Cause of death in patients attending multiple sclerosis clinics A.D. Sadovnick, PhD; K. Eisen, RN; G.C. Ebers, MD; and D.W. Paty, MD
Article abstract-Between 1972 and 1988,145 deaths occurred among 3,126 patients attending the Multiple Sclerosis (MS) Clinics in Vancouver, British Columbia (N = 1,583),and London, Ontario (N = 1,543).We could determine the exact cause of death in 82.1% of cases (119 of 145).Of the 119 patients for whom the cause of death was known, 56 deaths (47.1%)were directly attributed to complications of MS. Of the remaining 63 deaths, 18 (28.6%)were suicides, 19 (30.2%)were due to malignancy, 13 (20.6%)to an acute myocardial infarction, seven (11.1%)to stroke, and the remainder (9.5%)to miscellaneous causes, of which two may have been suicides. The proportion of suicides among MS deaths was 7.5 times that for the age-matched general population, and the proportion of MS deaths from malignancy was 0.67 times that for the age-matched general population. The proportion of deaths due to malignancy and stroke was the same for the MS patients and the age-matched general population. NEUROLOGY 1991;41:1193-1196
A diagnosis of multiple sclerosis (MS) frequently prompts t h e question of whether the disease is fatal. Most studies on mortality and MS focus o n mortality rather t h a n the actual cause of patterns and death. Those studies addressing cause of death tend t o be relatively old,6-8based on selective populations (such as autopsy seriess), or focus on a specific cause of death such as neoplasms.1° T h e present study is based o n a series of patients followed up t o 16 years at two large Canadian MS clinics in London, Ontario, and Vancouver, British Columbia, during the period 1972-1988. T h e universal coverage medical insurance program in Canada gives all patients essentially equal financial access t o these clinics. T h e clinic populations are representative of the general MS popu1ation.l1J2 Methods. Multiple sclerosis clinics. The mandate of Canadian MS clinics is to assess patients for diagnostic purposes, to monitor and manage the course of MS over time, and to conduct research. The majority of MS patients in the geographic regions served by the clinics in this study-southwestern Ontario (“London” Clinic), established in 1972,13and British Columbia (“Vancouver” Clinic), established in 198014-attend the clinics. Notification of patient deuths. Clinic personnel become aware of patient deaths in several ways. The clinic is notified immediately if the body is willed for research. In many other cases, relatives or referring physicians inform the clinic. Also, patients are contacted at least annually for follow-up evaluations as part of ongoing studies detailing the natural history of MS. Finally, on occasion, clinic personnel become aware of a
death by chance, eg, newspaper notice, other patient, etc. In British Columbia, all patients attending the Vancouver Clinic are registered with the Health Surveillance Registry, Division of Vital Statistics, Ministry of Health. As a “registering source,” the clinic is informed by the Division of Vital Statistics of all patient deaths occurring in the province. Statistical analyses. Differences between sample proportions were tested using 2 X k contingency chi-square tests with k - 1 degrees of freedom. Differences between means were compared using a two-tailed t test, with no correction for the multiplicity of comparisons. Differences were considered significant at the 5% level. The data were analyzed to look at the proportion (frequency)of a specific cause of death among all the deaths for the MS study population compared with the age-matched general population of British Columbia.16Differences were considered significant at the 5% level.
Results. Study population. A total of 145 deaths were identified among 3,126 patients diagnosed with MS according to recognized criteria.16J7 Table 1 presents t h e data for the Vancouver and London Clinics separately. The higher proportion of deaths in the London Clinic probably reflects the fact that this clinic was established 8 years earlier than the Vancouver Clinic, and the London population is thus older. Cause of death. Cause of death could be determined from hospital, physician, or autopsy records for 119 of 145 deaths (82.1%). Complete autopsy reports were available for 38 of 119 cases (31.9%).Cause of death could n o t be determined for 25 patients from t h e London Clinic. Most of these deaths occurred in t h e early years of t h e clinic’s operation. Review of the clini-
From the Multiple SclerosisClinic (Dr. Sadovnick, K. Eisen, and Dr. Paty), University Hospital-UBC Site and the Department of Medical Genetics (Dr. Sadovnick), University of British Columbia, Vancouver, B C and Multiple Sclerosis Clinic (Dr. Ebers),University Hospital, University of Western Ontario, London, ON, Canada. Supported by the Multiple SclerosisSociety of Canada and the Molson Foundation.Dr. Sadovnick’spersonal support is, in part, from the Multiple Sclerosis Society of Canada, British Columbia Division. Received October 26,1990. Accepted for publication in final form January 28, 1991. Address correspondence and reprint requests to Dr. A.D. Sadovnick, Department of Medical Genetics, University of British Columbia, 226-6174 University Blvd., Vancouver, BC, V6T 123, Canada.
