Mortality in multiple sclerosis: a review - Wiley Online Library

European Journal of Neurology 2008, 15: 123–127

doi:10.1111/j.1468-1331.2007.02019.x

REVIEW ARTICLE

Mortality in multiple sclerosis: a review P. Ragonese, P. Aridon, G. Salemi, M. DÕAmelio and G. Savettieri Dipartimento Universitario di Neuroscienze Cliniche, Universita` di Palermo, Palermo, Italy

Keywords:

cause of death, epidemiology, mortality, multiple sclerosis, prognosis, survival Received 13 July 2007 Accepted 12 November 2007

This work was undertaken to evaluate studies on mortality caused by multiple sclerosis (MS), to evaluate if useful inferences can be drawn from survival studies that can be applied to clinical practice. A literature search was carried out to find epidemiological studies on MS prognosis, survival, mortality and causes of death relevant to our aim. The World Health Organization (WHO) reports on worldwide cause-specific mortality were also considered. Studies were evaluated according to the duration of the follow-up study, the year of publication and the methodology used. We evaluated MS survival from a methodological point of view and considered if time trends could be drawn from study results. We conclude that mortality is only slightly higher in MS patients when compared with that in the general population. Mortality is higher particularly for older patients and those with longer disease duration.

Introduction Multiple sclerosis (MS) is a disease of the central nervous system whose pathogenic mechanism is supposed to involve the immune system, but neurodegeneration plays a role as well. MS is one of the major causes of disability in the young, affecting people between 20 and 45 years of age. The risk of MS is almost twice in women compared with that in men and its frequency is reported to be increasing in more recent surveys. Disability accumulation is evidenced by many symptoms: fatigue, urinary incontinence, vision loss, impairment of coordination, spasticity, muscle weakness and cognitive impairment. Genetic factors play a role in the pathogenesis of the disease, but environmental factors also contribute to MS risk [1]. Descriptive epidemiology [1] of MS aims at defining incidence, prevalence and mortality caused by the disease in populations and subgroups to evaluate possible geographic and temporal differences. In recent years, several descriptive studies have contributed relevant information regarding incidence and prevalence of MS [1]. Although MS survival and causes of death have been studied in several populations, not many studies have evaluated data in large populations and determined mortality rates in population-based studies to calculate the Ôexcess mortalityÕ caused by MS. Excess mortality is the excess number of deaths recorded compared with the expected number in the general population. Differences in disease survival may refer to a change in Correspondence: Giovanni Savettieri MD, Dipartimento Universitario di Neuroscienze Cliniche, Universita` di Palermo, Via Gaetano La Loggia 1 – 90129 Palermo, Italy (tel.: +39-091-6555146; fax: +39-091-6555147; e-mail: [email protected]).

Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS

general population survival. It is therefore important to establish whether excess mortality for a disease is really changed, how causes of death have eventually become different in persons with MS compared with the referent population and, finally, how these differences have been realized across the years. In this review we analyse studies on MS mortality to draw inferences from survival studies, applicable to clinical practice. We focus in particular on studies of mortality rates, life expectancy and causes of death. Our literature search identified 114 papers matching the search criteria (multiple sclerosis, survival, mortality, prognosis, life expectancy, natural course). Studies based on series derived by clinical trials were excluded. We finally considered 33 papers. We did not perform a pooled analysis because of the heterogeneity of the studies analysed. The more relevant limitations are represented by the extremely variable duration of follow-up across the studies and by the lack of uniformity in the presentation of the results (standardized mortality ratios, annual mortality rates, percentage of survival, Kaplan–Meier plots and so on). It was not possible at last, as we originally planned, to perform a meta-analysis. There are two major issues to analyse, when investigating MS survival: (a) causes of death and (b) survival estimates. Causes of death. These are a potential useful tool to investigate temporal trends and, at the same time provide important information on the events that can occur in late stages of a disease leading to death. Life expectancy and survival estimates. These are gaining more importance when we consider long-term therapies and treatments with potential heavy side effects. The study of mortality predictors is crucial to investigate any differences determined by possible

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31 4254 9881 1949–1998 Denmark Brønnum-Hansen et al. [17] Population based

40 219 1614 Finland Sumelahti et al. [16]

1964–1993

22.3 27.1 14.0 18.1 34.0 101 117 43 70 2059 216 479 206 251 2489 Canada Norway USA Norway USA Survival series

Cottrell et al. [11] Riise et al. [12] Wynn et al. [13] Midgard et al. [14] Wallin et al. [15]

1972–1996 1953–1987 1905–1985 1950–1984 1956–1996

36.1 12% by 25 years 1259 Turkey Kantarci et al. [10]

1994–1997

29.0 31 245 New Zealand Miller et al. [9]

1968–1983

20.3 17.4 35.0 30.0 15.1 43 52 93 20% by 20 years 16 360 266 762 349 1099 Italy Israel USA France Canada Ragonese et al. [3] Leibowitz et al. [5] Kurtzke et al. [6] Confavreux et al. [7] Weinshenker, et al. [8] Natural history

