CME/CNE ARTICLE • 2016 SERIES • NUMBER 1
Fatigue and Comorbidities in Multiple Sclerosis Kirsten M. Fiest, PhD; John D. Fisk, PhD; Scott B. Patten, MD, PhD; Helen Tremlett, PhD; Christina Wolfson, PhD; Sharon Warren, PhD; Kyla A. McKay, BSc; Lindsay I. Berrigan, PhD; Ruth Ann Marrie, MD, PhD; for the CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (ECoMS)
CME/CNE Information The authors (listed in the article’s author byline) and the anonymous peer reviewers for the IJMSC have disclosed no relevant financial relationships.
Activity Available Online: To access the article, post-test, and evaluation online, go to http:// www.cmscscholar.org. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Be able to discuss the risk of new onset of fatigue and comorbidities associated with increased fatigue with MS patients and their families 2) Be able to identify and address comorbidities that are most associated with fatigue in MS patients Accreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPA designates this enduring material for a maximum of 1.0 Continuing Nursing Education credits. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships.
Method of Participation: Release Date: April 1, 2016 Valid for Credit Through: April 1, 2017 In order to receive CME/CNE credit, participants must: 1) Review the CME/CNE information, including learning objectives and author disclosures. 2) Study the educational content. 3) Complete the post-test and evaluation, which are available at http:// www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/ or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the authors and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.
From the Department of Internal Medicine, College of Medicine, Faculty of Health Sciences (KMF, RAM), and Department of Community Health Sciences, College of Medicine (RAM), University of Manitoba, Winnipeg, MB, Canada; Departments of Psychiatry, Medicine, Psychology, and Neuroscience, Dalhousie University, Halifax, NS, Canada (JDF); Departments of Psychiatry and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (SBP); Division of Neurology, Faculty of Medicine (HT), and Department of Experimental Medicine (KAM), University of British Columbia, Vancouver, BC, Canada; Departments of Epidemiology and Biostatistics, Occupational Health, and Medicine, McGill University, Montreal, QC, Canada (CW); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, Canada (SW); and Department of Psychology, St. Francis Xavier University, Antigonish, NS, Canada (LIB). Correspondence: Ruth Ann Marrie, MD, PhD, Health Sciences Centre, GF 543-820 Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada; e-mail: [email protected]. Note: Supplementary material for this article is available on IJMSC Online at ijmsc.org. DOI: 10.7224/1537-2073.2015-070 © 2016 Consortium of Multiple Sclerosis Centers.
International Journal of MS Care 96
Fatigue and Comorbidities in Multiple Sclerosis
Background: Fatigue is commonly reported by people with multiple sclerosis (MS). Comorbidity is also common in MS, but its association with the presence of fatigue or fatigue changes over time is poorly understood. Methods: Nine hundred forty-nine people with definite MS were recruited from four Canadian centers. The Fatigue Impact Scale for Daily Use and a validated comorbidity questionnaire were completed at three visits over 2 years. Participants were classified into groups with no fatigue versus any fatigue. Logistic regression was used to determine the relationship between fatigue and each comorbidity at baseline, year 1, year 2, and overall. Results: The incidence of fatigue during the study was 38.8%. The prevalence of fatigue was greater in those who were older (P = .0004), had a longer time since symptom onset (P = .005), and had greater disability (P < .0001). After adjustment, depression (odds ratio [OR], 2.58; 95% confidence interval [CI], 2.03-3.27), irritable bowel syndrome (OR, 1.71; 95% CI, 1.18-2.48), migraine (OR, 1.69; 95% CI, 1.272.27), and anxiety (OR, 1.57; 95% CI, 1.15-2.16) were independently associated with fatigue that persisted during the study. There was also an individual-level effect of depression on worsening fatigue (OR, 1.49; 95% CI, 1.08-2.07). Conclusions: Comorbidity is associated with fatigue in MS. Depression is associated with fatigue and with increased risk of worsening fatigue over 2 years. However, other comorbid conditions commonly associated with MS are also associated with persistent fatigue, even after accounting for depression. Further investigation is required to understand the mechanisms by which comorbidities influence fatigue. Int J MS Care. 2016;18:96–104.
