Introduction
Multiple sclerosis (MS) is an immune-mediated demyelinating condition affecting the central nervous system.1 MS impacts approximately 2.8 million people globally,2 contributing to a loss of occupational productivity,3 diminished quality of life4 and reduced life expectancy.5 Common clinical presentations include visual impairment, motor weakness or sensory abnormalities.1 People with MS also experience a substantial burden of neuropsychiatric sequelae.6 For example, compared with the general population, people with MS experience a two to fourfold increase in depression,7 an elevated risk of anxiety disorders8 and high rates of cognitive impairment.9 These symptoms are significant predictors of unemployment, morbidity and all-cause mortality in MS10–12 but are often neglected.13 To date, there has been little exploration of MS and obsessive-compulsive disorder (OCD).
OCD is a distressing psychiatric condition characterised by obsessions (ie, unwanted intrusive thoughts, urges or images) and compulsions (ie, ritualised recurrent behaviours).14 This psychiatric condition afflicts approximately 1.3% of the global population, leading to marked functional impairment, worsened quality of life and elevated mortality.15–17 Compared with other anxiety disorders, OCD has unique symptomatology, neuro-circuitry and treatments.14 18 19 Based on these distinct clinical features, OCD and its similar conditions of body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder) and excoriation disorder, form the grouping of obsessive-compulsive and related disorders (OCRD).14
In understanding the pathophysiology of OCRD, investigators have long hypothesised the existence of an ‘autoimmune OCD’ subtype.20 21 In models of this subtype, a T-cell-mediated response or antibodies against intracellular or cell-surface antigens may trigger inflammation along the cortico-striato-thalamo-cortical network, vital in idiopathic OCD.21 Published cases of immune-mediated paediatric acute neuropsychiatric syndromes, autoimmune encephalitis and systemic autoimmune diseases support the possibility of this subtype.21–24 This autoimmune model is reinforced by an elevated risk of OCD in people with a previous positive streptococcal test result and a twofold increased incidence of systemic autoimmune diseases among people with OCD.25 26 Although this work remains preliminary, it highlights the potential role of immunological factors in OCD.
In MS, the estimated lifetime prevalence of OCD is 8.6%,13 approximately 6.6 times higher than in the general population.15 Early findings highlight shared genes of interest in OCD and MS, including STAT3 and NTRK2,27 involved in autoimmunity and neural development. The possibility of a pathophysiological connection between OCD and MS is also suggested by recent literature examining candidate generic medications that could serve as disease-modifying treatments for MS.28 Investigators identified clomipramine—the gold-standard pharmacotherapy for OCD—as a promising treatment for MS.28 29 Clomipramine possesses distinct immunological properties related to iron-mediated neurotoxicity, anti-oxidation and T-cell and B-cell multiplications.28 The researchers emphasised that these characteristics may make clomipramine a potentially effective therapy for managing MS. However, little work examines the connections between the other OCRD and MS. Nonetheless, these intriguing findings emphasise the need to investigate the co-occurrence of these conditions.
Examining the co-morbidity between OCRD and MS, there are several potential explanations. The increased prevalence of OCD in MS could be a spurious finding.13 In this case, it would not hold up to replication in future studies. Another possibility is that this link reflects selection bias, where OCD is more likely to be detected in care recipients. These would both be examples of false associations. Valderas and colleagues highlight four models of genuine etiological associations.30 First, MS or OCD could cause either condition. Second, the risk factors for both illnesses could be correlated, such as smoking in MS and alcohol use disorder in OCD.31 32 Third, these conditions could have shared risk factors, such as an infectious trigger or vitamin D deficiency.31 33 Fourth, there could be a third disease causing OCD and MS. Explorations of the overlap between OCRD and MS need to consider diverse explanatory models of co-occurrence.
Given the considerable neuropsychiatric burden of illness and potential links between OCD and MS, a broad literature review would create a foundation for further examination of co-morbid OCRD and MS. A previous paper on all psychiatric syndromes in MS included a section on obsessive-compulsive syndromes.6 Although this article is a valuable summary, its limitations include its narrow search strategy (only incorporating two databases), its assumption of psychiatric syndromes as a component of MS (rather than incorporate the possibility of co-occurring conditions) and its incomplete report of the search strategy or study selection process. These limitations hinder the breadth of its summary of OCRD and MS and the replicability of this review. No review has specifically examined the clinical dimensions of specific people with OCRD and MS.
