Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis
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《英国医生杂志》
1 Department of Psychiatry, University of California, San Francisco, CA 94142, USA, 2 Department of Medicine, University of California, San Francisco, 3 Department of Neurology, University of California, San Francisco
Correspondence to: D Mohr dmohr@itsa.ucsf.edu
Abstract
Multiple sclerosis is a chronic, often disabling disease in which the immune system attacks the myelin sheath of axons of the central nervous system.1 Most people with multiple sclerosis have a relapsing form of the disease, characterised in part by exacerbations in which symptoms appear suddenly within 24 hours. These symptoms remit slowly over the course of weeks or months but often can leave some residual impairment. Symptoms vary considerably across patients and can include loss of function or feeling in limbs, loss of bowel or bladder control, sexual dysfunction, debilitating fatigue, blindness due to optic neuritis, double vision, loss of balance, pain, loss of cognitive functioning, and emotional changes.
Numerous triggers of exacerbation have been proposed, including bacterial or viral infections that cause T cells to "mistake" myelin proteins for these antigens, bacterial "superantigens," physical injury, or stressful life events.2 Of these, the role of stressful life events has been by far the most controversial.3
The notion that psychological stress might trigger exacerbation dates back more than 100 years to Charcot, who speculated that grief, vexation, and adverse changes in social circumstance were related to the onset.4 Most patients with multiple sclerosis believe that stressful events can cause or contribute to their exacerbations.5 Over the past decades numerous empirical studies of the question have been published. Goodin et al's qualitative literature review on the effects of stress on clinical exacerbation arrived at an equivocal conclusion.3 While the review contained careful discussions of each paper included, it did not include all relevant studies and did not use quantitative meta-analytic techniques. Furthermore, several important studies have been published since this review.
To clarify the present state of empirical research we conducted a systematic review and quantitative meta-analysis to evaluate and quantify the association between stress and clinical exacerbation in multiple sclerosis.
Methods
The literature search produced a total of 20 articles. Six papers were excluded because they did not meet inclusion criteria.5 10-14 The table shows the general characteristics of the 14 included studies, including sample sizes, available details of participants and the disease, study design, length of follow up, exacerbation criteria, and measurement of stress. Of the 14 studies, seven were case-control studies and seven were longitudinal prospective studies. Two studies examined first exacerbations, which led to a diagnosis of multiple sclerosis, and 12 examined exacerbations after diagnosis.
Characteristics of patients with multiple sclerosis (MS), study design, and measures of stress for primary studies included in meta-analysis
Outcomes
The figure shows the mean effect sizes and standard deviations for each study. The primary analysis for the main hypothesis found that the weighted average effect sizes for the impact of stress on exacerbation over the 14 included studies was d = 0.53 (95% confidence interval 0.40 to 0.65), P < 0.0001. The studies' effects sizes were homogenous (Q = 16.62, P = 0.22), with a low degree of inconsistency (I2 = 21.8%).
Effect of stress on exacerbations in multiple sclerosis
Effect sizes were not significantly affected by any study design characteristics, including the use of longitudinal prospective v case-control designs (P = 0.31), the use of first exacerbation v exacerbation after diagnosis as an outcome criterion (P = 0.59), the use of validated v unvalidated assessment of stress (P = 0.12), the use of self report v structured interview in the assessment of stress (P = 0.12), and the inclusion of relapsing-remitting multiple sclerosis only or relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis (P = 0.11). Regarding sample characteristics, neither the proportions of female participants (P = 0.11) nor age of participants (P = 0.89) were significantly related to effect size. None of the methods of determining exacerbation was related to outcomes, including the use of the expanded disability status score v neurologist judgment (P = 0.45), the use of expanded disability status score 1.0, or the use of retrospective neurologist verification with standardised data27 (P = 0.41).
Discussion
This is Version 2 of the paper. In this version, there has been a change in the table to the entry for Gasperini under the heading "Stress measure." Where it read "1.0 increase in EDSS" this has been corrected to read "Unvalidated questionnaire."
We thank Irina Fonareva for assisting in the preparation of the manuscript and presentation of the data.
Contributors: DCM initially conceived the paper and is guarantor. All authors participated in data acquisition, analysis, and writing.
Funding: US National Institutes of Health grants R01 MH59708-01 and R01 HD043323-01 and National Multiple Sclerosis Society grants FG 1481-A1 and FG 1376A1.
Competing interests: None declared.
Ethical approval: Not required.
References
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343: 938-52.
Hohlfeld R, Meinl E, Weber F, Zipp F, Schmidt S, Sotgiu S, et al. The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis. Neurology 1995;45(6 suppl 6): S33-8.
Goodin DS, Ebers GC, Johnson KP, Rodriguez M, Sibley WA, Wolinsky JS. The relationship of MS to physical trauma and psychological stress: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 1999;52: 1737-45.