F
atigue is the most common symptom of multiple sclerosis (MS),1 and many people with MS consider fatigue to be among their worst symptoms.2 The prevalence of fatigue in MS ranges from 50% to 83%1-3; this reported variability may be explained by differences in sample characteristics and by how fatigue is operationalized and measured. Fatigue in MS has been conceptualized as “a significant lack of physical and/ or mental energy that is perceived by the individual or caretaker to interfere with usual or desired activity.”4(p2) Fatigue is associated with reduced employment and lower quality of life.5 Despite its importance, however, few studies have examined fatigue in MS over time,6-10 and only one incidence estimate of 25% over 1 year has been reported.10 Fatigue is a prominent and chronic symptom of many neurologic conditions and can be characterized as peripheral (ie, arising at the neuromuscular junction) or central, with the latter reflecting its effect on cognitive and motor functioning and arising in the context of central nervous system dysfunction, as in MS.11 In MS, fatigue has also been conceptualized as either primary (ie, a direct consequence of MS pathology) or secondary to other factors, which may or may not be related in some way to MS.12 A few studies have explored determinants of secondary fatigue in MS, but they are
limited to sociodemographics,3 pain, and psychiatric comorbidities, which are more common in individuals with fatigue.6-9,13,14 The impact of nonpsychiatric comorbidities on fatigue in MS has received limited attention, although preliminary evidence suggests that they can affect fatigue management.15 Such medical comorbidities are common in MS and have deleterious effects on outcomes, including mortality.16 Still, it remains poorly understood how comorbidities affect the risk and pattern of fatigue in MS. We aimed to 1) determine the incidence of fatigue and changes in fatigue over time in MS and 2) identify physical and mental comorbid conditions that are associated with fatigue and with changes in fatigue over time in MS.
Materials and Methods Study Population We recruited consecutive patients attending routine visits between July 1, 2010, and March 31, 2011, at four MS clinics across Canada: British Columbia, Alberta, Manitoba, and Nova Scotia. A trained research coordinator approached potential participants using a standardized recruitment script. The inclusion criteria were as follows: a confirmed diagnosis of MS according to the prevailing diagnostic criteria at the time the participant
International Journal of MS Care 97
Fiest et al.
was diagnosed,17-20 age 18 years or older at enrollment, sufficient knowledge of English to be able to complete the questionnaires, and ability to provide informed consent. Ethics approval was obtained at all of the sites.
Clinical Information A trained reviewer used a standard form to extract demographic and clinical information from medical records: sex, date of birth, race, clinical course,21 age at MS symptom onset, Expanded Disability Status Scale (EDSS) score22 logged by the treating neurologist on the day of recruitment and at follow-up visits, history of relapses (location, resolution, and treatment) since the last visit, and disease-modifying therapy use.
Questionnaires Participants completed questionnaires at each of three assessments over 2 years (baseline, year 1, and year 2). All self-report measures were administered to participants at their routine clinic visits. Because we aimed to obtain a representative consecutive series of patients as they presented to the clinics, we attempted to minimize the response burden for participants. Twenty-one physical and psychiatric comorbidities (such as diabetes and depression), including those that could be considered secondary to MS (such as osteoporosis) were captured via a questionnaire that asked, “Has a doctor ever told you that you have any of the following conditions?” to which a yes or no answer was required.23 The comorbidities selected had been reported to affect outcomes in MS, were potentially modifiable with treatment, and affected a sufficient number of individuals with MS to be relevant at the population level, and the questionnaire had been validated previously against medical record review.23 We also included an alcohol dependence measure (assessed by the four-item CAGE [Cutting down, Annoyance by criticism, Guilty feeling, Eye-openers] questionnaire)24 given the high prevalence of alcohol dependence in the MS population25 and its associations with anxiety and depression.26 We measured current symptoms of depression using the depression subscale of the Hospital Anxiety and Depression Scale, which has been validated for use in MS, and we used the recommended cutoff score of 8 or greater to define clinically significant depressive symptoms.27,28 Lifetime history of depression was measured using the aforementioned comorbidity questionnaire. To account for current and past depression in the analyses, four mutually exclusive groups were defined: 1) no
history of depression and no current depressive symptoms (reference group); 2) no history of depression and current depressive symptoms; 3) a history of depression (diagnosed before the study visit when questionnaires were administered) and no current depressive symptoms; and 4) a history of depression and current depressive symptoms. If depression was diagnosed before completion of the Hospital Anxiety and Depression Scale (and not at the same visit), a person was considered to have a history of depression. Multiple self-report questionnaires exist for the evaluation of fatigue, all of which have limitations.29 We selected a brief scale that minimized participant burden and measured fatigue using the Fatigue Impact Scale for Daily Use (D-FIS).30 This unidimensional scale with item content derived from the Fatigue Impact Scale2 examines perceived effect on cognitive and physical functioning. It has been validated in patients with MS previously27 and has data available regarding clinically important change. Scores range from 0 to 36, with higher scores indicating worse fatigue. Based on the responsiveness of this scale in its original validation study to flu-related fatigue30 and based on the clinically meaningful difference values suggested from its subsequent validation study in people with MS (ie, standard error of the mean = 3.18, and ½ standard deviation = 3.65),31 a change of at least 4 points on the D-FIS between visits was considered clinically important.30 Fatigue was operationalized in two ways: 1) no versus any fatigue (D-FIS scores
Fatigue and Comorbidities in Multiple Sclerosis Kirsten M. Fiest, PhD; John D. Fisk, PhD; Scott B. Patten, MD, PhD; Helen Tremlett, PhD; Christina Wolfson, PhD; Sharon Warren, PhD; Kyla A. McKay, BSc; Lindsay I. Berrigan, PhD; Ruth Ann Marrie, MD, PhD; for the CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (ECoMS)
CME/CNE Information The authors (listed in the article’s author byline) and the anonymous peer reviewers for the IJMSC have disclosed no relevant financial relationships.