August 1991 NEUROLOGY 41 1 1 9 3
Table 1. Deaths among 3,126 patients attending MS clinics in Vancouver and London
Source London Vancouver
Total
MS* caseload
Total no. of deaths
No. (70) deaths with known cause
1,543 1,583
105 40
80 (76.2%) 39 (97.5%)
3,126
145
Table 2. Profile of MS patients according to cause of death Mean Mean age duration Male: of of Female Mean death MS ratio “EDSS” (yrs) (yrs) “Complications of
MS Suicide Malignancy Acute myocardial infarct Stroke
119 (82.1%)
* Excludes patients diagnosed as “possible” MS. and “not” MS, as well as those for whom the diagnosis is pending.
cal data on these patients indicated that the majority had advanced disease, high disability scores, and relatively advanced age. In Vancouver, cause of death was never clearly determined for one patient whose death was a coroner’s case. Deaths were separated into six categories: complications of MS, suicide, malignancy, acute myocardial infarction, stroke, miscellaneous. Table 2 profiles the patients in each category according to male :female ratio, disability as measured by the Expanded Disability Status Scale (EDSS),’*mean age of death, and mean duration of MS. As shown in table 2, patients dying from complications of MS were significantly more disabled (mean EDSS = 8.0) compared with the other groups. Conversely, those committing suicide were significantly less disabled (mean EDSS = 4.6), younger (mean age = 44 years), and had the disease for a shorter period (mean duration = 12.9 years) compared with the other groups. For the majority of patients, an EDSS score was available within 1year of death. Deaths due to complications of MS. Fifty-six of the 119 deaths (47.1%)with a known cause were directly due to complications of MS. In 22 cases (39.3%) from the London Clinic, occurring mostly during the 1970s, records clearly indicated that death was due to “complications of MS,” but information on the exact underlying cause of death (eg, pneumonia, renal failure, etc.) could not be obtained. In the remaining 34 cases, death was due to the following: pneumonia (17), aspiration pneumonia (4), pulmonary edema with choking (4), pulmonary embolism (3), respiratory failure (2), renal failure (2), accidental asphyxiation (I),pericarditis (1). In the case of accidental asphyxiation, a very disabled patient choked when her clothing caught in the wheelchair. As her MS disabilities prevented her from freeing herself, this death was classified as a complication of MS rather than an accident. Deaths not due to direct complications of MS. Sixtythree of the 119 deaths (52.9%)were not directly due to complications of MS. Suicide. Eighteen of the 63 deaths (28.6%) were classified by the coroner as suicide. The method used could be determined for 13 cases: drug overdose (81, gunshot (4), deliberate starvation (1). Two additional deaths, classified as “miscellaneous,” may have actually been suicide. In one case, a patient 1194 NEUROLOGY 41 August 1991
I
”
1:o.g 1:l.Z
4.6’ 5.1 5.1
51.0 44.0* 58.5 60.0
16.3 12.9* 22.8 22.1
1:0.8
6.6
63.5
23.8
1:l.l 1:l.Z
8.0*
* p < 0.05 for all the pairwise comparisons within the column
with a previous suicide attempt died in a single car motor vehicle accident that occurred under excellent driving conditions. There was no evidence of alcohol or any medical conditions (blackout, stroke, heart attack) being a factor in the accident. The second case also involved a patient with a history of a previous suicide attempt. Blood nortriptyline was 1.2 mg/l. (Levels over 0.5 are in the toxic range.) Although not classified as suicide, the coroner’s report stated: “The drug overdose is sufficiently high to prevent reflexesagainst aspiration and may, in fact, have been high enough to cause death on its own.” As shown in table 3, the proportion of deaths due to suicide in the MS population was 7.5 times that for the age-matched general p~pulation.’~ Malignancy. Nineteen of the 63 deaths (30.2%)were due to malignancy, but no specific malignancy was predominant. The primary malignancy could be determined for 14 of 19 cases (73.7%): bronchogenic (2), adenocarcinoma (Z), colon (l),lymphoma in gut (l), intra-abdominal malignancy (l),leukemia (l),glioma (l),bladder (l),prostate (l), cervical (l), oat cell carcinoma (I),vocal cords (1). The proportion of MS deaths due to malignancy was significantly less (0.67X ) than that for the age-matched general p ~ p u l a t i o n (table ’~ 3). Acute myocardial infarction. Thirteen of the 63 deaths (20.6%) were due to acute myocardial infarction. This proportion was not significantly different from that for the age-matched general p~pulation’~ (table 3). Stroke. Seven of the 63 deaths (5.9%) resulted from stroke. This proportion was not significantly different from that for the age-matched general population15 (table 3). Miscellaneous causes. Six (9.5%) MS deaths were in this category: accidents (2, including one possible suicide), aspiration (1,possibly suicide), herpes encephalitis (l),perforated ulcer and peritonitis (l), aortic aneurysm (1). Discussion. Some clinic patients may be lost to followup over time, and deaths reported in this study are an underestimation. However, as the protocol of the two
