9)

Moderately bothered

1819 (25.0)

572 (26.9)

2391 (25.4)

1502 (20.6)

463 (21.8)

1965 (20.9)

1244 (17.1)

469 (22.1)

1713 (18.2)

Severely bothered

1015 (13.9)

381 (17.9)

1396 (14.9)

623 (8.6)

206 (9.7)

829 (8.8)

1213 (16.7)

718 (33.8)

1931 (20.5)

Declined to answer

69 (0.9)

27 (1.3)

96 (1)

69 (0.9)

20 (0.9)

89 (0.9)

620 (8.5)

98 (4.6)

718 (7.6)

Note: Values are presented as number (%).

3787 respondents (40.3%; 95% CI, 39.3-41.3): 2834 females (39.8%) versus 953 males (44.8%) (P < .001). Moderate-to-severe bowel symptoms were reported by 2794 respondents (29.7%; 95% CI, 28.8-30.7): 2125 females (29.8%) versus 669 males (31.5%) (P = .039). Despite a large number of respondents who opted not to answer questions about sexual dysfunction (718 respondents, or 7.6%), a sizeable number reported moderateto-severe sexual problems (3644 respondents, or 38.8%; 95% CI, 37.8-39.8), with results differing significantly by gender: 2457 females (34.5%) versus 1187 males (55.8%) (P < .001). Increased disability as gauged by the PDDS was significantly correlated with the presence of bladder (r = 0.483; 95% CI, 0.468-0.498), bowel (r = 0.364; 95% CI, 0.347-0.381), and sexual dysfunction (r = 0.140; 95% CI, 0.120-0.159) (all P < .001). The presence of bladder dysfunction significantly increased the likelihood of concurrent bowel (r = 0.505; 95% CI, 0.4900.520; P < .001) and sexual dysfunction (r = 0.240; 95% CI, 0.221-0.259; P < .001). Respondents were much more likely to have been asked about bladder and bowel dysfunction than about sexual dysfunction by their health-care providers in the last year. Overall, 61.3% (5763 respondents; 95% CI, 60.3-62.3) had been queried about bladder dysfunction in the last year: 4430 (60.9%) female patients and 1333 (62.7%) male patients (P = .245). Fifty percent (4733 respondents; 95% CI, 49.4-51.4) had been asked about bowel problems: 3573 (49.1%) females and 1160 (54.6%) males (P < .001). In contrast, only 20.1% overall (1892 respondents; 95% CI, 19.3-20.9) recalled being asked about sexual dysfunction issues in the last year by their health-care providers. This differed signifi-

cantly by gender, with 1202 (16.5%) females versus 690 (32.4%) males responding positively (P < .001). Patients with significant pelvic floor symptoms were more likely to have been assessed for pelvic floor disorders than were respondents as a whole. In patients with moderate-to-severe bladder symptoms, 2630 of 3787 patients (69.4%; 95% CI, 68.0-70.9) reported evaluation of this issue by their current MS health-care providers: 1958 of 2834 (69.1%) females and 672 of 953 (70.5%) males (P = .557). For patients with moderateto-severe bowel symptoms, 1638 of 2794 (58.6%; 95% CI, 56.8-60.5) reported undergoing evaluation for their symptoms: 1217 of 2125 (57.3%) females and 421 of 669 (62.9%) males (P = .014). And among patients with moderate-to-severe sexual problems, only 870 of 3644 (23.9%; 95% CI, 22.5-25.3) reported evaluation for these symptoms in the last year. There was a significant difference by gender, with only 455 of 2457 (18.5%) females reporting such evaluation, compared with 415 of 1187 (35.0%) males (P < .001). Despite low-to-moderate rates of questioning about pelvic floor issues, patients were generally satisfied with the evaluation and treatment of bladder and bowel complaints, but less satisfied with the management of sexual dysfunction, by their health-care providers (Table 2). Respondents were most pleased with the management of bladder symptoms (urinary incontinence or retention), with 5825 of 7008 patients overall (83.1%; 95% CI, 82.2-84.0), 4415 of 5354 (82.5%) females, and 1410 of 1654 (85.2%) males reporting moderate-to-complete satisfaction. Respondents were comparably satisfied with the evaluation and treatment of bowel symptoms (fecal incontinence, diarrhea, and constipation), with 4766 of 5985 patients overall (79.6%; 95% CI, 78.6-80.6) reporting moderate-to-complete satisfaction: 3508 of 4485

International Journal of MS Care 22

Pelvic Floor Disorders and MS Table 2. Patient satisfaction with provider evaluation and treatment of bladder, bowel, and sexual problems (N = 9397) Degree of satisfaction with provider

Bladder

Bowel

Sexual

Female

Male

Total

Female

Male

Total

Female

Male

Total

Not at all

437 (6.0)

105 (4.9)

542 (5.8)

461 (6.3)

110 (5.2)

571 (6.1)

883 (12.1)

257 (12.1)

1140 (12.1)

Slightly satisfied

502 (6.9)

139 (6.5)

641 (6.8)

516 (7.1)

132 (6.2)

648 (6.9)

420 (5.8)

180 (8.5)

600 (6.4)

Moderately satisfied

1160 (15.9)

402 (18.9)

1562 (16.6)

905 (12.4)

353 (16.6)

1258 (13.4)

561 (7.7)

323 (15.2)

884 (9.4)

Very satisfied

1601 (22.0)

506 (23.8)

2107 (22.4)

1194 (16.4)

426 (20.0)

1620 (17.2)

600 (8.3)

276 (13.0)

876 (9.3)

Completely satisfied

1654 (22.7)

502 (23.6)

2156 (22.9)

1409 (19.4)

479 (22.5)

1888 (20.1)

852 (11.7)

326 (15.3)

1178 (12.5)

Not applicable or not answered

1917 (26.4)

472 (22.2)

2389 (25.4)

2786 (38.3)

626 (29.0)

3412 (36.3)

3955 (54.4)

764 (35.9)

4719 (50.2)

Note: Values are presented as number (%).

(78.2%) females and 1258 of 1500 (83.9%) males. Satisfaction was much lower, however, among those responding to questions about sexual dysfunction. Many patients opted not to answer these questions (50%, or 4719 respondents). Of the 4768 patients who did respond, only 2938 (61.6%; 95% CI, 60.2-63.0) reported moderate-to-complete satisfaction with their care: 2013 of 3316 (60.7%) females versus 925 of 1362 (67.9%) males (P < .001). Thirty-seven percent of respondents were “not at all” to “slightly” satisfied with the care received for sexual dysfunction. Increased bother from bladder, bowel, or sexual problems was inversely correlated with satisfaction with provider evaluation and treatment (bladder: r = −0.206; 95% CI, −0.228 to −0.184; bowel: r = −0.339; 95% CI, −0.361 to −0.317; sexual: r = −0.400; 95% CI, −0.423 to −0.376; all P < .001). Among patients with moderate-to-severe pelvic floor problems, rates of satisfaction with care were higher among those with bowel and bladder symptoms than among those with sexual dysfunction (Table 3). Although no difference was found regarding the care of urinary symptoms, men tended to be more satisfied than women with the care of bowel and sexual problems. Of patients with moderate-to-severe bladder symptoms, 70.2% (2632; 95% CI, 68.7-71.6) of respondents reported moderate-to-complete satisfaction with their evaluation and care: 69.2% of females and 73.0% of males (P = .025). Among those with moderate-to-severe bowel symptoms, 60% (1661; 95% CI, 58.3-61.9) reported moderate-to-complete satisfaction: 58.1% of females and 66.4% of males (P < .001). In contrast, of respondents with moderate-to-severe sexual dysfunction,

only 33.9% (95% CI, 32.4-35.5) were moderately to completely satisfied with their care, while 24.2% (95% CI, 22.8-25.6) were “not at all satisfied”: 26.5% of females and 19.4% of males (P < .001). Age did not affect patient satisfaction with the management of their pelvic floor problems. For the majority of patients, treatment of pelvic floor dysfunction had either a positive effect or no effect on QOL. Although the results were skewed by the large number of patients who chose not to respond to this question, of the 5134 who did respond, 43% reported no effect on QOL and 47% reported an improvement, ranging from “a little better” to “much better” on a 7-point Likert scale. Nine percent (467 respondents) believed that treatment of their pelvic floor problems had negatively affected their QOL.

Discussion Despite significant efforts to educate patients, families, and health-care providers on the importance of bowel, bladder, and sexual dysfunction in MS patients, the impact of these efforts remains unclear. In a previous study, we demonstrated that 65% of men and women with MS reported moderate-to-severe urinary symptoms and that the majority of these patients had not been evaluated or treated for these problems.3 Those patients who had received treatment were often given older and significantly more morbid therapeutic options than members of the general population. Given these findings, we sought to explore the prevalence of bladder, bowel, and sexual dysfunction in a large sampling of the MS population. Most importantly, we sought to deter-

International Journal of MS Care 23

Mahajan et al. Table 3. Satisfaction with provider evaluation and treatment of pelvic floor problems among patients with moderate-to-severe symptoms only Degree of satisfaction with provider

Bladder (n = 3751)

Bowel (n = 2764)

Sexual (n = 3606)

Female

Male

Total

Female

Male

Total

Female

Male

Total

Not at all

247 (8.8)

69 (7.3)

316 (8.4)

274 (13.0)

71 (10.7)

345 (12.5)

645 (26.5)

227 (19.4)

872 (24.2)

Slightly satisfied

289 (10.3)

86 (9.1)

375 (10.0)

271 (12.9)

75 (11.4)

346 (12.5)

266 (10.9)

144 (12.3)

410 (11.4)

Moderately satisfied

660 (23.5)

261 (27.6)

921 (24.5)

520 (24.7)

207 (31.4)

727 (26.3)

305 (12.5)

238 (20.3)

543 (15.1)

Very satisfied

721 (25.7)

257 (27.2)

978 (26.1)

389 (18.5)

135 (20.4)

524 (18.9)

185 (7.6)

157 (13.4)

342 (9.5)

Completely satisfied

560 (20.0)

173 (18.3)

733 (19.5)

314 (14.9)

96 (14.5)

410 (14.8)

201 (8.3)

138 (11.8)

339 (9.4)

Not applicable or not answered

328 (11.7)

100 (10.6)

428 (11.4)

336 (16.0)

76 (11.5)

412 (14.9)

834 (34.2)

266 (22.7)

1100 (30.5)

Note: Values are presented as number (%).

mine whether the significant educational efforts by MS organizations were having any effect on the satisfaction of MS patients with the care they receive for pelvic floor problems and the impact of this care on QOL. Our results demonstrate that moderate-to-severe pelvic floor symptoms are extremely common among MS patients, with 41% reporting bladder, 30% reporting bowel, and 42% reporting sexual dysfunction. Our results may be skewed by selection bias. The sampling of patients participating in the NARCOMS Registry may not be representative of the general population of MS patients. Although patients who agree to participate in NARCOMS surveys may tend to be more willing to discuss their medical and personal issues, a significant number of patients opted not to answer questions about sexual dysfunction. Bladder and bowel symptoms as well as sexual dysfunction remain difficult topics to discuss, and our limited questionnaire responses may reflect widespread discomfort even in an anonymous format. Selection bias and differences in symptom measures may also explain why only 41% of respondents reported moderate-to-severe bladder symptoms in the fall 2010 survey, compared with 65% in the survey administered in the fall of 2005. Patients who had previously completed the fall 2005 questionnaire may have opted not to answer similar questions in the 2010 survey. In addition, different tools were used in the two questionnaires to measure symptom severity, with the validated Urinary Distress Index used in 2005 versus a self-described Likert scale in 2010.8 The resulting difference in the definition of “moderate-to-severe” pelvic floor symptoms may significantly contribute to the variation in our results.

Despite the large numbers of patients who chose not to answer questions on sexual dysfunction, a significant number of respondents did report such dysfunction (42%). Sexual dysfunction appears to be a significant concern for both men and women with MS. Men reported significantly higher rates of moderate-to-severe sexual dysfunction. Again, selection bias may hinder our ability to accurately estimate the prevalence of these complaints. Were patients with severe sexual dysfunction simply not comfortable answering these questions (suggesting that the true incidence is higher)? No evidence suggests this to be the case. Or were the patients with the most severe symptoms the ones most likely to respond (suggesting that the true incidence is much lower)? In addition, the elective nature of sexual activity versus the universal need to urinate and defecate may further skew our results. Nonetheless, our findings serve as a good starting point for determining the true rates of sexual and all pelvic floor disorders in MS patients. Although further studies are needed, men seem to be more bothered by sexual dysfunction than women. Further research is required to establish the true prevalence of these symptoms in the MS population. Respondents reported being asked about bowel and bladder complaints more frequently than sexual complaints within the last year by a health-care provider. Bladder (61%) and bowel (50%) symptoms were discussed with a health-care provider within the last year by at least half of respondents. Given recent significant educational efforts, however, we had hoped that these percentages would be higher. Unfortunately, only 20% of respondents had been asked about sexual dysfunc-

International Journal of MS Care 24

Pelvic Floor Disorders and MS

tion issues, although 40% reported moderate-to-severe symptoms. Pelvic floor issues may not be a high priority in the often-complicated medical care of MS patients as their disease progresses. Although increased bladder, bowel, and sexual dysfunction may be routinely acknowledged signs of worsening MS, our study is the first to demonstrate a clear correlation between worsening pelvic floor symptoms and MS progression. Healthcare providers should not ignore these important issues, no matter what stage of disease the patient exhibits. Rates of patient satisfaction with the care received from health-care providers and its impact on QOL were surprising. Despite relatively low rates of evaluation of pelvic floor symptoms, most patients reported moderateto-complete satisfaction with the care received (70%). Although patients with the most severe symptoms tended to be less satisfied with their care, minor attention to these issues appeared to adequately satisfy most patients. In general, female respondents tended to be less satisfied with the care received for pelvic floor problems than male respondents, although the difference did not always reach statistical significance. Although male respondents reported higher rates of moderate-to-severe sexual dysfunction, men were generally more satisfied than women with the care they received for these issues. In general, male sexual dysfunction is more easily treated, with excellent pharmacologic options available, while treatments for women are limited, possibly explaining this difference. Despite relatively high rates of satisfaction with evaluation and treatment of pelvic floor disorders overall, such treatment did not have a clear impact on patient QOL for the majority of respondents. Although these results may be surprising, they may indicate that pelvic floor issues are not a major concern for most of our respondents, and perhaps for MS patients in general. Finally, our survey did not involve screening for depression or other psychosocial issues. As a result,

the potential significant impact of these factors on satisfaction with the care of pelvic floor disorders, especially sexual dysfunction, and QOL was not assessed. Psychosocial factors are well known to affect female sexual function in general; these unassessed factors may contribute to the lower rates of satisfaction with sexual dysfunction care among female respondents.9,10 Further studies examining this complex relationship would strengthen our understanding of these issues. This study demonstrates significant patient satisfaction with current levels of evaluation and treatment of bladder and bowel dysfunction in MS. Recent efforts to increase patient, family, and clinician awareness of the importance of pelvic floor issues appear to have made some impact on the QOL of MS patients. However, these results are not universal; with regard to sexual dysfunction, outcomes remain poor. Many patients do not appear to receive adequate care from their health-care providers for these issues, nor are they satisfied with the care they do get. Future efforts must also be directed at more aggressive identification and treatment of sexual dysfunction among men and women with MS. o Acknowledgments: The authors would like to acknowledge the Consortium of Multiple Sclerosis Centers (CMSC) and its Foundation for their support of NARCOMS; and Robert Fox, MD, Tuula Tyry, PhD, MAED, and Kerry Grimberg, PhD, for their assistance with the editing of this manuscript. Financial Disclosures: The authors have no conflicts of interest to disclose.

References  1. Seland P. Paper presented at: “Urinary Dysfunction and Multiple Sclerosis: Evidence-Based Management Strategies for Urinary Dysfunction in Multiple Sclerosis” (conference of the Multiple Sclerosis Council for Clinical Practice Guidelines [MSCCPG]); 1999; Washington, DC.  2. Namey M, et al. Elimination dysfunction in multiple sclerosis: proceedings of a consensus conference. Int J MS Care. 2012;14(suppl 1):1–26.  3. Mahajan S, Patel P, Marrie R. The undertreatment of overactive bladder symptoms in women with multiple sclerosis: an ancillary analysis of the NARCOMS patient registry. J Urol. 2010;183:1432–1437.  4. Schwartz C, Vollmer T, Lee H; North American Research Consortium on Multiple Sclerosis Outcomes Study Group. Reliability and validity of two self-report measures of impairment and disability for MS. Neurology. 1999;52:63–71.  5. Hohol M, Orav E, Weiner H. Disease steps in multiple sclerosis: a simple approach to evaluate disease progression. Neurology. 1995;45:251–255.   6. Hohol M, Orav E, Weiner H. Disease steps in multiple sclerosis: a longitudinal study comparing disease steps and EDSS to evaluate disease progression. Mult Scler. 1999;5:349–354.   7. Kurtzke J. Rating disability in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:144.  8. Uebersax J, Wyman JF, Shumaker SA, McClish DK, Fantl JA; Continence Program for Women Research Group. Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Neurourol Urodyn. 1995;14:131–139.   9. Orasanu B, Wyman A, Mahajan S. Sexual dysfunction in patients with multiple sclerosis. Mult Scler Relat Disord. 2013;2:117–123. 10. Crayton H, Rossman H. Managing the symptoms of multiple sclerosis: a multimodal approach. Clin Ther. 2006;28:445–460.

PracticePoints • Although educational efforts have led to significant improvements in the management of bowel and bladder dysfunction among men and women with MS, treatments for sexual dysfunction remain inadequate. • Many patients are very satisfied with the care they receive for their urinary and bowel symptoms but are dissatisfied with the treatment of sexual dysfunction issues associated with MS.

International Journal of MS Care 25

Interest in Providing Multiple Sclerosis Care and Subspecializing in Multiple Sclerosis Among Neurology Residents Michael T. Halpern, MD, PhD; Stephanie Teixeira-Poit, MS; Heather L. Kane, PhD; A. Corey Frost, BA; Michael Keating, MA; Murrey Olmsted, PhD Background: Although detailed knowledge regarding treatment options for multiple sclerosis (MS) patients is largely limited to neurologists, shortages in the neurologist workforce, including MS subspecialists, are predicted. Thus, MS patients may have difficulties in gaining access to appropriate care. No systematic evaluation has yet been performed of the number of neurology residents planning to pursue MS subspecialization. This study identifies factors affecting interest in providing MS patient care or MS subspecialization among current neurology residents. Methods: We randomly selected half of all Accreditation Council of Graduate Medical Education–certified neurology residency programs in the continental United States to receive the neurology resident survey. Completed surveys were received from 218 residents. Results: Residents were significantly more likely to have increased interest in MS care when they participated in MS research, were interested in teaching, and indicated that the “ability to improve patient outcomes and quality of life” was a positive factor influencing their desire to provide MS patient care. Residents who were interested in providing MS care, interested in teaching, and indicated that “research opportunities” was a positive factor for providing MS patient care were significantly more likely to express interest in MS subspecialization. Conclusions: Increasing opportunities to interact with MS patients, learn about MS care, and participate in MS research may increase interest in MS care and subspecialization among neurology residents. Opportunities to educate residents regarding MS patient care may affect residents’ attitudes. Int J MS Care. 2014;16:26–38.

