Appendix-e3. Review of comorbidity and outcomes in MS: Methods and Flowchart

Preparatory to the workshop we also reviewed the association of comorbidity with relapses, disability, functional status, MRI outcomes (brain atrophy, lesion burden), cognition, pain, and fatigue. These outcomes were chosen to reflect those commonly reported in clinical trials of MS. For this review we chose the same comorbidities as those considered in our recent systematic review of the incidence and prevalence of comorbidity in MS. Those comorbidities were selected by consensus of 5 individuals with expertise in clinical neurology, epidemiology and clinical trials. They included diabetes, hypertension, hyperlipidemia, ischemic heart disease, valvular disease, cardiac arrhythmias, congestive heart failure, cerebrovascular disease (stroke, transient ischemic attack), peripheral vascular disease, autoimmune disease (alopecia areata, ankylosing spondylitis, autoimmune thyroid disease, bullous pemphigoid, celiac disease, dermatomyositis, idiopathic thrombocytopenic purpura, inflammatory bowel disease, myasthenia gravis, pemphigus vulgaris pernicious anemia, polymyositis, primary adrenocortical insufficiency, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus systemic sclerosis, uveitis, vitiligo, Wegener’s granulomatosis), chronic lung disease (asthma, chronic obstructive pulmonary disease), gastrointestinal disease (gallbladder and biliary tract disease, gastroesophageal reflux disease, irritable bowel syndrome, liver disease, peptic ulcer disease), renal disease, visual disorders (cataracts, glaucoma, retinal disease), musculoskeletal disorders (crystal arthropathies, fibromyalgia, osteoarthritis,), epilepsy, renal disease, cancer and psychiatric comorbidity (alcohol abuse, anxiety, bipolar disorder, depression, personality disorders, psychosis, substance abuse).

Search Strategy and Study SelectionIn consultation with a research librarian we performed a comprehensive literature search for the outcomes of interest (see below for search strategies). The comorbidity search strategies were those used in our review of the incidence and prevalence of comorbidity in MS.7 We hand searched the reference lists of original studies and reviews identified during the initial search to identify other potentially relevant studies, and searched conference proceedings using the Web of Knowledge. References were imported into Eppi-Reviewer 4 (eppi.ioe.ac.uk/cms/er4/). Two independent reviewers read the abstracts to determine if they met the inclusion criteria. Eligible studies had to be (i) conducted in an MS population, (ii) include original data, (iii) specify the comorbidity or comorbidities of interest, (iv) report the association of comorbidity with at least one of the outcomes of interest, and (v) be published in English. We did not restrict the search to population-based studies as we anticipated that few studies would meet these criteria, and the purpose was to inform the workshop discussion. Abstracts selected by either reviewer at this stage went on to full text review. Two independent reviewers independently reviewed the full-text of selected articles to determine if they met the inclusion criteria. Disagreements were resolved by consensus.

Data were extracted by one reviewer and verified by a second reviewer. The data extracted included general study information (e.g. region where conducted, year of publication), characteristics of the study population, criteria used to define MS and the comorbidity(ies) of interest, methodological information (e.g. study design, source of the population), and outcome.

Search Strategies

A. Autoimmune Disease

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (hypothyroidism or myxedema or hyperthyroidism or thyrotoxosis or "Graves disease" or thyroiditis or Hashimoto's or "rheumatoid arthritis" or "Felty syndrome OR rheumatoid nodule OR Rheumatoid vasculitis OR adult onset Still's disease OR dermatomyositis OR polymyositis OR idiopathic inflammatory myopathies OR myositis OR ankylosing spondylitis or spondylitis ankylosing OR rheumatoid spondylitis OR vertebral ankylosis OR spondyloarthropathy OR bechterew* OR Bechterew's disease OR Marie-Strumpell* OR inflammatory bowel disease OR IBD OR Crohn's OR ulcerative colitis OR uveitis OR uveiti* OR panuveitis OR iridocyclitis OR iridocycliti* OR 'anterior scleritis" or iritis or iriti* or pars planitis or lupus or "lupus erythematosus" or "systemic lupus erythematosus" or "lupus vulgaris" or psoriasis or "palmoplantaris pustulosis" or "pustular psoriasis" or pemphigus or "pemphigus vulgaris" or "phemigus foliaceus" or "primary biliary cirrhosis" or "liver cirrhosis" or biliary or "bullous pemphigoid" or pemphigoid or myasthenia or "myasthenia gravis" or "anti-acetylcholine receptor antibody" or AChR or MuSK or "anti-muscle specific kinase antibody" or "seronegative MG" or "seronegative myasthenia gravis congenital" or myasthenia or "congenital myasthenic syndrome" or "systemic sclerosis" or scleroderma or "pernicious anemia" or "atrophic gastritis" or "type A gastritis" or "macrocytic anemia" or "cobalamin deficiency" or "vitamin B12 deficiency" or "intrinsic factor deficiency autoimmune" or "adrenal-cortex-diseases" or "adrenal-gland-diseases" or "adrenal insufficiency" or gastritis or "idiopathic thrombocytopenic purpura" or ITP or thrombocytopeni* or "Addison's disease" or "Addison disease" or "primary adrenal insufficiency" or "primary adrenocortical insufficiency" or "Wegener granulomatosis" or vasculitis or "wegnener vascul*" or "small vessel vascul*" or celiac or sprue or "gluten sensitive enteropathy" or "villous atrophy" or antigliadin or endomyseal or "tissue transglutaminase" or "alopecia areata" or "alopecia totalis" or "alopecia universalis" or "alopecia celsi" or ophiasis or "non-scarring hair loss" or vitiligo or leukoderma or leucoderma or "Sjogren's syndrome" or SS).mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/