negligible. If suicide is not considered a complication of MS, 18 of 63 (28.6%) “non-MS” deaths were suicide. This proportion could be as high as 31.7% or 20 out of 63 if the two possible cases of suicide are included. Comparison of MulleP stated that “. . . mental changes are not unproportions for usual in this disease (MS). Patients who committed MS population suicide have been counted among those who died of the British Columbia and the British MS deathst Columbia disease.” The literature, however, is inconsistent in (N = 119) (N = 2 1 , 1 1 3 ) t age-matched classifying suicide as a “complication of MS.” Allen et No. Proportion No. Proportion population a19 reported three suicides among 120 MS deaths Suicide 18 0.15 452 0.02 7.5X$ (2.5%), and Leibowitz et a18 reported four suicides 19 0.16 5.121 0.24 067x8 Malignancy among 73 deaths (5.5%),much lower rates than in the Acutemyocardial 13 0.11 2,423 0.11 1.oox infarction current study. Both groups considered suicide an “MSStroke 7 0.06 1,011 0.05 1.2ox related” cause of death. Kurtzke et a17 reported one * Note that these are not mortality rates. but rather relative frequencies (proportions) suicide among 121deaths (0.8%)and considered suicide of death by cause among those with known cause. unrelated to MS. t Data are from Prov. of British Columbia,Ministry of Health, Div. of Vital Statistics. Annual Report, 1987.15 While 15% of all patients with a depressive disorder $The proportionof deaths due to suicide in the MS population is significantly greater commit suicide,29not all suicides are secondary to de(7.5X, p < 0.01)than that for the age-matched British Columbia population. 5 The proportion of deaths due to malignancy in the MS population is significantly pressive disorders. Thus, it is not surprising that the lower ( 0 . 6 7 X p < 0.01) than that for the age-matched British Columbiapopulation. exact relationship between depression, suicide, and MS remains ~ n c e r t a i n . ~ O Indeed, - ~ ~ most of the studies that only examine the relationship between depression and clinics is to maintain ongoing contact with patients, we MS have major methodologic flaws limiting the are aware of the majority of deaths. In addition, there is usefulness and generalizability of their findings. These no reason to believe that “missed” deaths would be include the following: (a) lack of standardized objective biased according to cause of death. criteria for a diagnosis of depressive disorder, (b) case Our data, based on an MS population followed proascertainment not usually representative of the general spectively up to 16 years, are more accurate than those population of MS patients, and (c) only a few studies from death certificates where the accuracy of recording have controlled for neurologic disability or cognitive MS is p00r.’~-~’ impairment. Data from this study indicate that approximately In reviewing the literature on MS and depression, it half of the patients died from complications of MS, with is important to compare data on depression in other pneumonia being the most frequent underlying cause, serious, chronic medical/neurologic diseases. The lifein agreement with other s t u d i e ~ . ~ . ~ . ~ ~ time frequency of depression in patients with chronic The proportion of MS deaths due to suicide was medical disorders was recently reported to be 12.9% significantly greater (7.5X) that for the age-matched compared with 9.7% in the general p ~ p u l a t i o nthis ; ~ ~is general population, whereas the proportion of MS still far below the frequency for a mood disorder redeaths due to malignancy was significantly less (0.67 X ) ported in MS. than that for the age-matched general population. The Rheumatoid arthritis is, in some ways, comparable proportions of death from acute myocardial infarction with MS as a chronic disease causing disability. Howand stroke were not significantly different for the MS ever, MS, unlike rheumatoid arthritis, is characterized population and the age-matched general population. by white matter changes that could be responsible for