Epidemiology of Progessive Supranuclear Palsy and Multiple System Atrophy

Transcription

1 Epidemiology of PSP and MSA 23 Epidemiology of Progessive Supranuclear Palsy and Multiple System Atrophy 3 Adam Zermansky and Yoav Ben-Shlomo INTRODUCTION Epidemiology seeks to prevent disease by identifying risk factors, be they genetic and/or environmental, that are of etiological relevance through the use of descriptive studies, natural experiments, and very occasionally randomized trials. In addition, clinical epidemiology can examine the utility of diagnostic tests, determine predictors of disease prognosis, and test whether therapies can modify disease progression. This chapter will focus on descriptive studies that have either measured disease frequency (prevalence or incidence) or estimated the risk associated with environmental exposures. We have chosen to focus solely on progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) as there is hardly any data for other atypical parkinsonian disorders such as corticobasal degeneration or dementia with Lewy bodies. For any uncommon disease, undertaking epidemiological studies presents several major challenges: case identification, representativeness of cases, and obtaining adequate sample sizes. For both PSP and MSA, there are additional problems as both these conditions can be difficult to diagnose. As there are no adequate tests that are both highly sensitive and specific, the gold standard remains the diagnostic expertise of a movement disorders specialist (1). THE PREVALENCE AND INCIDENCE OF PSP AND MSA Measuring the prevalence and incidence of disease serves several important functions. First, each measure enables health planners to estimate the number of existing cases (prevalence) and new cases (incidence) that one would expect to find in a community and hence provide the appropriate health staff required for their care. Second, by comparing age-standardized rates in different populations or over different time periods, one may observe differences, which if not artifactual or merely because of chance, that provide etiological clues and enable the formulation of hypotheses concerning risk factors. Marked changes over time, unless a result of increased disease awareness and hence a greater likelihood of diagnosis, strongly suggest an environmental factor or a genetic environmental interaction. Geographical variations are more complex as they may reflect differences in health services, variations in disease survival if only comparing prevalence rates, methodological differences in study design and/or diagnostic criteria, chance variations, or genuine population differences in genetic and/ or environmental factors. Current consensus diagnostic criteria for PSP and MSA were only published in 1996 and 1999 respectively (2,3). Prevalence studies prior to these dates relied upon heterogeneous groups of published criteria and some used none (or did not state which were used) at all. This makes any interpre- From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan Humana Press Inc., Totowa, NJ 23