M

ultiple sclerosis (MS) is a chronic neurologic disease resulting in demyelination and axonal loss within the central nervous system. Over the past several years, treatment options for individuals with MS have expanded, including additional disease-modifying agents that can reduce relapses and decrease disease progression.1 Detailed knowledge regarding appropriate treatment options for MS patients is largely limited to neurologists and, within this physician specialist population, to MS subspecialists. More From RTI International, Washington, DC, USA. Correspondence: Michael T. Halpern, MD, PhD, RTI International, 701 13th St, Washington, DC 20005; e-mail: [email protected]. DOI: 10.7224/1537-2073.2013-009 © 2014 Consortium of Multiple Sclerosis Centers.

than 90% of MS patients have indicated that they receive treatment, assistance in obtaining medications, support, and education about their disease from neurologists.2 Further, receipt of treatment from neurologists is associated with higher quality of care3 and greater likelihood of receipt of disease-modifying agents.4 No systematic evaluation has been performed of the number of neurologists specializing in MS care. Reports of shortages among the overall neurologist workforce have existed for almost 3 decades. 5 A report by the Workforce Task Force of the American Academy of Neurology6 projects a 19% shortfall in supply of neurologists by the year 2025. Anecdotal evidence suggests an inadequate supply of MS subspecialists, based on difficulty in filling MS subspecialist positions, waiting lists for new patients, and patient groups describing dif-

International Journal of MS Care 26

Interest in Providing MS Care and Subspecializing in MS

ficulties finding available MS subspecialists. Information on the projected future workforce of MS physicians is critical to ensure optimal care among individuals with MS. The objective of this study was to elucidate factors associated with interest in providing care to individuals with MS or subspecializing in MS care among current neurology residents.

Methods Instrument Development To develop the MS Physician Workforce Study Neurology Resident Survey, we initially reviewed previously developed physician career surveys to identify items relevant to assessing neurology residents’ current interest in providing care to MS patients and pursuing MS subspecialization. After compiling these items, we selected and adapted existing questions and crafted new items to create a draft neurology resident survey. The draft survey included questions on respondents’ future career plans (ie, following residency training) including subspecialization programs of interest, factors influencing subspecialization decisions (in general, not specific to MS), interest in providing MS care and MS subspecialization, exposure to MS patients and MS patient care resources during residency training, and factors indicating limits on or positive influences toward providing MS patient care once the resident was in clinical practice. Plans for future time to be spent in research, teaching, and providing MS patient care (following residency training) were rated using a 5-point Likert scale ranging from “none” to “all my time.” Factors influencing subspecialization decisions were also rated using a 5-point Likert scale ranging from “not at all important” to “extremely important.” For assessing factors influencing future provision of MS patient care, residents were asked to respond to the questions “Which of the following factors could play a role in limiting the number of MS patients you would want to see once you have a clinical practice?” (eight choices) and “Which of the following factors could have a positive influence on your desire to provide care to MS patients once you have a clinical practice?” (seven choices). Residents were instructed to “mark all that apply,” and could indicate any, all, or none of these factors. Exposure to MS patient care resources during residency included MS clinics and MS care teams. Although the term was not defined on the survey, we expected that residents would consider MS clinics to be outpatient encounters in a venue offering a range of medical care

services and involving health-care professionals who specialize in MS care. MS care teams represent a coordinated group of health-care professionals with expertise in MS, but are not necessarily located in a specific clinic or venue dedicated to MS care. We also tested the comprehensiveness and usability of the survey. The final version of the survey was approved by the RTI International Institutional Review Board prior to distribution. The survey is published as a supplementary file in the online version of this article at http://ijmsc.org.

Survey Administration We developed a two-stage survey design in which Stage 1 randomly sampled geographically stratified neurology residency programs and Stage 2 obtained responses from neurology residents within these programs. The sampling frame consisted of all Accreditation Council of Graduate Medical Education (ACGME)–certified neurology residency programs in the continental United States and Puerto Rico. We stratified each residency program into one of four census regions (Northeast, South, West, and Midwest) and randomly selected half of the residency programs in each census region, for a total of 64 programs. We sent directors of the selected residency programs a cover letter describing the study and requesting that the directors distribute paper copies of the survey and return mailing materials (included with the cover letter) to all program residents. The cover letter, which indicated endorsement of this study by the National Multiple Sclerosis Society, also offered residents the opportunity to take the survey online. Residents who completed the survey received a $25 Visa gift card. We tracked responses to determine whether residents from particular programs had submitted any completed surveys; if no residents from a given program submitted responses, we sent a reminder letter to the resident director at 2 weeks and then again at 6 weeks after the initial mailing. We received at least one survey response from 44 of the sampled programs (Stage 1 response rate of 70%). Among the responding programs, 218 residents submitted survey responses (Stage 2 response rate of 31%).

Analysis For analyses, the study population was categorized based on self-reported demographic characteristics, including age group (categorized in quartiles), sex, race

International Journal of MS Care 27

Halpern et al.

(white, Asian or Pacific Islander, and black or other race, the latter two groups being combined because of small numbers of black respondents), and ethnicity (Hispanic/ Latino or not). Number of MS patients seen per year was categorized in approximate tertiles of 0 to 10, 11 to 30, and 31 or more. The primary study outcome measures were interest in providing MS care and interest in MS subspecialization. Neurology residents’ interest in providing MS care was classified into three categories based on the time they would ideally like to devote to MS patient care following completion of training: “none” or “a little” (categorized as “not interested”), “some” (categorized as “moderately interested”), or “a lot” or “all my time” (categorized as “very interested”). Similar criteria were applied to corresponding questions on time devoted to research and time devoted to teaching to identify residents not, moderately, or very interested in research or teaching, respectively. Residents’ ratings of the importance of factors influencing decisions to pursue subspecialty training (not restricted to MS) were classified into only two categories owing to more limited distribution of responses: “somewhat or less important” versus “very or extremely important.” Residents were classified as interested in MS subspecialization if they responded affirmatively to the survey question “Have you considered or are you considering a fellowship in MS as subspecialty training?” This “interest in MS subspecialization” variable did not take into account other areas of interest for subspecialization. We therefore also explored a dependent variable of “focused interest in MS subspecialization,” defined as an indication of interest in MS subspecialization as their only subspecialization choice or as one of two clinical areas specified for subspecialization. There were insufficient numbers of residents (n = 13) to examine factors associated with interest in only MS subspecialization. We used χ2 tests (or, as necessary because of small cell sizes, Fisher’s exact tests) to examine relationships between discrete variables and multivariate logistic regression models to identify predictors of increased interest in providing MS care (ordered logistic regression, with three-level dependent variable) and of interest in MS subspecialization. These models included independent variables related to MS patient exposure during residency, future interest in research or teaching, attitudes toward MS patient care, and demographic characteristics that were statistically significant (P < .05)

or approached statistical significance (P < .10) in bivariate analyses of either dependent variable (interest in MS care or interest in MS subspecialization), as presented in Tables 1 to 3. The regression model examining interest in MS subspecialization also included interest in providing MS care and factors associated with the decision to pursue subspecialty training as independent variables. All variables included in regression analyses were examined for multicollinearity (Variance Inflation Factor > 5) prior to inclusion in the final model. Missing data generally comprised less than 2% of responses, and individuals with missing data for descriptive, bivariate, or regression analyses were excluded from those analyses. We defined P < .05 as the criterion for statistical significance and classified analysis results with P > .05 but < .10 as marginally significant.

Results Population Characteristics The study population consisted of 218 neurology residents. After excluding 4 neurology residents who did not respond to the question on interest in providing MS care, 142 (66%) expressed interest in providing MS care (ie, indicated that they would like to devote at least some of their time to providing MS care) and 72 (34%) were not interested. After excluding 8 neurology residents who were not aware of MS fellowships or did not respond to the question, 74 (35%) expressed interest in MS subspecialization and 136 (65%) were not interested.

Characteristics Associated with Interest in Providing MS Care Neurology residents very interested in MS care (ie, indicating spending “a lot” or “all my time” in MS care in the resident survey) were more likely to be in the youngest age group and the first or second year of their residency program (Table 1). Male residents were marginally more interested in MS subspecialization than were females. Neurology residents from larger residency programs did not differ significantly in interest in providing MS care or interest in MS subspecialization from residents from smaller programs (data not shown). All residency programs in our sample were located in metropolitan core areas, so we were unable to examine differences based on urban versus rural locale. As shown in Table 2, participation in any MS research, level of interest in research, and level of interest in teaching were also significantly associated with level of

International Journal of MS Care 28

Interest in Providing MS Care and Subspecializing in MS Table 1. Characteristics of study population by interest in providing MS care and interest in MS subspecialization Total study population Population characteristics Total study population

Number 218

% within column 100.00

Interested in MS subspecialization (% within row)

Interested in providing MS care (% within row) None or a little time

Some time

A lot or all their time

33.64

50.00

16.36

Age at survey, y

P value

Yes



35.24

.043

26–29

50

23.70

24.00

50.00

26.00

50.00

46

21.80

50.00

43.48

6.52

17.39

31–32

56

26.54

33.93

46.43

19.64

29.63

≥33

59

27.96

29.31

58.62

12.07

42.11

61

28.37

23.33

51.67

25.00

1 or 2

.038

.000 55.36

3

76

35.35

28.38

56.76

14.86

35.14

4

78

36.28

44.16

44.16

11.69

22.08

116

53.95

31.90

53.45

14.66

99

46.05

35.71

45.92

18.37

Sex Female Male

.527

Race White

.058 29.46 42.11

.101

.575

115

54.25

36.52

46.96

16.52

36.36

Asian or Pacific Islander

68

32.08

38.81

49.25

11.94

30.77

Black or other racea

29

13.68

13.79

58.62

27.59

Ethnicity Hispanic/Latino Not Hispanic/Latino

– .005

30

Year in residency program

P value, Yes vs. No

41.38 .103

.757

12

5.66

8.33

66.67

25.00

41.67

200

94.34

35.68

48.24

16.08

34.90

Abbreviation: MS, multiple sclerosis. a Of the 29 respondents in the “Black or other race” category, 2 respondents were black/African American, 3 were American Indian/Native American or Alaska Native, and 24 reported being another race.

interest in providing MS care. Residents very interested in MS care were more likely to have participated in MS research and to be very interested in research and teaching than were residents not interested in MS care. Residents indicating “MS patients are often difficult to treat” as a factor that could limit the number of MS patients they would see once in clinical practice were less likely to express interest in providing MS care (Table 3). In contrast, the percentage of neurology residents very interested in MS care was significantly higher among those who indicated several positive factors associated with MS patient care: “ability to improve patient outcomes and quality of life,” “dynamic area with evolving treatment options,” “research opportunities,” and “community of dedicated professional colleagues with which to interact.” Residents very interested in MS care were also significantly more likely to indicate four or more

positive factors influencing their desire to provide MS patient care once in clinical practice. We used an ordered logistic regression model to examine the association of resident demographic characteristics, exposure to MS patients during residency, research and teaching plans, and attitudes toward MS patient care with level of interest in providing MS care (Table 4). All survey items that had significant or marginally significant associations with self-reported interest in providing MS care or interest in MS subspecialization in bivariate analyses (Tables 1–3) were included as independent variables in this regression model. In this analysis, residents were significantly more likely to have increased interest in MS care when they participated in any MS research, were very interested in teaching (compared with those not interested in teaching), and indicated that the “ability to improve patient outcomes and quality of life” was a positive factor influencing their

International Journal of MS Care 29

Halpern et al. Table 2. Relationship of MS patient exposure during residency and research/teaching plans with interest in MS care and interest in providing MS subspecialization Total study population Number

% within column

Interested in MS subspecialization (% within row)

Interested in providing MS care (% within row) None or a little time

Some time

A lot or all their time

MS patients seen/year

P value

Yes

.885

.038

0–10

42

20.29

39.02

46.34

14.63

17.95

11–30

106

51.21

30.48

52.38

17.14

39.81

59

28.5

35.59

47.46

16.95

39.66

≥31 MS clinic at residency institution

.443

.884

Yes

170

80.19

36.31

47.62

16.07

35.37

No

42

19.81

26.19

57.14

16.67

34.15

MS care team at residency institution

.742

.783

Yes

136

63.55

33.58

48.51

17.91

35.66

No

78

36.45

33.33

52.56

14.10

33.77

MS faculty at residency institution

.629

Yes

195

90.7

34.72

48.70

16.58

No

20

9.3

25.00

60.00

15.00

MS research at residency institution

.641 34.76 40.00

.152

.022

Yes

141

66.82

36.43

45.00

18.57

40.15

No

70

33.18

30.00

58.57

11.43

23.88

Participated in any MS research

.000

.000

Yes

23

10.70

4.55

45.45

50.00

73.91

No

192

89.30

37.17

50.26

12.57

29.89

Participated in any neurology research

.392

.831

Yes

148

69.16

36.30

48.63

15.07

35.42

No

66

30.84

27.27

53.03

19.70

33.87

Interested in providing MS care None or a little time



.000

72

33.64







7.14

107

50.00







43.69

35

16.36







66.67

106

49.77

32.08

56.60

11.32

26.92

Some time

79

37.09

36.71

48.10

15.19

38.67

A lot or all their time

28

13.15

32.14

28.57

39.29

57.69

Some time A lot or all their time Interested in research None or a little time

.006

Interested in teaching None or a little time Some time A lot or all their time

.010

.001

.000

46

21.80

47.83

43.48

8.70

11.11

107

50.71

28.97

59.81

11.21

38.61

58

27.49

31.03

36.21

32.76

49.12

Abbreviation: MS, multiple sclerosis.

International Journal of MS Care 30

P value, Yes vs. No

Interest in Providing MS Care and Subspecializing in MS Table 3. Relationship of attitudes toward MS patient care with interest in providing MS care and interest in MS subspecialization Total study population Attitude

Number

% within column

Interested in providing MS care (% within row) None or a little time

Some time

A lot or all their time

Care for MS patients takes too much time

P value

Interested in MS subspecialization (% within row) Yes

.230

.019

Yes

66

30.56

41.54

46.15

12.31

23.44

No

150

69.44

30.20

51.68

18.12

40.28

Lack of sufficient training/ knowledge regarding best medical care practices

.818

.075

Yes

51

23.61

33.33

52.94

13.73

24.49

No

165

76.39

33.74

49.08

17.18

38.36

MS patients are often difficult to treat

.016

.015

Yes

53

24.54

50.00

38.46

11.54

21.15

No

163

75.46

28.40

53.70

17.90

39.74

Three or more limiting attitudes indicated

.602

.107

Yes

69

31.94

38.24

45.59

16.18

27.27

No

147

68.06

31.51

52.05

16.44

38.73

Ability to improve patient outcomes and quality of life

.014

.599

Yes

166

76.85

28.48

53.94

17.58

36.08

No

50

23.15

51.02

36.73

12.24

32.00

Dynamic area with evolving treatment options

.002

.009

Yes

125

57.87

25.00

53.23

21.77

42.50

No

91

42.13

45.56

45.56

8.89

25.00

Research opportunities

.001

.000

Yes

59

27.31

22.41

46.55

31.03

60.00

No

157

72.69

37.82

51.28

10.90

26.14

Community of dedicated professional colleagues with which to interact

.020

.287

Yes

85

39.35

25.00

51.19

23.81

39.51

No

131

60.65

39.23

49.23

11.54

32.28

Four or more positive attitudes indicated

.000

.034

Yes

88

40.74

19.54

55.17

25.29

43.53

No

128

59.26

43.31

46.46

10.24

29.27

Abbreviation: MS, multiple sclerosis.

International Journal of MS Care 31

P value, Yes vs. No

Halpern et al. Table 4. Ordered logistic regression analysis of factors associated with interest in providing MS care Factor

Odds ratio

95% CI

P value

30

0.56

0.21-1.51

.256

31–32

1.61

0.63-4.13

.325

≥33

1.05

0.43-2.55

.916

3

0.87

0.39-1.91

.723

4

0.31

0.13-0.75

.009

1.34

0.70-2.58

.376

11–30

1.02

0.44-2.35

.966

≥31

0.86

0.34-2.17

.742

0.77

0.38-1.57

.467

9.00

3.04-26.68

.000

Some time

0.44

0.20-0.95

.037

A lot or all their time

1.47

0.48-4.50

.504

Some time

2.06

0.85-5.02

.110

A lot or all their time

3.20

1.09-9.38

.034

1.02

0.50-2.05

.967

0.96

0.46-1.99

.908

0.38

0.18-0.81

.012

2.58

1.10-6.04

.029

1.32

0.62-2.78

.468

1.87

0.78-4.49

.162

0.99

0.48-2.07

.984

1.48

0.59-3.74

.405

Age at survey (26–29 reference), y

Year in residency program (1/2 reference)

Sex (male reference) Female MS patients seen/year (0–10 reference)

MS research at residency institution Yes Participation in any MS research Yes Interested in research (none or a little time reference)

Interested in teaching (none or a little time reference)

Indicated “care for MS patients takes too much time” as a limiting factor Yes Indicated “lack of sufficient training/knowledge regarding best medical care practices” as a limiting factor Yes Indicated “MS patients are often difficult to treat” as a limiting factor Yes Indicated “Ability to improve patient outcomes and quality of life” as a positive factor Yes Indicated “Dynamic area with evolving treatment options” as a positive factor Yes Indicated “Research opportunities” as a positive factor Yes Indicated “Community of dedicated professional colleagues with which to interact” as a positive factor Yes Four or more positive attitudes indicated Yes Abbreviations: CI, confidence interval; MS, multiple sclerosis.

International Journal of MS Care 32

Interest in Providing MS Care and Subspecializing in MS

desire to provide MS patient care once in clinical practice. Residents were significantly less likely to be interested in MS care when they were in the fourth year of their residency program (compared with those in the first or second year of their residency program) and indicated that “MS patients are often difficult to treat” as a factor that could limit the number of MS patients seen once in clinical practice. Residents who indicated moderate interest in research were also significantly less likely to be interested in MS care (compared with those not interested in research). In contrast, residents very interested in research or indicating “research opportunities” as a positive factor were more interested in providing MS care, but these effects did not reach statistical significance.

Characteristics Associated with Interest in MS Subspecialization Neurology residents who were interested in MS subspecialization were more likely to be in the youngest or oldest age category and in the first or second year of their residency program (Table 1). They were more likely to have seen greater numbers of MS patients, have ongoing MS research studies at their residency institutions, have participated in any MS research, and express interest in spending more time providing MS care, conducting research, and teaching (Table 2). Residents interested in MS subspecialization were less likely to indicate that the following factors could limit the number of MS patients seen once in clinical practice: “care for MS patients takes too much time,” “lack of sufficient training/knowledge regarding best medical care practices,” and “MS patients are often difficult to treat.” These residents were more likely to indicate “dynamic area with evolving treatment options” and “research opportunities” as factors that could have a positive influence on their desire to provide MS patient care once in clinical practice and to indicate four or more positive factors (Table 3). Among factors potentially influencing the decision whether to pursue subspecialty training in general, residents indicating that loan repayment opportunities were an important factor in subspecialty decisions were more likely to express interest in MS subspecialization. In logistic regression analysis including all significant or marginally significant variables from Tables 1 to 3 and Table 5, several factors were significantly associated with residents’ interest in MS subspecialization (Table 6). Residents in their fourth program year were significantly less likely to be interested in MS subspecialization compared with those in their first or second year. Resi-

dents who were moderately or very interested in providing MS care, moderately or very interested in teaching, and indicated that “research opportunities” was a positive factor influencing their desire to provide MS patient care once in clinical practice were significantly more likely to express interest in MS subspecialization. We also examined whether these same variables (from Tables 1–3 and Table 5) were significantly associated with “focused interest” in MS subspecialization (Table 6). As discussed in the Methods section, we classified residents as having focused interest in MS subspecialization if they were considering MS subspecialization plus at most one additional subspecialization area. This measure therefore indicates more selective interest in MS subspecialization than does the outcome of any interest in this area of subspecialization. In logistic regression analysis, residents who were moderately or very interested in providing MS care and indicated that “research opportunities” was a positive factor influencing their desire to provide MS patient care once in clinical practice were significantly more likely to express a focused interest in MS subspecialization; these results were very similar to those from regression analyses of any interest in MS subspecialization. Residents indicating “care for MS patients takes too much time” and “MS patients are often difficult to treat” as factors that could limit the number of MS patients they would see once in clinical practice were significantly less likely to express a focused interest in MS subspecialization. Interestingly, while overall interest in MS subspecialization decreased among residents in their third or fourth program year, focused interest in MS subspecialization increased in these lateryear residents, although this increase was not statistically significant.

