Brain, Vol. 123, No. 3, 641-649,
March 2000
© 2000 Oxford University Press
Invited review |
The natural history of multiple sclerosis: a geographically based study
8: Familial multiple sclerosis
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
Correspondence to:
Dr G. C. Ebers, Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK E-mail: george.ebers{at}clneuro.ox.ac.uk
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We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.
multiple sclerosis; familial outcome
DSS = Kurtzke disability status scale; PP = primary progressive; RR = relapsing–remitting; SP = secondary progressive
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Introduction |
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The cause of multiple sclerosis remains uncertain, although recent evidence has solidified the view that both genetic and environmental factors determine susceptibility (Ebers and Sadovnick, 1994
). There is very strong evidence from the classical tools of genetic epidemiology that familial aggregation is determined by multiple genes. This includes data from twins (Ebers et al., 1986; Sadovnick et al., 1993; Mumford et al., 1994), adoptees (Ebers et al., 1995), half-siblings (Sadovnick et al., 1996) and the offspring of conjugal pairs (Robertson et al., 1997). The gradual reduction in risk as one goes from first- to second- to third-degree relatives supports early suggestions that multiple sclerosis susceptibility is polygenic (Pratt et al., 1951; Ebers et al., 1982; Ebers, 1983; Ebers and Sadovnick, 1994). However, the search for specific chromosomal regions or genes which underlie the basis of familial aggregation has had limited success to date.
Although the specific factors determining susceptibility remain indeterminate, there is certainty that the clinical and pathological phenotype is variable in the extreme. There is little reason to be confident that multiple sclerosis represents a homogeneous and discrete entity. Even the age of onset can span more than five decades in large population-based samples (Weinshenker et al., 1989). Nevertheless, the difference in disability outcome, which can range from non-existent in asymptomatic multiple sclerosis discovered at autopsy to a disease that is fatal in <12 months, is readily demonstrable in multiple sclerosis surveys.
It would not be surprising if it were concluded that genes play a role in outcome, although little direct evidence has been put forward to support this view. If multiple sclerosis is a heterogeneous group of disorders, the resolution of the problem of susceptibility will be difficult by conventional methods. The identification of discrete subgroups of multiple sclerosis would have implications both for genetic studies and for the understanding of factors determining outcome. The subdivision of patients by clinical or demographic features is a familiar approach and is easily done, although it lacks established biological meaning.
We report a comparison of the long-term outcome in familial and sporadic multiple sclerosis based on a large population-based sample in which we search for heterogeneity in outcome. Observations of this population have been reported previously with respect to short- and intermediate-term outcome up to 1984 (Weinshenker et al., 1990). For patients with familial and sporadic multiple sclerosis derived from the same population-based sample, we report here an evaluation of the long-term clinical outcome up to 1997. Long-term observations provide three clear advantages in such a comparison. Since multiple sclerosis has a relatively discrete age of onset curve, in which risk is strongly related to age, the recognition of familial and non-familial cases becomes much more definitive with time, and the recurrence risk for colineal relatives requires little or no correction for age. In addition, long-term survival curves of populations destined to differ in outcome have had the opportunity to diverge, thereby enhancing the opportunity to show differences. Finally, disability outcomes in the long term are advanced, unambiguous and of undeniable clinical relevance. In this population, more than half of the patients were confined to bed or chair, or were dead.
The observations reported here serve the following purposes: (i) they establish the frequency of familial multiple sclerosis in a large population base; (ii) they test the hypothesis that familial multiple sclerosis is different phenotypically from sporadic disease; (iii) they document the clinical outcome for familial multiple sclerosis in this population-based sample; and (iv) they test the validity of age-correction of empirical recurrence risks in families by identifying actual rates of recurrence in relatives of both sporadic and familial cases.