2 24 Zermansky and Ben-Shlomo tation of data from such studies even more complex as these different criteria would have had differing sensitivities and specificities (4). Even the current consensus criteria, which at least enable a more standardized approach, have yet to be tested in large-scale representative prognostic cohorts with postmortem-validated diagnoses so their true diagnostic utility remains to be elucidated. Despite these difficulties, such studies provide the empirical basis for suggesting or testing ideas concerning causal agents. Prevalence of PSP and MSA Measures of the prevalence of PSP vary from 0.97 to 6.54 per 100,000 (eight studies) and for MSA from 2.29 to 39.3 per 100,000 (five studies) (Table 1). A study from Sicily (8) reported one of the highest rates of 28.6 per 100,000 but this was for unspecified parkinsonism, so this category may have included cases other than MSA and PSP. The results presented in Table 1 are simple crude rates for the whole population rather than age-standardized rates. Though some studies do report such standardized rates, each study generally uses a different standard population and some studies fail to present age-specific rates making it impossible to restandardize the rates to a single population. The purpose of standardization is to remove any confounding effect owing to the age structure of the population. As all the studies except one from Libya (7) have been undertaken in a developed world population, it is likely that such confounding is not too large. In fact, differences between the crude and standardized rates are often small. For example, the crude rate for the New Jersey study is 1.38 per 100,000 and after standardization this increases to 1.39 per 100,000 (6). In the London study, the crude PSP rate of 4.9 per 100,000 increased to 6.4 per 100,000 (14). However, the incidence rate from Benghazi, Libya, is misleadingly small as a large proportion of this population will be under 55 yr of age and standardizing this rate to a European population will certainly increase this rate by a large degree. Despite the various different diagnostic criteria, the rates for PSP and MSA across all studies are not too dissimilar. One obvious observation is that studies with very large populations, e.g., New Jersey (6) or United Kingdom (15), produce lower prevalence estimates whereas very small populations produce high rates. The effect of varying population size and hence intensity of case finding is most elegantly demonstrated by the Russian Doll Method method employed by Nath and colleagues (15). This general pattern is also well noted with prevalence studies for multiple sclerosis (16). This is unsurprising because, although large populations give precise estimates, they are likely to be biased downward as it is easier to miss a proportion of cases. On the other hand, smaller populations will enable much more thorough case ascertainment and hence less biased but imprecise estimates. The highest prevalence rate (39.3 per 100,000) was observed in a study from rural Bavaria (10). However being based on only three cases in a very small population, its lower 95% confidence interval is still 8.1 per 100,000, which will overlap with most of the other estimates. Almost all the studies except that from Nath and colleagues (15) estimate rates based on 11 or fewer cases, which demonstrates the problem with studying rare neurological disorders. Some studies have specifically aimed to detect cases of PSP and/or MSA whereas others have been generic prevalence studies for parkinsonism. Interestingly, there is little difference between the estimates for these different studies. Perhaps more surprising is that studies that have screened a whole population (9,10) did not find higher rates than those using existing medical records or other databases. It is well recognized in the Parkinson s disease (PD) literature that a proportion of PD cases will be detected de novo by the screening procedure, though this varies across European centers (17). It is possible that this clinical iceberg phenomenon is less important for PSP and MSA because their symptoms and disease progression make them less likely to be undetected. However, studies aimed at parkinsonism may underestimate rates of MSA since cases with predominantly cerebellar features may be undetected. Similarly, excluding patients who became demented before the onset of parkinsonism (14) will assist in the exclusion of dementia with Lewy bodies, in which a supranuclear gaze palsy may occur, but may also exclude cases of PSP.

3 Table 1 Prevalence Studies of PSP and MSA PSP Prevalence MSA Prevalence Lead Author Year of Generic (G) Population Size Case Diagnostic per 100,000 per 100,000 (Ref. No.) Publication or Specific (S) Location (Total Estimated) Ascertainment Criteria (No. of Cases) (No. of Cases) Golbe (6) 1988 S New Jersey, USA 799,022 Neurologists, Clinical diagnosis 1.38* (11) PD support group, aimed at specificity nursing homes Morgante (8) 1992 G 3 areas in Sicily 24,496 Two-phase screening Vaidated screening tool 28.6 (7) but no specific criteria unspecified for PSP, MSA parkinsonism so covers both MSA and PSP as well as other conditions de Rijk (9) 1995 G Suburb of Rotterdam 6969 ( 55 yr) Two phase screening Clinical diagnosis 2.87* (1) 5.74* (2) Netherlands (34,845)* assuming 20% = 55 Trenkwalder (10) 1995 G Rural villages in 1190 (7628) Two phase screening Quinn criteria for MSA 39.3 (3) Bavaria, Germany Wermuth (12) 1997 G Faroe Islands 43,709 Neurologists, GPs, Clinical diagnosis 4.58 (2) 2.29 (1) nursing homes, pharmacies Chio (13) 1998 G Cosatto, Italy 61,830 Neurologists, GPs, Clinical diagnosis 3.23 (2) 4.85 (3) hospital records, pharmacies Schrag (14) 1999 S London, UK 121,608 GP records Quinn criteria for MSA 4.93 (6) 3.29 (4) & NINDS criteria for PSP Nath (15) 2001 S United Kingdom 59,236,500 Neurologist (BNSU), PSP support group NINDS criteria for PSP 0.97 (577) Nath (15) 2001 S North of England Region, UK 2,589,240 Neurologists, care of NINDS criteria for PSP 3.09 (80) the elderly consultants, hospital records & databases Nath (15) 2001 S Newcastle-upon- Tyne, UK 259,998 GP records NINDS criteria for PSP 6.54 (17) *Estimated from paper Epidemiology of PSP and MSA 25