12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 and 2 and 3 and 4 and 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (hypothyroidism or myxedema or hyperthyroidism or thyrotoxosis or "Graves disease" or thyroiditis or Hashimoto's or "rheumatoid arthritis" or "Felty syndrome OR rheumatoid nodule OR Rheumatoid vasculitis OR adult onset Still's disease OR dermatomyositis OR polymyositis OR idiopathic inflammatory myopathies OR myositis OR ankylosing spondylitis or spondylitis ankylosing OR rheumatoid spondylitis OR vertebral ankylosis OR spondyloarthropathy OR bechterew* OR Bechterew's disease OR Marie-Strumpell* OR inflammatory bowel disease OR IBD OR Crohn's OR ulcerative colitis OR uveitis OR uveiti* OR panuveitis OR iridocyclitis OR iridocycliti* OR 'anterior scleritis" or iritis or iriti* or pars planitis or lupus or "lupus erythematosus" or "systemic lupus erythematosus" or "lupus vulgaris" or psoriasis or "palmoplantaris pustulosis" or "pustular psoriasis" or pemphigus or "pemphigus vulgaris" or "phemigus foliaceus" or "primary biliary cirrhosis" or "liver cirrhosis" or biliary or "bullous pemphigoid" or pemphigoid or myasthenia or "myasthenia gravis" or "anti-acetylcholine receptor antibody" or AChR or MuSK or "anti-muscle specific kinase antibody" or "seronegative MG" or "seronegative myasthenia gravis congenital" or myasthenia or "congenital myasthenic syndrome" or "systemic sclerosis" or scleroderma or "pernicious anemia" or "atrophic gastritis" or "type A gastritis" or "macrocytic anemia" or "cobalamin deficiency" or "vitamin B12 deficiency" or "intrinsic factor deficiency autoimmune" or "adrenal-cortex-diseases" or "adrenal-gland-diseases" or "adrenal insufficiency" or gastritis or "idiopathic thrombocytopenic purpura" or ITP or thrombocytopeni* or "Addison's disease" or "Addison disease" or "primary adrenal insufficiency" or "primary adrenocortical insufficiency" or "Wegener granulomatosis" or vasculitis or "wegnener vascul*" or "small vessel vascul*" or celiac or sprue or "gluten sensitive enteropathy" or "villous atrophy" or antigliadin or endomyseal or "tissue transglutaminase" or "alopecia areata" or "alopecia totalis" or "alopecia universalis" or "alopecia celsi" or ophiasis or "non-scarring hair loss" or vitiligo or leukoderma or leucoderma or "Sjogren's syndrome" or SS ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY hypothyroidism or myxedema or hyperthyroidism or thyrotoxosis or "Graves disease" or thyroiditis or Hashimoto's or "rheumatoid arthritis" or "Felty syndrome OR rheumatoid nodule OR Rheumatoid vasculitis OR adult onset Still's disease OR dermatomyositis OR polymyositis OR idiopathic inflammatory myopathies OR myositis OR ankylosing spondylitis or spondylitis ankylosing OR rheumatoid spondylitis OR vertebral ankylosis OR spondyloarthropathy OR bechterew* OR Bechterew's disease OR Marie-Strumpell* OR inflammatory bowel disease OR IBD OR Crohn's OR ulcerative colitis OR uveitis OR uveiti* OR panuveitis OR iridocyclitis OR iridocycliti* OR