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Methods |
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Study population
From 1972 to 1984, a cohort of 1099 consecutive patients was followed at the multiple sclerosis clinic at University Campus, London Health Sciences Centre, London, Ontario. With continued follow-up now reaching a mean of 25 years, the long-term natural history of multiple sclerosis in this population continues to be described (Cottrell et al., 1999a
, b; Kremenchutzky et al., 1999). From the original cohort, 1044 patients were evaluated for outcome. Some 55 patients were excluded for the following reasons: (i) 15 duplicates were not recognized initially because of name changes; and (ii) 40 patients were found not to have multiple sclerosis. The great majority of the latter represented possible cases in whom multiple sclerosis was initially thought to be the most likely diagnosis but who proved to have other conditions on follow-up. (Cottrell et al., 1999a). This patient population was seen on a more or less yearly basis, although this proved to be increasingly difficult with increasing disability of the patients, and largely ceased when they became bed-bound. Efforts were made to follow them up in nursing homes where possible, although this was usually restricted to a single occasion. It was possible to trace the great majority of these patients at the most recent systematic follow-up in 1997, although some of the highest disability levels had to be determined by history for the most disabled patients. Almost a third of the patients had died by the time of this final evaluation.
During the nearly three decades of the clinic's operation, patients have been routinely and serially asked about the occurrence of multiple sclerosis among their family members. At the time of the last systematic global follow-up between the years 1995 and 1997, all surviving patients were again questioned about the existence of multiple sclerosis in their families. This was of doubtful value in those who had lost cognitive function to a degree that made it difficult for them to comply, and was of low yield and/or unverifiable in those who had little or no contact with their families. Accordingly, familial rates reported were certain to be underestimated to some extent, the more so for the more distant relatives.
A more detailed description of the general methods used in following this population has been described elsewhere (Weinshenker et al., 1990; Cottrell et al., 1999a). For the purposes of this study, however, patients reporting an affected family member were asked for further documentation (i.e. records), with the consent of such a member when this was possible. For patients or affected relatives who had died, medical records were obtained. Affected relatives were also seen frequently at the clinic, although they were only rarely part of the 1044 patient cohort, most often because they were seen before or after the accrual period of 1972–84, or lived elsewhere.
As in other papers in this series, a separate analysis was performed for the Middlesex County cohort, a restricted epidemiological subgroup (Hader et al., 1988) with high ascertainment and almost complete follow-up. At 25 years, only seven out of the 203 patients in this subgroup were untraceable. The low rate of out-migration of area families was helpful. Pedigree size and age of relatives were identified for all probands.
The diagnostic criteria were those of Poser and colleagues (Poser et al., 1983). Other heredofamilial disorders, especially system degenerations commonly confused with multiple sclerosis, are seen on a weekly basis in the multiple sclerosis clinic. A low threshold for recognizing such disorders has existed since the early days of operation of the clinic. In an early study on multiple sclerosis sib-pairs, we restricted analysis to those having at least one affected individual with optic neuritis, internuclear ophthalmoplegia or oligoclonal banding in the CSF (Ebers et al., 1982), but we did not demand this from patients in this series since diagnostic ambiguities were pointedly resolved as a background for collecting natural history data.
The total multiple sclerosis population was somewhat arbitrarily divided into the following categories, as previously described (Weinshenker et al., 1990): (i) sporadic multiple sclerosis: no affected relatives identified; (ii) first degree: a single affected first-degree relative; (iii) first degree plus: multiple affected relatives including at least one first-degree relative, as previously described; (iv) second or third degree: one or more affected second- or third-degree relatives.
Statistical analysis
All analysis was performed using SAS (SAS Institute, Cary, NC, USA). Survival analysis was performed with SAS/LIFE TEST using the life table (actuarial) method with intervals of 1 year. In this analysis, patients who had not yet reached the given Kurtzke disability status scale (DSS) level but who had been followed for a known period of time were included as right-censored. The log-rank statistic was used to test the significance of the equality of survival distributions.