4 26 Zermansky and Ben-Shlomo The study by Schrag and colleagues (14) had an additional important feature in that all subjects that were categorized as unclassifiable parkinsonism, were reevaluated at 1 yr for signs of PSP or MSA. This approach is clearly helpful, as some patients who look like PSP or MSA may not fulfill diagnostic criteria at the time of screening but with further follow-up will develop these features. Incidence of PSP and MSA There are even fewer estimates of incidence and two of these are based in almost the same population (5,11) (Table 2). The relatively low rate from the first paper from Rochester, Minnesota (5), may have reflected less recognition for PSP than in the later study (11). The estimates by Schrag and colleagues (14) are remarkably similar to that by Bower and colleagues (11), though the former are only indirect estimates based on prevalence data and dividing this by the median survival. This was probably a fortuitous coincidence but further studies are required to confirm these rates. Implications From Prevalence and Incidence Data Despite rather limited data, there are no clear signs that there are widespread geographical differences in PSP and MSA, however there are almost no data from developing countries and one cannot exclude that in other populations or ethnic groups there may be higher rates. Atypical parkinsonism has been reported with greater frequency in the Caribbean (18) and among South Asians and African Caribbeans (19) in the United Kingdom, though these latter observations remain controversial. Little obvious differences exist across Europe, as has been noted for PD (17), or North America, yet more higher-quality studies are required especially to estimate incidence rates. RISK FACTORS FOR PSP AND MSA The epidemiology of PD has been greatly aided by two natural experiments that generated important hypotheses regarding its etiology. The first was the encephalitis lethargica epidemic, which suggested a role for an infective agent (20). The second was the strange occurrence of MPTP-induced parkinsonism (21), which suggested the role of a neurotoxic agent and led to studies examining the role of pesticides because of its similarity with paraquat (22). The relevance of these models for the etiology of PSP and/or MSA is far more questionable. However, in the absence of any other clues, most researchers have simply used risk factors that have been suggested to be important for PD, e.g., smoking behavior, head injury, pesticides, well water, etc., and tested them out in PSP and MSA as essentially a hypothesis-generating exercise. Risk Factors for PSP One possible natural experiment has been the study of an atypical form of parkinsonism in Guadeloupe, clinically indistinguishable from PSP, which was prompted by the discovery that an unexpectedly high proportion of parkinsonian patients were unresponsive to levodopa (23). Based upon the hypothesis that some of the herbal tea and tropical fruits consumed in Guadeloupe contain benzyltetrahydoisoquinolones, which are known to be neurotoxic, a case-control study was undertaken (see Table 3). During a 1-yr period, they compared herbal tea and tropical fruit consumption among 87 parkinsonism patients referred to the sole neurological center in Guadeloupe (22 had IPD [idiopathic Parkinson s disease], 31 PSP, 30 could not be classified, and 4 had atypical parkinsonism with motor neurone disease) with 65 hospital inpatients with non-neurodegenerative diseases. They demonstrated a higher consumption of herbal teas and tropical fruits in PSP patients and atypical parkinsonism. This was associated with a fourfold increased risk for both groups compared to controls. Although the confidence intervals for the odds ratios are wide and approach unity, further evidence supporting a causal role for these agents comes from the observation that two of the PSP patients and four of the atypical cases improved significantly after stopping their consumption of these substances, one patient being able to return to work. It remains unclear whether these atypical

5 Table 2 Incidence Studies of PSP and MSA PSP Incidence MSA Incidence Lead Author Year of Generic (G) Population Case Diagnostic per 100,000 per 100,000 (Ref. No.) Publication or Specific (S) Location Size Ascertainment Criteria (No. of Cases) (No. of Cases) Rajput (5) 1984 G Rochester, USA 53,885* Hospital medical Clinical diagnosis 0.29* (2) 0.71* (5) records Radhakrishnan (7) 1988 G Benghazi, Libya 519,000 Polyclinics, hospitals, rehab centers, and neurology dept. Clinical diagnosis 0.29 (6) Bower (11) 1997 S Olmsted County, USA 94,965 Hospital medical MSA consensus 1.12 (16) 0.63 (9) records 1996 & Collins 1995 Schrag (14) 1999 S London, UK 121,608 GP records Quinn criteria for MSA &NINDS criteria for PSP 1.41** 0.46** *Estimated from paper. **Indirect estimates based on prevalence and median survival. Epidemiology of PSP and MSA 27