Scotland Phadke et al. [4] DC based

1960–1998 1960–1966 1942–1962 1957–1976 1972–1984

24.5 216

Mean survival Deaths Patients Follow-up Country Study Type of Study

Table 1 MS survival by year and type of the study

This study design is often used to investigate secular or geographical distribution of diseases. An example of this is represented by a death certificate (DC)-based study whose results showed a north-to-south mortality gradient for MS in Italy [2]. The authors of this study concluded that environmental factors could be responsible for the latitudinal gradient evidenced. The pattern of the geographical distribution of a disease in a given country can be derived from mortality studies based on official statistics first, if the accuracy of DC recording is high and homogeneous. Second, because these studies consider long time periods, the diagnostic definition must be homogeneous. This is not the case with MS [3]. Table 1 indicates a summary of mortality statistics for MS [3–17]. Among the reported studies there are methodological differences. These studies were also performed across long time intervals while diagnostic definitions have been not always homogeneous. Death rates are of course derived from official statistics drawn from municipality records or national statistics records based on the International Classification of Diseases (ICD), whose coding has changed as well during the time intervals considered in those studies. Although probably not significantly, accuracy of death recording has also changed over time. All of these limitations reduce the reliability of comparisons for all the reported studies. The advantage of using mortality data is the straightforward availability of standardized data spanning a longer period. They are also routinely collected. Data based on this kind of studies showed a decrease in mortality rates in Scotland (from 2.5 to 1.8), Switzerland (from 2.2 to 1.2), Germany (from 1.9 to 0.7) and the Netherlands (from 1.7 to 1.0). These rates compared the two periods 1968–1970 and 1983–1984 with the WHO rates reported in 2004 [17–20]. In the 2004 report of the WHO, age-adjusted mortality rate in Italy was 0.4 [20]. A study performed in Austria during the period 1970–2001, showed a decrease in the annual mortality rate from 1.41 per 100 000 population to 0.70. Rates were higher in women compared with men in that study but this observation was not confirmed by others [17– 19]. In a study performed in Austria at the term of the follow-up (32 years), 43.2% of patients had died. The reported observations are not homogeneous as already

Remarks

Studies on official mortality statistics and causes of death

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prognostic factors in modifying survival by time, space or past treatments. At present, many of the issues are not well established and we consider them one by one below.

Includes patients deceased with MS over a sample of 1055 enrolled in surveys. No comparison group Hospitalized consecutive MS patients Comparison between subgroups of patients Schumaker diagnostic criteria Modified MacAlpine criteria. Not focused on mortality Partially cross-sectional. Suicide excluded. Poser diagnostic criteria Retrospective analysis of clinical records. McDonald-Halliday diagnostic criteria Retrospective analysis of database from nine MS centres. 209 with a follow-up of at least 15 years. No comparison group Focused on primary progressive MS. No comparison group MacAlpine criteria. No comparison group Record linkage system. Comparison with general population Retrospective clinical definition. Hospitalized patients White male represent the 78% of the prevalent cohort. US population figures for SMR comparisons Survival incident cohort. Poser diagnostic criteria. National mortality statistics used for comparisons Population registry-based study. Death rates compared with the general population

P. Ragonese et al.

1970–1980

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Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 15, 123–127

MS mortality

mentioned because of the methodological differences between the studies in the statistical methods adopted and consequently in reporting the results. Causes of death derived from series of patients, cohorts or population-based studies, all indicate respiratory diseases, infections, cardiovascular diseases and cancers as the most common in patients with MS [21– 25]. While the first three mentioned causes of death seem more frequent in MS patients compared with the general population, cancers are supposed to be equally distributed in patients and referent subjects or, as suggested by some studies, persons affected by MS are at a lower cancer risk [23,25,26]. There is another important issue that official mortality statistics make clear. All the studies performed do not show significant changes in causes of death for MS. Despite the methodological concerns indicated, this is notable because it means that even though efforts have been expended to increase life expectancy of people with MS, the main problem is still represented by the complications arising from the high disability of patients with a longer disease duration.

Life expectancy and survival estimates These studies are mainly based on the natural history cohort of prevalent cases. Table 1 shows a summary of studies indicating mean MS survival and in Table 2 studies reporting SMR and annual mortality rates are presented [17,20,27,28]. Little information is derived from population-based studies and they have several methodological differences and pitfalls. Moreover, sample size is often too small to verify the presence of possible secular trends and to clarify if there exists a real gender difference in survival. Mortality rates reported in those studies indicate a slight although significant increase in mortality of persons with MS compared with the general population. This pattern is homogeneous across studies but, on the contrary, gender differences are often inconsistent.

Table 2 Standardized mortality rates for MS Study

Country

Study period

SMR

Redelings et al. [27] Ekestern et al. [20]

USA Austria

Sadovnick et al. [28] Brønnum-Hansen et al. [17]

Canada Denmark

1990–2001 1970–1979 1980–1989 1990–2001 198–1991 1949–1998

1.44 1.41a 0.96a 0.70a 1.4–1.6 2.89

SMR, standardized mortality rates. a Annual mortality rates.