Discussion This study yielded information on interest in providing care for individuals with MS and in subspecializing in MS among a sample of neurology residents. An important finding of this study was overall high levels of interest in MS patient care, with 66% of residents expressing an interest in MS care and 35% expressing interest in MS subspecialization. However, the levels of interest in MS care and subspecialization were significantly lower among fourth-year residents (Table 1). There are a number of possible explanations for this finding. When starting a neurology residency program, residents may be aware of only a limited number of

International Journal of MS Care 33

Halpern et al. Table 5. Relationship of factors potentially influencing the decision to pursue subspecialty training with interest in MS subspecialization Total study population Factor

Number

% within column

Interested in MS subspecialization (% within row) Yes

Medical content of specialty

P value, Yes vs. No .605

Somewhat or less important

18

8.41

41.18

Very or extremely important

196

91.59

34.92

Availability of open slots in subspecialty training programs

.952

Somewhat or less important

101

46.98

35.05

Very or extremely important

114

53.02

35.45

Training program location

.391

Somewhat or less important

60

27.91

40.00

Very or extremely important

155

72.09

33.55

Potential for increased income

.740

Somewhat or less important

89

41.59

34.12

Very or extremely important

125

58.41

36.36

Influence of mentor/teacher/role model

.105

Somewhat or less important

68

31.92

27.27

Very or extremely important

145

68.08

38.85

Personal/family member or friend’s experiences with specific medical conditions

.755

Somewhat or less important

155

73.11

34.67

Very or extremely important

57

26.89

37.04

Loan repayment opportunity

.028

Somewhat or less important

149

69.95

30.77

Very or extremely important

64

30.05

46.77

Length of training program

.957

Somewhat or less important

114

53.52

35.78

Very or extremely important

99

46.48

35.42

Abbreviation: MS, multiple sclerosis.

subspecialty opportunities. Because individuals with MS are frequently encountered at academic medical centers, new residents may be aware of opportunities to provide care for MS patients and subspecialize in their care. As residents progress through their training programs, they may learn of other subspecialization opportunities (eg, clinical neurophysiology) that they did not know of previously and may decide to focus on other groups of patients and pursue subspecialties other than MS. Although interest in MS subspecialization decreases with year of residency, interest in a number of other subspecialties also decreases with time in residency program (data not shown). This may reflect neurology residents’ becoming more focused and considering fewer subspe-

cialties over time. We observed that the average number of subspecialty programs considered by neurology residents decreases over time, from 1.92 among first- or second-year residents to 1.59 among third-year residents to 1.13 among fourth-year residents (data not shown). The significant decrease in resident interest in MS subspecialization over time likely reflects (at least in part) more specific focus by residents on their career path of interest. In addition, while any interest in MS subspecialization decreased with year in residency program (likely reflecting the decreased number of subspecialty programs of interest going from the start of residency to year 4), focused interest in MS subspecialization was greater among residents in their third or fourth pro-

International Journal of MS Care 34

Interest in Providing MS Care and Subspecializing in MS Table 6. Logistic regression analysis of factors associated with interest in MS subspecializationa Focused interest in MS subspecializationb

Any interest in MS subspecialization Factor Age at survey (26–29 reference), y 30

Odds ratio

95% CI

P value

Odds ratio

95% CI

P value

0.81

0.20-3.21

.765

0.66

0.14-3.07

.600

31–32

1.13

0.31-4.16

.857

0.59

0.15-2.24

.437

≥33

2.34

0.69-7.87

.171

0.84

0.24-2.95

.781

0.44

0.15-1.27

.129

1.84

0.55-6.13

.322

0.24

0.07-0.80

.020

2.03

0.57-7.19

.272

0.82

0.33-2.00

.657

0.82

0.31-2.17

.695

Year in residency program (1/2 reference) 3 4 Sex (male reference) Female MS patients seen/year (0–10 reference) 11–30

2.86

0.76-10.77

.119

2.08

0.47-9.17

.336

1.95

0.45-8.46

.373

3.48

0.69-17.63

.132

MS research at residency institution Yes

2.20

0.75-6.46

.151

1.10

0.35-3.49

.875

Participation in any MS research Yes

1.71

0.38-7.57

.482

1.09

0.25-4.67

.911

≥31

Interest in providing MS care (none or a little time reference) Some time

7.69

2.16-27.33

.002

8.20

1.74-38.70

.008

13.92

2.74-70.70

.001

19.28

3.04-122.20

.002

0.85

0.30-2.43

.765

0.94

0.28-3.18

.920

1.30

0.28-6.01

.734

0.97

0.19-4.85

.971

5.01

1.13-22.18

.034

2.12

0.44-10.22

.348

8.73

1.60-47.77

.012

1.94

0.33-11.52

.464

Indicated “care for MS patients takes too much time” as a limiting factor Yes

0.77

0.29-2.07

.602

0.26

0.07-0.92

.037

Indicated “lack of sufficient training/knowledge regarding best medical care practices” as a limiting factor Yes

0.70

0.24-2.09

.523

0.53

0.17-1.64

.272

Indicated “MS patients are often difficult to treat” as a limiting factor Yes

0.55

0.17-1.73

.306

0.13

0.03-0.71

.018

Indicated “Ability to improve patient outcomes and quality of life” as a positive factor Yes

1.41

0.42-4.71

.577

0.64

0.18-2.25

.488

Indicated “Dynamic area with evolving treatment options” as a positive factor Yes

2.23

0.71-6.93

.168

1.26

0.38-4.24

.706

A lot or all their time Interested in research (none or a little time reference) Some time A lot or all their time Interested in teaching (none or a little time reference) Some time A lot or all their time

Continued on page 36

International Journal of MS Care 35

Halpern et al. Continued from page 35

Table 6. Logistic regression analysis of factors associated with interest in MS subspecializationa Focused interest in MS subspecializationb

Any interest in MS subspecialization Factor

Odds ratio

95% CI

P value

Odds ratio

95% CI

P value

Indicated “Research opportunities” as a positive factor Yes

4.41

1.26-15.37

.020

4.83

1.29-18.12

.020

Indicated “Community of dedicated professional colleagues with which to interact” as a positive factor Yes

0.61

0.20-1.88

.385

1.04

0.34-3.22

.942

Four or more positive attitudes indicated Yes

0.39

0.10-1.48

.165

0.53

0.12-2.33

.401

Importance of loan repayment opportunity in making the decision to pursue subspecialty training (somewhat or less important reference) Very or extremely important

2.03

0.81-5.11

.132

0.76

0.28-2.12

.607

Abbreviations: CI, confidence interval; MS, multiple sclerosis. a Analysis includes only respondents who answered yes or no to interest in MS subspecialization; missing responses and responses “I’m not aware of MS fellowships” excluded. b “Focused interest in MS subspecialization” is defined as indication of interest in MS subspecialization as their only subspecialization choice or as one of two clinical areas for subspecialization.

gram year, although this difference was not statistically significant. Therefore, residents who have more specific interest in MS subspecialization at the start of residency appear to either maintain this interest or show a trend for increased focus on this subspecialty while excluding other potential areas of subsequent training. Our analyses found a significant association between number of MS patients seen per year and interest in MS subspecialization (Table 2), although this was not statistically significant in multivariate regression analysis (Table 6). This association may reflect greater exposure to individuals with MS during residency training leading to increased interest in careers focusing on this patient group. Alternatively, it is possible that residents who are more interested in MS subspecialization will select MS electives during their residency and thus see more MS patients because of prior interest in this area. It is not possible to determine the direction of this association with our available data, and both of these factors may be important. We can, however, examine differences in residents’ attitudes toward MS patient care to explore whether the association between number of MS patients seen and interest in MS subspecialization reflects a priori interest in MS care versus interest in MS that develops following greater patient exposure. During required rotations,

neurology residents may predominantly see MS patients whose disease is not well managed, potentially leading to a skewed view of MS patient care. In contrast, MS electives often include interactions with individuals in ambulatory care settings, exposing residents to MS patients whose disease may be better controlled and who have fewer symptoms and less disability. If residents who saw more MS patients did so through MS electives, these residents would likely have greater interactions with MS patients having well-controlled disease. As a consequence, we would expect that residents seeing more MS patients would be less likely to indicate limiting attitudes about MS patient care such as “MS patients are difficult to care for” or “MS patients have multiple comorbidities.” We found no significant association between numbers of MS patients seen and agreement with these two limiting attitudes on MS patient care (data not shown). We therefore assume that, at least in part, residents who have the opportunity to see more individuals with MS do so as part of their required rotations, and are more likely to develop interest in this clinical area as a career focus after this increased MS patient exposure. In bivariate analyses (Table 5), residents who expressed interest in MS subspecialization were more likely to indicate that loan repayment opportunities

International Journal of MS Care 36

Interest in Providing MS Care and Subspecializing in MS

were a moderately or very important factor in making subspecialty training decisions in general. Loan repayment opportunities were not significantly associated with interest in MS subspecialization in the multivariate regression model (Table 6). MS subspecialization may have lower income prospects compared to other neurology subspecialties, according to members of this study’s advisory panel. As such, individuals interested in MS subspecialization may have increased concerns regarding their ability to repay educational loans if they were to pursue additional training in this area. However, this factor appears to have only a limited impact on subspecialization choice. Our findings indicate that interest and participation in research was associated with greater interest in MS. As presented in Tables 4 and 6, participation in MS research, desire to spend a lot or all of their time performing research, and viewing “research opportunities” as a positive factor for MS patient care were associated with increased interest in both MS patient care and MS subspecialization, although not all of these associations reached statistical significance. However, the questions on research in the resident survey correspond to three different dimensions. Participation in MS research captured previous experience among residents; those who had participated in MS research were highly motivated to provide MS patient care. In contrast, desired time to be spent performing research as a part of future careers (ie, following residency training) may relate to type of career track. Residents who responded that they wanted to spend a lot or all of their time in research were likely interested in academic careers. Finally, viewing “research opportunities” as a positive factor for MS patient care may relate to both interest in performing research and interest in providing care for individuals with MS. These residents are among those most likely to indicate focused interest in MS subspecialization (Table 6). Thus, while interest in research is generally associated with interest in MS care, the differences in type of research interest may provide important information on differences in career plans and desired future role related to MS patient care. Analyses of differences between any interest in MS subspecialization and “focused interest” in this area of subspecialization (Table 6) showed an additional important finding. Residents indicating that “care for MS patients takes too much time” and “MS patients are often difficult to treat” were significantly less likely to express a focused interest in MS subspecialization. How-

ever, neither of these limiting factors was significantly associated with overall interest in MS subspecialization. This suggests that these attitudes may have critical impacts, discouraging residents with some interest in MS from pursuing this area of subspecialization. These results suggest several approaches to addressing potential shortages among neurologists providing care for individuals with MS or subspecializing in MS patient care. Exposure to a broader range of MS patients, including those whose disease is well controlled, and education regarding expected outcomes among individuals whose disease is well managed, may affect interest in MS care and subspecialization. In particular, exposure to broader groups of MS patients could affect the limiting attitudes of MS patient care being too difficult and requiring too much time, which differentiate any interest from focused interest in MS subspecialization. Providing educational opportunities regarding the range of disease among individuals with MS may also be relevant for medical students, prior to selection of a residency field. In addition, more information on research opportunities related to MS and additional programs to facilitate resident research in this area may increase interest in MS care and subspecialization. Among neurology residents responding to this survey who were not interested in MS patient care, approximately 30% indicated that mini-grant funding in MS research or the availability of a mentor directing MS research would have encour-

PracticePoints • Predicted shortages among neurologists may increase the difficulty of people with MS in obtaining care. Identifying factors that encourage neurology residents’ interest in providing MS patient care and pursuing MS subspecialization may help to address these potential physician shortages. • Providing educational opportunities that give neurology residents exposure to a broader range of MS patients, including those whose disease is well controlled, may increase interest in providing MS care and subspecializing in MS and decrease perceptions that MS patient care is too difficult and requires too much time. • Offering additional MS research opportunities (eg, mini-grants) and providing research mentors may promote neurology residents’ interest in MS care and MS subspecialization.

International Journal of MS Care 37

Halpern et al.

aged them to participate in research in MS (data not care. Several actionable items, such as increasing exposhown). Similarly, among residents not interested in sure to MS patients and to research opportunities related MS subspecialization, 30% indicated that mini-grant to MS patient care, may increase interest in MS. Our funding would have encouraged their participation in subsequent work to project the adequacy of the future MS research and 47% indicated that a research mentor MS physician workforce will explore the potential would have encouraged participation in this research impacts of these actions and assist in developing policy area (data not shown). Thus, additional information on recommendations to address physician shortages that MS research and new opportunities to participate in this research may be important steps to address shortages in may adversely affect MS patient care. o the MS physician workforce. Acknowledgments: The authors would like to thank Dr. Nicholas A number of limitations are associated with this LaRocca and the National Multiple Sclerosis Society for their fundstudy. First, although neurology residency programs ing of this study and guidance during the study. We would also like identified to receive the survey were randomly selected to thank members of the MS Physician Workforce Study Advisory from all US neurology programs, distribution of the Panel for their thoughtful comments on earlier versions of the manusurvey to the residents was dependent on the residency script. Advisory Panel members include Dr. Corey Ford, Dr. Barbara Giesser, Ms. June Halper, Dr. Shana Johnson, Dr. Aaron Miller, and director. Also, residents self-selected whether to respond Dr. Steven Ringel. to the survey. Either of these factors could bias the study population, reducing the generalizability of the Funding/Support: This study was funded by the National Multiple results. The study population of 218 residents, while Sclerosis Society (Award No. HC0121). representing a Stage 2 response rate of more than 30% Financial Disclosures: The authors have no conflicts of interest to (and thus not unusual for this type of survey), is fairly disclose. small; factors that were only marginally associated with the study outcome measures (interest in MS patient care References 1. Bandari DS, Sternaman D, IJMSC Chan T, ProstkoARTICLE CR, Sapir T. Evaluating risks, HERNDON FOR OUTSTANDING and MS subspecialization)AWARD may actually have stronger costs, and benefits of new and emerging therapies to optimize outcomes associations. In addition, all data were collected by selfin multiple sclerosis. Manag Care Pharm. 2012;18:1–17. The Consortium of Multiple Sclerosis Centers (CMSC) presents an J annual Tests of Information Processing Speed response to the survey; no attempt was made to validate 2. National Multiple Sclerosis Society and Teva Neuroscience. Multiple award, the Herndon Award for Outstanding IJMSC Article, for the best article Sclerosis Trend Report: Perspectives from Managed Care, Providers, and these responses. Finally, as with any survey, we were published in the International Journal of MS Care duringPatients. a given calendarDC: year. Washington, Kikaku America International; 2007. limited in the number of items included and the range 3. Buchanan R, Kaufman M, Zhu L, James W. Patient perceptions of multiThe winners of the 2012 award are Lisa A.S. Walker (The Ottawa Hospital of responses to the items. Although we included opensclerosis-related care: comparisons by practice specialty of principal and the University of Ottawa) and colleagues, for their ple article “Tests of Inforcare physician. NeuroRehabilitation. 2008;23:267–272. ended response opportunities with several items and an mation Processing Speed: What Do People with Multiple Sclerosis Think open-ended comment section at the end of the survey, 4. Minden SL, Hoaglin DC, Hadden L, CFrankel D, Robbins T, Perloff J. About Them?” published in the Summer 2012 issue of IJMSC. Theutilization award carAccess to and of neurologists by people with multiple sclerowe likely did not capture all factors related to interest sis. Neurology. ries a $1000 stipend. Robert M. Herndon was the founding editor2008;70(13 of IJMSCPt 2):1141–1149. in providing MS care and MS subspecialization among 5. Dyken ML. The continuing undersupply of neurologists in the and currently serves as Editor Emeritus. 1980s: impressions based on data from three studies. Neurology. neurology residents. 1982;32:651–656. Despite these limitations, this study provides impor6. Dall TM, Storm MV, Chakrabarti R, et al. Supply and demand tant new information for addressing potential shortages analysis of the current and future US neurology workforce. Neurology. 2013;81:470–478. among neurologists focused on providing MS patient What Do People with Multiple Sclerosis Think About Them? Lisa A.S. Walker, PhD; Amy Cheng, BA; Jason Berard, BScH, Lindsay I. Berrigan, PhD; Laura M. Rees, PhD; Mark S. Freedman, MD

Reduction in information processing speed (IPS) is a key deficit in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and Computerized Test of Information Processing (CTIP) are used to measure IPS. Both the PASAT and SDMT are sensitive to deficits in IPS. The CTIP, a newer task, also shows promise. The PASAT has several limitations, and it is often perceived negatively by patients. Yet little supporting quantitative evidence of such perceptions has been presented. Therefore, in this study, subjective ratings of likeability, difficulty, and appropriateness of the PASAT, CTIP, and SDMT were obtained. Ratings were compared between MS patients and healthy controls. It was hypothesized that ratings of the PASAT would differ significantly from those of the SDMT and CTIP. The relationship between subjective ratings and objective performance was evaluated. Sixty-nine MS patients and 68 matched controls rated the three tests in terms of likeability, difficulty, and appropriateness for capturing cognitive deficits often associated with MS using a Likert scale. Both groups rated the PASAT as most difficult and least likeable. The MS group rated the PASAT and SDMT as more appropriate for measuring MS-related deficits than the CTIP. Subjects who performed better on the PASAT were more likely to rate it as easier. Ratings of the SDMT and CTIP did not vary consistently with performance. The findings lend quantitative support to the common belief that the PASAT is perceived as unpleasant. Other tests are available that are similarly sensitive to deficits in IPS and more palatable to the patient. Int J MS Care. 2012;14:92–99.

ognitive impairment is common in multiple sclerosis (MS), affecting 40% to 65% of patients and contributing to functional limitations that result in poor health-related quality of life (HRQOL).1,2 The predictive value of cognitive dysfunction in HRQOL remains even after controlling for subjective distress variables such as depression and fatigue.3 The most commonly identified cognitive difficulties associated with MS include problems with working memory, as well as learning and memory for new information.4,5 Information processing speed has also been From the Neuropsychology Service, The Ottawa Hospital, Ottawa, Ontario, Canada (LASW, LMR); The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (LASW, LIB, LMR, MSF); Division of Neurology, Faculty of Medicine (LASW, MSF), and School of Psychology, University of Ottawa, Ottawa, Ontario, Canada (LASW, AC, JB, LMR); and Department of Psychology, Carleton University, Ottawa, Ontario, Canada (LIB, LMR). Correspondence: Lisa A.S. Walker, PhD, Psychology, The Ottawa Hospital, 501 Smyth Rd., Ste. 7300, Ottawa, Ontario K1H 8L6, Canada; email: [email protected].

identified as a primary cognitive deficit in MS.6-8 Cognitive difficulties can lead to problems for people with MS in their daily lives, such as their ability to maintain employment.1,9 Such deficits can also negatively affect their relationships with intimate partners, family members, caregivers, coworkers, and their health-care team.10 A challenge with any type of cognitive assessment is selecting measures that possess good psychometric properties (ie, reliability, validity, sensitivity to impairment, specificity to the types of impairment encountered in MS). While it is important for clinicians to select tests that do not cause stress for the individual completing the test, it is also important to ensure that even subtle cognitive deficits are detected. Thus, some measures that are designed to be quite challenging to complete must also be included. One such task that has been reported anecdotally to be unpleasant, both for the patients undergoing it and for the clinicians administering it, is the Paced Audi-

International Journal of MS Care 92

HERNDON AWARD FOR OUTSTANDING IJMSC ARTICLE The Consortium of Multiple Sclerosis Centers (CMSC) presents an annual award, the Herndon Award for Outstanding IJMSC Article, for the best article published in the International Journal of MS Care during a given calendar year. The award carries a $1000 stipend. Robert M. Herndon was the founding editor of IJMSC. The winner of the 2013 award will be announced at the 2014 Annual Meeting of the CMSC in May. International Journal of MS Care 38

Information for Authors The International Journal of MS Care (IJMSC) publishes peerreviewed articles in areas of interest to multiple sclerosis (MS) healthcare professionals. Topics include neurologic, nursing, rehabilitative, psychological, and psychosocial care and quality-of-life issues of people with MS and reflect the diversity of the journal’s readership. Categories of manuscripts considered include original research, clinically relevant reviews of the literature, case reports, consensus statements, controversies, book reviews, and letters to the editor.