cognitive changes and depression. A recent prospective Previous studies reported a frequency of malignancy in MS comparable with controls,6J0although some have study in Saskatchewan followed 1,018 patients with found an increased rate. Zimmerman and N e t ~ k rey ~ ~ rheumatoid arthritis for 17 years. There were 251 deaths in this The suicide rate for this group of paported a 20% frequency of malignant tumors in 50 tients was not increased compared with that for the autopsied cases of MS, including two brain tumors. general population of Saskatchewan. Others have also reported concurrent MS and primary Our finding, that there is no significant difference brain t ~ m o r s .Allen ~ ~ -et~ a1,9 ~ in an autopsy series of 120 between the proportion of deaths from acute myocarcases, found neither an increase in the malignancy rate among MS patients compared with general controls nor dial infarct and stroke in MS patients compared with any cases with brain tumors. In the present study, mathe matched population, is in agreement with the study by Allen et a12 The significant stresses and inactivity lignancy was the cause of death significantly less often than expected. While changes in the immune system associated with MS do not translate into a detectably increased role of atherosclerosis. may “protect” MS patients from malignancy, it may be less readily diagnosed in MS patients not having had autopsies, as some manifestations of a malignancy may be attributed to MS. Acknowledgments In the present study, 18 of 119 deaths from a known cause (15.1%) were suicide. Accurate data on “atThe authors would like to thank Drs. S.A. Hashimoto, J. Hooge, L. tempted” suicides could not be obtained for the Clinic Kastrukoff,J. Noseworthy, J.J-F. Oger, G. Rice, and B. Weinshenker populations, although it appears that this number is not for their assistance in interpreting neurologic data on Multiple Scle-
Table 3.Comparison of relative proportions of death by cause among M S patients and the age-matched British Columbia DoDulation*
August 1991 NEUROLOGY 41 1196
rosis Clinic patients and their relatives. H. Armstrong, B. Bass, R. Donovan, K. Eisen, R. Farquhar, and V. Weinshenker assisted with data collection. M. Irwin, I.M.Y. Yee, and K. Redekop were very helpful with the data analyses. Dr. R. Remick’s helpful comments on the manuscript are greatly appreciated.
References 1. Dassel H. Mortality from multiple sclerosis in the Netherlands. Acta Neurol Scand 1973;49:459-474. 2. Enstrom JE, Operskalski EA. Multiple sclerosis among Spanishsurnamed Californians. Neurology 1978;28:434-438. 3. Iversen S. Multiple sclerosis: mortality in Scotland 1974-1980. J Epiderniol Community Health 1982;36:235-236. 4. Lai S-M, Zhang Z-X, Alter M, Sobel E. World-wide trends in multiple sclerosis mortality. Neuroepidemiology 1989;8:56-67. 5. Poser S, Kurtzke JF, Poser W, Schlaf G. Survival in multiple sclerosis. J Clin Epidemiol 1989;42:159-168. 6. Stazio A, Kurland LT, Bell LG, Saunders MG, Rogot E. Multiple sclerosis in Winnipeg, Manitoba: methodological considerations of epidemiologic survey. Ten-year follow-up of a community-wide study and population re-survey. J Chron Dis 1964;17:415-437. 7. Kurtzke JF, Beebe GW, Nagler B, Nefzger MD, Auth TL, Kurland LT. Studies on the natural history of multiple sclerosis. V. Longterm survival in young men. Arch Neurol 1970;22:215-225. 8. Leibowitz U, KahanaE, Jacobson SG, Alter M. The cause of death in multiple sclerosis. In: Leibowitz U, ed. Progress in multiple sclerosis. New York: Academic Press, 1972:196-209. 9. Allen IV, Millar JHD, Hutchinson MJ. General disease in 120 necropsy-proven cases of multiple sclerosis. Neuropath Appl Neurobiol 19784:279-284. 10. Sibley WA, Bamford CR, Laguna JF. Anamnestic studies in multiple sclerosis: a relationship between familial multiple sclerosis and neoplasia. Neurology 1978;28(no. 9, part 2):125-128. 11.Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a population-based study. I. Clinical course and disability. Brain 1989;112:133-146. 12. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a population-based study. 2. The predictive value of the early clinical course. Brain 1989;112:1419-1428. 13. Hader WJ, Elliot M, Ebers GC. Epidemiology of multiple sclerosis in London and Middlesex County, Ontario, Canada. Neurology 1988;38:617-621. 14. Sweeney VP, Sadovnick AD, Brandejs V. Prevalence of multiple sclerosis in British Columbia. Can J Neurol Sci 1986;13:47-51. 15. Province of British Columbia, Ministry of Health, Division of Vital Statistics, Annual Report, 1987. 16. Schumacher GA, Beebe G, Kibler RF, 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 NY Acad Med 1965;122:552-568. 17. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. In: Poser