Activity Available Online: To access the article, post-test, and evaluation online, go to http:// www.cmscscholar.org. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Be able to discuss the risk of new onset of fatigue and comorbidities associated with increased fatigue with MS patients and their families 2) Be able to identify and address comorbidities that are most associated with fatigue in MS patients Accreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPA designates this enduring material for a maximum of 1.0 Continuing Nursing Education credits. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships.
Method of Participation: Release Date: April 1, 2016 Valid for Credit Through: April 1, 2017 In order to receive CME/CNE credit, participants must: 1) Review the CME/CNE information, including learning objectives and author disclosures. 2) Study the educational content. 3) Complete the post-test and evaluation, which are available at http:// www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/ or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the authors and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.
From the Department of Internal Medicine, College of Medicine, Faculty of Health Sciences (KMF, RAM), and Department of Community Health Sciences, College of Medicine (RAM), University of Manitoba, Winnipeg, MB, Canada; Departments of Psychiatry, Medicine, Psychology, and Neuroscience, Dalhousie University, Halifax, NS, Canada (JDF); Departments of Psychiatry and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (SBP); Division of Neurology, Faculty of Medicine (HT), and Department of Experimental Medicine (KAM), University of British Columbia, Vancouver, BC, Canada; Departments of Epidemiology and Biostatistics, Occupational Health, and Medicine, McGill University, Montreal, QC, Canada (CW); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, Canada (SW); and Department of Psychology, St. Francis Xavier University, Antigonish, NS, Canada (LIB). Correspondence: Ruth Ann Marrie, MD, PhD, Health Sciences Centre, GF 543-820 Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada; e-mail: [email protected]. Note: Supplementary material for this article is available on IJMSC Online at ijmsc.org. DOI: 10.7224/1537-2073.2015-070 © 2016 Consortium of Multiple Sclerosis Centers.
International Journal of MS Care 96
Fatigue and Comorbidities in Multiple Sclerosis
Background: Fatigue is commonly reported by people with multiple sclerosis (MS). Comorbidity is also common in MS, but its association with the presence of fatigue or fatigue changes over time is poorly understood. Methods: Nine hundred forty-nine people with definite MS were recruited from four Canadian centers. The Fatigue Impact Scale for Daily Use and a validated comorbidity questionnaire were completed at three visits over 2 years. Participants were classified into groups with no fatigue versus any fatigue. Logistic regression was used to determine the relationship between fatigue and each comorbidity at baseline, year 1, year 2, and overall. Results: The incidence of fatigue during the study was 38.8%. The prevalence of fatigue was greater in those who were older (P = .0004), had a longer time since symptom onset (P = .005), and had greater disability (P < .0001). After adjustment, depression (odds ratio [OR], 2.58; 95% confidence interval [CI], 2.03-3.27), irritable bowel syndrome (OR, 1.71; 95% CI, 1.18-2.48), migraine (OR, 1.69; 95% CI, 1.272.27), and anxiety (OR, 1.57; 95% CI, 1.15-2.16) were independently associated with fatigue that persisted during the study. There was also an individual-level effect of depression on worsening fatigue (OR, 1.49; 95% CI, 1.08-2.07). Conclusions: Comorbidity is associated with fatigue in MS. Depression is associated with fatigue and with increased risk of worsening fatigue over 2 years. However, other comorbid conditions commonly associated with MS are also associated with persistent fatigue, even after accounting for depression. Further investigation is required to understand the mechanisms by which comorbidities influence fatigue. Int J MS Care. 2016;18:96–104.