'anterior scleritis" or iritis or iriti* or pars planitis or lupus or "lupus erythematosus" or "systemic lupus erythematosus" or "lupus vulgaris" or psoriasis or "palmoplantaris pustulosis" or "pustular psoriasis" or pemphigus or "pemphigus vulgaris" or "phemigus foliaceus" or "primary biliary cirrhosis" or "liver cirrhosis" or biliary or "bullous pemphigoid" or pemphigoid or myasthenia or "myasthenia gravis" or "anti-acetylcholine receptor antibody" or AChR or MuSK or "anti-muscle specific kinase antibody" or "seronegative MG" or "seronegative myasthenia gravis congenital" or myasthenia or "congenital myasthenic syndrome" or "systemic sclerosis" or scleroderma or "pernicious anemia" or "atrophic gastritis" or "type A gastritis" or "macrocytic anemia" or "cobalamin deficiency" or "vitamin B12 deficiency" or "intrinsic factor deficiency autoimmune" or "adrenal-cortex-diseases" or "adrenal-gland-diseases" or "adrenal insufficiency" or gastritis or "idiopathic thrombocytopenic purpura" or ITP or thrombocytopeni* or "Addison's disease" or "Addison disease" or "primary adrenal insufficiency" or "primary adrenocortical insufficiency" or "Wegener granulomatosis" or vasculitis or "wegnener vascul*" or "small vessel vascul*" or celiac or sprue or "gluten sensitive enteropathy" or "villous atrophy" or antigliadin or endomyseal or "tissue transglutaminase" or "alopecia areata" or "alopecia totalis" or "alopecia universalis" or "alopecia celsi" or ophiasis or "non-scarring hair loss" or vitiligo or leukoderma or leucoderma or "Sjogren's syndrome" or SS ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY hypothyroidism or myxedema or hyperthyroidism or thyrotoxosis or "Graves disease" or thyroiditis or Hashimoto's or "rheumatoid arthritis" or "Felty syndrome OR rheumatoid nodule OR Rheumatoid vasculitis OR adult onset Still's disease OR dermatomyositis OR polymyositis OR idiopathic inflammatory myopathies OR myositis OR ankylosing spondylitis or spondylitis ankylosing OR rheumatoid spondylitis OR vertebral ankylosis OR spondyloarthropathy OR bechterew* OR Bechterew's disease OR Marie-Strumpell* OR inflammatory bowel disease OR IBD OR Crohn's OR ulcerative colitis OR uveitis OR uveiti* OR panuveitis OR iridocyclitis OR iridocycliti* OR 'anterior scleritis" or iritis or iriti* or pars planitis or lupus or "lupus erythematosus" or "systemic lupus erythematosus" or "lupus vulgaris" or psoriasis or "palmoplantaris pustulosis" or "pustular psoriasis" or pemphigus or "pemphigus vulgaris" or "phemigus foliaceus" or "primary biliary cirrhosis" or "liver cirrhosis" or biliary or "bullous pemphigoid" or pemphigoid or myasthenia or "myasthenia gravis" or "anti-acetylcholine receptor antibody" or AChR or MuSK or "anti-muscle specific kinase antibody" or "seronegative MG" or "seronegative myasthenia gravis congenital" or myasthenia or "congenital myasthenic syndrome" or "systemic sclerosis" or scleroderma or "pernicious anemia" or "atrophic gastritis" or "type A gastritis" or "macrocytic anemia" or "cobalamin deficiency" or "vitamin B12 deficiency" or "intrinsic factor deficiency autoimmune" or "adrenal-cortex-diseases" or "adrenal-gland-diseases" or "adrenal insufficiency" or gastritis or "idiopathic thrombocytopenic purpura" or ITP or thrombocytopeni* or "Addison's disease" or "Addison disease" or "primary adrenal insufficiency" or "primary adrenocortical insufficiency" or "Wegener granulomatosis" or vasculitis or "wegnener vascul*" or "small vessel vascul*" or celiac or sprue or "gluten sensitive enteropathy" or "villous atrophy" or antigliadin or endomyseal or "tissue transglutaminase" or "alopecia areata" or "alopecia totalis" or "alopecia