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CM, Paty DW, McDonald WI, Scheinberg L, Ebers GC, eds. The diagnosis of multiple sclerosis. New York: Thieme-Stratton, 1984:225-229. 18. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability s t a t u s scale (EDSS). Neurology 1983;33:1444-1452. 19.Percy AK, Nobrega FT, Okazaki H, Glattre E, Kurland LT. Multiple sclerosis in Rochester, Minnesota: a 60-year appraisal. Arch Neurol 1971;25:105-111. 20. Malmgren RM, Valdiviezo NL, Visscher BR, et al. Underlying cause of death as recorded for multiple sclerosis patients: associated factors. J Chron Dis 1983;36:699-705. 21. Larsen J P , Kvale G, Aarli JA. Multiple sclerosis and mortality statistics. Acta Neurol Scand 1985;71:237-241. 22. Phadke JG. Survival pattern and cause of death in patients with multiple sclerosis: results from an epidemiological survey in northeast Scotland. J Neurol Neurosurg Psychiatry 1987;50:523-531. 23. Zimmerman HM, Netsky MG. The pathology of multiple sclerosis. Res Pub1 Assoc Res Nerv Ment Dis 1950;28:271-312. 24. Castaigne P, Escourelle R, Brunet P, Gray F, Rouques C, Le Bigot P. Reticulosarcome cerebral primitif associe a des lesions de sclerose en plaques. Rev Neurol (Paris) 1974;130:181-188. 25. Currie S, Urich H. Concurrence of multiple sclerosis and glioma. J Neurol Neurosurg Psychiatry 1974;37:598-605. 26. Reagan T J , Frieman IS. Multiple cerebral gliomas in multiple sclerosis. J Neurol Neurosurg Psychiatry 1973;36523-528. 27. Lynch PG. Multiple sclerosis and malignant glioma. BMJ 1974;3:577. 28. Muller R. Studies on disseminated sclerosis with special reference to symptomatology, course and prognosis. Acta Medica Scandinavica 1949;122(suppl CCXXII):136. 29. Hirschfield RMA, Davidson L. Risk factors for suicide, ch 7. In: Frances AJ, Hales RE, eds. Review of psychiatry. Washington: American Psychiatric Press, 1988:307-333. 30. Schiffer RB, Caine ED, Bamford KA, Levy S.Depressive episodes i n p a t i e n t s w i t h multiple sclerosis. Am J P s y c h i a t r y 1983;140:1498-1500. 31. McIvor GP, Riklan M, Reznikoff M. Depression in multiple sclerosis as a function of length and severity of illness, age remissions, and perceived social support. J Clin Psycho1 1984;40:1028-1033. 32. Rabins PV, Brooks BR, O’Donnell P, et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986;109:585-597. 33. Honer WG, Hurwitz T, Li DKB, Palmer M, Paty DW. Temporal lobe involvement in multiple sclerosis patients with psychiatric disorders: a magnetic resonance imaging study. Arch Neurol 1987;44:187-190. 34. Joffe RT, Lippert GP, Gray TA, Sawa G, Horvath Z. Mood disorder and multiple sclerosis. Arch Neurol 1987;44:376-378. 35. Wells KB, Golding JA, Burnam MA. Psychiatric disorder in a sample of the general population with and without chronic medical conditions. Am J Psychiatry 1988;145:976-981. 36. Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF. Survival, prognosis and causes of death in rheumatoid arthritis. Arthritis Rheum 1986;29:706-714.
Cause of death in patients attending multiple sclerosis clinics A. D. Sadovnick, K. Eisen, G. C. Ebers, et al. Neurology 1991;41;1193 DOI 10.1212/WNL.41.8.1193 This information is current as of August 1, 1991 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1991 by Edgell Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Article abstract-Between 1972 and 1988,145 deaths occurred among 3,126 patients attending the Multiple Sclerosis (MS) Clinics in Vancouver, British Columbia (N = 1,583),and London, Ontario (N = 1,543).We could determine the exact cause of death in 82.1% of cases (119 of 145).Of the 119 patients for whom the cause of death was known, 56 deaths (47.1%)were directly attributed to complications of MS. Of the remaining 63 deaths, 18 (28.6%)were suicides, 19 (30.2%)were due to malignancy, 13 (20.6%)to an acute myocardial infarction, seven (11.1%)to stroke, and the remainder (9.5%)to miscellaneous causes, of which two may have been suicides. The proportion of suicides among MS deaths was 7.5 times that for the age-matched general population, and the proportion of MS deaths from malignancy was 0.67 times that for the age-matched general population. The proportion of deaths due to malignancy and stroke was the same for the MS patients and the age-matched general population. NEUROLOGY 1991;41:1193-1196