F
atigue is the most common symptom of multiple sclerosis (MS),1 and many people with MS consider fatigue to be among their worst symptoms.2 The prevalence of fatigue in MS ranges from 50% to 83%1-3; this reported variability may be explained by differences in sample characteristics and by how fatigue is operationalized and measured. Fatigue in MS has been conceptualized as “a significant lack of physical and/ or mental energy that is perceived by the individual or caretaker to interfere with usual or desired activity.”4(p2) Fatigue is associated with reduced employment and lower quality of life.5 Despite its importance, however, few studies have examined fatigue in MS over time,6-10 and only one incidence estimate of 25% over 1 year has been reported.10 Fatigue is a prominent and chronic symptom of many neurologic conditions and can be characterized as peripheral (ie, arising at the neuromuscular junction) or central, with the latter reflecting its effect on cognitive and motor functioning and arising in the context of central nervous system dysfunction, as in MS.11 In MS, fatigue has also been conceptualized as either primary (ie, a direct consequence of MS pathology) or secondary to other factors, which may or may not be related in some way to MS.12 A few studies have explored determinants of secondary fatigue in MS, but they are
limited to sociodemographics,3 pain, and psychiatric comorbidities, which are more common in individuals with fatigue.6-9,13,14 The impact of nonpsychiatric comorbidities on fatigue in MS has received limited attention, although preliminary evidence suggests that they can affect fatigue management.15 Such medical comorbidities are common in MS and have deleterious effects on outcomes, including mortality.16 Still, it remains poorly understood how comorbidities affect the risk and pattern of fatigue in MS. We aimed to 1) determine the incidence of fatigue and changes in fatigue over time in MS and 2) identify physical and mental comorbid conditions that are associated with fatigue and with changes in fatigue over time in MS.
Materials and Methods Study Population We recruited consecutive patients attending routine visits between July 1, 2010, and March 31, 2011, at four MS clinics across Canada: British Columbia, Alberta, Manitoba, and Nova Scotia. A trained research coordinator approached potential participants using a standardized recruitment script. The inclusion criteria were as follows: a confirmed diagnosis of MS according to the prevailing diagnostic criteria at the time the participant
International Journal of MS Care 97
Fiest et al.
was diagnosed,17-20 age 18 years or older at enrollment, sufficient knowledge of English to be able to complete the questionnaires, and ability to provide informed consent. Ethics approval was obtained at all of the sites.
Clinical Information A trained reviewer used a standard form to extract demographic and clinical information from medical records: sex, date of birth, race, clinical course,21 age at MS symptom onset, Expanded Disability Status Scale (EDSS) score22 logged by the treating neurologist on the day of recruitment and at follow-up visits, history of relapses (location, resolution, and treatment) since the last visit, and disease-modifying therapy use.
Questionnaires Participants completed questionnaires at each of three assessments over 2 years (baseline, year 1, and year 2). All self-report measures were administered to participants at their routine clinic visits. Because we aimed to obtain a representative consecutive series of patients as they presented to the clinics, we attempted to minimize the response burden for participants. Twenty-one physical and psychiatric comorbidities (such as diabetes and depression), including those that could be considered secondary to MS (such as osteoporosis) were captured via a questionnaire that asked, “Has a doctor ever told you that you have any of the following conditions?” to which a yes or no answer was required.23 The comorbidities selected had been reported to affect outcomes in MS, were potentially modifiable with treatment, and affected a sufficient number of individuals with MS to be relevant at the population level, and the questionnaire had been validated previously against medical record review.23 We also included an alcohol dependence measure (assessed by the four-item CAGE [Cutting down, Annoyance by criticism, Guilty feeling, Eye-openers] questionnaire)24 given the high prevalence of alcohol dependence in the MS population25 and its associations with anxiety and depression.26 We measured current symptoms of depression using the depression subscale of the Hospital Anxiety and Depression Scale, which has been validated for use in MS, and we used the recommended cutoff score of 8 or greater to define clinically significant depressive symptoms.27,28 Lifetime history of depression was measured using the aforementioned comorbidity questionnaire. To account for current and past depression in the analyses, four mutually exclusive groups were defined: 1) no
history of depression and no current depressive symptoms (reference group); 2) no history of depression and current depressive symptoms; 3) a history of depression (diagnosed before the study visit when questionnaires were administered) and no current depressive symptoms; and 4) a history of depression and current depressive symptoms. If depression was diagnosed before completion of the Hospital Anxiety and Depression Scale (and not at the same visit), a person was considered to have a history of depression. Multiple self-report questionnaires exist for the evaluation of fatigue, all of which have limitations.29 We selected a brief scale that minimized participant burden and measured fatigue using the Fatigue Impact Scale for Daily Use (D-FIS).30 This unidimensional scale with item content derived from the Fatigue Impact Scale2 examines perceived effect on cognitive and physical functioning. It has been validated in patients with MS previously27 and has data available regarding clinically important change. Scores range from 0 to 36, with higher scores indicating worse fatigue. Based on the responsiveness of this scale in its original validation study to flu-related fatigue30 and based on the clinically meaningful difference values suggested from its subsequent validation study in people with MS (ie, standard error of the mean = 3.18, and ½ standard deviation = 3.65),31 a change of at least 4 points on the D-FIS between visits was considered clinically important.30 Fatigue was operationalized in two ways: 1) no versus any fatigue (D-FIS scores