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Results |
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Demographic characteristics
The demographic characteristics of the four subgroups of multiple sclerosis patients derived from the original cohort are summarized in Table 1
. Eight hundred and thirty-six patients had sporadic disease and 208 had familial multiple sclerosis according to the definitions which have been outlined. There was a relative excess of males in the first-degree group and even greater excess in the first-degree plus group, although this fell short of statistical significance. The mean age of onset was similar among the four groups, as was the mean duration of multiple sclerosis. Small numbers of patients in each group remained as possible cases. In all groups, these were patients in whom follow-up was truncated by death or loss to follow-up. The Middlesex County cohort enjoyed a 97% follow-up rate (mean 25.9 ± 8.6 years) and only one patient remained `probable'.
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Initial presentation and clinical course
The initial symptom(s) among the four groups did not differ substantially. Optic neuritis was somewhat more common among the first-degree plus group but not more common when the first-degree group was compared with the second-/third-degree subgroup (Table 2
). The relative frequencies of clinical course were also rather similar among the different groups subclassified as having primary progressive (PP), secondary progressive (SP) and relapsing–remitting (RR) multiple sclerosis, although the percentage of patients with primary progressive disease was slightly lower in the first degree plus subgroup (Table 3).
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Early relapse and disease progression
Following the initial exacerbation, the likelihood of relapse in the first and second year of disease, the interval between the first and second attack and the time to onset of progressive deficit in those patients with secondary progressive disease were identified for each of the four subgroups (Table 4
). The likelihood of a second attack in the first 2 years was lower in the primary plus subgroup, the interval between the first and second attack was greater, and there was a longer time to onset of progressive deficit in this group. These differences approach statistical significance or are of borderline significance (Table 4) only when correction for multiple comparisons is forgone.
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Outcome
Initially we compared survival curves for each of the four subgroups as given in Fig. 1
for times to DSS 3, 6, 8 and 10. Visually, these show little difference within any pair of comparisons or when survival curves are compared for all familial cases versus all sporadic cases (Fig. 2). Next we compared patients with the clinical phenotypes of RR and PP disease between and among familial groups. Survival curves for time to DSS 3, 6, 8 and 10 for (i) familial RR versus sporadic RR, and (ii) familial PP versus sporadic PP were derived (the data are not shown but are available from author G.C.E.). Little difference was noted among these pairwise comparisons. The number of patients for each comparison and the P values for differences between them are given in Table 5.
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Middlesex County cohort
In the Middlesex County cohort (n = 203) there were 16 affected siblings among full brothers (mean age 56.23 years, range 31–95 years) and sisters (mean age 56.00 years, range 27–80 years) (total sibs, n = 451) of clinic probands. This gives an observed recurrence risk of 3.5% and, with a slight adjustment for remaining risk, suggests a final rate of ~4.0%. The breakdown for this cohort among the four identified subgroups is given in Table 6
. The overall observed familial rate of 22.8% (Table 6) is slightly higher than the overall rate of 19.9% for the entire population, perhaps because of slightly better follow-up in this cooperative subgroup (Ebers, 1983).
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Discussion |
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We have examined long-term outcomes in 1044 multiple sclerosis patients from a largely population-based sample having a mean follow-up of 25 years. The extended clinical follow-up of this population has allowed the evolution of widely diverging survivals for times to DSS 3, 6 and 8 and death from multiple sclerosis. Furthermore, at least for colineal relatives, much of the risk for being identified as having multiple sclerosis had elapsed. These factors should have enhanced the ability to detect differences in outcome between familial and sporadic disease, a comparison which was the primary focus of this study. The results establish a natural history for the ~20% of patients identified as having familial disease. These observations, from a sample in which detailed natural history observations have been made previously, indicate that patients with familial disease have a clinical course which differs little from those whose disorder remains sporadic even after several decades of follow-up. Accordingly, they provide little or no support for the hypothesis that familial multiple sclerosis is a disorder distinct from the more common sporadic variety.