A diagnosis of multiple sclerosis (MS) frequently prompts t h e question of whether the disease is fatal. Most studies on mortality and MS focus o n mortality rather t h a n the actual cause of patterns and death. Those studies addressing cause of death tend t o be relatively old,6-8based on selective populations (such as autopsy seriess), or focus on a specific cause of death such as neoplasms.1° T h e present study is based o n a series of patients followed up t o 16 years at two large Canadian MS clinics in London, Ontario, and Vancouver, British Columbia, during the period 1972-1988. T h e universal coverage medical insurance program in Canada gives all patients essentially equal financial access t o these clinics. T h e clinic populations are representative of the general MS popu1ation.l1J2 Methods. Multiple sclerosis clinics. The mandate of Canadian MS clinics is to assess patients for diagnostic purposes, to monitor and manage the course of MS over time, and to conduct research. The majority of MS patients in the geographic regions served by the clinics in this study-southwestern Ontario (“London” Clinic), established in 1972,13and British Columbia (“Vancouver” Clinic), established in 198014-attend the clinics. Notification of patient deuths. Clinic personnel become aware of patient deaths in several ways. The clinic is notified immediately if the body is willed for research. In many other cases, relatives or referring physicians inform the clinic. Also, patients are contacted at least annually for follow-up evaluations as part of ongoing studies detailing the natural history of MS. Finally, on occasion, clinic personnel become aware of a
death by chance, eg, newspaper notice, other patient, etc. In British Columbia, all patients attending the Vancouver Clinic are registered with the Health Surveillance Registry, Division of Vital Statistics, Ministry of Health. As a “registering source,” the clinic is informed by the Division of Vital Statistics of all patient deaths occurring in the province. Statistical analyses. Differences between sample proportions were tested using 2 X k contingency chi-square tests with k - 1 degrees of freedom. Differences between means were compared using a two-tailed t test, with no correction for the multiplicity of comparisons. Differences were considered significant at the 5% level. The data were analyzed to look at the proportion (frequency)of a specific cause of death among all the deaths for the MS study population compared with the age-matched general population of British Columbia.16Differences were considered significant at the 5% level.
Results. Study population. A total of 145 deaths were identified among 3,126 patients diagnosed with MS according to recognized criteria.16J7 Table 1 presents t h e data for the Vancouver and London Clinics separately. The higher proportion of deaths in the London Clinic probably reflects the fact that this clinic was established 8 years earlier than the Vancouver Clinic, and the London population is thus older. Cause of death. Cause of death could be determined from hospital, physician, or autopsy records for 119 of 145 deaths (82.1%). Complete autopsy reports were available for 38 of 119 cases (31.9%).Cause of death could n o t be determined for 25 patients from t h e London Clinic. Most of these deaths occurred in t h e early years of t h e clinic’s operation. Review of the clini-
From the Multiple SclerosisClinic (Dr. Sadovnick, K. Eisen, and Dr. Paty), University Hospital-UBC Site and the Department of Medical Genetics (Dr. Sadovnick), University of British Columbia, Vancouver, B C and Multiple Sclerosis Clinic (Dr. Ebers),University Hospital, University of Western Ontario, London, ON, Canada. Supported by the Multiple SclerosisSociety of Canada and the Molson Foundation.Dr. Sadovnick’spersonal support is, in part, from the Multiple Sclerosis Society of Canada, British Columbia Division. Received October 26,1990. Accepted for publication in final form January 28, 1991. Address correspondence and reprint requests to Dr. A.D. Sadovnick, Department of Medical Genetics, University of British Columbia, 226-6174 University Blvd., Vancouver, BC, V6T 123, Canada.
August 1991 NEUROLOGY 41 1 1 9 3
Table 1. Deaths among 3,126 patients attending MS clinics in Vancouver and London
Source London Vancouver
Total
MS* caseload
Total no. of deaths
No. (70) deaths with known cause
1,543 1,583
105 40
80 (76.2%) 39 (97.5%)
3,126
145
Table 2. Profile of MS patients according to cause of death Mean Mean age duration Male: of of Female Mean death MS ratio “EDSS” (yrs) (yrs) “Complications of
MS Suicide Malignancy Acute myocardial infarct Stroke
119 (82.1%)
* Excludes patients diagnosed as “possible” MS. and “not” MS, as well as those for whom the diagnosis is pending.