This scoping review aims to survey the available knowledge on the clinical dimensions of people with co-occurring OCRD and MS. This could include information related to the epidemiology of this population, potential aetiologies of co-occurring OCRD and MS, the clinical course of these conditions and management considerations when caring for this population. In contrast to a systematic review methodology, we selected a scoping review methodology based on our objective of mapping the available knowledge on OCRD and MS.34 OCRD-MS is an under-explored area, and people with these co-occurring conditions may be nested within the samples of other studies. We anticipate that few studies have focused on this population, but a precise estimate of the number of records is unknown. Relevant articles may also be dispersed across the published and grey literatures. With its emphasis on determining the extent of scholarship, identifying gaps and summarising research for practitioners, a scoping review methodology was deemed appropriate.34 35 We hope the review will stimulate research, and by summarising knowledge on this topic, it could aid the practicing clinician in caring for people with OCRD and MS.
Methods and analysis
We developed a team with expertise in MS neurology, neuropsychiatry, information sciences (including the conduct of medical reviews) and lived experience of MS. This team collaborated on all aspects of study design and protocol development. Any amendments to this protocol following publication will be detailed in the corresponding published review.
We base this study on the Arksey and O’Malley framework for scoping reviews,36 incorporating adaptations from Levac, Peters, Pham and their respective colleagues.37–39 We will also align our report of this scoping review with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist extension.40 See online supplemental appendix A for a completed Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols checklist.41 This protocol is structured with the five stages of (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting the data and (5) collating, summarising and reporting the results.36
Supplemental material
Stage 1: identifying the research question
The research question is, ‘What is known about the clinical dimensions of people with co-occurring OCRD and MS?’ The population is ‘people with co-occurring OCRD and MS and their care providers or families’ to incorporate the full population of interest without restriction by age, sex, gender, disease course or specific OCRD diagnosis. We select the term ‘co-occurring’ to imply that neither OCRD nor MS predominates over the other. In some individuals, people could have OCRD with a relatively benign course of MS, while in others, in managing MS, OCRD may be diagnosed. In a third group, both conditions may be equally present and distressing. The temporal course of illness could also vary. By selecting a discrete population, we hope the results will benefit clinicians working with these individuals and clarify areas for future development.
The principal concept of the scoping review is the clinical dimensions of this population, which may include epidemiology, clinical course, potential aetiologies, management considerations or others. There may be scarce evidence in some of these sub-domains, but we hope to clarify gaps with this encompassing approach. The context of this review is broad, involving a wide timeframe and a range of settings (eg, outpatient or inpatient care, community or academic settings), only limited by articles needing to be available in English.
Stage 2: identifying relevant studies
A comprehensive database search strategy was developed in collaboration with an information specialist. Through March 2024, the following electronic databases were searched, chosen for relevance and range: Ovid Medline, Ovid Embase, Ovid PsycINFO, the Ovid Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO’s CINAHL, Clarivate’s Web of Science and ProQuest Dissertations & Theses. Key concepts were ‘obsessive-compulsive and related disorders’ and ‘multiple sclerosis’, adapted for each database’s search strategy. Each database was searched from inception to present with no language or study design limitations. This search strategy will encompass conference abstracts from major MS conferences organised by organisations, such as the European Committee for Treatment and Research in Multiple Sclerosis, the Americas Committee for Treatment and Research in Multiple Sclerosis, the Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis, the Latin American Committee for Treatment and Research in Multiple Sclerosis and the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis. For search strategy details, see online supplemental appendix B.
Results will be de-duplicated by the information specialist using the Bramer Method.42 Supplementary search methods include forward and backward citation tracking of included studies and any relevant review articles. Results will be transferred to Covidence, a research review software platform for study selection.43
Stage 3: study selection
A two-stage screening process will select appropriate records for inclusion. For abstract/title screening, two independent reviewers will collaboratively assess ten records to ensure consistent application of inclusion criteria. In unresolvable discrepancies, the study team will determine the course of action. The reviewers will then screen 20% of the articles for inclusion. Next, if Cohen’s K is more than 0.7, indicative of moderate inter-rater reliability,44 reviewers will complete abstract/title screening, but if not, the reviewers will address disagreements and restart screening. Full-text screening will follow these same principles. Encompassing studies on anxiety disorders in MS may include some participants with OCRD. To ensure a sensitive review process, we will take an inclusive approach in abstract/title screening and a more selective approach for full-text screening.