The high familial rate identified in this study (22.8% in the Middlesex County cohort) supports the indications from previous population-based studies in which relatively high familial risks were derived from age of onset curves compiled from general multiple sclerosis population data (Sadovnick et al., 1988; Robertson et al., 1996a; Carton et al., 1997). Given the relatively low concordance of age of onset in non-twin sibs with familial disease (Doolittle et al., 1990; Bulman et al., 1991) it would be expected that population-based correction would suffice. However, the sib-pair data were based on smaller numbers, and it should be apparent that even in a study with a long follow-up there is potential for ascertainment to bias results towards age of onset concordance. For example, it can be appreciated that concordant pairs with late onset in one member would tend to be under-represented. This problem would be most evident with short follow-up and the effect should wane with time, assuming similar likelihood of ascertainment over the period of observation. Examination of the Middlesex County cohort, in which long-term follow-up has been the most comprehensive, serves to specifically validate previous descriptions of recurrence risk for first-degree relatives derived from different populations within Canada. In this and three other Canadian sites, familial recurrence risks of 
20% have now been found (Hader, 1997; Sadovnick, 1988; T. J. Murray, personal communication).
We recognize limitations in the identification of familial rates. These are likely to be most accurate for the Middlesex County subcohort. However, in patients who had long since died, the reporting of familial occurrence stopped at the time of their last evaluation in the clinic, although the awareness of their death may not have come until many years later. Since very few patients were lost to follow-up in Middlesex County, there was no bias or selection for familial multiple sclerosis, and these results should give the closest approximation to the actual risks for sibs and for offspring. We have not attempted to ascertain the recurrence risks for parents, given the diagnostic difficulties inherent in going back one or two generations. The first neurologist in London, Ontario did not arrive until the early 1950s. Although several studies show that there are clinical, pathological and MRI features which are relatively different between PP, RR and SP multiple sclerosis (Thompson et al., 1997), we found little correlation of phenotypes within multiple sclerosis families using this simple classification. The phenotype of the index case had little or no influence on the phenotype of the affected relative (Kremenchutzky et al., 1999), confirming our earlier observations (Weinshenker et al., 1990) and subsequent observations from the UK (Robertson et al., 1996b). These findings establish observation-derived risks which are applicable at least to our Canadian population.
The familial recurrence risks identified in this paper are likely to represent an underestimate, since ascertainment occurred most often through the reporting by multiple sclerosis clinic probands of the occurrence of affected relatives (either in response to repeated surveys or spontaneously). The independent ascertainment of relatives of other index cases within the London multiple sclerosis clinic system has been frequent, and commonly this is unknown to the originally ascertained individual. We have observed that there remains a mean duration between clinical onset and diagnosis of some 3–4 years, typically most evident in the later-onset cases (Cottrell et al., 1999a), and we estimate that, on average, an additional period of 4 years elapses between the diagnosis of the second member of a family to be affected and the awareness of this by the first. Although this additional period is highly variable, these observations have implications for correction for age of onset since this refinement makes the now unwarranted assumption that onset would be synonymous with recognition by all previously affected family members.