cal data on these patients indicated that the majority had advanced disease, high disability scores, and relatively advanced age. In Vancouver, cause of death was never clearly determined for one patient whose death was a coroner’s case. Deaths were separated into six categories: complications of MS, suicide, malignancy, acute myocardial infarction, stroke, miscellaneous. Table 2 profiles the patients in each category according to male :female ratio, disability as measured by the Expanded Disability Status Scale (EDSS),’*mean age of death, and mean duration of MS. As shown in table 2, patients dying from complications of MS were significantly more disabled (mean EDSS = 8.0) compared with the other groups. Conversely, those committing suicide were significantly less disabled (mean EDSS = 4.6), younger (mean age = 44 years), and had the disease for a shorter period (mean duration = 12.9 years) compared with the other groups. For the majority of patients, an EDSS score was available within 1year of death. Deaths due to complications of MS. Fifty-six of the 119 deaths (47.1%)with a known cause were directly due to complications of MS. In 22 cases (39.3%) from the London Clinic, occurring mostly during the 1970s, records clearly indicated that death was due to “complications of MS,” but information on the exact underlying cause of death (eg, pneumonia, renal failure, etc.) could not be obtained. In the remaining 34 cases, death was due to the following: pneumonia (17), aspiration pneumonia (4), pulmonary edema with choking (4), pulmonary embolism (3), respiratory failure (2), renal failure (2), accidental asphyxiation (I),pericarditis (1). In the case of accidental asphyxiation, a very disabled patient choked when her clothing caught in the wheelchair. As her MS disabilities prevented her from freeing herself, this death was classified as a complication of MS rather than an accident. Deaths not due to direct complications of MS. Sixtythree of the 119 deaths (52.9%)were not directly due to complications of MS. Suicide. Eighteen of the 63 deaths (28.6%) were classified by the coroner as suicide. The method used could be determined for 13 cases: drug overdose (81, gunshot (4), deliberate starvation (1). Two additional deaths, classified as “miscellaneous,” may have actually been suicide. In one case, a patient 1194 NEUROLOGY 41 August 1991
I
”
1:o.g 1:l.Z
4.6’ 5.1 5.1
51.0 44.0* 58.5 60.0
16.3 12.9* 22.8 22.1
1:0.8
6.6
63.5
23.8
1:l.l 1:l.Z
8.0*
* p < 0.05 for all the pairwise comparisons within the column
with a previous suicide attempt died in a single car motor vehicle accident that occurred under excellent driving conditions. There was no evidence of alcohol or any medical conditions (blackout, stroke, heart attack) being a factor in the accident. The second case also involved a patient with a history of a previous suicide attempt. Blood nortriptyline was 1.2 mg/l. (Levels over 0.5 are in the toxic range.) Although not classified as suicide, the coroner’s report stated: “The drug overdose is sufficiently high to prevent reflexesagainst aspiration and may, in fact, have been high enough to cause death on its own.” As shown in table 3, the proportion of deaths due to suicide in the MS population was 7.5 times that for the age-matched general p~pulation.’~ Malignancy. Nineteen of the 63 deaths (30.2%)were due to malignancy, but no specific malignancy was predominant. The primary malignancy could be determined for 14 of 19 cases (73.7%): bronchogenic (2), adenocarcinoma (Z), colon (l),lymphoma in gut (l), intra-abdominal malignancy (l),leukemia (l),glioma (l),bladder (l),prostate (l), cervical (l), oat cell carcinoma (I),vocal cords (1). The proportion of MS deaths due to malignancy was significantly less (0.67X ) than that for the age-matched general p ~ p u l a t i o n (table ’~ 3). Acute myocardial infarction. Thirteen of the 63 deaths (20.6%) were due to acute myocardial infarction. This proportion was not significantly different from that for the age-matched general p~pulation’~ (table 3). Stroke. Seven of the 63 deaths (5.9%) resulted from stroke. This proportion was not significantly different from that for the age-matched general population15 (table 3). Miscellaneous causes. Six (9.5%) MS deaths were in this category: accidents (2, including one possible suicide), aspiration (1,possibly suicide), herpes encephalitis (l),perforated ulcer and peritonitis (l), aortic aneurysm (1). Discussion. Some clinic patients may be lost to followup over time, and deaths reported in this study are an underestimation. However, as the protocol of the two
negligible. If suicide is not considered a complication of MS, 18 of 63 (28.6%) “non-MS” deaths were suicide. This proportion could be as high as 31.7% or 20 out of 63 if the two possible cases of suicide are included. Comparison of MulleP stated that “. . . mental changes are not unproportions for usual in this disease (MS). Patients who committed MS population suicide have been counted among those who died of the British Columbia and the British MS deathst Columbia disease.” The literature, however, is inconsistent in (N = 119) (N = 2 1 , 1 1 3 ) t age-matched classifying suicide as a “complication of MS.” Allen et No. Proportion No. Proportion population a19 reported three suicides among 120 MS deaths Suicide 18 0.15 452 0.02 7.5X$ (2.5%), and Leibowitz et a18 reported four suicides 19 0.16 5.121 0.24 067x8 Malignancy among 73 deaths (5.5%),much lower rates than in the Acutemyocardial 13 0.11 2,423 0.11 1.oox infarction current study. Both groups considered suicide an “MSStroke 7 0.06 1,011 0.05 1.2ox related” cause of death. Kurtzke et a17 reported one * Note that these are not mortality rates. but rather relative frequencies (proportions) suicide among 121deaths (0.8%)and considered suicide of death by cause among those with known cause. unrelated to MS. t Data are from Prov. of British Columbia,Ministry of Health, Div. of Vital Statistics. Annual Report, 1987.15 While 15% of all patients with a depressive disorder $The proportionof deaths due to suicide in the MS population is significantly greater commit suicide,29not all suicides are secondary to de(7.5X, p < 0.01)than that for the age-matched British Columbia population. 