Abstract
Article abstract-A systematic review of the neurologic literature identified 433 cases of pathologically proven multiple system atrophy over a 100-year period. Earlier case reports included patients younger in age with more frequent cerebellar involvement. Mean age of onset was 54.2 years (range 31 to 78) and survival was 6.2 years (range 0.5 to 24). Survival analysis showed a secular trend from a median duration of 4.9 years for publications between 1887 and 1970 to 6.8 years between 1991 and 1994. Older age of onset was associated with shorter survival; the hazard ratio for patients with onset after 60 years was 1.8 (95% CI 1.4 to 2.3) compared with patients between 31 and 49 years. Cerebellar features were associated with marginally increased survival (6.1 years versus 5.4 years; p = 0.04). There were no differences in survival according to gender, parkinsonian, or pyramidal features or whether the patient was classified as striatonigral degeneration or olivopontocerebellar atrophy type. These results demonstrate the poor prognosis for patients with multiple system atrophy but may be biased toward the worst cases. Future research needs to recruit more representative samples.
NEUROLOGY 1997;48: 384-393
Multiple system atrophy (MSA) is increasingly recognized as a common cause of atypical parkinsonism. Most MSA patients respond poorly to levodopa therapy, and almost all develop some degree of autonomic failure, often preceding the onset of motor disturbance. [1,2] Cerebellar and pyramidal signs are each observed in about 50% of patients. Compared with idiopathic Parkinson's disease (IPD), there is much faster disease progression, with death occurring in recent clinical series on average 8 to 10 years after disease onset. [1,3] The natural history of pathologically proven MSA appears even more devastating, probably due to selection bias toward severely progressive cases. The mean survival period in a previously reported series of 188 pathologically confirmed literature cases was only 6 years. [4] However, there is considerable range of survival in individual MSA patients ranging from 2 to 20 years in a recent series of 100 clinical cases. [1] The various factors predicting survival in MSA are currently not established, although one study suggested gender differences and age at disease onset. [1] Another smaller study noted that striatonigral degeneration (SND) cases fared worse than olivopontocerebellar atrophy (OPCA) cases. [3] We performed a survival analysis of more than 400 pathologically proven MSA cases from published literature reports and from the UK Parkinson's Disease Society Brain Bank (UKPDSBB) to determine whether clinical features predicted survival. The results of our analysis may be of importance for counseling patients with MSA.
Methods.
Case selection and definition.
Cases reported up to February 1995 were identified using MEDLINE and searches of published reference lists. [5] The minimal pathologic criteria (modified from [4]) for inclusion in the study were degenerative cell loss and gliosis in any two of the following sites, substantia nigra, putamen, inferior olives, pontine nuclei, or cerebellar Purkinje cells, or the additional presence of characteristic glial and/or neuronal inclusions, for cases published after 1989. The minimal clinical criteria are outlined in Table 1.
Table 1. Proposed clinical diagnostic criteria for multiple system atrophy
Classification of clinical features.
The clinical subtype of MSA was retrospectively classified according to the predominant motor impairment (i.e., parkinsonism or cerebellar signs) (see Table 1). If both had been recorded in life but parkinsonism predominated, or if there was parkinsonism without cerebellar signs, such cases were classified as predominant or pure SND. Conversely, cases with predominant or isolated cerebellar involvement were labeled as predominant or pure OPCA. These designations do not take into account the additional presence of autonomic failure or pyramidal signs. Thus, for example, many cases of pure SND or OPCA also had autonomic failure or pyramidal signs, or both. In keeping with the recent trend to divide MSA cases according to their predominant motor disorder (parkinsonian or cerebellar), a separate category for dysautonomic MSA was not used because recent studies [1] showed that some degree of dysautonomia, if sphincter disturbance is included, almost invariably develops and because other signs in addition to autonomic failure are necessary to make a clinical diagnosis of MSA.
Many cases of idiopathic late-onset cerebellar ataxia never develop additional neurologic dysfunction. The presence of additional parkinsonism or pyramidal signs suggests more widespread pathology corresponding to sporadic OPCA (sOPCA). However, not all cases of sOPCA necessarily have MSA. Clinically, the presence of additional autonomic failure appears to be the best indicator of MSA. [6] Using the case definitions chosen for this study, we attempted to exclude cases of ILOCA. However, some cases of sOPCA that did not have MSA, particularly from the pre-glial cytoplasmic inclusions era, may have been included.
If no mention of a clinical feature could be found in the report, then the feature was coded as absent. The number of subjects with a feature should be treated as a conservative estimate. Although we selected only those cases from the literature with adequate clinical data, the completeness of the clinicopathologic reports varied considerably, and this should be kept in mind when interpreting the results.