SUBMISSION REQUIREMENTS Submissions. Submissions should adhere to the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals (www.icmje.org). The text, including references, generally should not exceed 5000 words. References should be limited to about 30 if possible. Only essential tables and figures should be included. Manuscripts should be submitted using the online submission system located at http://ijmsc.msubmit.net. The submission should be accompanied by a cover letter stating that the paper is being submitted exclusively to IJMSC. Questions regarding the suitability or status of a submission should be directed to Dr. Francois Bethoux or Maria Stadtler at [email protected]. Authorship. Individuals designated as authors must 1) contribute to the conception and design or analysis and interpretation of data, 2) draft or critically revise the article for important content, AND 3) approve the final version. Authors or other contributors who do not meet all three criteria should be recognized in an Acknowledgments section. Generally, no more than six authors should be listed. For further details, refer to our Authorship and Contributorship Policy at http://ijmsc.org. Disclosure of Conflicts of Interest. Authors must disclose all relationships (financial and nonfinancial) that could be viewed as presenting conflicts of interest. Disclosures for all authors should be listed in a Disclosures section at the end of the manuscript, following the Acknowledgments section and preceding the References. If an author has no conflicts of interest to disclose, this should be stated. In addition, each author must declare conflicts of interest as part of the online manuscript submission process. Ethical Approval of Studies. For studies involving human participants, institutional review board or ethics committee approval should be reported in the Methods section. All human investigation must be conducted according to the principles expressed in the World Medical Association Declaration of Helsinki (October 2013 version; for the full text, see www. wma.net/en/30publications/10policies/b3/index.html). Reports of studies involving animals must state that guidelines for the use and care of laboratory animals of the authors’ institution or the National Research Council or any national law were followed. Patient/Research Participant Privacy and Confidentiality. Patients and research participants have a right to privacy that should not be violated without informed consent. Authors must ensure that only information that is clinically or scientifically relevant and important is included in a submitted manuscript. Nonessential identifying details should be omitted. If a manuscript contains detailed case descriptions or photographs that might permit a patient or study participant to be identified, the author must obtain written permission from the identifiable patient (or legally authorized representative) to publish the information, and send a copy of this permission to the journal. Such informed consent should include an opportunity for the patient to read the manuscript to be submitted for publication or waive the right to do so. If such informed consent has been obtained, this should be indicated in the Methods or Acknowledgments section.

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Manuscripts should include a title page, keywords, “practice points,” abstract, text, references, and tables and figures, if applicable. All elements of the manuscript should be typed, double spaced, in MS Word. Refer to the American Medical Association (AMA) Manual of Style, 10th ed. (Oxford University Press, 2007) for guidelines. Do not use special formatting of any kind, headers, footers, embedded footnotes or endnotes, or hyperlinks. Title Page. Include article title; full name and highest degree of each author; name and location of departments and institutions with which each author is affiliated (in English); name, address, telephone

number, fax number, and e-mail address of the corresponding author; and 3 to 5 keywords. Practice Points. In one or two sentences each, summarize the two or three most important concepts in your article for practicing MS clinicians, and list these as key “practice points” on a separate page following the title page and preceding the abstract. Abstract. Summarize the content of the paper in 250 words or less. The abstract should be understandable without reference to the text and should not contain references. Abstracts for reports of original data, systematic reviews (including meta-analyses), and clinical reviews should be structured using the following headings: Background, Materials (or Patients) and Methods, Results, Conclusions. For other types of manuscripts, use an unstructured abstract. References. References should be numbered consecutively. Recent references (published within the past 5 years) are preferred. Follow AMA style guidelines. Examples: Journal—Author SW, Author K, Author ER, et al. Article title. J Title. 1992;27:1893–1898. Book—Author J, Author C, Author L. Chapter title. In: Editor J, ed. Book Title. Publisher City, State: Publisher Name; 2001: 175–212. Electronic publication—US Department of Agriculture. Food Guide Pyramid 1992. http://fnic.nal.usda.gov/nal. Accessed April 15, 2007. Tables and Figures. Tables and figures must be numbered separately and cited in the text. Each table should have a title, and figure legends should appear at the end of the text. Digital figures are preferred and must be submitted as separate files. Photographs should have a minimum resolution of 300 dpi. All tables and figures reprinted from other publications should be accompanied by a complete citation of the source. Written reprint permission must be obtained by the author from the copyright owner and sent with the submission.

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PUBLISHER

Joseph J. D’Onofrio International Journal of MS Care 66 S. Maple Avenue, Ridgewood, NJ 07450 201-612-7676 • fax 201-612-8282 • [email protected]

The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study Bhupendra O. Khatri, MD; John F. Foley, MD; Jennifer Fink, MS; John F. Kramer, BA, PA-C; Choon Cha, MD; Xiaojun You, PhD; John D. Warth, PhD; Pam Foulds, MD Background: Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. Methods: The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumabnaive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. Results: Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. Conclusions: Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment. Int J MS Care. 2014;16:40–47.

M

ultiple sclerosis (MS) is a progressive, degenerative disease of the central nervous system (CNS) characterized by a variety of clinical courses.1,2 The majority of MS patients present with episodic neurologic symptoms and will have bouts of disease activity (relapses) separated by periods of total or partial remission.1,2 Patients with MS may experience symptoms such as bladder dysfunction, fatigue, spasticity, pain, and depres-

sion.1 Bladder dysfunction is common in MS patients3-5 and may increase with increasing spinal cord involvement.4,6-9 The types of bladder dysfunction that typically occur in MS are failure to store, failure to empty, and a combination of both.10,11 The Urogenital Distress Inventory (UDI) and the Incontinence Impact Questionnaire (IIQ) were both developed to assess the impact of urinary incontinence on quality of life (QOL) in women.12 Shorter versions

From the Center for Neurological Disorders and the Regional Multiple Sclerosis Center, Wheaton Franciscan Health Care, Milwaukee, WI, USA (BOK, JFK); Rocky Mountain Multiple Sclerosis Center, Salt Lake City, UT, USA (JFF); Aurora St. Luke’s Medical Center, Milwaukee, WI, USA (JF); Elan Pharmaceuticals, Inc, San Francisco, CA, USA (CC); and Biogen Idec Inc, Cambridge, MA, USA (XY, JDW, PF). Dr. Warth is now with Genzyme Corporation, Cambridge, MA, USA. Correspondence: Bhupendra O. Khatri, MD, Center for Neurological Disorders and the Regional Multiple Sclerosis Center, Wheaton Franciscan Health Care, 3237 S. 16, Milwaukee, WI 53215; e-mail: [email protected]. DOI: 10.7224/1537-2073.2013-003 © 2014 Consortium of Multiple Sclerosis Centers.

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TRUST Study: Bladder Function During Natalizumab Treatment

of the UDI and the IIQ, the UDI-6 and the IIQ-7, have become standard, validated measures for urologic investigations.13,14 The North American Research Committee on Multiple Sclerosis (NARCOMS) validated the bladder/bowel subscale (PSB) of its patient-reported Performance Scale (PS).15,16 In the phase 3 pivotal AFFIRM and SENTINEL studies, natalizumab (Tysabri; Biogen Idec Inc, Cambridge, MA, and Elan Pharmaceuticals, Inc, South San Francisco, CA) reduced MS relapse rates, slowed progression of MS-related disability, and improved QOL in patients with relapsing forms of MS.17-19 This observation, coupled with anecdotal reports, led us to hypothesize that natalizumab may have a demonstrable beneficial effect on bladder function in MS patients. The primary study endpoint in the TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was change in bladder function, as measured by the UDI-6 score from baseline through 24 weeks of natalizumab treatment. Secondary study endpoints included change from baseline over 24 weeks in the following parameters: IIQ-7 score, NARCOMS PSB score, the number of urinary incontinence episodes per patient per week, and the number of micturitions per patient per day.

Materials and Methods Study Design The TRUST study was an open-label, two-center (Center for Neurological Disorders and the Regional Multiple Sclerosis Center, Aurora St. Luke’s Medical Center, Milwaukee, WI, and Rocky Mountain Multiple Sclerosis Center, Salt Lake City, UT), single-arm, 24-week proof-of-concept study to evaluate potential effects of natalizumab on bladder function in patients with relapsing forms of MS. Patients were treated with natalizumab 300 mg by intravenous infusion every 4 weeks for 6 months. Enrollment began in March 2009, and the final patient visit was in April 2011. The study was conducted in agreement with the International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines and followed Declaration of Helsinki recommendations. The Aurora Internal Review Board approved the study. All patients provided written informed consent. The trial was registered with www.clinicaltrials.gov (NCT00818038).

Patients Natalizumab-naive patients with a relapsing form of MS and bladder dysfunction who were aged 18 years

or older were enrolled into the study. Urinary incontinence in enrolled patients was defined as at least 3 incontinence episodes per week or at least 8 micturitions per day (both mean numbers). Patients were required to have a UDI-6 score of 6 or greater and an Expanded Disability Status Scale (EDSS) score of 0.0 to 6.5 at the screening visit. Patients who were taking medications for the control of bladder symptoms or that could affect urinary output were required to maintain stable dosing of that medication for at least 1 month before the study and also during the study. All patients were requested to maintain current hydration and caffeine intake during the study. Patients were excluded from the study if they had a history of recurrent or chronic urinary tract infection or a urinary tract infection within 30 days of initiating natalizumab treatment, used an indwelling Foley catheter or suprapubic catheter, or had a history of symptomatic benign prostatic hyperplasia or prostate cancer. In addition, patients were required to meet all prescribing criteria for natalizumab20 and be enrolled in the TOUCH® (TYSABRI® Outreach: Unified Commitment to Health) Prescribing Program (http://www.tysabri.com/tysbProject/ tysb.portal/_baseurl/threeColLayout/SCSRepository/ en_US/tysb/home/treatment-with-tysabri/touch-prescribing-program.xml).

Endpoints and Assessments The primary study endpoint was change in bladder function, as measured by the UDI-6 score (range 0–18),14 from baseline through 24 weeks of natalizumab treatment. The UDI-6 is composed of six questions on irritative symptoms, obstruction/discomfort, and stress symptoms. Respondents rate each question on a 4-step ordered category scale from “not at all” (score = 0) to “greatly” (score = 3) based on how much they experienced impaired function or were bothered by a symptom. Lower scores indicate better bladder function.14 Secondary study endpoints included change from baseline over 24 weeks in the following parameters: IIQ-7 score (range 0–21),14 NARCOMS PSB score (range 0–5),15 the number of urinary incontinence episodes per patient per week, and the number of micturitions per patient per day. The IIQ-7 is composed of seven questions that measure the impact of bladder symptoms on physical activity, travel, social activities, and emotional health. Scoring is the same as for the UDI-6, and a lower score indicates higher bladder-relat-

International Journal of MS Care 41

Khatri et al.

ed QOL.14 The NARCOMS PSB measures disability secondary to bowel and bladder symptoms, presumably due to MS, and is scored from 0 (no) to 5 (total disability).15 No safety analyses were conducted as part of this trial. During the study, UDI-6, IIQ-7, NARCOMS PSB, and concomitant medication for urinary incontinence were recorded at baseline (week 0) and then every 4 weeks before each natalizumab infusion for 24 weeks. Bladder diary entries documenting incontinence episodes per week and micturitions per day were completed by the patient every 4 weeks from week 2 through week 22. The bladder diary was collected by the investigative site at each clinic visit. In the event that a natalizumab infusion was administered more than 4 weeks from the last dose, subsequent diaries were completed every 14 ± 4 days from the last patient visit.

Statistical Analysis This exploratory study was planned to enroll approximately 30 patients from two US centers. Because no prior data are available on the effect of natalizumab on bladder function, the sample size was exploratory and not based on statistical power considerations. The efficacy analyses were performed on all patients completing the study, and were based only on observations obtained at each assessment (ie, without imputation of missing data). Sensitivity analyses that included data from all enrolled patients were also performed. All bladder efficacy data were summarized by presenting frequency distributions and/or summary statistics (mean, standard deviation, median, and range). All analyses were conducted using a two-sided test and a significance of .05. For continuous endpoints, a paired t test was initially used to compare the change of these endpoints from baseline over 6 months of natalizumab treatment. Categorical data were analyzed using χ2, Fisher exact, and/or McNemar tests. Nonparametric analyses (eg, Wilcoxon signed rank test) were utilized as appropriate. Analyses were conducted to assess the influence of baseline characteristics (eg, age, gender, and baseline bladder functions) on the endpoints, including an analysis of variance model adjusted for covariates (ANCOVA) where appropriate. Time effect was analyzed using a longitudinal data analysis model adjusted for baseline UDI-6 or IIQ-7 score, age, EDSS score, total number of relapses within the past 12 months and the past 3 years, disease duration, and use of medications for bladder problems.

Correlations between baseline disease characteristics (age, EDSS score, total number of relapses within the past 12 months and the past 3 years, disease duration) and UDI-6 and IIQ-7 scores were assessed. Extrapolating from previous research (Corcos et al., 2002),21 the following three assumptions regarding the relationship between IIQ-7 raw score and urinary incontinence health-related QOL (UI HRQOL) were made: 1) An IIQ-7 score less than 10.5 indicates good UI HRQOL; 2) an IIQ-7 score of 10.5 to 14.7 indicates moderate UI HRQOL; and 3) an IIQ-7 score greater than 14.7 indicates poor UI HRQOL.

Results Patients A total of 30 patients were enrolled, and 28 patients completed the study. One patient voluntarily discontinued natalizumab prior to the first infusion (data were available for baseline and week 4 and were included in the sensitivity analysis), and another patient withdrew consent and later received three infusions (no postbaseline data were available and thus were not included in sensitivity analysis). Baseline demographics and clinical characteristics of the 28 patients who completed the study are shown in Table 1. Seventeen patients were taking medication for bladder symptoms at study entry and continued their baseline dosage throughout the study. Bladder medications used by study participants included darifenacin, Table 1. Baseline characteristics of patients in TRUST Characteristic Age, y Female, No. (%) Time since first MS symptoms, y Number of relapses   Past year    Past 3 years Baseline EDSS score Baseline UDI-6 score Baseline IIQ-7 score Patients with any previous MS treatment, No. (%) Patients with any treatment for bladder leakage,a No. (%)   Medication   Other (nonmedication)

Value (N = 28) 49.9 (9.96) 22 (78.6) 19.3 (10.51) 2.4 (2.56) 4.6 (3.27) 4.6 (1.47) 10.4 (2.65) 12.3 (4.67) 28 (100) 18 (64.3) 17 (60.7) 2 (7.1)

Abbreviations: EDSS, Expanded Disability Status Scale; IIQ-7, Incontinence Impact Questionnaire; UDI-6, Urogenital Distress Inventory. Note: Values are presented as mean (SD) unless otherwise specified. a Patients could have more than 1 treatment type.

International Journal of MS Care 42

TRUST Study: Bladder Function During Natalizumab Treatment

Urogenital Distress Inventory Questionnaire (UDI-6)

A Mean (SD) Change From Baseline in UDI-6 Score

desmopressin, doxazosin, oxybutynin, solifenacin, tamsulosin, and trospium. There were no meaningful correlations between bladder function, as assessed by UDI-6 and IIQ-7 scores, and baseline relapse history.

2 1 0 -1 -2 -3 -4 -5 -6 -7 -8

P < .0001 for Time Effect in Weeks

0

4

8

12

16

20

24

Mean (SD) Change From Baseline in IIQ-7 Score

Beginning at week 4, mean Time (Weeks) UDI-6 score was significantly lower than at baseline (P < B .0001), with a mean improveP < .0001 for Time Effect 3 in Weeks 2 ment at 24 weeks of 4.4 points 1 (Figure 1A). At week 24, 85.7% 0 of patients demonstrated an -1 improvement from baseline in -2 -3 the UDI-6 score, while scores -4 had worsened in 10.7% and -5 were stable in 3.6% of patients -6 -7 (P < .0001) (Figure 2A). -8 Patients on natalizumab with a -9 worse (higher) UDI-6 score at -10 -11 baseline showed a greater initial 4 8 12 16 20 24 0 improvement than patients with a better UDI-6 score at baseline, Time (Weeks) as indicated by a significant coefficient for baseline UDI-6 Figure 1. Mean improvement from baseline to week 24 in (A) score (−0.3666, P = .0192) total UDI-6 score and (B) total IIQ-7 score A, Improvement (decrease) in UDI-6 score from baseline was significant over the course of in the regression model. This the study (P = .0001 for time effect in weeks) and at each individual time point (P < .0001 improvement was maintained for all weeks except week 8, P = .0004). B, Improvement (decrease) in IIQ-7 score from over time (data not shown). baseline was significant over the course of the study (P = .0001 for time effect in weeks) and at each individual time point: week 4, P = .0005; week 8, P = .003; week 12, P < .0001; The changes in UDI-6 score week 16, P = .0004; week 20, P < .0001; week 24, P < .0001. Negative (downgrade) from baseline were also analyzed slope indicates improvement. Data were available for 27 patients at week 12 and for all 28 patients at all other time points. UDI-6, Urogenital Distress Inventory; IIQ-7, Incontinence using a more rigorous definiImpact Questionnaire. tion as follows: improvement: score decreased by at least 3 points; stable: score unchanged or decreased by less than 11% of patients showed score improvement, stability, 3 points; worsened: score increased from baseline (>0 and worsening, respectively (P < .01). point). With the use of these criteria, there were signifiThe improvement in UDI-6 score suggested an cant differences in the proportions of improved, stable, overall reduced impact of urinary symptoms. For each and worsened patients at 12, 16, 20, and 24 weeks. At UDI-6 question, the combined percentage of patients week 12, 56%, 33%, and 11% of patients showed score who reported being bothered only “slightly” or “not at improvement, stability, and worsening, respectively (P all” by symptoms increased between baseline and week < .01). These proportions remained relatively stable for 24 (Figure 3A). Additional analyses adjusting for the the remainder of the study; at week 24, 64%, 25%, and time since the most recent relapse (≤3 months versus >3 International Journal of MS Care 43

Khatri et al.

A

Change in UDI-6 Score From Baseline

Worsened Stable Improved

100 90 80 Patients (%)

70 60 50 40 30 20 10 0 4

8

12

16

20

24

Time (Weeks)

B

Change in IIQ-7 Score From Baseline

Worsened Stable

100

Improved

90 80 Patients (%)

70 60 50

stable in 3.6% of patients (P = .0011) (Figure 2B). With regard to each individual IIQ-7 question, the combined percentage of patients reporting that urine leakage affected them only “slightly” or “not at all” consistently increased during the study (Figure 3B). Participants with a worse (higher) IIQ-7 score at baseline had a more pronounced initial improvement than patients with a better IIQ-7 score at baseline. This was illustrated by a significant coefficient for baseline IIQ-7 score (−0.5783, P < .0001) from the regression model that was maintained over the study period.

NARCOMS Bowel/ Bladder Performance Subscale (NARCOMS PSB)

40 30 20 10 0 4

8

12

16

20

24

Time (Weeks)

Figure 2. Change from baseline to week 24 in the proportion of patients with worsened, stable, or improved (A) UDI-6 score and (B) IIQ-7 score Worsening was defined as an increase of ≥1 from baseline score; stability was defined as no change in score; improvement was defined as a decrease of ≥1 from baseline score. Change was calculated as the mean change of (A) all six individual UDI-6 items or (B) all seven individual IIQ-7 items. Baseline was the average of screening and week 0 scores. A, Difference in proportions between groups (worsened, stable, and improved) are statistically significant at all time points (P values <.01 at all time points, McNemar test). B, Difference in proportions between groups (worsened, stable, and improved) are statistically significant at all time points (P values <.02 at all time points, McNemar test). UDI-6, Urogenital Distress Inventory; IIQ-7, Incontinence Impact Questionnaire.

months) or use of medications for bladder symptoms showed no significant impact on natalizumab’s effect on UDI-6 score (data not shown).