universalis" or "alopecia celsi" or ophiasis or "non-scarring hair loss" or vitiligo or leukoderma or leucoderma or "Sjogren's syndrome" or SS) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (hypothyroidism or myxedema or hyperthyroidism or thyrotoxosis or "Graves disease" or thyroiditis or Hashimoto's or "rheumatoid arthritis" or "Felty syndrome OR rheumatoid nodule OR Rheumatoid vasculitis OR adult onset Still's disease OR dermatomyositis OR polymyositis OR idiopathic inflammatory myopathies OR myositis OR ankylosing spondylitis or spondylitis ankylosing OR rheumatoid spondylitis OR vertebral ankylosis OR spondyloarthropathy OR bechterew* OR Bechterew's disease OR Marie-Strumpell* OR inflammatory bowel disease OR IBD OR Crohn's OR ulcerative colitis OR uveitis OR uveiti* OR panuveitis OR iridocyclitis OR iridocycliti* OR 'anterior scleritis" or iritis or iriti* or pars planitis or lupus or "lupus erythematosus" or "systemic lupus erythematosus" or "lupus vulgaris" or psoriasis or "palmoplantaris pustulosis" or "pustular psoriasis" or pemphigus or "pemphigus vulgaris" or "phemigus foliaceus" or "primary biliary cirrhosis" or "liver cirrhosis" or biliary or "bullous pemphigoid" or pemphigoid or myasthenia or "myasthenia gravis" or "anti-acetylcholine receptor antibody" or AChR or MuSK or "anti-muscle specific kinase antibody" or "seronegative MG" or "seronegative myasthenia gravis congenital" or myasthenia or "congenital myasthenic syndrome" or "systemic sclerosis" or scleroderma or "pernicious anemia" or "atrophic gastritis" or "type A gastritis" or "macrocytic anemia" or "cobalamin deficiency" or "vitamin B12 deficiency" or "intrinsic factor deficiency autoimmune" or "adrenal-cortex-diseases" or "adrenal-gland-diseases" or "adrenal insufficiency" or gastritis or "idiopathic thrombocytopenic purpura" or ITP or thrombocytopeni* or "Addison's disease" or "Addison disease" or "primary adrenal insufficiency" or "primary adrenocortical insufficiency" or "Wegener granulomatosis" or vasculitis or "wegnener vascul*" or "small vessel vascul*" or celiac or sprue or "gluten sensitive enteropathy" or "villous atrophy" or antigliadin or endomyseal or "tissue transglutaminase" or "alopecia areata" or "alopecia totalis" or "alopecia universalis" or "alopecia celsi" or ophiasis or "non-scarring hair loss" or vitiligo or leukoderma or leucoderma or "Sjogren's syndrome" or SS) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

B. Cancer

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (cancer or neoplasm* or carcinoma or carcinoid or leukemia or lymphoma or malignan* or melanoma or myeloma or sarcoma or tumor).mp.

3. exp cancer/4. 2 or 35. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]6. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]7. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.8. exp disease progression/ or exp prognosis/9. 7 or 810. (MRI or "magnetic resonance imagining").mp.11. exp gray matter/ or exp white matter/12. 10 or 1113. exp pain/ or exp fatigue/14. (pain* or fatigu*).mp.15. 13 or 1416. (relaps* or reoccurr* or recur*).mp.17. 9 or 12 or 15 or 1618. 1 or 4 or 5 or 6 or 17

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cancer or neoplasm* or carcinoma or carcinoid or leukemia or lymphoma or malignan* or melanoma or myeloma or sarcoma or tumor) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cancer or neoplasm* or carcinoma or carcinoid or leukemia or lymphoma or malignan* or melanoma or myeloma or sarcoma or tumor ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cancer or neoplasm* or carcinoma or carcinoid or leukemia or lymphoma or malignan* or melanoma or myeloma or sarcoma or tumor) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR

retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cancer or neoplasm* or carcinoma or carcinoid or leukemia or lymphoma or malignan* or melanoma or myeloma or sarcoma or tumor) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

C. Cardiovascular Disease

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. ("cardiac arrhythmia*" or "cardiac dysrhythmia" or "atrialfibrillation" or "sinus arrhythmia" or "atrial flutter" or bradycardia or "Brugada syndrome" or "premature cardiac complexes" or "commotio cordis" or "heart block" or "long qt syndrome" or "parasystole" or "pre-excitation syndromes" or "tachycardia" or "ventricular fibrillation" or "ventricular flutter").mp.3. (stroke or "brain ischemia" or "cerebrovascular accident" or "cerebrovascular disorder" or "cerebral infarction" or "ischemic attack").mp.4. ("congestive heart failure" or "heart failure" or "left ventricular dysfunction" or "diastolic health failure" or cardiac or failure).mp.5. exp diabetes/ or diabetes.mp.6. ("high blood pressure" or hypertension).mp.7. ("peripheral vascular disease" or "peripheral arterial disease atherosclerosis" or "peripheral occlusive artery disease" or claudication or "peripheral ischemia" or PAD or PVD).mp.8. ("heart valve disease*" or "aortic valve*" or "mitral valve*" or "pulmonary atresia" or "pulmonary valve*" or tricuspid).mp.9. exp vascular disease/10. 2 or 3 or 4 or 5 or 6 or 7 or 8 or 911. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]12. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]13. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.14. exp disease progression/ or exp prognosis/15. 13 or 1416. (MRI or "magnetic resonance imagining").mp.17. exp gray matter/ or exp white matter/18. 16 or 17

