The relationship between stress and disease onset and relapse in multiple sclerosis: A systematic review

Published:August 22, 2022DOI:


      • This systematic review examines papers published on stress in multiple sclerosis.
      • It is the first review on the impact of stress on multiple sclerosis onset/relapse.
      • It novelly considers the timing of stressors on multiple sclerosis onset/relapse.
      • There is conflicting evidence that stress impacts multiple sclerosis onset.
      • Evidence supports a link between stress at any age and multiple sclerosis relapse.



      The impact of stress in persons with multiple sclerosis (MS) is an area of ongoing inquiry. A limited number of published systematic reviews have reported an association between stress and MS onset. In addition to reviewing more recently published evidence, this review expands upon existing systematic reviews by considering the timing of stress exposure (childhood or adulthood).


      A review of human-subjects literature published in English after 2010 was conducted between April 2020 and May 2020. In total, 6 databases were searched using the terms ‘allostatic load’, ‘multiple sclerosis (MS)’, ‘chronic stress’, and ‘stress’, and 13 relevant studies were analyzed. Each article was read by at least two of the authors to confirm its relevance. Studies were categorized based on the timing of stress exposure (childhood or adulthood). Study designs included longitudinal cohort, cross-sectional cohort, cross-sectional case-control, and longitudinal case-control studies. The NIH study quality assessment tools and Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) checklist were used to assess study quality. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews were followed.


      Manuscripts reviewed included 8 studies on MS onset, 2 studies on MS relapse, and 3 studies on MS onset and relapse. In total, 5 studies examined childhood stress, 7 studies examined adulthood stress, and 1 study examined both childhood and adulthood stress in 2 respective cohorts. Studies of varying design consistently reported an association between MS relapse and stress, regardless of the timing of stress exposure. However, the link between stress and MS onset was conflicting for both childhood and adult stress exposures.


      This systematic review is the first to report the strong association between stress and MS relapse, and, contradictory to past reports, an inconsistent relationship between stress and MS onset. Notably, the timing of stress (childhood or adulthood) seems to have little effect on the occurrence of either MS onset or relapse, though no study examined both childhood and adult stress within the same participant. Most studies were conducted in small, homogeneous samples using self-reported stress measures, which ultimately limits the generalizability of the findings. Overall, the state of the science remains tentative for all areas examined in this review, necessitating future research.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Abdollahpour I.
        • Nedjat S.
        • Mansournia M.A.
        • Eckert S.
        • Weinstock-Guttman B.
        Stress-full life events and multiple sclerosis: a population-based incident case-control study.
        Mult. Scler. Rel. Disord. 2018; 26: 168-172
        • Alsaadi T.
        • el Hammasi K.
        • Shahrour T.M.
        • et al.
        Prevalence of depression and anxiety among patients with multiple sclerosis attending the MS Clinic at Sheikh Khalifa Medical City, UAE: cross-Sectional Study.
        Mult. Scler. Int. 2015; (2015)
        • Alzahrani A.S.
        • Alshamrani F.J.
        • Al-Khamis F.A.
        • et al.
        Association of acute stress with multiple sclerosis onset and relapse in Saudi Arabia.
        Saudi Med. J. 2019; 40: 372-378
        • Artemiadis A.K.
        • Anagnostouli M.C.
        • Alexopoulos E.C.
        Stress as a risk factor for multiple sclerosis onset or relapse: a systematic review.
        Neuroepidemiology. 2011; 36: 109-120
        • Beiske A.G.
        • Svensson E.
        • Sandanger I.
        • et al.
        Depression and anxiety amongst multiple sclerosis patients.
        Eur. J. Neurol. 2008; 15: 239-245
        • Brenner P.
        • Granqvist M.
        • Königsson J.
        • Nimer F.
        • Piehl F.
        • Jokinen J.
        Depression and fatigue in multiple sclerosis: relation to exposure to violence and cerebrospinal fluid immunomarkers.
        Psychoneuroendocrinology. 2018; 89: 53-58
        • Briones-Buixassa L.
        • Milà R.
        • Ma Aragonès J.
        • Bufill E.
        • Olaya B.
        • Arrufat F.X.
        Stress and multiple sclerosis: a systematic review considering potential moderating and mediating factors and methods of assessing stress.
        Health Psychol. Open. 2015; 2
        • Briones-Buixassa L.
        • Milà R.
        • Arrufat F.X.
        • et al.
        A case-control study of psychosocial factors and their relationship to impairment and functionality in multiple sclerosis.
        J. Health Psychol. 2019; 24: 1023-1032
        • Burns M.N.
        • Nawacki E.
        • Kwasny M.J.
        • Pelletier D.
        • Mohr D.C.
        Do positive or negative stressful events predict the development of new brain lesions in people with multiple sclerosis?.
        Psychol. Med. 2014; 44: 349-359
        • DjelilovicVranic J.
        • Alajbegovic A.
        • TiricCampara M.
        • et al.
        Stress as provoking factor for the first and repeated multiple sclerosis seizures.
        Materia Socio Medica. 2012; 24: 142
        • Feinstein A.
        Multiple sclerosis, depression, and suicide. Clinicians should pay more attention to psychopathology.
        Br. Med. J. 1997; 315: 691-692
        • Gasperini C.
        • Grasso M.G.
        • Fiorelli M.
        • et al.
        A controlled study of potential risk factors preceding exacerbation in multiple sclerosis.
        J. Neurol., Neurosurg. Psychiatry. 1995; 59: 303-305
        • Gunnarsson M.
        • Udumyan R.
        • Bahmanyar S.
        • Nilsagård Y.
        • Montgomery S.
        Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study.
        Eur. J. Neurol. 2015; 22: 1131-1137
        • Hunter S.
        Overview and diagnosis of multiple sclerosis.
        Am. J. Manag. Care. 2016; 22
        • Karimi S.
        • Andayeshgar B.
        • Khatony A.
        Prevalence of anxiety, depression, and stress in patients with multiple sclerosis in Kermanshah-Iran: a cross-sectional study.
        BMC Psychiatry. 2020; 20
        • Kern S.
        • Rohleder N.
        • Eisenhofer G.
        • Lange J.
        • Ziemssen T.
        Time matters - Acute stress response and glucocorticoid sensitivity in early multiple sclerosis.
        Brain Behav. Immun. 2014; 41: 82-89
        • Marrie R.A.
        • Reingold S.
        • Cohen J.
        • et al.
        The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review.
        Mult. Scler. J. 2015; 21: 305-317
        • Mohr D.C.
        • Hart S.L.
        • Julian L.
        • Cox D.
        • Pelletier D.
        Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis.
        Br. Med. J. 2004; 328: 731-733
        • Munger K.L.
        • Zhang S.M.
        • O'Reilly E.
        • et al.
        Vitamin D intake and incidence of multiple sclerosis.
        Neurology. 2004; 62: 60-65
        • Nielsen N.M.
        • Bager P.
        • Simonsen J.
        • et al.
        Major stressful life events in adulthood and risk of multiple sclerosis.
        J. Neurol., Neurosurg. Psychiatry. 2014; 85: 1103-1108
        • Nielsen N.M.
        • Pedersen B.v.
        • Stenager E.
        • Koch-Henriksen N.
        • Frisch M.
        Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study.
        Mult. Scler. J. 2014; 20: 1609-1615
      1. Oveisgharan S., Hosseini S., Arbabi M., Nafissi S.Stress Differently Predicts Multiple Sclerosis Relapses.; 2014.