5 The proportion of deaths due to malignancy in the MS population is significantly pressive disorders. Thus, it is not surprising that the lower ( 0 . 6 7 X p < 0.01) than that for the age-matched British Columbiapopulation. exact relationship between depression, suicide, and MS remains ~ n c e r t a i n . ~ O Indeed, - ~ ~ most of the studies that only examine the relationship between depression and clinics is to maintain ongoing contact with patients, we MS have major methodologic flaws limiting the are aware of the majority of deaths. In addition, there is usefulness and generalizability of their findings. These no reason to believe that “missed” deaths would be include the following: (a) lack of standardized objective biased according to cause of death. criteria for a diagnosis of depressive disorder, (b) case Our data, based on an MS population followed proascertainment not usually representative of the general spectively up to 16 years, are more accurate than those population of MS patients, and (c) only a few studies from death certificates where the accuracy of recording have controlled for neurologic disability or cognitive MS is p00r.’~-~’ impairment. Data from this study indicate that approximately In reviewing the literature on MS and depression, it half of the patients died from complications of MS, with is important to compare data on depression in other pneumonia being the most frequent underlying cause, serious, chronic medical/neurologic diseases. The lifein agreement with other s t u d i e ~ . ~ . ~ . ~ ~ time frequency of depression in patients with chronic The proportion of MS deaths due to suicide was medical disorders was recently reported to be 12.9% significantly greater (7.5X) that for the age-matched compared with 9.7% in the general p ~ p u l a t i o nthis ; ~ ~is general population, whereas the proportion of MS still far below the frequency for a mood disorder redeaths due to malignancy was significantly less (0.67 X ) ported in MS. than that for the age-matched general population. The Rheumatoid arthritis is, in some ways, comparable proportions of death from acute myocardial infarction with MS as a chronic disease causing disability. Howand stroke were not significantly different for the MS ever, MS, unlike rheumatoid arthritis, is characterized population and the age-matched general population. by white matter changes that could be responsible for cognitive changes and depression. A recent prospective Previous studies reported a frequency of malignancy in MS comparable with controls,6J0although some have study in Saskatchewan followed 1,018 patients with found an increased rate. Zimmerman and N e t ~ k rey ~ ~ rheumatoid arthritis for 17 years. There were 251 deaths in this The suicide rate for this group of paported a 20% frequency of malignant tumors in 50 tients was not increased compared with that for the autopsied cases of MS, including two brain tumors. general population of Saskatchewan. Others have also reported concurrent MS and primary Our finding, that there is no significant difference brain t ~ m o r s .Allen ~ ~ -et~ a1,9 ~ in an autopsy series of 120 between the proportion of deaths from acute myocarcases, found neither an increase in the malignancy rate among MS patients compared with general controls nor dial infarct and stroke in MS patients compared with any cases with brain tumors. In the present study, mathe matched population, is in agreement with the study by Allen et a12 The significant stresses and inactivity lignancy was the cause of death significantly less often than expected. While changes in the immune system associated with MS do not translate into a detectably increased role of atherosclerosis. may “protect” MS patients from malignancy, it may be less readily diagnosed in MS patients not having had autopsies, as some manifestations of a malignancy may be attributed to MS. Acknowledgments In the present study, 18 of 119 deaths from a known cause (15.1%) were suicide. Accurate data on “atThe authors would like to thank Drs. S.A. Hashimoto, J. Hooge, L. tempted” suicides could not be obtained for the Clinic Kastrukoff,J. Noseworthy, J.J-F. Oger, G. Rice, and B. Weinshenker populations, although it appears that this number is not for their assistance in interpreting neurologic data on Multiple Scle-
Table 3.Comparison of relative proportions of death by cause among M S patients and the age-matched British Columbia DoDulation*
August 1991 NEUROLOGY 41 1196
rosis Clinic patients and their relatives. H. Armstrong, B. Bass, R. Donovan, K. Eisen, R. Farquhar, and V. Weinshenker assisted with data collection. M. Irwin, I.M.Y. Yee, and K. Redekop were very helpful with the data analyses. Dr. R. Remick’s helpful comments on the manuscript are greatly appreciated.
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Cause of death in patients attending multiple sclerosis clinics A. D. Sadovnick, K. Eisen, G. C. Ebers, et al. Neurology 1991;41;1193 DOI 10.1212/WNL.41.8.1193 This information is current as of August 1, 1991 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1991 by Edgell Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