19. exp pain/ or exp fatigue/20. (pain* or fatigu*).mp.21. 19 or 2022. (relaps* or reoccurr* or recur*).mp.23. 15 or 18 or 21 or 2224. 1 and 10 and 11 and 12 and 23

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("cardiac arrhythmia*" or "cardiac dysrhythmia" or "atrialfibrillation" or "sinus arrhythmia" or "atrial flutter" or bradycardia or "Brugada syndrome" or "premature cardiac complexes" or "commotio cordis" or "heart block" or "long qt syndrome" or "parasystole" or "pre-excitation syndromes" or "tachycardia" or "ventricular fibrillation" or "ventricular flutter") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("cardiac arrhythmia*" or "cardiac dysrhythmia" or "atrialfibrillation" or "sinus arrhythmia" or "atrial flutter" or bradycardia or "Brugada syndrome" or "premature cardiac complexes" or "commotio cordis" or "heart block" or "long qt syndrome" or "parasystole" or "pre-excitation syndromes" or "tachycardia" or "ventricular fibrillation" or "ventricular flutter") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("cardiac arrhythmia*" or "cardiac dysrhythmia" or "atrialfibrillation" or "sinus arrhythmia" or "atrial flutter" or bradycardia or "Brugada syndrome" or "premature cardiac complexes" or "commotio cordis" or "heart block" or "long qt syndrome" or "parasystole" or "pre-excitation syndromes" or "tachycardia" or "ventricular fibrillation" or "ventricular flutter") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("cardiac arrhythmia*" or "cardiac dysrhythmia" or "atrialfibrillation" or "sinus arrhythmia" or "atrial flutter" or bradycardia or "Brugada syndrome" or "premature cardiac complexes" or "commotio cordis" or "heart block" or "long qt syndrome" or "parasystole" or "pre-excitation syndromes" or "tachycardia" or "ventricular fibrillation" or "ventricular flutter") ) AND ( TITLE-ABS-KEY

( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

D. Epilepsy

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (seizure* or epilepsy or convuls* or epilep*).mp.3. exp epilepsy/4. 2 or 35. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]6. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]7. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.8. exp disease progression/ or exp prognosis/9. 7 or 810. (MRI or "magnetic resonance imagining").mp.11. exp gray matter/ or exp white matter/12. 10 or 1113. exp pain/ or exp fatigue/14. (pain* or fatigu*).mp.15. 13 or 1416. (relaps* or reoccurr* or recur*).mp.17. 9 or 12 or 15 or 1618. 1 or 4 or 5 or 6 or 17

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ( seizure* OR epilepsy OR convuls* OR epilep* ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ( seizure* OR epilepsy OR convuls* OR epilep* ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND

( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ( seizure* OR epilepsy OR convuls* OR epilep* ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ( seizure* OR epilepsy OR convuls* OR epilep* ) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )E. Gastrointestinal Disorders

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. ("gastroesophageal reflux" or GERD or GORD or heartburn or esophagitis or oesophagitis or "liver disease" or hepatitis or cirrhosis or fibrosis or "fatty liver" or "alcoholic liver disease" or "alcoholic hepatitis" or "peptic ulcer" or "duodenal ulcer" or "gastroduodenal ulcer" or "gallbladder disease" or cholelithiasis or choledocholithiasis or cholangitis or bilary or "irritable bowel syndrome" or "irritable colon").mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. function* near5 impair*.mp.6. (disabil* or progress* or disabl*).mp.7. "EDSS".mp.8. exp disease progression/ or exp prognosis/9. 5 or 6 or 7 or 810. 1 and 2 and 3 and 4 and 9

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("gastroesophageal reflux" or GERD or GORD or heartburn or esophagitis or oesophagitis or "liver disease" or

hepatitis or cirrhosis or fibrosis or "fatty liver" or "alcoholic liver disease" or "alcoholic hepatitis" or "peptic ulcer" or "duodenal ulcer" or "gastroduodenal ulcer" or "gallbladder disease" or cholelithiasis or choledocholithiasis or cholangitis or bilary or "irritable bowel syndrome" or "irritable colon") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("gastroesophageal reflux" or GERD or GORD or heartburn or esophagitis or oesophagitis or "liver disease" or hepatitis or cirrhosis or fibrosis or "fatty liver" or "alcoholic liver disease" or "alcoholic hepatitis" or "peptic ulcer" or "duodenal ulcer" or "gastroduodenal ulcer" or "gallbladder disease" or cholelithiasis or choledocholithiasis or cholangitis or bilary or "irritable bowel syndrome" or "irritable colon") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("gastroesophageal reflux" or GERD or GORD or heartburn or esophagitis or oesophagitis or "liver disease" or hepatitis or cirrhosis or fibrosis or "fatty liver" or "alcoholic liver disease" or "alcoholic hepatitis" or "peptic ulcer" or "duodenal ulcer" or "gastroduodenal ulcer" or "gallbladder disease" or cholelithiasis or choledocholithiasis or cholangitis or bilary or "irritable bowel syndrome" or "irritable colon") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("gastroesophageal reflux" or GERD or GORD or heartburn or esophagitis or oesophagitis or "liver disease" or hepatitis or cirrhosis or fibrosis or "fatty liver" or "alcoholic liver disease" or "alcoholic hepatitis" or "peptic ulcer" or "duodenal ulcer" or "gastroduodenal ulcer" or "gallbladder disease" or cholelithiasis or choledocholithiasis or cholangitis or bilary or "irritable bowel syndrome" or "irritable colon") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