We have not corrected for doubly ascertained family members. Recalculation of proband-wise concordance rates (recurrence risk) would elevate the observed crude risks. This determination is problematic since the presence or absence of complete ascertainment is a much more graded determination in practice. Even in our strictest epidemiological sample, the Middlesex County population, ascertainment is incomplete and correction for this could only be approximated. Finally, we are aware that examination and investigation of family members may identify another cohort of affected relations who are not known to the proband, or are even aware they have test results which are seen in multiple sclerosis (Ebers, 1983; Duquette and Charest, 1986; Lynch et al., 1990; Duquette; 1991)
The outcomes were examined in several ways, including the comparison of all sporadic with all familial cases, and were similar. Such comparisons are weakly powered to show a difference when done early in the clinical course. Many patients who are described as sporadic early on will eventually have affected relatives. Similarly, benign or adverse outcomes identified in the early years of disease are only moderately predictive and commonly change when viewed in long-term retrospect. Accordingly, we view these results at 25 years as being nearly definitive for the total group of familial versus sporadic cases. Most patients in this study have reached the hard outcomes of DSS 6, and most of those who have not may never do so. Many have gone to DSS 8 and 10 and the comparative data for the familial versus the sporadic groups would appear to exclude only a small difference in clinical course. However, the power to address this question is probably not great among the four specific small subgroups of familial disease. We cannot exclude there being small subgroups with clinical outcome which could differ materially from that of sporadic patients. Furthermore, we recognize that our grouping of familial cases is somewhat arbitrary and is unfounded in any known difference in pathogenesis. However, some modest trends support the observations that, among individuals with a single affected parent and having early age of onset, a higher familial risk combined with earlier age of onset, on average, is present. These findings support previous observations (Sadovnick et al., 1997). Families with high recurrence risks were found to have a lower age of onset in the proband (Sadovnick et al., 1998). This does not show up in the mean onset ages of our subgroups but is present when we used the divisions applied by Sadovnick and colleagues (Sadovnick et al., 1998) (data not shown). A modestly more benign outcome of the first degree plus group early in the disease occurred in the presence of an excess of positive prognostic features. These included a higher frequency of onset with optic neuritis and a longer inter-attack interval.
Although demographic features were very similar among the different groups, the elevated male : female ratio in the group which putatively includes the most heavily genetically loaded families is consistent with previous suggestions that this should be expected in polygenic disorders (Childs and Scriver, 1986). This prediction for complex traits was theory-based. A heavier than average background of susceptibility factors in families identified by having more affected relatives should lower the threshold for the more resistant sex (males in the case of multiple sclerosis). Relatively little concordance in clinical phenotype within families was found, as previously reported (Weinshenker et al., 1990; Robertson et al, 1996b; M. Kremenchutzky and G. C. Ebers, unpublished results). The distribution of phenotypes, time to onset of progressive deficit and survival curves for times to EDSS 6, 8 and 10 were remarkably similar between familial and sporadic cases. At least in this analysis there appears little rationale to justify considering adequately evaluated familial cases as a separate entity or as unsuitable for entry into clinical trials of therapeutic agents.
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Acknowledgments |
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We thank Lamia Abid, Tracey Bentall, Doris Bucciarelli, Cristina Goia, Jennifer Moussa, Rita Schuhmacher and Mary Van de Ven for their help and the Multiple Sclerosis Society of Canada for their financial support.
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Received June 10, 1999. Revised August 25, 1999. Accepted September 9, 1999.
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 C. J. Willer, D. A. Dyment, N. J. Risch, A. D. Sadovnick, and G. C. Ebers Twin concordance and sibling recurrence rates in multiple sclerosis PNAS, October 28, 2003; 100(22): 12877 - 12882. [Abstract] [Full Text] [PDF]
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 J. S. Burks, B. G. Arnason, P. K. Coyle, C. C. Ford, A. Noronha, and K. W. Rammohan Issues and Practices in Multiple Sclerosis Neurorehabil Neural Repair, December 1, 2002; 16(4): 307 - 320. [Abstract] [PDF]
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D. A. Dyment, M. Z. Cader, C. J. Willer, N. Risch, A. D. Sadovnick, and G. C. Ebers A multigenerational family with multiple sclerosis Brain, July 1, 2002; 125(7): 1474 - 1482. [Abstract] [Full Text] [PDF]
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M. G. Marrosu, M. Lai, E. Cocco, V. Loi, G. Spinicci, M. P. Pischedda, S. Massole, G. Marrosu, and P. Contu Genetic factors and the founder effect explain familial MS in Sardinia Neurology, January 22, 2002; 58(2): 283 - 288. [Abstract] [Full Text] [PDF]
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M Siger-Zajdel and K Selmaj Magnetisation transfer ratio analysis of normal appearing white matter in patients with familial and sporadic multiple sclerosis J. Neurol. Neurosurg. Psychiatry, December 1, 2001; 71(6): 752 - 756. [Abstract] [Full Text] [PDF]
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