Incontinence Impact Questionnaire (IIQ-7) Mean IIQ-7 score was significantly lower than at baseline from week 4 onward (P = .0001), with a mean improvement at 24 weeks of 4.9 points (Figure 1B). Compared with baseline, 78.6% of patients demonstrated an improvement in the IIQ-7 score at week 24. Conversely, IIQ-7 score worsened in 17.9% and was

On the NARCOMS PSB, the proportion of patients who reported moderate to severe bladder/bowel disability decreased over time: 85.7%, 50.0%, 39.3%, and 35.7% at weeks 0, 8, 16, and 24, respectively. There were corresponding increases in the proportions of patients reporting normal, minimal, or mild bladder/ bowel disability during the course of the study.

Urinary Incontinence Episodes and Micturitions (Diary Entry Data) The majority of patients showed improvement or stability in incontinence episodes and micturitions starting at week 2 (Figure 4). At week 22, 64% of patients reported a decrease (improvement) from baseline in the number of weekly incontinence episodes reported, while incontinence episodes increased in 24% (three patients reported increased weekly incontinence episodes across all time points) and were stable in 12%

International Journal of MS Care 44

TRUST Study: Bladder Function During Natalizumab Treatment

Discussion

A

Experienced and Were Bothered: Not at All-Slightly Moderately-Greatly Baseline

Week 24

100

Proportion by UDI-6 Question Score (%)

of patients (P = .033) (Figure 4A). Similarly, 52% of patients reported a decrease (improvement) in the number of daily micturitions, while micturitions increased in 16% and were stable in 32% of patients at 22 weeks (P = .029) (Figure 4B). Diary data were not available for all patients at all time points. Sensitivity analyses that included data from the one patient who voluntarily discontinued natalizumab showed similar results.

80

14.3

14.3

85.7

85.7

42.9

28.6

39.3

75

46.4

57.2

78.6

71.4

60.7

92.9

71.4 60 57.1

60.7 53.6

40

42.8 25

20

39.3 28.6 21.4 7.1

0

r , , r r r n to to ge io ge ity ity de i de we a we a at at ed cy ctiv ing aka ps) lad ed cy ctiv ing aka ps) lad Lo Are Lo Are in at en z Le ro at en z rin o l l r B e A A B n r n e e i l i l e U e g L U to ne of (D ing to ne of (D ing R Ur R Urg rt ta rt ta nt nt y fo eni fo eni y ge of ated or S nts ge of ated or S nts ue ue pt pt l , om r G l , om r G ka ing u ka ing m eq u m eq c c e e r a o a g r g o E s l o E s o l F R n R n F Le ee Le ee Di al Di al e hi e hi l Am lty Am lty F F l or in or in ag ug all ag ug cu icu ffi in dom iff in dom ak Co Sm ak Co ma i a a e e D D S L P Ab L P Ab on

Proportion by IIQ-7 Question Score (%)

Bladder dysfunction is a Experienced and Were Bothered: B Not at All-Slightly common and distressing sympModerately-Greatly tom of MS that negatively affects QOL.22 Improvements Baseline Week 24 100 in QOL have been shown in 46.4 32.1 35.7 35.7 32.1 39.3 21.4 85.7 67.9 71.4 71.4 67.9 78.6 57.1 MS patients treated with natal80 78.6 izumab, 19 but the effects of 67.9 67.9 60 64.3 64.3 60.7 natalizumab on bladder func53.6 40 tion and bladder function–relat42.9 32.1 32.1 ed QOL have not been studied 28.6 28.6 20 21.4 to date. 14.3 0 In this study, we demonstrats s n s s n d th d th es es es es io io tie tie te al te al ut itie itie or ut or at at ra ivi ivi in in He tra tiv tiv He re re Ch st ct ct Ch l s c c M l c M c ed that patients with a relapsing u A A a u d d l 0 l t n lA tA na Fr Re Fr Re ol 30 io ho io >3 en g cia en g cia al al eh ot l> ot in m se in el m So m So m sic el us in ve sic el in ou av form of MS who were treated y E e o a a y E e a r t r t h H F r H F T r T P Ph te te En En with natalizumab experienced significant improvement in Figure 3. Scores at baseline and week 24 for each (A) UDI-6 and (B) IIQ-7 question incontinence-related QOL as UDI-6, Urogenital Distress Inventory; IIQ-7, Incontinence Impact Questionnaire. measured by mean improvements in UDI-6 and IIQ-7 scores. Patients with worse (higher) UDI-6 or IIQ-7 improvements in the number of incontinence episodes scores as well as more weekly incontinence episodes per week and the number of micturitions per day. Several guidelines are available for the diagnosis and at baseline also showed greater initial improvement in scores and maintained improvement over time while management of bladder symptoms in patients with MS.24-27 These guidelines suggest that when approprireceiving natalizumab. On the basis of other studies,12,14,16,21,23 the magnitude ate, pharmacologic adjunctive treatment for neuroof the treatment effect seen in this pilot study suggests genic bladder in patients with MS can be considered. that natalizumab may be capable of decreasing the Although somewhat effective, these approaches can impact of urinary incontinence on QOL from moderate increase the risk of additional side effects, add to the to mild. The QOL improvements may have been driven cost of treating MS, and do not resolve symptoms for in part by the finding that the majority of patients had all patients. Use of a disease-modifying therapy that has International Journal of MS Care 45

Khatri et al.

ing a disease-modifying theraWorsened py.28 Adjunctive therapies and Stable nonpharmacologic approaches 100 Improved 90 could then be considered for 80 * * * * patients with refractory bladder 70 60 symptoms. However, data on 50 the impact of approved dis40 ease-modifying therapies on 30 20 bladder function are lacking. 10 To our knowledge, our study is 0 the first prospective clinical trial 2 6 10 14 18 22 Time (Weeks) to demonstrate improvement in bladder symptoms during B Change in Number of Micturitions per Patient per Day Worsened From Baseline treatment with an approved disStable 100 ease-modifying therapy. Improved 90 The study is limited by the 80 70 small sample size and lack of a * 60 * comparator arm. While it does 50 suggest significant benefits of 40 30 natalizumab on bladder func20 tion, larger, controlled studies 10 0 would be required to confirm 2 6 10 14 18 22 these preliminary findings. Also, Time (Weeks) the UDI-6 and IIQ-7 scales Figure 4. Change from baseline to week 22 in the proportion used in this study have been of patients with worsened, stable, or improved (A) number of validated for women,14 although urinary incontinence episodes per patient per week, and (B) use of these measures with male number of micturitions per patient per day patients has been described.29,30 Worsening was defined as an increase; stability was defined as no change; improvement In conclusion, patients treatwas defined as a decrease in (A) urinary incontinence episodes per week and (B) micturitions per day as compared with baseline. *P < .05 for difference in proportions between groups ed with natalizumab experience (worsened, stable, and improved), McNemar test. Data were available for 24 patients at significantly improved incontiweek 2, 25 patients at week 22, and 26 patients at all other time points. nence-related QOL as measured been shown to reduce bladder symptoms while hav- by UDI-6 and IIQ-7 scores. The magnitude of this ing a positive impact on disease progression, relapses, effect suggests that natalizumab may decrease the impact magnetic resonance imaging (MRI) lesions, and other of incontinence on QOL. Further studies evaluating the symptoms may be preferable; however, benefits should impact of natalizumab on urologic QOL are needed to always be balanced with potential risks when consider- support these analyses. o A

Patients (%)

Patients (%)

Change in Number of Urinary Incontinence Episodes per Patient per Week From Baseline

PracticePoints • Bladder dysfunction is a common and distressing symptom of MS. • Changes in incontinence-related quality of life (QOL) during natalizumab treatment were evaluated using Urogenital Distress Inventory short form (UDI-6) and Incontinence Impact Questionnaire short form (IIQ-7) scores. • UDI-6 and IIQ-7 scores were significantly improved in patients with MS following natalizumab treatment. • The majority of patients showed improvement or stability in number of incontinence episodes per week and in number of micturitions per day after starting natalizumab. • Natalizumab may reduce the impact of incontinence on QOL.

International Journal of MS Care 46

TRUST Study: Bladder Function During Natalizumab Treatment 13. Lemack GE, Zimmern PE. Predictability of urodynamic findings based on the Urogenital Distress Inventory-6 questionnaire. Urology. 1999;54:461–466. 14. Uebersax JS, Wyman JF, Shumaker SA, McClish DK, Fantl JA; Continence Program for Women Research Group. Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Neurourol Urodyn. 1995;14:131–139. 15. Marrie RA, Cutter G, Tyry T, Vollmer T, Campagnolo D. Disparities in the management of multiple sclerosis-related bladder symptoms. Neurology. 2007;68:1971–1978. 16. Schwartz CE, Vollmer T, Lee H; North American Research Consortium on Multiple Sclerosis Outcomes Study Group. Reliability and validity of two self-report measures of impairment and disability for MS. Neurology. 1999;52:63–70. 17. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910. 18. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–923. 19. Rudick RA, Miller D, Hass S, et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol. 2007;62:335–346. 20. Tysabri (natalizumab) [prescribing information]. Cambridge, MA: Biogen Idec, Inc; 2012. 21. Corcos J, Behlouli H, Beaulieu S. Identifying cut-off scores with neural networks for interpretation of the incontinence impact questionnaire. Neurourol Urodyn. 2002;21:198–203. 22. Hemmett L, Holmes J, Barnes M, Russell N. What drives quality of life in multiple sclerosis? QJM. 2004;97:671–676. 23. Ross S, Soroka D, Karahalios A, Glazener CM, Hay-Smith EJ, Drutz HP. Incontinence-specific quality of life measures used in trials of treatments for female urinary incontinence: a systematic review. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17:272–285. 24. Multiple Sclerosis Council for Clinical Practice Guidelines. Urinary Dysfunction and Multiple Sclerosis: Evidence-Based Strategies for Urinary Dysfunction in Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1999. http://www.pva.org/site/c.ajIRK9NJLcJ2E/ b.8907639/k.298E/PDFs_Multiple_Sclerosis_MS_Publications.htm. Accessed February 4, 2014. 25. de Seze M, Ruffion A, Denys P, Joseph PA, Perrouin-Verbe B. The neurogenic bladder in multiple sclerosis: review of the literature and proposal of management guidelines. Mult Scler. 2007;13:915–928. 26. Fowler CJ, Panicker JN, Drake M, et al. A UK consensus on the management of the bladder in multiple sclerosis. Postgrad Med J. 2009;85:552–559. 27. Ghezzi A, Carone R, Del Popolo G, et al. Recommendations for the management of urinary disorders in multiple sclerosis: a consensus of the Italian Multiple Sclerosis Study Group. Neurol Sci. 2011;32:1223–1231. 28. Sorensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18:143–152. 29. Naughton MJ, Donovan J, Badia X, et al. Symptom severity and QOL scales for urinary incontinence. Gastroenterology. 2004;126(1 suppl 1):S114–S123. 30. Rapp DE, Lucioni A, Katz EE, O’Connor RC, Gerber GS, Bales GT. Use of botulinum-A toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology. 2004;63:1071–1075.

Acknowledgments: Medical writing assistance was provided by Ryan Woodrow, BS, and Britt Anderson, PhD, and editorial support was provided by Jackie Cannon of Infusion Communications. Their work was funded by Biogen Idec Inc and Elan Pharmaceuticals, Inc. Financial Disclosures: Dr. Khatri has been a consultant for Bayer, Biogen Idec, Cardian, Medtronic, Pfizer, and Serono. Dr. Foley has been a consultant for Biogen Idec, Genzyme, and Teva and has received honoraria from Biogen Idec and Teva. Mr. Kramer has been a consultant for Bayer, Biogen Idec, Novartis, Pfizer, Serono, and Teva. Dr. Cha is an employee of Elan Pharmaceuticals. Drs. You and Foulds are employees of Biogen Idec. Dr. Warth was an employee of Biogen Idec at the time of the study and is currently an employee of Genzyme Corporation. Ms. Fink has no conflicts of interest to disclose. Funding/Support: This study was funded by Biogen Idec Inc and Elan Pharmaceuticals, Inc.

References  1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372: 1502–1517.  2. Lublin FD, Reingold SC, National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis. Neurology. 1996;46:907–911.  3. Goldstein I, Siroky MB, Sax DS, Krane RJ. Neurourologic abnormalities in multiple sclerosis. J Urol. 1982;128:541–545.  4. Hawker KS, Frohman EM. Bladder, bowel, and sexual dysfunction in multiple sclerosis. Curr Treat Options Neurol. 2001;3:207–214.   5. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol. 1999;161:743–757.  6. Betts CD, D’Mellow MT, Fowler CJ. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1993;56:245–250.  7. Koldewijn EL, Hommes OR, Lemmens WA, Debruyne FM, van Kerrebroeck PE. Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis. J Urol. 1995;154:169–173.   8. Awad SA, Gajewski JB, Sogbein SK, Murray TJ, Field CA. Relationship between neurological and urological status in patients with multiple sclerosis. J Urol. 1984;132:499–502.   9. Ukkonen M, Elovaara I, Dastidar P, Tammela TL. Urodynamic findings in primary progressive multiple sclerosis are associated with increased volumes of plaques and atrophy in the central nervous system. Acta Neurol Scand. 2004;109:100–105. 10. Andrews KL, Husmann DA. Bladder dysfunction and management in multiple sclerosis. Mayo Clin Proc. 1997;72:1176–1183. 11. Fowler CJ, van Kerrebroeck PE, Nordenbo A, Van PH; Committee of the European Study Group of SUDIMS (Sexual and Urological Disorders in Multiple Sclerosis). Treatment of lower urinary tract dysfunction in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1992;55:986–989. 12. Shumaker SA, Wyman JF, Uebersax JS, McClish D, Fantl JA; Continence Program in Women (CPW) Research Group. Health-related quality of life measures for women with urinary incontinence: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Qual Life Res. 1994;3:291–306.

International Journal of MS Care 47

Comparing Two Conditions of Administering the Six-Minute Walk Test in People with Multiple Sclerosis Brian M. Sandroff, MS; Lara A. Pilutti, PhD; Deirdre Dlugonski, BS; Yvonne C. Learmonth, PhD; John H. Pula, MD; Robert W. Motl, PhD Objective: This quasi-experimental study was conducted to determine whether differences existed in the total distance walked and energy expended between two conditions of administering the 6-Minute Walk test (6MW) across different levels of disability in people with multiple sclerosis (MS). Methods: The sample comprised 160 individuals with MS. One group of participants (n = 82) completed a 6MW while wearing a portable metabolic unit (K4b2, Cosmed, Italy) in a square hallway with four corridors and performing 90° turns. Another group (n = 78) completed a 6MW while wearing the same metabolic unit in a single corridor and performing 180° turns. Main outcome measures included total distance walked (in feet) and oxygen consumption (in milliliters per minute) expressed as 30-second averages for 1 minute before the 6MW and over the entire 6MW. Disability status was assessed using the Patient-Determined Disease Steps scale. Results: Participants undertaking the 6MW in a single corridor (1412 ft) walked 37 ft (2.7%) farther than those undertaking the test in a square hallway (1375 ft), but this difference was not statistically significant (F = 0.45, P = .51). Those completing the 6MW in a single corridor expended more energy than those completing the 6MW in the square hallway with four corridors (F = 3.41, P < .01). Conclusions: Either protocol is acceptable, but researchers should be aware of the additional physiological demands when administering the 6MW in a single corridor with 180° turns. Int J MS Care. 2014;16: 48–54.

W

alking impairment is a common and lifealtering feature of both early and advanced multiple sclerosis (MS) 1,2 and is commonly measured using performance tests such as the 6-Minute Walk test (6MW) and the Timed 25-Foot Walk (T25FW).3 The 6MW, in particular, provides a measure of walking endurance in people with MS.3-6 The distance traveled during the 6MW has differentiFrom the Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA (BMS, LAP, DD, YCL, RWM); and Division of Neuro-ophthalmology, University of Illinois College of Medicine at Peoria and the Illinois Neurologic Institute, Peoria, IL, USA (JHP). Correspondence: Robert W. Motl, PhD, University of Illinois at Urbana-Champaign, Department of Kinesiology and Community Health, 233 Freer Hall, 906 South Goodwin Ave, Urbana, IL; e-mail: [email protected]. DOI: 10.7224/1537-2073.2013-014 © 2014 Consortium of Multiple Sclerosis Centers.

ated between those with MS and healthy controls4,7 and across stages of disability in MS samples.4,8 There is further evidence that the 6MW may be more precise in defining disability than other measures of walking performance such as the T25FW.4 Researchers have standardized 6MW instructions regarding participant effort/behavior (ie, walking as fast and as far as possible without stopping for rest) and researcher behavior (ie, no encouragement)4 when the 6MW is administered in individuals with MS. To date, there has been no standardization of the walking-course conditions for the 6MW in MS. One walking-course condition involves walking laps within a single corridor and performing 180° turns (ie, straight-line course),4,9,10 whereas another involves walking laps around a square hallway with four corridors and performing 90° turns (ie, square course). 7,8 These different conditions of administering the 6MW may influence the total dis-

International Journal of MS Care 48

Six-Minute Walk in MS

tance traveled and/or the associated amount of energy expended by individuals with MS, particularly as a function of disability status (involving lesser or greater walking impairment). Although no such comparisons between 6MW conditions have been made in MS, one study in people with chronic obstructive pulmonary disease (COPD) reported that 6MW distance was significantly greater when the test was completed on a continuous track (ie, oval or square administration) than when it was completed in a straight-line course.11 One limitation of that study was that the instructions were not standardized as in MS (ie, walking as fast and far as possible without rest or encouragement for 6 minutes). Moreover, that study did not measure energy expenditure to examine the metabolic demands of each 6MW administration. The current study adopted a quasi-experimental design and compared the total distance walked and energy expended between two conditions of administering the 6MW (ie, “straight-line” or “square” 6MW courses) with standardized instructions across two different levels of disability in individuals with MS: those with and those without gait impairment. We hypothesized that participants undertaking the “straight-line” 6MW would walk a shorter distance and expend more energy than those undertaking the “square” 6MW based on evidence in COPD11 and the logic that 180° turns presumably require more frequent deceleration/acceleration and a greater change of direction than 90° turns. The study also examined the comparable validity of each 6MW administration by assessing associations among 6MW distance and disability status, objectively measured walking performance, and self-reported walking impairment. We hypothesized that distance traveled from each 6MW administration would be strongly associated with those outcomes. If our hypotheses are supported, such information might further inform the ongoing dialogue regarding the demands of administering the 6MW in MS research.

Methods Participants This study involved a quasi-experimental design in which we compared data collected from two separate investigations of people with MS. The first dataset was from the baseline testing session of an ongoing behavioral intervention for increasing physical activity, and the second was from a cross-sectional study of physical activ-

ity and imaging outcomes. Recruitment for both studies was undertaken concurrently, and testing was completed by the same assessors at two different sites; this afforded an opportunity to compare between the conditions of administering the 6MW. Participants in both studies were recruited by 1) mail through a flyer that was distributed to patients in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry; 2) e-mail through a flyer that was distributed to participants in a database from previous studies conducted in our laboratory over the past 5 years; or 3) announcements in local media outlets, promotional flyers, and direct invitation based on medical records. A total of 402 participants initially expressed interest in both studies and were contacted via telephone by the project coordinator. After explaining the study protocols, the project coordinator undertook screening for inclusion, the criteria for which were 1) definite diagnosis of MS (participants provided a physician’s verification of MS diagnosis); 2) relapse-free status for the past 30 days; 3) ability to walk with or without an assistive device (ie, cane, crutch, or walker); and 4) willingness and ability to travel to the testing site to complete the 6MW among other measures. Of the 402 people who were screened, 242 did not meet the inclusion criteria, with the primary reason being unwillingness to travel to the testing site(s) due to scheduling conflicts. This resulted in a final sample of 160 individuals with MS. Eighty-two participants were enrolled into the cross-sectional study (ie, “square” group) and 78 were enrolled into the behavioral intervention (ie, “straight-line” group) (Table 1).