Inclusion criteria for records are (1) its availability in English, (2) an available full-text version (eg, full-text of a published article, full conference abstract, dissertation or theses), (3) the inclusion of participants with established diagnoses of both OCRD and MS or the family or care providers of these individuals and (4) appropriate article types. Diagnoses of OCRD could be established by experienced clinicians, with semi-structured clinical interviews (eg, Structured Clinical Interview for DSM-545) or by surrogate measures of diagnosis, such as a high Yale-Brown Obsessive-Compulsive Scale or a self-reported diagnosis.46 We recognise that self-reported diagnosis of OCRD can be unreliable, but in the interest of broadly surveying the literature, if information was collected in a clinical study not focused on OCRD, study coordinators may rely on self-report. The diagnosis of MS should be confirmed with the McDonald diagnostic criteria.47 The diagnostic methods will be recorded in our data charting form. As part of the MS spectrum of illness, we will include people with diagnoses of radiologically isolated syndrome or clinically isolated syndrome. In keeping with a relational perspective in which individuals are embedded in a social network of relationships,48 we will also include studies focused on the family or care providers of people with OCRD and MS. These may include caregivers or healthcare providers. Article types could be commentaries, case studies, programme evaluations, quality improvement initiatives, conference presentations, dissertations or empirical research. This includes experimental, quasi-experimental, analytical observational, descriptive observational or qualitative studies.
Exclusion criteria include (1) articles not available in English as a full-text, (2) reviews and book chapters, (3) records that do not involve the target population, (4) records focused on those with only ‘obsessive-compulsive’ personality traits, (5) records focused on people with neuro-immune disorders other than MS (eg, neuromyelitis optica, acute-disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody disease) and (6) duplicate articles. In abstract/title screening, we will not exclude reviews with the purpose of reviewing their reference lists to identify any additional relevant articles missed in the literature search. Reviews will be excluded from the full-text screening. We will exclude those with high ‘obsessive-compulsive’ personality traits as these likely reflect a different condition compared with OCRD.49
Stage 4: charting the data
Grounded in principles from the data charting form of Freedman and colleagues,50 we will use a created standardised charting form for this scoping review, included in online supplemental appendix C. In line with the review’s objective, this charting form contains an extended section on participant details to highlight the population of MS and OCRD. This includes detailed information on the content (eg, quality or severity of symptoms) and timeline of their illnesses (eg, duration or sequence of diagnoses). For refinement, this form was piloted with some studies that would meet our inclusion criteria. After being trained in charting, two full-text reviewers will independently extract data from each record and provide feedback to enhance the form in an iterative manner. Finally, charted data will be confirmed and unified by a study investigator. This investigator will also combine multiple records referring to the same study or initiative into one line for analysis.
Stage 5: collating, summarizing and reporting the results
Data will be summarised using descriptive statistics. Article details (ie, article type, year of publication, country of origin and conflict of interest declared) will be summarised with frequencies (eg, percentage of records that declared conflicts of interest) in a tabular format. Year of publication will be subdivided into 5-year increments. For details regarding participants, studies, initiatives and commentaries, categorical variables will be summarised with frequencies, while continuous variables will be summarised with means, SD and ranges (or numerical tabulation if calculating the former descriptive statistics is not possible). A narrative description will complement the charted results and explain how these results link to the study question. Findings will be stratified into epidemiology, clinical course, potential aetiologies (including neuroimaging findings) and management considerations and presented in both tabular and visual formats. We may need to create other sub-domains to capture the breadth of relevant information. The organisation of data about studies, initiatives and commentaries depends on the number of available records. While results may be limited by the existing state of research on MS and OCRD, we endeavour to provide readers with a conclusive synthesis of current knowledge. Some records will not have pre-established tools for assessing the risk of bias. In keeping with other scoping studies and without intending to produce a systematic review, there is no planned formal quality assessment. Limitations and biases of the existing literature will not be systematically assessed.
Patient and public involvement
We consulted with a person who has lived experience with MS in the development of the scoping review protocol, including identifying the research question, study design and dissemination plan. They contributed to all aspects of scoping review development. After collating the results from the scoping review, we plan to hold a consultation meeting with MS clinicians and people with MS to elicit feedback on the findings.
Discussion
In this paper, we detail a scoping review protocol to summarise the published and grey literatures on people with OCRD and MS. A significant limitation could be too few records suitable for inclusion. This in itself would be an intriguing finding to highlight the need for more research, and by structuring this review with sub-domains, investigations can target barren areas. We also risk missing relevant articles due to the previous classification of OCRD under other diagnostic categories, such as anxiety disorders. To lessen this concern, we will incorporate a broad database search, an inclusive approach to abstract/title screening, bibliography checks and reverse searches using Google Scholar. This inclusive approach will also pertain to articles that could concern the families or care providers of people with both OCRD and MS. Our findings may also be limited in global scope due to the exclusion of articles unavailable in English.
While aware of the above limitations, we hope this review will aid clinicians and patients in appreciating the current knowledge about co-occurring OCRD and MS. It should also create a framework for future studies to address gaps in the literature. In both respects, this will hopefully enhance understanding and care for people with co-occurring OCRD and MS.
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