Charcot JM. Lectures on diseases of the nervous system. London: New Sydenham Society, 1877.
Rabins PV, Brooks BR, O'Donnell P, Pearlson GD, Moberg P, Jubelt B, et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986;109: 585-97.
Schumacher GA, Beebe G, Kibler RF, Durland LT, Kurtzke JF, McDowell F, et al. Problems of experimental trials of therapy in multiple sclerosis. Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965;122: 552-6.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: 227-31.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-52],
Lipsey MW, Wilson DB. Practical meta-analysis. Thousand Oaks, CA: Sage, 2001.
Pratt RTC. An investigation of the psychiatric aspects of disseminated sclerosis. J Neurol Neurosurg Psychiatry 1951;14: 326-36.
Antonovsky A, Leibowitz U, Medalie JM, Smith A, Halpern L, Alter M. Reappraisal of possible etiologic factors in multiple sclerosis. Am J Public Health 1968;58: 836-48.
Mei-Tal V, Meyerowitz S, Engel GL. The role of psychological process in a somatic disorder: multiple sclerosis. 1. The emotional setting of illness onset and exacerbation. Psychosom Med 1970;32: 67-86.
Schwartz CE, Foley FW, Rao SM, Bernardin LJ, Lee H, Genderson MW. Stress and course of disease in multiple sclerosis. Behav Med 1999;25: 110-6.
Ackerman KD, Rabin B, Heyman R, Frank E, Anderson B, Baum A. Stressful life events precede multiple sclerosis disease exacerbations. Psychosom Med 2000;62: 147.
Warren S, Greenhill S, Warren KG. Emotional stress and the development of multiple sclerosis: case-control evidence of a relationship. J Chronic Dis 1982;35: 821-31.
Franklin GM, Nelson LM, Heaton RK, Burks JS, Thompson DS. Stress and its relationship to acute exacerbations in multiple sclerosis. J Neurol Rehabil 1988;2: 7-11.
Grant I, Brown GW, Harris T, McDonald WI, Patterson T, Trimble MR. Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52: 8-13.
Warren S, Warren KG, Cockerill R. Emotional stress and coping in multiple sclerosis (MS) exacerbations. J Psychosom Res 1991;35: 37-47.
Gaiatto G, Loperfido A, Fortunaso P. Eventi stressanti e ricadute nella sclerosi multipla; Uno studio pilota . Medicina Psicosomatica 1992;37: 19-27.
Nisipeanu P, Korczyn AD. Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology 1993;43: 1311-2.
Stip E, Truelle JL. . Can J Psychiatry 1994;39: 27-33.
Morrison W, Nelson J. Environmental triggers in multiple sclerosis. Fact or fallacy? Axone 1994;16: 23-6.
Gasperini C, Grasso MG, Fiorelli M, Millefiorini E, Morino S, Anzini A, et al. A controlled study of potential risk factors preceding exacerbation in multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;59: 303-5.
Sibley WA. Risk factors in multiple sclerosis. In: Raine CS, McFarland HF, Tourtellotte WW, eds. Multiple sclerosis: clinical and pathogenetic basis. London: Chapman and Hall, 1997: 141-8.
Palumbo R, Fontanillas L, Salmaggi A, La Mantia L, Milanese C. Stressful life events and multiple sclerosis: a retrospective study. Ital J Neurol Sci 1998;19: 259-60.
Mohr DC, Goodkin DE, Bacchetti P, Boudewyn AC, Huang L, Marrietta P, et al. Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 2000;55: 55-61.
Ackerman KD, Stover A, Heyman R, Anderson BP, Houck PR, Frank E, et al. Relationship between cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity. Brain Behavior Immun 2003;17: 141-51.
Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA, et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003;327: 646.
Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D'Amico R, et al. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 2003;361: 545-52.
Whitacre CC, Dowdell K, Griffin AC. Neuroendocrine influences on experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 1998;840: 705-16.
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332: 1351-62.
Correa SG, Rodriguez-Galaan MC, Rivero VE, Riera CM. Chronic varied stress modulates experimental autoimmune encephalomyelitis in Wistar rats. Brain Behav Immunity 1998;12: 134-48.
Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol 2001;58: 1081-6.
Munck A, Naray-Fejes-Toth A. Glucocorticoids and stress: permissive and suppressive actions. Ann N Y Acad Sci 1994;746: 115-30,131-3.
Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes. J Endocrinol 2001;169: 437-45.
Zappulla JP, Arock M, Mars LT, Liblau RS. Mast cells: new targets for multiple sclerosis therapy? J Neuroimmunol 2002;131: 5-20.