Measures Six-Minute Walk Test Participants were instructed to walk as fast and as far as possible without rest or encouragement for 6 minutes (ie, standardized instructions for 6MW administration in MS)4; when necessary, participants were permitted to use an assistive device for both conditions of administering the 6MW (ie, “straight-line” and “square”). The “straight-line” 6MW was completed within a single corridor measuring 75 ft in length, with cones placed on opposite ends, while performing 180° turns around the cones. The “square” 6MW was completed in a square hallway with four corridors, each measuring 100 ft in length, while performing 90° turns around corners. One researcher followed approximately 3 ft behind the participant with a measuring wheel (Stanley MW50, New

International Journal of MS Care 49

Sandroff et al. Table 1. Demographic characteristics of 160 individuals with MS completing two different conditions of the 6MW Variable Age, y Sex, No. (%) female Height, cm Weight, kg

Square (n = 82)

Straight-line (n = 78)

50.3 (9.7)

49.5 (8.7)

66 (80.5) 168.9 (9.1)

60 (76.9) 169.1 (8.5)

82.1 (21.0)

81.1 (22.0)

3.0 (0–6)

3.0 (0–6)

MSWS-12

45.0 (28.0)

41.9 (28.0)

T25FW, s

6.8 (3.2)

6.8 (5.0)

PDDS, median (range)

Abbreviations: MSWS-12, 12-item Multiple Sclerosis Walking Scale; PDDS, Patient-Determined Disease Steps; 6MW, 6-Minute Walk; T25FW, Timed 25-Foot Walk. Note: Data are presented as mean (SD) unless noted otherwise.

Briton, CT) and recorded total distance traveled as the primary outcome measure of the 6MW for both 6MW conditions. Oxygen Consumption Energy expenditure was expressed based on oxygen . consumption (Vo2) and measured breath by breath during the 6MW using a commercially available portable metabolic unit (K4b2, Cosmed, Italy). The O2 and CO2 analyzers of the portable metabolic unit were calibrated using verified concentrations of gases, and the flowmeter was calibrated using a 3-L syringe (Hans Rudolph, Kansas City, MO). Oxygen consumption (milliliters per minute) was calculated as 30-second averages for 1 minute before the 6MW and over the entire 6MW. Walking Performance The 12-item Multiple Sclerosis Walking Scale (MSWS-12) and T25FW were used as additional measures of walking performance in both samples as outcomes for establishing group equivalence in walking functions. The T25FW was administered as a measure of walking speed; participants walked 25 ft as quickly and safely as possible in a hallway clear of debris over two trials.12 The main outcome measure was the mean time (seconds) taken to complete the T25FW on two trials.12 The MSWS-12 is a 12-item patient-rated measure of the impact of MS on walking.13 The 12 items on the MSWS-12 are rated on a scale ranging from 1 (not at all) to 5 (extremely). The total MSWS-12 score ranges from 0 to 100 and is computed by summing the individual item scores, subtracting the minimum pos-

sible score of 12, dividing by 48 (ie, the maximum score on the summed items after subtracting the minimum possible score), and then multiplying the result by 100.13 Disability Status The Patient-Determined Disease Steps (PDDS) scale14 was included as a measure of disability level for further establishing group equivalence in disability status. The PDDS is a self-report outcome that was developed as an inexpensive surrogate to clinical assessments of disability (eg, Expanded Disability Status Scale; EDSS). The PDDS contains a single item for measuring self-reported neurologic impairment on an ordinal level, ranging from 0 (normal) through 8 (bedridden). This scale has been reported to be valid based on a strong correlation with the physician-administered EDSS.14 We then formed groups of 72 individuals without gait disability and 88 individuals with gait disability based on PDDS scores of 0 to 2 and 3 to 6, respectively15; 37 individuals without gait disability completed the “square” 6MW while 35 participants completed the “straight-line” 6MW. Further, 45 people with gait disability completed the “square” 6MW and 43 completed the “straight-line” 6MW.

Protocol Both of the protocols were approved by university institutional review boards, and all participants provided written informed consent. The protocols were completed at different testing sites, but included a single session for collecting all data. All participants initially completed a battery of questionnaires including a demographics inventory, MSWS-12, and PDDS. Participants then completed two trials of the T25FW, followed by 10 minutes of seated rest. During this rest period, participants were fitted with the portable metabolic system. Once wearing the system, participants were given standardized instructions for undertaking the 6MW. Participants subsequently completed the 6MW in either a “square” hallway or a “straight-line” corridor. We provided a $15 gift card to cover travel expenses upon completion of data collection.

Data Analysis Data were analyzed using PASW Statistics 18 (SPSS Inc, Chicago, IL). We first examined differences between “square” and “straight-line” groups in terms of age, sex, height, weight, disability status, T25FW performance, and MSWS-12 scores (ie, possible variables that might differ between samples and confound the

International Journal of MS Care 50

Six-Minute Walk in MS

comparison of conditions for administering the 6MW) using independent-samples t tests or χ2 difference tests. We performed Spearman rho nonparametric rank-order correlations among 6MW distance and PDDS scores, T25FW performance, and MSWS-12 scores for establishing comparable validity of each condition of 6MW administration; we used nonparametric correlations to determine whether outliers or nonlinearity was biasing the associations among variables. We performed a 2 (6MW administration: square vs. straight-line) by 2 (disability status: no gait disability vs. gait disability) analysis of variance (ANOVA) on total distance walked during the 6MW. We further performed a similar 2 (6MW administration: square vs. straight-line) by 2 (disability status: no gait disability vs. gait disability) ANOVA with . repeated measures on all 12, 30-second Vo2 averages over the course of the 6MW and controlling for resting energy expenditure as a covariate.

Results Demographic Characteristics Demographic characteristics for both the “square” and “straight-line” groups are presented in Table 1. The groups did not differ in terms of age (t = 0.55, P = .59), sex (χ2 = 0.30, P = .58), height (t = −0.09, P = .93), weight (t = 0.29, P = .77), PDDS scores (t = −0.39, P = .70), MSWS-12 scores (t = 0.72, P = .47), or T25FW performance (t = 0.02, P = .98). Such initial group equivalence is important considering the quasi-experimental design of the study.

Correlations Among 6MW Distances and Clinical Measures Six-Minute Walk distances for the square and straight-line administrations, as well as for both administrations combined, were significantly and similarly associated with disability status, T25FW performance, and MSWS-12 scores (Table 2).

Table 2. Correlations among 6MW distance and PDDS scores, T25FW performance, and MSWS-12 scores in people with MS 6MW administration

PDDS

T25FW performance

MSWS-12

a

Square (n = 82)

−0.720

−0.911

−0.725a

Straight-line (n = 78)

−0.779a

−0.896a

−0.806a

Overall (n = 160)

−0.745a

−0.903a

−0.771a

a

Abbreviations: PDDS, Patient-Determined Disease Steps; 6MW, 6-Minute Walk; T25FW, Timed 25-Foot Walk; MS, multiple sclerosis; MSWS-12, 12-item Multiple Sclerosis Walking Scale. a P < .001 with 2-tailed test.

37 ft (2.7%) farther (1412 ft) than those undertaking the “square” 6MW (1375 ft) (Table 3). That difference was not clinically meaningful,16 and the condition of 6MW administration explained less than 1% of the variance in 6MW distance. There was a significant main effect for disability status (F1,156 = 107.87, P < .01, partial-η2 = 0.41), indicating that across 6MW conditions those without gait disability walked significantly farther (571 ft, 51.6%) than those with gait disability. This main effect explained a noteworthy 41% of the variance in 6MW distance.

Six-Minute Walk Energy Expenditure Overall, when controlling for resting metabolic rate as a covariate, there was not a 3-way 6MW administra. tion × disability status × time interaction on Vo2 (F11,1705 = 0.23, P = .99, partial-η2 < 0.01). This indicated that change in energy expenditure over time did not differ based on 6MW administration between levels of disability status. There was a significant time × disability status . interaction on Vo2 (F11,1705 = 9.52, P < .01, partial-η2 = 0.06; Figure 1), indicating that those without gait disability expended more energy initially (first 3 minutes of 6MW) and then maintained this higher level of energy Table 3. 6MW distances based on administration condition and disability status in people with MS

Six-Minute Walk Distance There was not a significant 6MW administration × disability status interaction on distance traveled (F1,156 = 0.01, P = .93, partial-η2 < 0.01). This indicated that there was no difference in distance walked between conditions of 6MW administration as a function of disability status. Further, there was not a significant main effect for 6MW administration on distance traveled (F1,156 = 0.45, P = .51, partial-η2 < 0.01). Participants undertaking the “straight-line” 6MW in a single corridor walked

Variable

Square 6MW Straight-line distance, ft 6MW distance, ft

Overall sample (n = 160)

1375 (431)

1412 (463)

No gait disability (PDDS 0–2) (n = 72)

1699 (254)

1658 (274)

Gait disability (PDDS 3–8) (n = 88)

1124 (435)

1091 (364)

Abbreviations: MS, multiple sclerosis; PDDS, Patient-Determined Disease Steps; 6MW, Six-Minute Walk. Note: Data are presented as mean (SD).

International Journal of MS Care 51

 !  4 " "    $&!$( Sandroff et al.

line” 6MW versus the “square” 6MW primarily occurred in /2.. the first 3 minutes of the 6MW and was small in magnitude. /0.. Such results suggest that both /... administrations of the 6MW yield similar end results regard6.. ing distance walked, but with a slightly higher energy expendi4.. ture for the straight-line 6MW 2.. condition. This similarity in distance traveled is likely attrib0.. utable to the standardization of 1. 4. 7. /0. /3. /6. 0/. 02. 05. 1.. 11. 14. the instructions and researcher *+ behavior for the 6MW in MS4 Figure 1. Energy expenditure in people with MS over the and indicates that researchers duration of the 6MW with (n = 88) and without (n = 72) gait can confidently perform the disability 6MW under either condition, if using standardized instruction; expenditure over the remainder of the 6MW compared however, they should be aware that the straight-line to those with gait disability; the interaction explained administration is slightly more metabolically demanding . 6% of the variance in Vo2. There was a small but statis- for participants. This might be attributed to the potentically significant time × 6MW administration interac- tially greater metabolic demand of making 180° turns, . tion on Vo2 (F11,1705 = 3.41, P < .01, partial-η2 = 0.02). requiring more frequent deceleration/acceleration and a change of turns.w The This indicated that those completingFigure   the “straight-line” 2:  Energy  egreater xpenditure   in  direction 82  and  than 78  p90° ersons   ith  shorter 6MW expended more energy over MS   the first 3 minutes hallway of theustraight-line administration over   the  dura;on   of  length the  6MW   nder  straight-­‐line   and  is a of the 6MW than those completing the “square” 6MW, possible explanation for the greater energy expenditure square  hallway  condi;ons,  respec;vely.   and energy expenditure then remained steady over the associated with this condition; however, research in last 3 minutes of the 6MW (Figure 2). This interaction explained 2% of the variance . in Vo2.   $

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Discussion The primary novel finding of this quasi-experimental, crosssectional study was that energy expenditure, but not total distance traveled, differed when the 6MW was administered in a single, straight-line corridor with 180° turns compared with a square hallway consisting of four corridors and 90° turns. That pattern of results was not influenced by disability status. The greater energy expenditure for the “straight-

Figure 2. Energy expenditure in people with MS over the duration of the 6MW under square (n = 82) and straight-line (n = 78) hallway conditions International Journal of MS Care 52

Six-Minute Walk in MS

COPD suggests that course length does not influence total distance walked during the 6MW.11 Standardized instruction for the 6MW is important, as demonstrated by research in COPD where participants demonstrated a greater distance traveled in a continuous (oval or square) administration than a straight-line administration of the 6MW.11 In that study, however, multiple sites that adopted different instructions for standardizing participant effort and behavior than in MS (ie, delivering standardized encouragement and neglecting to emphasize walking as fast as possible without stopping) were included; moreover, the study did not establish group equivalence in walking dysfunction. We believe that inclusion of MS-specific instructions that standardize participant effort and behavior (ie, walking as fast and far as possible without rest for 6 minutes) will overcome possible differences in 6MW administration such that either method is acceptable in individuals with MS. Six-minute walk distance was strongly and similarly associated with disability status, T25FW performance, and MSWS-12 scores regardless of condition for administering the 6MW. Such correlations are consistent with previous reports indicating strong associations among 6MW distance and other disability/walking performance measures.4,7 The current results regarding differences in 6MW distance by disability status are also consistent with two previous studies indicating that people with MS who had severe disability walked shorter 6MW distances than those with moderate and mild disability.4,8 The current study generally replicates the findings that, in people with MS, energy expenditure increased during the first 3 minutes of the 6MW before reaching a plateau8,17 and the rate and plateau were greater for those without gait disability than for those with gait disability.8 This consistency is important, as it situates our results within other research in MS, but in a substantially larger sample and across conditions of administering the 6MW. The current study has several strengths, including the large sample of individuals with MS, objective measurement of energy expenditure, adoption of standardized instructions for 6MW, and replication of previous results regarding the 6MW; however, there are important limitations. Longer walking tests such as the 6MW might result in an increased risk of falls and excessive fatigue in people with MS, but, as previously reported, the 6MW represents a measure of walking endurance in this population3-6 that may be more precise in defin-

ing disability than shorter walking tests such as the T25FW.4 One limitation was the quasi-experimental nature of the study. We established that both groups were similar in demographic, clinical, disability, and walking characteristics, but the samples were not matched based on these characteristics or randomized into conditions for administering the 6MW. There may be subtle differences between groups of 6MW administration that account for our results and that were not controlled for in the present analysis (eg, aerobic fitness level or fatigue). Another limitation of the current investigation was the inclusion of a self-reported measure of disability rather than an EDSS score generated by a neurologist as an approach for generating groups by gait disability. Such groups may not purely reflect gait/walking impairment, as other factors such as cognitive impairment could influence PDDS scores. It is important to note that the current study used previously reported standardized instructions of the 6MW4 for consistency, as the majority of research that has included the 6MW as a primary outcome measure in MS has adopted those instructions. We did not compare 6MW performance using the aforementioned standardized instructions4 with alternative instructions allowing rest or providing standardized encouragement. Nevertheless, we provide evidence supporting either condition of administering the 6MW, given the standardized instructions, across a range of disability in people with MS.

PracticePoints • It is unknown whether alternate conditions of administration of the 6-Minute Walk test (6MW) result in similar total distance traveled and energy expenditure in people with MS. • Overall, the current study offers novel evidence that energy expenditure, but not total distance traveled, differed when the 6MW was administered in a single corridor with 180° turns compared with a square hallway with four corridors and 90° turns; this did not depend on disability status. • These results suggest that either protocol is acceptable, as total distance traveled is the primary outcome measure of the 6MW, but researchers and clinicians should be aware of the additional physiological demands when administering the 6MW in a single corridor with 180° turns.

International Journal of MS Care 53

Sandroff et al.

HERNDON AWARD FOR OUTSTANDING ARTICLE  5. Goldman MD, Motl RW,IJMSC Rudick RA. Possible clinical outcome meaConclusion sures for clinical trials in patients with multiple sclerosis. Ther Adv Neu-

Overall, the current study offers novel evidence that(CMSC) rol Disord. 2010;3:229–239. The Consortium of Multiple Sclerosis Centers presents an annual Tests of Information Processing Speed   6. Motl RW. Ambulation and multiple sclerosis. Phys Med Rehabil Clin N energyaward, expenditure, but not total distance traveled, difthe Herndon Award for Outstanding IJMSC Article, for the best article Am. 2013;24:325–336. fered when the 6MW administered in aofsingle cor-during  7. Motl RW, Balantrapu Pilutti L, et al. Symptomatic correlates of sixpublished in the was International Journal MS Care a given calendar S,year. ridor with 180° turns compared with a square hallway minute walk performance in persons with multiple sclerosis. Eur J Phys The winners of the 2012 award are Lisa A.S. Walker (The Ottawa Hospital Rehabil Med. 2013;49:59–66. with four and 90° turns. This not depend and corridors the University of Ottawa) anddid colleagues, for their “Tests of Infor  8. article Motl R, Suh Y, Balantrapu S, et al. Evidence for the different physiologion disability status. These findings suggest that either cal significance of 6- and 2-minute walk tests in multiple sclerosis. mation Processing Speed: What Do People with Multiple Sclerosis theThink C BMC Neurol. 2012;12:6. protocol is acceptable, as total in distance traveled is the About Them?” published the Summer 2012 issue of 9.IJMSC. The award car Savci S, Inal-Ince D, Arikan H, et al. Six-minute walk distance as a primary the 6MW, but researchers riesoutcome a $1000measure stipend.ofRobert M. Herndon was the founding editor of IJMSC measure of functional exercise capacity in multiple sclerosis. Disabil shouldand be aware of the additional physiological Rehabil. 2005;27:1365–1371. currently serves as Editor Emeritus. demands when administering the 6MW in a single corridor with 10. Dalgas U, Severinsen K, Overgaard K. Relations between 6 minute walking distance and 10 meter walking speed in patients with multiple 180° turns. o sclerosis and stroke. Arch Phys Med Rehabil. 2012;93:1167–1172. What Do People with Multiple Sclerosis Think About Them? Lisa A.S. Walker, PhD; Amy Cheng, BA; Jason Berard, BScH, Lindsay I. Berrigan, PhD; Laura M. Rees, PhD; Mark S. Freedman, MD

Reduction in information processing speed (IPS) is a key deficit in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and Computerized Test of Information Processing (CTIP) are used to measure IPS. Both the PASAT and SDMT are sensitive to deficits in IPS. The CTIP, a newer task, also shows promise. The PASAT has several limitations, and it is often perceived negatively by patients. Yet little supporting quantitative evidence of such perceptions has been presented. Therefore, in this study, subjective ratings of likeability, difficulty, and appropriateness of the PASAT, CTIP, and SDMT were obtained. Ratings were compared between MS patients and healthy controls. It was hypothesized that ratings of the PASAT would differ significantly from those of the SDMT and CTIP. The relationship between subjective ratings and objective performance was evaluated. Sixty-nine MS patients and 68 matched controls rated the three tests in terms of likeability, difficulty, and appropriateness for capturing cognitive deficits often associated with MS using a Likert scale. Both groups rated the PASAT as most difficult and least likeable. The MS group rated the PASAT and SDMT as more appropriate for measuring MS-related deficits than the CTIP. Subjects who performed better on the PASAT were more likely to rate it as easier. Ratings of the SDMT and CTIP did not vary consistently with performance. The findings lend quantitative support to the common belief that the PASAT is perceived as unpleasant. Other tests are available that are similarly sensitive to deficits in IPS and more palatable to the patient. Int J MS Care. 2012;14:92–99.

ognitive impairment is common in multiple sclerosis (MS), affecting 40% to 65% of patients and contributing to functional limitations that result in poor health-related quality of life (HRQOL).1,2 The predictive value of cognitive dysfunction in HRQOL remains even after controlling for subjective distress variables such as depression and fatigue.3 The most commonly identified cognitive difficulties associated with MS include problems with working memory, as well as learning and memory for new information.4,5 Information processing speed has also been From the Neuropsychology Service, The Ottawa Hospital, Ottawa, Ontario, Canada (LASW, LMR); The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (LASW, LIB, LMR, MSF); Division of Neurology, Faculty of Medicine (LASW, MSF), and School of Psychology, University of Ottawa, Ottawa, Ontario, Canada (LASW, AC, JB, LMR); and Department of Psychology, Carleton University, Ottawa, Ontario, Canada (LIB, LMR). Correspondence: Lisa A.S. Walker, PhD, Psychology, The Ottawa Hospital, 501 Smyth Rd., Ste. 7300, Ottawa, Ontario K1H 8L6, Canada; email: [email protected].