F. Lung Disease

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (asthma or "chronic obstructive pulmonary disease" or bronchitis or emphysema).mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (asthma or "chronic obstructive pulmonary disease" or bronchitis or emphysema) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (asthma or "chronic obstructive pulmonary disease" or bronchitis or emphysema) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (asthma or "chronic obstructive pulmonary disease" or bronchitis or emphysema) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR

population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) ( TITLE-ABS-KEY (asthma or "chronic obstructive pulmonary disease" or bronchitis or emphysema) ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

G. Musculoskeletal Disease

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (gout or "gouty arthritis" or arthritis or osteoarthritis or "hip osteoarthritis" or "knee osteoarthritis" or "spine osteoarthritis" or fibromyalgia or fibromyositis or fibrositis or "diffuse myofascial pain syndrome").mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (gout or "gouty arthritis" or arthritis or osteoarthritis or "hip osteoarthritis" or "knee osteoarthritis" or "spine osteoarthritis" or fibromyalgia or fibromyositis or fibrositis or "diffuse myofascial pain syndrome") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY

( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (gout or "gouty arthritis" or arthritis or osteoarthritis or "hip osteoarthritis" or "knee osteoarthritis" or "spine osteoarthritis" or fibromyalgia or fibromyositis or fibrositis or "diffuse myofascial pain syndrome") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (gout or "gouty arthritis" or arthritis or osteoarthritis or "hip osteoarthritis" or "knee osteoarthritis" or "spine osteoarthritis" or fibromyalgia or fibromyositis or fibrositis or "diffuse myofascial pain syndrome") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) ( TITLE-ABS-KEY (gout or "gouty arthritis" or arthritis or osteoarthritis or "hip osteoarthritis" or "knee osteoarthritis" or "spine osteoarthritis" or fibromyalgia or fibromyositis or fibrositis or "diffuse myofascial pain syndrome") ) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

H. Psychiatric Disorders

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. ("alcohol-related disorders" or "drinking behavior" or alcoholic* or alcoholism or "alcohol abuse" or "alcohol use" or "alcohol misuse" or "alcohol problem" or "alcohol depend*" or "anxiety disorder" or "generalized anxiety disorder" or "phobia" or "panic disorder" or "obsessive compulsive disorder" or "posttraumatic stress disorder" or "bipolar disorder" or "manic depression" or "manic depressive disorder" or mania or "depressive disorder" or "major depression" or dysthymia or "depressive symptoms" or depression or depressed or psychosis or "psychotic disorders" or schizophrenia or "disorders with psychotic features" or "delusional disorder" or hebephreni* or psychotic* or "schizoaffective disorder" or "thought disturbances" or psychoses or "substance-related disorders" or drug or substance or chemical or addict* or disorder* or abuse* or depend* or narcotic* or opiates or opioid or heroin or crack or cocaine or amphetamine* or marijuana or cannabis or phencyclidine or "street drugs" or "designer drugs" or