Goodkin DE, Rooney WD, Sloan R, Bacchetti P, Gee L, Vermathen M, et al. A serial study of new MS lesions and the white matter from which they arise. Neurology 1998;51: 1689-97.(David C Mohr, associate p)
Correspondence to: D Mohr dmohr@itsa.ucsf.edu
Abstract
Multiple sclerosis is a chronic, often disabling disease in which the immune system attacks the myelin sheath of axons of the central nervous system.1 Most people with multiple sclerosis have a relapsing form of the disease, characterised in part by exacerbations in which symptoms appear suddenly within 24 hours. These symptoms remit slowly over the course of weeks or months but often can leave some residual impairment. Symptoms vary considerably across patients and can include loss of function or feeling in limbs, loss of bowel or bladder control, sexual dysfunction, debilitating fatigue, blindness due to optic neuritis, double vision, loss of balance, pain, loss of cognitive functioning, and emotional changes.
Numerous triggers of exacerbation have been proposed, including bacterial or viral infections that cause T cells to "mistake" myelin proteins for these antigens, bacterial "superantigens," physical injury, or stressful life events.2 Of these, the role of stressful life events has been by far the most controversial.3
The notion that psychological stress might trigger exacerbation dates back more than 100 years to Charcot, who speculated that grief, vexation, and adverse changes in social circumstance were related to the onset.4 Most patients with multiple sclerosis believe that stressful events can cause or contribute to their exacerbations.5 Over the past decades numerous empirical studies of the question have been published. Goodin et al's qualitative literature review on the effects of stress on clinical exacerbation arrived at an equivocal conclusion.3 While the review contained careful discussions of each paper included, it did not include all relevant studies and did not use quantitative meta-analytic techniques. Furthermore, several important studies have been published since this review.
To clarify the present state of empirical research we conducted a systematic review and quantitative meta-analysis to evaluate and quantify the association between stress and clinical exacerbation in multiple sclerosis.
Methods
The literature search produced a total of 20 articles. Six papers were excluded because they did not meet inclusion criteria.5 10-14 The table shows the general characteristics of the 14 included studies, including sample sizes, available details of participants and the disease, study design, length of follow up, exacerbation criteria, and measurement of stress. Of the 14 studies, seven were case-control studies and seven were longitudinal prospective studies. Two studies examined first exacerbations, which led to a diagnosis of multiple sclerosis, and 12 examined exacerbations after diagnosis.
Characteristics of patients with multiple sclerosis (MS), study design, and measures of stress for primary studies included in meta-analysis
Outcomes
The figure shows the mean effect sizes and standard deviations for each study. The primary analysis for the main hypothesis found that the weighted average effect sizes for the impact of stress on exacerbation over the 14 included studies was d = 0.53 (95% confidence interval 0.40 to 0.65), P < 0.0001. The studies' effects sizes were homogenous (Q = 16.62, P = 0.22), with a low degree of inconsistency (I2 = 21.8%).
Effect of stress on exacerbations in multiple sclerosis
Effect sizes were not significantly affected by any study design characteristics, including the use of longitudinal prospective v case-control designs (P = 0.31), the use of first exacerbation v exacerbation after diagnosis as an outcome criterion (P = 0.59), the use of validated v unvalidated assessment of stress (P = 0.12), the use of self report v structured interview in the assessment of stress (P = 0.12), and the inclusion of relapsing-remitting multiple sclerosis only or relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis (P = 0.11). Regarding sample characteristics, neither the proportions of female participants (P = 0.11) nor age of participants (P = 0.89) were significantly related to effect size. None of the methods of determining exacerbation was related to outcomes, including the use of the expanded disability status score v neurologist judgment (P = 0.45), the use of expanded disability status score 1.0, or the use of retrospective neurologist verification with standardised data27 (P = 0.41).
Discussion
This is Version 2 of the paper. In this version, there has been a change in the table to the entry for Gasperini under the heading "Stress measure." Where it read "1.0 increase in EDSS" this has been corrected to read "Unvalidated questionnaire."
We thank Irina Fonareva for assisting in the preparation of the manuscript and presentation of the data.
Contributors: DCM initially conceived the paper and is guarantor. All authors participated in data acquisition, analysis, and writing.
Funding: US National Institutes of Health grants R01 MH59708-01 and R01 HD043323-01 and National Multiple Sclerosis Society grants FG 1481-A1 and FG 1376A1.
Competing interests: None declared.
Ethical approval: Not required.
References
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343: 938-52.
Hohlfeld R, Meinl E, Weber F, Zipp F, Schmidt S, Sotgiu S, et al. The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis. Neurology 1995;45(6 suppl 6): S33-8.
Goodin DS, Ebers GC, Johnson KP, Rodriguez M, Sibley WA, Wolinsky JS. The relationship of MS to physical trauma and psychological stress: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 1999;52: 1737-45.