Autonomic failure was arbitrarily defined as any one of the following four symptoms: urinary incontinence, urinary retention, fecal incontinence, or syncope. Impotence was defined as a further symptom of autonomic failure in male patients. However, neither impotence nor postural faintness alone were sufficient for autonomic failure. Despite defining autonomic failure in this traditional way, it should be stressed that much of the sphincteric disturbance does not represent pathology in the autonomic nervous system per se. Akinesia (usually with rigidity) was required for a diagnosis of parkinsonism and tremor alone was neither obligatory nor sufficient for a diagnosis of PD. Cerebellar signs comprised gait or limb ataxia or dysmetria. Nystagmus intention, or terminal tremor alone were insufficient for cerebellar signs of PD. Pyramidal signs included unilateral or bilateral extensor plantar responses or equivocal plantar responses together with hyperreflexia, spasticity, or both.
Definition of survival time.
Length of survival was estimated by calculating the difference between age at death and age at onset of symptoms. In most cases, these two figures were given as integers, and thus the survival was similarly a whole value. Most cohort studies measure exact dates of death, usually from a death certificate for a more precise estimate of survival. For example, a subject may have had disease onset at age 50 years and died at 55 years; hence, survival was 5 years' duration. In reality, this survival could actually vary between 4.01 to 5.99 years. Although using our crude data will not affect mean values, it will artifactually result in large changes to the survival probability at every year of follow-up. It will also make the 95% CIs for the median survival less precise. To compensate, we added or subtracted a value between 0 and 1, using a random number generator to all observations. One result was 0 years of survival because the subject died in the same year as apparent onset; we reclassified this as 0.5 years survival.
Statistical analysis.
Differences between values were tested using the chi-square test, and ANOVA was used for mean differences. Survival was examined graphically using Kaplan-Meier plots and differences between various subgroups tested using the log-rank test. Cox's proportional hazard modeling was used to calculate the hazard ratios and 95% CIs for clinical subgroups. Assumptions of proportionality were tested by including an interaction term for log-time. [7] The mean values of duration were checked both with and without the random value, and all significant results from the nonparametric analysis were repeated on the raw data.
Results.
One hundred seventy-one reports relating to 445 cases were identified up to February 1995 (see appendix for a complete list of references). Twelve cases of multisystem degeneration were not deemed MSA and were therefore excluded. The survival analysis is thus based on 433 MSA cases including 38 cases collected at the UKPDSBB. Some of the clinicopathologic features were previously published. [8]
The mean age of onset was 54.2 years (SD 9.0, range 31 to 78), and the mean age of death was 60.5 years (SD 8.7, range 34 to 84). Mean survival was 6.2 years (range 0.5 to 24) and skewed to the right.
The number of reported cases started to increase around the mid-1960s, and the median date for all publications was 1986. Table 2 shows the distribution of demographic and clinical features for the whole sample by year of publication. Contemporary patients were more likely to have autonomic and parkinsonian features documented, and this is reflected in the greater proportion of SND-type patients. Patients in the early reports (1887 to 1970) were also younger at presentation. Pyramidal features showed no consistent trend over time.
Table 2. Demographic and clinical features of series by year of publication
(Table 3) shows the relationship between demographic data, clinical features, and survival. The relationship between age of onset and the probability of death is illustrated by the Kaplan-Meier plot shown in Figure 1. The only significant predictors of increased survival were younger age at onset, more recent publication, and the presence of cerebellar features. The latter was of borderline significance, and there was no significant difference between OPCA and SND patients although there was a trend for OPCA patients to have longer survival. Similarly, patients presenting with more than one clinical feature (parkinsonism, autonomic, cerebellar, pyramidal) had worse survival, but this again failed to reach significance (p = 0.09). These results were not altered by repeating the analysis with the raw data. The secular change in survival of 1.5 years between 1971 and 1980 and 1991 and 1994 is comparable but slightly less than changes in life expectancy for the general population. Routine mortality statistics from the United Kingdom show that changes in life expectancy for 55 year olds over the same period has improved by 2.4 years for men and 1.9 years for women.
Table 3. Years of survival according to various demographic and clinical features
Figure 1. Kaplan-Meier plots showing probability of death for cases published after 1980 for (A) striatonigral type and (B) olivopontocerebellar type of cases diagnosed with MSA.
Age of onset did show a significant interaction with time in the proportional hazard model (p = 0.002). This indicates that the hazard ratio is not constant over time and that the difference between age groups diminishes with further follow-up.