"personality disorder*" or antisocial or avoidant or borderline or dependent or histrionic or narcissistic or "obsessive compulsive" or paranoid or "passive aggressive" or sadomasochistic or schizoid or schizotypal).mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("alcohol-related disorders" or "drinking behavior" or alcoholic* or alcoholism or "alcohol abuse" or "alcohol use" or "alcohol misuse" or "alcohol problem" or "alcohol depend*" or "anxiety disorder" or "generalized anxiety disorder" or "phobia" or "panic disorder" or "obsessive compulsive disorder" or "posttraumatic stress disorder" or "bipolar disorder" or "manic depression" or "manic depressive disorder" or mania or "depressive disorder" or "major depression" or dysthymia or "depressive symptoms" or depression or depressed or psychosis or "psychotic disorders" or schizophrenia or "disorders with psychotic features" or "delusional disorder" or hebephreni* or psychotic* or "schizoaffective disorder" or "thought disturbances" or psychoses or "substance-related disorders" or drug or substance or chemical or addict* or disorder* or abuse* or depend* or narcotic* or opiates or opioid or heroin or crack or cocaine or amphetamine* or marijuana or cannabis or phencyclidine or "street drugs" or "designer drugs" or "personality disorder*" or antisocial or avoidant or borderline or dependent or histrionic or narcissistic or "obsessive compulsive" or paranoid or "passive aggressive" or sadomasochistic or schizoid or schizotypal)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("alcohol-related disorders" or "drinking behavior" or alcoholic* or alcoholism or "alcohol abuse" or "alcohol use" or "alcohol misuse" or "alcohol problem" or "alcohol depend*" or "anxiety disorder" or "generalized anxiety disorder" or "phobia" or "panic disorder" or "obsessive compulsive disorder" or "posttraumatic stress disorder" or "bipolar disorder" or "manic depression" or "manic depressive disorder" or mania or "depressive disorder" or "major depression" or dysthymia or "depressive symptoms" or depression or depressed or psychosis or "psychotic disorders" or schizophrenia or "disorders with psychotic features" or "delusional disorder" or hebephreni* or psychotic* or "schizoaffective disorder" or "thought disturbances" or psychoses or "substance-related disorders" or drug or substance or chemical or addict* or disorder* or abuse* or depend* or narcotic* or opiates or opioid or heroin or crack or cocaine or amphetamine* or marijuana or cannabis or phencyclidine or "street drugs" or "designer drugs" or "personality disorder*" or antisocial or avoidant or borderline or dependent or histrionic or narcissistic or "obsessive compulsive" or paranoid or "passive aggressive" or sadomasochistic or schizoid or schizotypal)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("alcohol-related disorders" or "drinking behavior" or alcoholic* or alcoholism or "alcohol abuse" or "alcohol use" or "alcohol misuse" or "alcohol problem" or "alcohol depend*" or "anxiety disorder" or "generalized anxiety disorder" or "phobia" or "panic disorder" or "obsessive compulsive disorder" or "posttraumatic stress disorder" or "bipolar disorder" or "manic depression" or "manic depressive disorder" or mania or "depressive disorder" or "major depression" or dysthymia or "depressive symptoms" or depression or depressed or psychosis or "psychotic disorders" or schizophrenia or "disorders with psychotic features" or "delusional disorder" or hebephreni* or psychotic* or "schizoaffective disorder" or "thought disturbances" or psychoses or "substance-related disorders" or drug or substance or chemical or addict* or disorder* or abuse* or depend* or narcotic* or opiates or opioid or heroin or crack or cocaine or amphetamine* or marijuana or cannabis or phencyclidine or "street drugs" or "designer drugs" or "personality disorder*" or antisocial or avoidant or borderline or dependent or histrionic or narcissistic or "obsessive compulsive" or paranoid or "passive aggressive" or sadomasochistic or schizoid or schizotypal)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("alcohol-related disorders" or "drinking behavior" or alcoholic* or alcoholism or "alcohol abuse" or "alcohol use" or "alcohol misuse" or "alcohol problem" or "alcohol depend*" or "anxiety disorder" or "generalized anxiety disorder" or "phobia" or "panic disorder" or "obsessive compulsive disorder" or "posttraumatic stress disorder" or "bipolar disorder" or "manic depression" or "manic depressive disorder" or mania or "depressive disorder" or "major depression" or

dysthymia or "depressive symptoms" or depression or depressed or psychosis or "psychotic disorders" or schizophrenia or "disorders with psychotic features" or "delusional disorder" or hebephreni* or psychotic* or "schizoaffective disorder" or "thought disturbances" or psychoses or "substance-related disorders" or drug or substance or chemical or addict* or disorder* or abuse* or depend* or narcotic* or opiates or opioid or heroin or crack or cocaine or amphetamine* or marijuana or cannabis or phencyclidine or "street drugs" or "designer drugs" or "personality disorder*" or antisocial or avoidant or borderline or dependent or histrionic or narcissistic or "obsessive compulsive" or paranoid or "passive aggressive" or sadomasochistic or schizoid or schizotypal)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

I. Renal Diseases

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. ("renal insufficiency" or "kidney insufficiency" or "renal failure" or "kidney failure" or "end stage renal disease").mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("renal insufficiency" or "kidney insufficiency" or "renal failure" or "kidney failure" or "end stage renal disease"))

AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("renal insufficiency" or "kidney insufficiency" or "renal failure" or "kidney failure" or "end stage renal disease")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("renal insufficiency" or "kidney insufficiency" or "renal failure" or "kidney failure" or "end stage renal disease")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("renal insufficiency" or "kidney insufficiency" or "renal failure" or "kidney failure" or "end stage renal disease")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