identified as a primary cognitive deficit in MS.6-8 Cognitive difficulties can lead to problems for people with MS in their daily lives, such as their ability to maintain employment.1,9 Such deficits can also negatively affect their relationships with intimate partners, family members, caregivers, coworkers, and their health-care team.10 A challenge with any type of cognitive assessment is selecting measures that possess good psychometric properties (ie, reliability, validity, sensitivity to impairment, specificity to the types of impairment encountered in MS). While it is important for clinicians to select tests that do not cause stress for the individual completing the test, it is also important to ensure that even subtle cognitive deficits are detected. Thus, some measures that are designed to be quite challenging to complete must also be included. One such task that has been reported anecdotally to be unpleasant, both for the patients undergoing it and for the clinicians administering it, is the Paced Audi-

International Journal of MS Care 92

11. Sciurba F, Criner GJ, Lee SM, et al. Six-minute walk distance in chronic obstructive pulmonary disease: reproducibility and effect of walking course layout and length. Am J Respir Crit Care Med. 2003;167:1522–1527. 12. Fischer JS, Jak AJ, Knicker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional Composite (MSFC): Administration and Scoring Manual. New York, NY: National Multiple Sclerosis Society; 2001. 13. Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. MeasurFinancial Disclosures: Dr. Motl has been a consultant for Biogen ing the impact of MS on walking ability: the 12-Item MS Walking and Acorda, but neither had a role in designing the current study. Scale (MSWS-12). Neurology. 2003;60:31–36. The other authors have no conflicts of interest to disclose. The Consortium of Multiple Sclerosis Centers (CMSC) presents anO,annual award, the Herndon Award 14. Hadjimichael Kerns RD, Rizzo MA, Cutter G, Vollmer T. Persistent pain and uncomfortable sensations in persons with multiple for Outstanding IJMSC Article, for the best article published in the International Journal of MS Caresclerosis. References Pain. 2007;127:35–41.  1. Heesen C, Segal J, Reich C, et al.year. Patient information cognitive during a given calendar The award on carries a $1000 stipend. Robert M. Herndon was the founding 15. Marrie RA, Goldman M. Validity of performance scales for disability symptoms in multiple sclerosis: acceptability in relation to disease duraeditor of IJMSC. The winner of the 2013 award will be announced at thesclerosis. 2014 Annual of the assessment in multiple Mult Scler.Meeting 2007;13:1176–1182. tion. Acta Neurol Scand. 2006;114:268–272. 16. Learmonth YC, Dlugonski D, Pilutti L, Sandroff BM, Motl RW. The reliCMSC in May.  2. Larocca NG. Impact of walking impairment in multiple sclerosis: perability, precision and clinically meaningful change of walking mobility spectives of patients and care partners. Patient. 2011;4:189–201. assessments in multiple sclerosis. Mult Scler. 2013;19:1784–1791.  3. Kieseier BC, Pozzilli C. Assessing walking disability in multiple sclero17. Motl RW, Sandroff BM, Suh Y, Sosnoff JJ. Energy cost of walking sis. Mult Scler. 2012;18:914–924. and its association with gait parameters, daily activity, and fatigue  4. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute in persons with mild multiple sclerosis. Neurorehabil Neural Repair. walk in multiple sclerosis subjects and healthy controls. Mult Scler. 2008;14:383–390. 2012;26:1015–1021.

Acknowledgments: We would like to thank Yoojin Suh and Swathi Balantrapu for assistance in data acquisition. Data from this study were presented as a poster during the 26th Annual Meeting of the Consortium of Multiple Sclerosis Centers held in 2012 in San Diego, California.

HERNDON AWARD FOR OUTSTANDING IJMSC ARTICLE

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The International Journal of MS Care has a Web-based system for manuscript submission and peer review. The system is available at http://ijmsc.msubmit.net and can also be accessed from the IJMSC website at http:// ijmsc.org. Authors: To submit a new manuscript, first log into the system with your username and password. If you have not yet created an account in the system, create one by clicking on “Register for an Account” from the system home page. Reviewers: If you have reviewed previously for IJMSC, you may already have an account. Please go to the site and update your personal and specialty information. From the system home page, click on “Unknown/Forgotten Password” to obtain a password and access your individual home page. Then click on “Modify Profile/Password” to update your profile. Complete instructions on using the online manuscript system appear on the system website. If you have any questions or comments, please direct them to Maria Stadtler at [email protected]. International Journal of MS Care 54

CONSENSUS STATEMENT

Nurses’ Perspective on Approaches to Limit Flu-Like Symptoms During Interferon Therapy for Multiple Sclerosis Mary L. Filipi, PhD, APRN; Jill Beavin, RN, MSCN; Raquel T. Brillante, ANP-BC; Kathleen Costello, MS, ANP-BC, MSCN; Gail C. Hartley, MSN, NP, MSCN; Kay Hartley, RN, BSN; Marie Namey, RN, MS, MSCN; Shirley O’Leary, MS, NP-C, MSCN; Gina Remington, RN Background: Several interferon beta (IFNβ) formulations are approved for first-line use as disease-modifying therapies to treat patients with multiple sclerosis (MS). Systemic post-injection reactions, often termed flu-like symptoms (FLS), occur in approximately half of all patients treated with IFNβs and can affect adherence to therapy. These symptoms, which include pyrexia, chills, malaise, myalgia, and headaches, usually resolve within 24 hours or persist intermittently following each injection. Because FLS, which usually occur early in the treatment course and diminish over time, are a primary cause of nonadherence to IFNβ therapy, it is important to employ strategies that can attenuate these side effects. Methods: To identify interventions effective in limiting FLS, a panel of United States–based nurses with expertise in MS patient care was convened and a literature review completed. Results: Panel consensus was reached on specific interventions that can attenuate FLS. These prevention and mitigation strategies include dose titration, analgesia, and optimal injection timing, as well as other techniques that panel members have found useful in their clinical practice experience. Conclusions: These measures, in addition to effective patient education, will help to reduce the incidence of FLS secondary to IFNβ therapy, improve patient medication adherence, and positively affect long-term clinical outcomes. Int J MS Care. 2014;16:55–60.

M

ultiple sclerosis (MS) is a chronic, progressive, neurodegenerative disease characterized by demyelination and the subsequent loss of both gray and white matter in the central nervous system.1 It is currently estimated that 2.5 million people worldwide, including 400,000 people in the United

States, have MS. In the United States alone, approximately 200 people receive a diagnosis of MS each week.2 Treatment for relapsing-remitting MS is indicated to slow MS disease progression, minimize axonal damage, reduce the frequency and severity of relapses, delay the accumulation of irreversible neurologic damage, and

From the College of Nursing, University of Nebraska Medical Center, Omaha, NE, USA (MLF); Biogen Idec, Weston, MA, USA (substantial portion of contributions made while employed at Forget-Me-Not Home Memory Care, Raleigh, NC, USA) (JB); Biogen Idec, Weston, MA, USA (substantial portion of contributions made while employed at Rush Multiple Sclerosis Center, Chicago, IL, USA) (RTB); Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA (KC); Acadia Neurology Center, Acadia, CA, USA (GCH); Providence Multiple Sclerosis Center, Providence St. Vincent Medical Center, Portland, OR, USA (KH); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH, USA (MN); Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (substantial portion of contributions made while employed at Texas Neurology, Dallas, TX, USA) (SO); and Clinical Center for Multiple Sclerosis, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA (GR). Kay Hartley is now with Providence Home Health, Portland, OR, USA. Correspondence: Mary L. Filipi, PhD, APRN, University of Nebraska Medical Center, College of Nursing (Omaha Division), Room 5043, 985330 Nebraska Medical Center, Omaha, NE 68198; e-mail: [email protected]. DOI: 10.7224/1537-2073.2013-006 © 2014 Consortium of Multiple Sclerosis Centers.

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lessen the disability associated with the disease. Moreover, in long-term studies of individuals diagnosed with a clinically isolated syndrome, which often precedes relapsing MS, the benefits of early intervention were sustained, whereas delayed treatment was not associated with comparable therapeutic benefits.3,4 In general, early therapeutic intervention is associated with better longterm clinical outcomes in MS.5 Several therapeutic options are currently available to treat MS. Interferon beta is used in a number of different formulations as first-line MS therapy, based on its efficacy in slowing disease progression and in reducing the number and frequency of MS relapses.6,7 Interferons are members of a large class of glycoproteins, known as cytokines, that broadly activate immune cells and are involved in the upregulation of antigen presentation to T lymphocytes.8,9 However, these medications may have downstream effects that include aching muscles, fever, and a host of other systemic post-injection reactions, often referred to as flu-like symptoms (FLS).10,11 Adherence to therapy is increasingly recognized as critical to improving long-term outcomes in MS patients, yet long-term adherence rates for MS treatment rarely exceed 75%.12 While convenience-related factors, such as dosing frequency, can affect adherence,13 tolerability issues also represent an important potential barrier to adherence. Thus, effective management of side effects is essential to maintain treatment and prevent disease progression.14,15 Patients frequently report FLS as a concern, and untreated FLS negatively affect adherence to IFNβ therapy. However, such symptoms can often be effectively managed with minor lifestyle and medication modifications. Flu-like symptoms usually resolve within 24 hours after injection or persist intermittently following each injection; they typically diminish during the first few months of treatment and may cease completely over time.16,17 Clinicians working with the MS population need to be proactive in assessing the tolerability of treatment and providing education and strategies for managing treatment-related symptoms while setting realistic expectations. The goal of the panel was to generate a consensus statement about FLS mitigation, primarily aimed at nursing staff working with MS patients.

Methods A panel of nine United States–based expert MS nurses was convened and a literature review completed with

the goal of generating a set of practice guidelines for nurses and other caregivers of MS patients on managing FLS secondary to IFNβ therapy. Five FLS—pyrexia, chills, malaise, myalgia, and headache—were examined. A number of possible interventions derived from clinical trials (Class 1 evidence), clinical reports (Class 2 evidence), or the experts’ own 100-plus cumulative years of clinical experience with MS patients (anecdotal evidence) were discussed. Consensus regarding each of the proposed interventions was obtained, and treatment recommendations were made to generate a best practice model for addressing the most common FLS reported by patients treated with IFNβ.

Results The panel recommended combining early patient counseling regarding the possibility of developing FLS with specific interventions effective in limiting these injection-related reactions. Seven interventions were unanimously recommended by the panel, as described below and summarized in Table 1.

Titration The panel agreed that the most effective and bestsupported strategy to reduce FLS is dose titration during the initiation of IFNβ therapy.10,18,19 Dose-titration schedules are included in the prescribing information for IFNβ therapies currently approved for the treatment of MS20-23 and are supported by the results of several studies.16,19,24 A study of 98 patients randomized to either placebo or two different titration schedules of IFNβ-1b found that slower titration (reaching full dose on day 31) was associated with FLS in 32.9% of patients, while rapid titration (reaching full dose on day 15) was associated with FLS in 41.9% of patients.24 In an open-label pilot study of 47 patients, the combination of analgesics and quarter- or half-dose titration of intramuscular (IM) IFNβ-1a significantly reduced FLS during the first 2 weeks of therapy compared with analgesics alone.16 These findings were confirmed and extended by a larger, randomized, dose-blinded study assessing the frequency and severity of FLS in healthy volunteers using selfinjecting IM IFNβ-1a with no titration or with one of two titration schedules.19 One group increased its dosage by a quarter-dose each week for 3 weeks, reaching full dose at week 4; the other group underwent a longer 6-week titration, starting at a quarter-dose with quarter-dose increases every 2 weeks, reaching full dose after week 6. Compared with no titration, the incidence

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Nurses’ Perspective on Limiting FLS During Interferon Therapy for MS Table 1. Interventions for limiting the incidence of FLS Intervention

Consensus opinion

Evidence level

Titration

Highly effective

• Recommend starting with quarter-dose and increasing to a full dose over a period of 4–6 weeks; no consensus regarding the optimum speed of titration • Product labels for all IFNβ therapies approved for the treatment of MS provide dose titration schedules

Class 1

Analgesics

Highly effective

• Recommend starting with ibuprofen and using steroids only if NSAIDs provide insufficient relief • Product labels for all IFNβ therapies approved for the treatment of MS suggest that concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms

Class 1

Interferon preparation

Effective

• Lower incidence of FLS seen with lyophilized IFNβ; switching preparations recommended if FLS occur with prefilled syringe • Differences between preparations for FLS not addressed in product labels

Class 2

Timing

Effective

• Consensus that patients should self-inject at night so that FLS occur during sleep • Evening administration preferred according to the product label for IFNβ-1b

Class 2

Temperature

Probably effective

• Consensus that patients have fewer FLS when medication is warmed to body temperature prior to use • Temperature of medication not addressed in product labels

Anecdotal

Hydration

Probably effective

• FLS better tolerated in patients who are well hydrated • Hydration of patients not addressed in product labels

Anecdotal

Diet

Probably effective

• Better resistance to FLS seen in patients with good nutrition • Patient nutritional status not addressed in product labels

Anecdotal

Comments

Abbreviations: FLS, flu-like symptoms; IFNβ, interferon beta; NSAIDs, nonsteroidal anti-inflammatory drugs.

of FLS at the 4- to 6-hour time point and at the 12- to 15-hour time point was significantly reduced with both 3-week titration (P < .001 at 4–6 hours; P = .006 at 12–15 hours) and 6-week titration (P = .023 at 4–6 hours; P = .027 at 12–15 hours). The severity of FLS was reduced by 76% at 4–6 hours (P < .001) and by 37% at 12–15 hours (P < .001) with 3-week titration, while symptom severity was reduced by 50% at 4–6 hours (P < .001) and by 32% at 12–15 hours (P = .002) with 6-week titration, compared with no titration.19 Thus, there is compelling evidence in both healthy volunteer and MS patient populations that the incidence and severity of FLS can be reduced by carefully titrating IFNβ dosage as patients start therapy. The panel agreed that dose titration is critical to minimize FLS incidence when initiating any IFNβ therapy. Many participants on the panel customized the titration rate based on the patient’s tolerance and any reports of FLS during initiation of therapy.

Analgesic Management of FLS For patients who experience ongoing FLS, there is good evidence that analgesics are effective in limiting symptom occurrence and severity.16,25,26 Concurrent

use of analgesics and/or antipyretics to help ameliorate IFNβ-associated FLS is mentioned in the product labels for all IFNβ therapies currently approved for the treatment of MS.20-23 In clinical practice, clinicians recommend a variety of treatment protocols to prevent and mitigate FLS, including ibuprofen, naproxen, and oral steroids, as well as acetaminophen. The panel reviewed three studies25,27,28 that attempted to determine the most effective analgesic for FLS management. When the efficacies of acetaminophen, ibuprofen, and the steroid prednisone were compared, no significant difference was found between the treatment options in the first month of therapy with IM IFNβ-1a. However, ibuprofen appeared to provide better control of symptoms immediately after IM IFNβ-1a injection than either acetaminophen or steroids.27 Similarly, Reess et al.25 compared acetaminophen and ibuprofen and found them equally effective at FLS management in patients initiating IM IFNβ-1a. Leuschen et al.28 compared the efficacy of naproxen, ibuprofen, and acetaminophen and found that the first two were more effective than the last at minimizing many of the physical symptoms associated with IM IFNβ-1a. However, none of these therapies was as effective as originally hypothesized

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for minimizing fatigue or for effectively managing joint and muscle pain.28 Based on these studies, the panel recommended that patients take ibuprofen or naproxen 1 hour prior to IM IFNβ-1a injection, as both compounds were shown to be better than acetaminophen at providing overall prophylaxis of FLS. In one clinical trial a course of steroids with acetaminophen significantly reduced FLS compared to acetaminophen alone; however, patients taking steroids should be carefully monitored, and steroids should generally not be used for long-term symptom management.27 Using low-dose oral steroids to help manage FLS-related pain was recommended only if no improvement was noticed with nonsteroidal anti-inflammatory drugs (NSAIDs).

Timing of Injections Patient education regarding the potential impact of injection timing on the development of FLS is a key component of successful symptom management, especially during the first 6 months of therapy, when the risk of nonadherence is highest.29 Based on clinical reports,29-31 the panel recommended that IFNβ injections, in general, be administered in the evening to mitigate FLS. Patients are encouraged to determine when their symptoms peak and administer the injection at the appropriate interval prior to bedtime, thus allowing the worst of the side effects to occur during sleep and to fully resolve prior to waking. However, the panel underscored the importance of evaluating individual patients for alternate dosing times, especially in light of evidence that many patients suffered fewer FLS with morning injections.31 These data demonstrate the need for clinicians to counsel each patient to develop an individual routine that best allows the patient to manage any FLS, based on his or her own responses to IFNβ injection.

IFNβ Formulation IFNβ therapies for MS are available in a number of different formulations, including prefilled syringes and lyophilized preparations (reconstituted immediately prior to injection).20-23 Flu-like symptoms have been reported in 59% to 88% of patients during the initial dosing period using prefilled syringe preparation22,32 and in 49% to 57% of patients receiving reconstituted formulations.20-23,30,32 In their clinical practice, members of the panel noted that a substantial number of their patients who were switched from lyophilized preparations to prefilled syringes experienced more FLS with

the latter preparation. Therefore, the panel agreed that clinicians should consider evaluating the IFNβ formulation for those patients who continue to experience FLS despite following the dose-titration, analgesic, and administration timing recommendations.

Solution Temperature A review of the literature did not identify any formal reports on the effect of solution temperature on FLS, and this issue is not discussed in the prescribing information for the IFNβ products used to treat patients with MS.20-23 However, in the panel’s experience, the severity and duration of FLS are reduced when the prepared medication is near body temperature at the time of administration. Thus, to optimize solution temperatures, IFNβ therapies should be removed from the refrigerator several hours prior to dosing.21 Patients need to be cautioned that these medications should never be artificially warmed in hot water, in a microwave, or with another intense heat source, as they will lose potency. However, gently warming the solution by holding the vial or syringe in hands, axilla, or a pocket can safely bring the medication closer to a more comfortable temperature. While this evidence is anecdotal, the panel concluded that gently warming the solution prior to injection is associated with a reduced incidence of FLS in a substantial number of their patients and is, therefore, recommended, especially as no risks to the patients are incurred.

Hydration Low-grade fever is often a significant component of FLS. Because fever can cause dehydration, it is important to counsel patients to hydrate themselves adequately, particularly during the period they experience FLS. Hydration is also important for many aspects of normal cognitive and physical functioning.30 Patients should be counseled on the importance of maintaining adequate fluid intake, as well as on the signs of dehydration, such as dry skin, headache, fatigue, irritability, confusion, and reduced urine output. As patients with MS experience urinary bladder symptoms including incontinence, urine leakage, and hesitancy, they may restrict their fluid intake to limit these bladder-related issues.33 These symptoms may exacerbate FLS in patients with fever resulting from IFNβ treatment. Maintenance of adequate hydration is particularly important in patients who inject during the evening, as restricting fluid intake

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Nurses’ Perspective on Limiting FLS During Interferon Therapy for MS

in the hours before sleep is often recommended to manage nocturia. The panel recommended that MS therapy guidelines for injectable IFNβs emphasize the importance of patients’ maintaining adequate hydration, particularly prior to IFNβ injection, in order to minimize any effects of fever-induced dehydration. The guidelines should recognize that for patients who suffer from FLS and nocturia, fluid loading prior to evening injections may not be appropriate and alternative dosing times should be considered. This recommendation is not based on formal clinical trial data, but on the panel’s clinical experience in their efforts to mitigate discomfort during low-grade fever.