        • Razazian N.
        • Yavari Z.
        • Farnia V.
        • et al.
        Exercising impacts on fatigue, depression, and paresthesia in female patients with multiple sclerosis.
        Med. Sci. Sports Exerc. 2016; 48: 796-803
        • Reynard A.K.
        • Sullivan A.B.
        • Rae-Grant A
        A systematic review of stress-management interventions for multiple sclerosis patients.
        Int. J. MS Care. 2014; 16: 140-144
        • Riise T.
        • Mohr D.C.
        • Munger K.L.
        • Rich-Edwards J.W.
        • Kawachi I.
        • Ascherio A.
        Stress and the risk of multiple sclerosis.
        Neurology. 2011; 76: 1866-1871
        • Schwartz C.E.
        • Foley F.W.
        • Rao S.M.
        • Bernardin L.J.
        • Lee H.
        • Genderson M.W.
        Stress and course of disease in multiple sclerosis.
        Behav. Med. 1999; 25: 110-116
        • Shaw M.T.
        • Pawlak N.O.
        • Frontario A.
        • Sherman K.
        • Krupp L.B.
        • Charvet L.E.
        Adverse childhood experiences are linked to age of onset and reading recognition in multiple sclerosis.
        Front. Neurol. 2017; 8
        • Sorenson M.
        • Janusek L.
        • Mathews H.
        Psychological stress and cytokine production in multiple sclerosis: correlation with disease symptomatology.
        Biol. Res. Nurs. 2013; 15: 226-233
        • Spitzer C.
        • Bouchain M.
        • Winkler L.Y.
        • et al.
        Childhood trauma in multiple sclerosis: a case-control study.
        Psychosom. Med. 2012; 74: 312-318
        • Stuifbergen A.K.
        • Blozis S.
        • Becker H.
        • Harrison T.
        • Kullberg V.
        Selected health behaviors moderate the progression of functional limitations in persons with multiple sclerosis: eleven years of annual follow-up.
        Disabil. Health J. 2016; 9: 472-478
        • Tao C.
        • Simpson S.
        • van der Mei I.
        • et al.
        Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.
        J. Neurol., Neurosurg. Psychiatry. 2016; 87: 1343-1349
        • Warren S.
        • Greenhill S.
        • Warren K.G.
        Emotional stress and the development of multiple sclerosis: case-control evidence of a relationship.
        J. Chronic Dis. 1982; 35: 821-831
        • Weckesser L.J.
        • Dietz F.
        • Schmidt K.
        • Grass J.
        • Kirschbaum C.
        • Miller R.
        The psychometric properties and temporal dynamics of subjective stress, retrospectively assessed by different informants and questionnaires, and hair cortisol concentrations.
        Sci. Rep. 2019; 9: 1-12
        • Young E.S.
        • Farrell A.K.
        • Carlson E.A.
        • et al.
        The dual impact of early and concurrent life stress on adults’ diurnal cortisol patterns: a prospective study.
        Psychol. Sci. 2019; 30: 739-747