Charcot JM. Lectures on diseases of the nervous system. London: New Sydenham Society, 1877.
Rabins PV, Brooks BR, O'Donnell P, Pearlson GD, Moberg P, Jubelt B, et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986;109: 585-97.
Schumacher GA, Beebe G, Kibler RF, Durland LT, Kurtzke JF, McDowell F, et al. Problems of experimental trials of therapy in multiple sclerosis. Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965;122: 552-6.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: 227-31.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-52],
Lipsey MW, Wilson DB. Practical meta-analysis. Thousand Oaks, CA: Sage, 2001.
Pratt RTC. An investigation of the psychiatric aspects of disseminated sclerosis. J Neurol Neurosurg Psychiatry 1951;14: 326-36.
Antonovsky A, Leibowitz U, Medalie JM, Smith A, Halpern L, Alter M. Reappraisal of possible etiologic factors in multiple sclerosis. Am J Public Health 1968;58: 836-48.
Mei-Tal V, Meyerowitz S, Engel GL. The role of psychological process in a somatic disorder: multiple sclerosis. 1. The emotional setting of illness onset and exacerbation. Psychosom Med 1970;32: 67-86.
Schwartz CE, Foley FW, Rao SM, Bernardin LJ, Lee H, Genderson MW. Stress and course of disease in multiple sclerosis. Behav Med 1999;25: 110-6.
Ackerman KD, Rabin B, Heyman R, Frank E, Anderson B, Baum A. Stressful life events precede multiple sclerosis disease exacerbations. Psychosom Med 2000;62: 147.
Warren S, Greenhill S, Warren KG. Emotional stress and the development of multiple sclerosis: case-control evidence of a relationship. J Chronic Dis 1982;35: 821-31.
Franklin GM, Nelson LM, Heaton RK, Burks JS, Thompson DS. Stress and its relationship to acute exacerbations in multiple sclerosis. J Neurol Rehabil 1988;2: 7-11.
Grant I, Brown GW, Harris T, McDonald WI, Patterson T, Trimble MR. Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52: 8-13.
Warren S, Warren KG, Cockerill R. Emotional stress and coping in multiple sclerosis (MS) exacerbations. J Psychosom Res 1991;35: 37-47.
Gaiatto G, Loperfido A, Fortunaso P. Eventi stressanti e ricadute nella sclerosi multipla; Uno studio pilota . Medicina Psicosomatica 1992;37: 19-27.
Nisipeanu P, Korczyn AD. Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology 1993;43: 1311-2.
Stip E, Truelle JL. . Can J Psychiatry 1994;39: 27-33.
Morrison W, Nelson J. Environmental triggers in multiple sclerosis. Fact or fallacy? Axone 1994;16: 23-6.
Gasperini C, Grasso MG, Fiorelli M, Millefiorini E, Morino S, Anzini A, et al. A controlled study of potential risk factors preceding exacerbation in multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;59: 303-5.
Sibley WA. Risk factors in multiple sclerosis. In: Raine CS, McFarland HF, Tourtellotte WW, eds. Multiple sclerosis: clinical and pathogenetic basis. London: Chapman and Hall, 1997: 141-8.
Palumbo R, Fontanillas L, Salmaggi A, La Mantia L, Milanese C. Stressful life events and multiple sclerosis: a retrospective study. Ital J Neurol Sci 1998;19: 259-60.
Mohr DC, Goodkin DE, Bacchetti P, Boudewyn AC, Huang L, Marrietta P, et al. Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 2000;55: 55-61.
Ackerman KD, Stover A, Heyman R, Anderson BP, Houck PR, Frank E, et al. Relationship between cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity. Brain Behavior Immun 2003;17: 141-51.
Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA, et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003;327: 646.
Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D'Amico R, et al. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 2003;361: 545-52.
Whitacre CC, Dowdell K, Griffin AC. Neuroendocrine influences on experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 1998;840: 705-16.
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332: 1351-62.
Correa SG, Rodriguez-Galaan MC, Rivero VE, Riera CM. Chronic varied stress modulates experimental autoimmune encephalomyelitis in Wistar rats. Brain Behav Immunity 1998;12: 134-48.
Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol 2001;58: 1081-6.
Munck A, Naray-Fejes-Toth A. Glucocorticoids and stress: permissive and suppressive actions. Ann N Y Acad Sci 1994;746: 115-30,131-3.
Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes. J Endocrinol 2001;169: 437-45.
Zappulla JP, Arock M, Mars LT, Liblau RS. Mast cells: new targets for multiple sclerosis therapy? J Neuroimmunol 2002;131: 5-20.
Goodkin DE, Rooney WD, Sloan R, Bacchetti P, Gee L, Vermathen M, et al. A serial study of new MS lesions and the white matter from which they arise. Neurology 1998;51: 1689-97.(David C Mohr, associate p)