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Mortality rates and life expectancy seem to change significantly with a tendency to an increased lifespan and reduced mortality in recent years. This may simply be an artefact. Recent studies are in fact more homogeneous and may indicate different and longer survival of MS patients simply because of better case findings, different diagnostic definition and earlier diagnoses. However, the impression of a longer survival, observed in more recent studies, is encouraging, indicating improved cure of MS symptoms and treating complications arising from high disability in the advanced stages of MS. A particular example of MS prognostic study is represented by the nation-wide Danish study [16]. The reported standardized mortality ratios (SMR) – which is the proportion of deaths caused by a disease compared with those expected in the general population – in women was slightly higher (SMR 3.14; 95% CI 3.01– 3.27) compared with that in men (SMR 2.66; 95% CI 2.54–2.78). The median survival time reported was 28 years for men and 33 years for women. The reduced life expectancy with respect to that of the general population ranged between 10 and 12 years. Long-term survival trends tend to improve during the decades although they remain significantly higher in MS patients compared with the general population. This effect may be due to the increased MS frequency observed and, at the same time, to the changing mortality in the referent population. If incidence and prevalence of MS increase as a consequence of death rate calculations, we would probably observe a parallel increase in mortality rates particularly in that population with a decline in the general population mortality. Such an effect has been observed in other studies like those in Austria and in Italy [2,20]. This sort of artificial effect would have also some influence on gender-specific mortality rates. To our knowledge, only one study explored the possible effect of familial aggregation on MS survival, showing no differences between familial and non-familial cases regardless of the degree of familiarity [21]. When analysing all studies, gender differences remain an unresolved matter. Several authors suggested that mortality was higher in men compared with that in women because a higher proportion of men have disease onset in more advanced ages (nearly 40 years), and this often corresponds to a progressive course from the onset. In contrast to this common view there are two considerations: first, the few studies which included a multivariate analysis revealed mortality rates for men modified by the age at disease onset independently from the kind of the onset; second, gender-specific mortality, particularly in studies which are not population-based, is influenced by a possible selection bias of patients with a benign course and by gender-specific mortality rates


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and causes of death [27–33]. The rate of inclusion of patients with a benign course of course significantly influences the results of many studies, as they can improve by many years the overall survival of an MS cohort. As already mentioned, many studies performed in the past are based on data derived from death certificates. This instrument gives us information at a low cost. Unfortunately, recently published studies indicate that for diseases with a long-term survival prognosis such as MS, these information have a low accuracy (nearly 50%), do not represent the trend of the investigated disease in the whole population of patients affected by the disease, and do not consequently allow reliable international comparison of the results [3]. Other than methodological issues, generating difficulties in comparisons of studies, the clinical heterogeneity of MS itself limits in some way the internal and external validity of prognostic studies. Although the clinical aspects of the disease have been well studied, the current use of descriptive terms has changed over time. Difficulties still exist in comparing studies performed in a wide range of decades. The matter of the question relies just on the comparability of studies whose diagnostic criteria encompass so many years and on the inter-observer concordance in the definition of the clinical course. Moreover, the clinical characteristics of MS patients included in clinical trials are often different from those included in population-based studies and in natural history studies. For these reasons an accurate classification of patients, based on international consensus, is needed to allow the comparability of results. New therapeutic opportunities originating from the so-called Ôdisease-modifying drugsÕ come into view in different terms if we look at MS prognosis. Concerns on safety and tolerability, particularly for long-term treatment and for combination therapies comprising immunosuppressors are not still resolved. Studies on disease modifying drugs for MS, which are still in the experimental phase motivate once more the need to keep more attention, in front of a disabling but not lethal disease, to the possible long-term side effects of the possible therapeutic alternatives. It will be more difficult to verify the long-term efficacy of treatments based on robust end-points such as survival, if we miss the possibility of comparisons with studies performed prior to the introduction of new therapies.

Conclusions Despite the limits in comparisons between studies performed with different methodologies, several inferences can be drawn. First, mean survival is reported to be long, ranging from 20 to nearly 45 years from the onset

of disease symptoms. The number of years of life lost ranges between five and 10. Second, there are no significant differences in survival between familial and non-familial cases. The difference between men and women determined as regards age at onset of symptoms, gender distribution of clinical characteristics at onset, and disease course has not yet been definitely resolved. Secondary progressive and mostly, primary progressive patients have in fact a shorter survival as it happens for patients with more functional systems involved at the onset. Finally, MS is not lethal by itself but death is the result of remarkable disability, increasing age or concurrent diseases. Treatments adopted to improve MS symptoms and to prevent and cure complications in more disabled persons, are supposed to determine an improved survival in persons with MS. On these bases, future treatment options should consider safety and long-term effects of the chosen drug. The cure of MS complication caused by disability, and physical and rehabilitation therapy are needed in advanced stages of the disease not only as palliative care but also to improve life expectancy and quality of life. Future studies should take into account these recommendations. Population-based survival studies will be of outstanding importance for evaluating longterm MS prognosis differences yielded by new treatments.

Disclosure This study was financially supported by the Cesare Serono Foundation. The Serono Foundation approved and funded the research but had no role in the study design or the conduct of the research, nor has it any say over the results of the research.

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