Diet Finally, proper nutrition is critical for maintaining robust immune responses.34 While there is no evidence that a specific food can moderate FLS, it is axiomatic that maintenance of a healthy diet makes a large contribution to the body’s ability to withstand FLS. Proper nutrition that includes a reasonable combination of proteins, carbohydrates, and fats from fresh fruits and vegetables, grains, meats, fish, and dairy products has been associated with better health outcomes across all patient populations. Therefore, patients with MS can benefit by avoiding or limiting their intake of foods that are high in fat and sugar in the interest of their overall health. While no formal trials have been conducted on the effect of specific foods or diets on FLS, the panel felt that patients should be counseled on nutrition issues for overall health.

PracticePoints • Flu-like symptoms (FLS) associated with interferon beta (IFNβ) injections negatively affect patient adherence to therapy for MS, and strategies that limit FLS can improve adherence and, hence, overall clinical outcome. • FLS can be mitigated by dose titration, use of analgesics, evening dosing, drug formulation, solution temperature, adequate hydration, and a nutritious diet. • Overall adherence to IFNβ therapy can be significantly improved by working with patients to effectively incorporate all of these interventions into their daily routines and injection practices.

Discussion As the maximal therapeutic benefit requires good adherence to therapy, it is essential to address factors that lead to patient nonadherence. Adverse events, including FLS, are a major cause of discontinuation of IFNβ-1a therapy in MS patients.33,35,36 The majority of currently approved first-line therapies are IFNβ formulations, which may cause such FLS as fatigue/malaise, chills, fevers, headaches, and myalgia that many patients find difficult to tolerate over long periods. Moreover, the relatively low rate of clinically relevant relapses that most MS patients experience makes long-term adherence more challenging, because the clinical benefit of treatment may not be readily apparent while FLS may continue to occur regularly. Clinical trial data clearly show that effective management of FLS can increase patient adherence to IFNβbased disease-modifying therapies (DMTs).37,38 Because FLS most often occur during therapy initiation, it is critical that patients be counseled on both the probability of symptoms and their mitigation. Because FLS can occur in long-term users of IFNβ-based DMTs as well, it is important to routinely monitor patient adherence so that clinical staff can intervene as necessary. Nurses should be prepared to discuss the probability of FLS with patients initiating IFNβ therapy and offer practical methods to limit these side effects. This counseling has been shown to be an important aspect of patient care, as adherence rates are higher in patients with realistic expectations of treatment-related side effects.38 In summary, nurses play a crucial role in ensuring the best longterm clinical outcomes in MS patients by working with patients to develop strategies that increase their overall compliance and adherence to therapy. The guidelines described will help health-care providers educate their patients on effective strategies to limit FLS and thus increase the probability of long-term adherence. o Acknowledgments: Anne Williamson, PhD, and Joshua Safran from Infusion Communications copyedited and styled the manuscript according to journal requirements. Financial Disclosures: Dr. Filipi has served on speakers’ bureaus for Biogen Idec, Acorda, Teva, and the International Organization of Multiple Sclerosis Nurses (IOMSN), and on the clinical advisory board for the National Multiple Sclerosis Society. Ms. Beavin is an employee of Biogen Idec; a substantial portion of her contributions to this article were made while she was employed at Forget-Me-Not Home Memory Care, Raleigh, NC. She has also served on speakers’ bureaus for Biogen Idec, Novartis, the NMSS, the IOMSN, and the Consortium of Multiple Sclerosis Centers (CMSC) and has been a consultant for Biogen Idec, Genzyme, Janssen, and Pfizer. Ms.

International Journal of MS Care 59

Filipi et al. Brillante is an employee of Biogen Idec; a substantial portion of her contributions to this article were made while she was employed at Rush Multiple Sclerosis Center, Chicago, IL. Ms. Costello has been a scientific advisory participant and consultant for and received honoraria from Teva, Biogen Idec, EMD Serono, Genzyme, Acorda, Questcor, and Novartis; she has also received a research grant from Novartis. Gail C. Hartley has served on speakers’ bureaus and been a consultant for Acorda, Biogen Idec, EMD Serono, Genzyme, Novartis, Pfizer, Questcor, and Teva. Ms. Namey has served on speakers’ bureaus and been a consultant for Biogen Idec, Teva, Pfizer, EMD Serono, Acorda, Novartis, Genzyme, and Questcor; she has also been a consultant for Novartis and Allergan. Ms. O’Leary has served on speakers’ bureaus for Biogen Idec, Genzyme, and the IOMSN and has been a consultant for Novartis and Teva; a substantial portion of her contributions to this article were made while she was employed at Texas Neurology, Dallas, TX. Ms. Remington has served on speakers’ bureaus for Biogen Idec, Teva, the NMSS, the CMSC, and the IOMSN and been a consultant for Biogen Idec, Teva, Genzyme, and Acorda. Kay Hartley has no conflicts of interest to disclose. Funding/Support: Biogen Idec provided funding for editorial support in the development of this article, provided support for the Flu-Like Symptom Expert Panel, and reviewed the manuscript and provided feedback on it to the authors. The authors had full editorial control of the manuscript and provided final approval of all content.

References  1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221– 1231.  2. National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research: treatments to help reduce disease activity and progression. http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#193353215. Accessed December 17, 2012.   3. Kinkel RP, Kollman C, O’Connor P, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66:678–684.  4. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8:987–989.   5. Freedman MS. Long-term follow-up of clinical trials of multiple sclerosis therapies. Neurology. 2011;76(suppl 1):S26–S34.  6. Jacobs LD, Cookfair DL, Rudick RA, et al.; The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:285–294.  7. Zivadinov R, Locatelli L, Cookfair D, et al. Interferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy. Mult Scler. 2007;13:490–501.  8. Kieseier BC. The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs. 2011;25:491–502.  9. Wiendl H, Kieseier BC. Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and future strategies. Expert Opin Investig Drugs. 2003;12:689–712. 10. Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs. 2005;19:239–252. 11. Ruggieri RM, Settipani N, Viviano L, et al. Long-term interferon-beta treatment for multiple sclerosis. Neurol Sci. 2003;24:361–364. 12. Steinberg SC, Faris RJ, Chang CF, Chan A, Tankersley MA. Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study. Clin Drug Investig. 2010;30:89–100. 13. Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28: 51–61.

14. Devonshire V, Lapierre Y, Macdonell R, et al. The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2011;18:69–77. 15. Giovannoni G, Southam E, Waubant E. Systematic review of diseasemodifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012;18:932–946. 16. Brandes DW, Bigley K, Hornstein W, Cohen H, Au W, Shubin R. Alleviating flu-like symptoms with dose titration and analgesics in MS patients on intramuscular interferon beta-1a therapy: a pilot study. Curr Med Res Opin. 2007;23:1667–1672. 17. Moses H Jr, Brandes DW. Managing adverse effects of disease-modifying agents used for treatment of multiple sclerosis. Curr Med Res Opin. 2008;24:2679–2690. 18. Galetta SL. The controlled high risk Avonex multiple sclerosis trial (CHAMPS Study). J Neuroophthalmol. 2001;21:292–295. 19. Matson MA, Zimmerman TR Jr, Tuccillo D, Tang Y, Deykin A. Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation. Curr Med Res Opin. 2011;27:2271–2278. 20. Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2010. 21. Avonex [package insert]. Cambridge, MA: Biogen Idec Inc; 2011. 22. Rebif [package insert]. Rockland, MA: EMD Serono, Inc; 2009. 23. Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2011. 24. Wroe SJ. Effects of dose titration on tolerability and efficacy of interferon beta-1b in people with multiple sclerosis. J Int Med Res. 2005;33:309–318. 25. Reess J, Haas J, Gabriel K, Fuhlrott A, Fiola M. Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy. Mult Scler. 2002;8:15–18. 26. Rice GP, Oger J, Duquette P, et al. Treatment with interferon beta1b improves quality of life in multiple sclerosis. Can J Neurol Sci. 1999;26:276–282. 27. Río J, Nos C, Bonaventura I, et al. Corticosteroids, ibuprofen, and acetaminophen for IFNbeta-1a flu symptoms in MS: a randomized trial. Neurology. 2004;63:525–528. 28. Leuschen MP, Filipi M, Healey K. A randomized open-label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis. Mult Scler. 2004;10:636–642. 29. Kleinman NL, Beren IA, Rajagopalan K, Brook RA. Medication adherence with disease modifying treatments for multiple sclerosis among US employees. J Med Econ. 2010;13:633–640. 30. Singer B, Lucas S, Kresa-Rehal K, Ross AP, Blake P. Optimizing adherence to multiple sclerosis therapies. Int J MS Care. 2008;10:113–126. 31. Nadjar Y, Coutelas E, Prouteau P, et al. Injection of interferon-beta in the morning decreases flu-like syndrome in many patients with multiple sclerosis. Clin Neurol Neurosurg. 2011;113:316–322. 32. Phillips JT, Rice G, Frohman E, et al. A multicenter, open-label, phase II study of the immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis. Clin Ther. 2004;26:511–521. 33. Cohen BA. Identification, causation, alleviation, and prevention of complications (ICAP): an approach to symptom and disability management in multiple sclerosis. Neurology. 2008;71(24 suppl 3):S14–S20. 34. Issazadeh-Navikas S, Teimer R, Bockermann R. Influence of dietary components on regulatory T cells. Mol Med. 2012;18:95–110. 35. Bayas A, Rieckmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Saf. 2000;22:149–159. 36. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256: 568–576. 37. Denis L, Namey M, Costello K, et al. Long-term treatment optimization in individuals with multiple sclerosis using disease-modifying therapies: a nursing approach. J Neurosci Nurs. 2004;36:10–22. 38. Mohr DC, Goodkin DE, Likosky W, et al. Therapeutic expectations of patients with multiple sclerosis upon initiating interferon beta-1b: relationship to adherence to treatment. Mult Scler. 1996;2:222–226.

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Important Safety Information about COPAXONE® (glatiramer acetate injection) (cont’d) Transient chest pain was noted in 13% of COPAXONE 20 mg per mL patients compared to 6% of placebo patients, and approximately 2% of COPAXONE® 40 mg per mL patients compared to 1% on placebo. While some episodes of chest pain occurred in the context of the immediate postinjection reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than 1 such episode, and episodes usually began at least 1 month after the initiation of treatment. ®

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. Because COPAXONE® can modify immune response, it may interfere with immune functions. For example, treatment with COPAXONE® may interfere with recognition of foreign antigens in a way that would undermine the body’s tumor surveillance and its defenses against infection. There is no evidence that COPAXONE® does this, but there has not been a systematic evaluation of this risk. In a controlled study of COPAXONE® 40 mg per mL, the most common adverse reactions with COPAXONE® vs placebo were injection site reactions (ISRs), such as erythema (22% vs 2%). ISRs were one of the most common adverse reactions leading to discontinuation of COPAXONE®. ISRs, such as erythema, pain, pruritus, mass, edema, hypersensitivity, fibrosis, and atrophy, occurred at a higher rate with COPAXONE® than placebo.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR COPAXONE® (glatiramer acetate injection) SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE COPAXONE is indicated for the treatment of patients with relapsing forms of multiple sclerosis. 4 CONTRAINDICATIONS COPAXONE is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. 5 WARNINGS AND PRECAUTIONS 5.1 Immediate Post-Injection Reaction Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown. 5.2 Chest Pain Approximately 13% of COPAXONE 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown. 5.3 Lipoatrophy and Skin Necrosis At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to COPAXONE 40 mg per mL in a single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection. 5.4 Potential Effects on Immune Response Because COPAXONE can modify immune response, it may interfere with immune functions. For example, treatment with COPAXONE may interfere with the recognition of foreign antigens in a way that would undermine the body’s tumor surveillance and its defenses against infection. There is no evidence that COPAXONE does this, but there has not been a systematic evaluation of this risk. Because COPAXONE is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken. Although COPAXONE is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with COPAXONE may result in untoward effects. Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given COPAXONE 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 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.

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Incidence in Controlled Clinical Trials COPAXONE 20 mg per mL per day Among 563 patients treated with COPAXONE in blinded placebo-controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain. Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with COPAXONE than in patients treated with placebo. Adverse reactions were usually mild in intensity. Table 1: Adverse reactions in controlled clinical trials with an incidence ≥2% of patients and more frequent with COPAXONE (20 mg per mL daily) than with placebo

Blood And Lymphatic System Disorders Cardiac Disorders

Lymphadenopathy

Eye Disorders Gastrointestinal Disorders

Metabolism And Nutrition Disorders Musculoskeletal And Connective Tissue Disorders Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)

Placebo (n=564)

7%

3%

Palpitations

9%

4%

Tachycardia

5%

2%

Eye Disorder

3%

1%

Diplopia

3%

2%

Nausea

15%

11%

Vomiting

7%

4%

Dysphagia

2%

1%

43%

10%

40%

20%

27%

4%

General Injection Site Erythema Disorders And Injection Site Pain Administration Site Injection Site Pruritus Conditions Injection Site Mass

Immune System Disorders Infections And Infestations

COPAXONE 20 mg/mL (n=563)

26%

6%

Asthenia

22%

21%

Pain

20%

17%

Injection Site Edema

19%

4%

Chest Pain

13%

6%

Injection Site Inflammation Edema

9%

1%

8%

2%

Injection Site Reaction

8%

1%

Pyrexia

6%

5%

Injection Site Hypersensitivity Local Reaction

4%

0%

3%

1%

Chills

3%

1%

Face Edema

3%

1%

Edema Peripheral

3%

2%

Injection Site Fibrosis

2%

1%

Injection Site Atrophy*

2%

0%

Hypersensitivity

3%

2%

Infection

30%

28%

Influenza

14%

13%

Rhinitis

7%

5%

Bronchitis

6%

5%

Gastroenteritis

6%

4%

Vaginal Candidiasis

4%

2%

Weight Increased

3%

1%

Back Pain

12%

10%

Benign Neoplasm of Skin

2%

1%

COPAXONE 20 mg/mL (n=563)

Placebo (n=564)

Tremor

4%

2%

Migraine

4%

2%

Syncope

3%

2%

Speech Disorder

2%

1%

Psychiatric Disorders

Anxiety

13%

10%

Nervousness

2%

1%

Renal And Urinary Disorders Respiratory, Thoracic And Mediastinal Disorders Skin And Subcutaneous Tissue Disorders

Micturition Urgency

5%

4%

Dyspnea

14%

4%

Cough

6%

5%

Laryngospasm

2%

1%

Rash

19%

11%

Hyperhidrosis

7%

5%

Pruritus

5%

4%

Urticaria

3%

1%

Skin Disorder

3%

1%

Nervous System Disorders

Vascular Vasodilatation 20% 5% Disorders *Injection site atrophy comprises terms relating to localized lipoatrophy at injection site Adverse reactions which occurred only in 4 to 5 more subjects in the COPAXONE group than in the placebo group (less than 1% difference), but for which a relationship to COPAXONE could not be excluded, were arthralgia and herpes simplex. Laboratory analyses were performed on all patients participating in the clinical program for COPAXONE. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both COPAXONE and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment. Data on adverse reactions occurring in the controlled clinical trials of COPAXONE 20 mg per mL were analyzed to evaluate differences based on sex. No clinicallysignificant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with COPAXONE were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinicallyrelevant age subgroups. Other Adverse Reactions In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n=979), the role of COPAXONE in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used COPAXONE and reported a reaction divided by the total number of patients exposed to COPAXONE. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients. Body as a Whole: Frequent: Abscess Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction. Cardiovascular: Frequent: Hypertension. Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins. Digestive: Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer. Endocrine: Infrequent: Goiter, hyperthyroidism, and hypothyroidism. Gastrointestinal: Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.

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Hemic and Lymphatic: Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly. Metabolic and Nutritional: Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing, and xanthoma. Musculoskeletal: Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis. Nervous: Frequent: Abnormal dreams, emotional lability, and stupor. Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor. Respiratory: Frequent: Hyperventilation and hay fever. Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration. Skin and Appendages: Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts. Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash. Special Senses: Frequent: Visual field defect. Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss. Urogenital: Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency, and vaginal hemorrhage. Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis. COPAXONE 40 mg per mL three times per week Among 943 patients treated with COPAXONE 40 mg per mL three times per week in a blinded, placebo-controlled trial, approximately 3% of the subjects discontinued treatment because of an adverse reaction. The most common adverse reactions were injection site reactions, which were also the most common cause of discontinuation. Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 40 mg per mL in the blinded, placebocontrolled trial. These signs and symptoms were numerically more common in patients treated with COPAXONE 40 mg per mL than in patients treated with placebo. Adverse reactions were usually mild in intensity. Table 2: Adverse reactions in a controlled clinical trial with an incidence ≥2% of patients and more frequent with COPAXONE (40 mg per mL three times per week) than with placebo COPAXONE 40 mg/mL (n=943)

Placebo (n=461)

Injection Site Erythema Injection Site Pain

22%

2%

10%

2%

Injection Site Mass

6%

0%

Injection Site Pruritus

6%

0%

Injection Site Edema

6%

0%

Pyrexia

3%

2%

Influenza-like Illness Injection Site Inflammation Chills

3%

2%

2%

0%

2%

0%

Chest Pain

2%

1%

Nasopharyngitis Respiratory Tract Infection Viral Dyspnea

11%

9%

3%

2%

3%

0%

Vasodilatation

3%

0%

Gastrointestinal Disorders

Nausea

2%

1%

Skin And Subcutaneous Tissue Disorders

Erythema

2%

0%

Rash

2%

1%

General Disorders And Administration Site Conditions

Infections And Infestations

Respiratory, Thoracic And Mediastinal Disorders Vascular Disorders

No new adverse reactions appeared in subjects treated with COPAXONE 40 mg per mL three times per week as compared to subjects treated with COPAXONE 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of COPAXONE 40 mg per mL were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-eight percent of patients in this clinical trial were Caucasian and the majority were between the ages of 18 and 50. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age groups. 6.2 Postmarketing Experience The following adverse events occurring under treatment with COPAXONE 20 mg per mL since market introduction and not mentioned above have been identified during postapproval use of COPAXONE. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reaction Cardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris Digestive System: tongue edema; stomach ulcer; hemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemia Metabolic and Nutritional Disorders: hypercholesterolemia Musculoskeletal System: rheumatoid arthritis; generalized spasm Nervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung Special Senses: glaucoma; blindness Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency 7 DRUG INTERACTIONS Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferon beta. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on offspring development. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COPAXONE should be used during pregnancy only if clearly needed. In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed. 8.2 Labor and Delivery The effects of COPAXONE on labor and delivery in pregnant women are unknown. 8.3 Nursing Mothers It is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when COPAXONE is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of COPAXONE have not been established in patients under 18 years of age. 8.5 Geriatric Use COPAXONE has not been studied in elderly patients. 8.6 Use in Patients with Impaired Renal Function The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.

Marketed by: TEVA Neuroscience, Inc., Overland Park, KS 66211 Distributed by: TEVA Pharmaceuticals USA, Inc., North Wales, PA 19454 Product of Israel ©Teva Neuroscience, Inc. All rights reserved. COPAXONE is a registered trademark of Teva Pharmaceutical Industries Ltd. This brief summary is based on COPAXONE full Prescribing Information, Iss. 1/2014.

NOW AVAILABLE 3-TIMES-A-WEEK DOSE COPAXONE® (glatiramer acetate injection) 40 mg/mL

EXPERIENCE that inspires TRUST A proven mix of efficacy, safety, and tolerability that you and your patients can count on1

Learn more at copaxone.com/hcp COPAXONE® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Important Safety Information about COPAXONE® COPAXONE® is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. Approximately 16% of patients exposed to COPAXONE® 20 mg per mL compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE® 40 mg per mL compared to none on placebo experienced a constellation of symptoms immediately after injection that included at least 2 of the following: flushing, chest COPAXONE® is a registered trademark of Teva Pharmaceutical Industries Ltd. © 2014 Teva Neuroscience, Inc. COP-40806

pain, palpitations, anxiety, dyspnea, throat constriction, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience 1 or several episodes of these symptoms. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages. Reference: 1. COPAXONE® (glatiramer acetate injection) prescribing information. Teva Neuroscience, Inc.

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