Because publication between 1887 and 1970 was associated with younger cases, the relationship between age of onset and survival could be confounded by the secular trends. We therefore repeated the analysis both using multivariate modeling and then running the analyses to exclude all cases before 1971. The hazard ratios were hardly altered when age at onset, publication period, and cerebellar features were included together in a multivariate model (odds ratios in parentheses): 50 to 59 years (1.7), 60 years or older (2.0), cerebellar features present (0.79), publication between 1887 and 1970 (1.9), 1971 and 1980 (1.7), 1981 and 1990 (1.4). Excluding early reports, the median survival for each age group was increased (6.9 years, 6.1 years, and 5.5 years), but the relative hazard was unaltered.
Discussion.
This large series of pathologically confirmed cases indicates the poor prognosis of MSA patients with a mean age at onset of 54 years and a mean survival of around 6 years. Although there is marked individual variation in survival, with extremes of less than 1 year to 24 years, on average this reflects from 13 potential years of life lost for men and 18 years of potential years of life lost for women. The prognosis is far worse than for IPD and stresses the importance of recognizing MSA clinically so that a realistic prediction of survival can be made. However, this may be exceedingly difficult in those patients that closely mimic IPD. [9]
Survival in this study was far worse than in our previous results from a clinical series of MSA patients (9.5 years). [8] Several variables need to be considered to explain these differences. First, this meta-analysis covers a 100-year period with obvious secular changes in general survival. Even recent case reports will be, by definition, largely retrospective and reflect the survival experience of cohorts with onset between 1 and 15 years ago. However, it is unlikely that the 2.7-year difference for the most recent case reports could be explained solely by general secular changes. Second, clinical cases that subsequently come to autopsy often reflect atypical or more severe disease, resulting in an artifactually reduced survival time. For example, a good prognosis MSA case masquerading as an IPD patient is less likely to have a postmortem. Third, autonomic symptoms often appear several years before the onset of motor symptoms in MSA patients. In older reports, their significance may well not have been appreciated, so that disease onset was estimated solely from initial motor symptoms. In our recent clinical series, the careful elicitation of autonomic symptoms on history enabled us to detect onset at an earlier stage with a corresponding increase in survival from first symptom. This is analogous to "lead-time bias" observed in screening programs, where cancer survival is apparently extended simply by detecting disease at an earlier stage in its natural history. Fourth, there is a possibility that modern more aggressive management of the disease may have improved life expectancy. Finally, it is possible that some patients in the clinical series might have been erroneously diagnosed and could possibly be atypical cases of IPD, with a better prognosis. However, all 14 cases from the clinical series that have so far come to autopsy have had MSA confirmed pathologically.
Similar to our clinical series, we observed that older age of onset was associated with shorter survival as also reported in IPD patients. However, this does not mean that it is better to be a young patient with MSA than an old one, as the relative loss of potential years of life is far greater at younger ages, suggesting that aging may interact with the underlying pathologic processes. We could not confirm any gender difference in survival, which we had previously noted in our clinical series. We previously proposed that such a difference was probably artifactual due to disease onset being recognized at an earlier stage in male patients because of autonomic symptoms such as impotence. [10] This hypothesis is supported by the absence of gender difference in this current analysis, as we believe that subtle autonomic symptoms are less likely to have been identified and reported in the older literature. Instead, estimates of disease onset would be more likely to be based on motor symptoms, which should not be differentially affected by gender. Our data support the possibility that cerebellar features are associated with a better prognosis, but this difference is small and of borderline significance. Similarly, patients with more than one clinical feature at presentation appear to do slightly worse.
Although OPCA was firmly established in the neurologic literature in 1900, [11] it was not until the 1960s that investigators realized that some patients with predominant or pure parkinsonism did not have idiopathic or postencephalitic Parkinson's disease but instead had striatonigral degeneration with varying degrees of additional OPCA postmortem. [12,13] Moreover, it was only several years after the introduction of levodopa treatment in 1967 that poor or absent clinical response to levodopa pointed to nonidiopathic disease. Finally after parkinsonian brain banks were established, it was evident how commonly parkinsonism is due to MSA (3.6 to 22%, mean 8.2% of all brains received). [4] These factors together are probably sufficient to explain the shift in emphasis from predominantly OPCA to SND cases of MSA over the last 25 years.
We conclude that the prognosis for MSA patients is poor, although it has improved over the last 100 years. Because of the relatively young age at onset, it dramatically reduces life expectancy. Differentiating MSA from IPD is important to help patient management and to give realistic information on prognosis. However, the impression given in the pathologic literature may be unrepresentative, in particular giving a worse prognosis than is found in clinical series, as the former tends to bias results toward the most severe cases and to neglect early autonomic features preceding motor symptoms and signs. Future epidemiologic studies need to recruit more representative MSA patients from nonspecialist settings, such as primary care. It is only in this way that we will obtain a more accurate picture of the true natural history of this disease.
Appendix.
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- Copyright 1997 by Advanstar Communications Inc.
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