J. Sleep Disorders

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. ("sleep apnea" or "obstructive sleep apnea" or "sleep disordered breathing" or narcolepsy or cataplexy or "restless leg* syndrome" or "sleep-related leg movements" or "periodic movement disorder" or "sleep periodic limb" or "sleep myoclonus syndrome" or "sleep related").mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word,

subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("sleep apnea" or "obstructive sleep apnea" or "sleep disordered breathing" or narcolepsy or cataplexy or "restless leg* syndrome" or "sleep-related leg movements" or "periodic movement disorder" or "sleep periodic limb" or "sleep myoclonus syndrome" or "sleep related")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("sleep apnea" or "obstructive sleep apnea" or "sleep disordered breathing" or narcolepsy or cataplexy or "restless leg* syndrome" or "sleep-related leg movements" or "periodic movement disorder" or "sleep periodic limb" or "sleep myoclonus syndrome" or "sleep related")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("sleep apnea" or "obstructive sleep apnea" or "sleep disordered breathing" or narcolepsy or cataplexy or "restless leg* syndrome" or "sleep-related leg movements" or "periodic movement disorder" or "sleep periodic limb" or "sleep myoclonus syndrome" or "sleep related")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY ("sleep apnea" or "obstructive sleep apnea" or "sleep disordered breathing" or narcolepsy or cataplexy or "restless leg* syndrome" or "sleep-related leg movements" or "periodic movement disorder" or "sleep periodic limb" or "sleep myoclonus syndrome" or "sleep related")) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

L. Visual Disorders

MEDLINE/EMBASE

1. "multiple sclerosis".mp. or exp Multiple Sclerosis/2. (cataract* or pseudophakia or "lens opacity" or glaucoma or "angle-closure glaucoma O R neurovascular glaucoma" or "open-angle glaucoma" or "macular degeneration" or retinopathy).mp.3. (epidemiolog* or prevalence or incidence or frequenc* or "Co-occurrence" or occurrence or comorbid).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]4. (case or cases or cohort* or "follow-up" or observational or longitudinal or retrospective or "cross-sectional" or population).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]5. (disabil* or progress* or disabl* or "EDSS" or function* or impair*).mp.6. exp disease progression/ or exp prognosis/7. 5 or 68. (MRI or "magnetic resonance imagining").mp.9. exp gray matter/ or exp white matter/10. 8 or 911. exp pain/ or exp fatigue/12. (pain* or fatigu*).mp.13. 11 or 1214. (relaps* or reoccurr* or recur*).mp.15. 7 or 10 or 13 or 1416. 1 or 2 or 3 or 4 or 15

SCOPUS

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cataract* or pseudophakia or "lens opacity" or glaucoma or "angle-closure glaucoma O R neurovascular glaucoma" or "open-angle glaucoma" or "macular degeneration" or retinopathy)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases

OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( relaps* OR reocurr* OR recurr* ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cataract* or pseudophakia or "lens opacity" or glaucoma or "angle-closure glaucoma O R neurovascular glaucoma" or "open-angle glaucoma" or "macular degeneration" or retinopathy)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( disabil* OR disabl* OR progress* OR ( funct* W/5 impair* ) ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cataract* or pseudophakia or "lens opacity" or glaucoma or "angle-closure glaucoma O R neurovascular glaucoma" or "open-angle glaucoma" or "macular degeneration" or retinopathy)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( lesion* OR enhanc* OR atroph* OR mri OR "magnetic resonance imaging" ) )

( TITLE-ABS-KEY ( "multiple sclerosis" ) ) AND ( TITLE-ABS-KEY (cataract* or pseudophakia or "lens opacity" or glaucoma or "angle-closure glaucoma O R neurovascular glaucoma" or "open-angle glaucoma" or "macular degeneration" or retinopathy)) AND ( TITLE-ABS-KEY ( epidemiolog* OR prevalence OR incidence OR frequenc* OR "co-occurrence" OR occurrence OR comorbid* ) ) AND ( TITLE-ABS-KEY ( case OR cases OR cohort* OR "follow-up" OR observational OR longitudinal OR retrospective OR "cross-sectional" OR population ) ) AND ( TITLE-ABS-KEY ( pain* OR fatigu* ) )

Comorbidity-Outcome Review Flow Diagram

Abstracts from databases Screened

in Phase I(n=5140)

Excluded (n=5037)

Full-Text Articles

Assessed for Eligibility(n=104)

Included Studies(n=32)

Excluded (n=72)

Abstract only (n=38)

Comorbidity not the exposure (n=16)

Not original research (n=6)

Outcome not disability, pain/fatigue, relapse, MRI change (n=5)

Non-English (n=4)

Duplicate (n=3)

Articles identified through hand

searches(n=1)

Scre

enin

g

Iden

tific

atio

n

Incl

uded