6 Table 3 Case control studies of PSP and MSA Lead Author Year of Results - Odds (Ref. No.) Publication Design Location Cases Controls Ratios (95% CI) PSP Davis (24) 1988 Case-control study New Jersey, USA 50 cases from 100 hospital controls Finished high school 3.1, neurologists and finished college 2.9, tertiary center rural residence 2.4 Golbe (25) 1996 Case-control study New Jersey, USA 75 cases from tertiary 75 neurology outpatients At least 12 years education center (91 unmatched) excluding neurodegenrative 0.35 (0.12 to 0.96); no difdiseases (106 unmatched) ference by rurality Caparros-Lefebvre (23) 1999 Case-control study French West Indies 31 PSP and 30 atypical 65 hospital controls Fruit or herbal tea 4.35, parkinsonism from (1.25 to 15.2) for PSP, neurology dept. 4.27, (1.22 to 14.9), for atypical parkinsonism Vanacore (26) 2000 Case-control study Mainly Italy but also 55 cases from tertiary 134 relatives of patients Smoking OR 0.91 (0.42 Austria and Germany centers with non-neurological 1.98); no dose-response controls MSA Nee (27) 1991 Case-control study USA 60 cases from NINDS, 60 controls from spouses, College education 0.39 newsletters, or private friends, and volunteers ( ); significant doctors associations with metal dust and fumes 14.8, pesticides 5.8, plastic monomers and addditives 5.3 Vanacore (26) 2000 Case-control study Mainly Italy but also 75 cases from tertiary 134 relatives of patients Smoking 0.56 ( ); Austria and Germany centers with non-neurological dose-response effect controls 28 Zermansky and Ben-Shlomo

7 Epidemiology of PSP and MSA 29 cases represent PSP or not. Only one patient in their study had a neuropathological examination, which showed changes seen in amyotrophic lateral sclerosis (ALS). It is not clear whether this was one of the PSP, PSP and ALS, or unclassifiable patients. Circumstantial evidence that the PSP-like syndrome may be PSP comes from a neuropathological study of five PSP patients from Guadeloupe, all of whom consumed large amounts of either tropical fruits or herbal teas. All these cases had neuropathologically confirmed PSP, with four-repeat tau deposition. Although this study provides a model for the role of dietary factors or a neurotoxin, the specific dietary components are fairly unique to this population and can provide clues to other substances only by analogy. Two case-control studies in New Jersey, conducted by the same research group 8 yr apart tried to identify a wide range of possible factors. The first (24), in 1988, compared 50 PSP patients (Golbe diagnostic criteria) in a tertiary-referral center with 100 age- and sex-matched inpatients with non-neurological disorders. It examined 85 potential factors including educational attainment, family history, and toxin exposures. In an attempt to improve the quality of information and possibly reduce recall bias between control and patient groups, questionnaires were administered to surrogate respondents only (the patient s spouse or offspring or sibling). This may have led to reducing any true association as relatives may not have been aware of all occupational exposures resulting in nondifferential misclassification toward the null. The only significant finding was that PSP patients were more likely to have completed high school, completed 4 yr at college, and live in an area with a population of less than 10,000 as an adult. It is unsurprising that out of 85 hypothesis tests, 3 4 tests were significant by chance at the 5% level (type I error). These findings could also be explained, as discussed in the paper, by selection bias; patients identified from tertiary referral centers are more likely to have a higher educational level and come from a wider catchment area than inpatients with acute medical problems from the local community. These findings failed to replicate in the follow-up study in 1996 (25). On this occasion, to avoid selection bias, non-neurodegenerative controls were drawn from the same pool of neurology outpatient referrals as the patients. Using a self-completed postal questionnaire, the study examined factors that neared statistical significance in the previous study. Now, PSP patients were less likely to have completed 12 yr at school, but no other factors were significant. The authors hypothesized that this may be a proxy for either lower nutritional status, somehow leading to a propensity to develop PSP, or possibly exposure to an unknown neurotoxin in early life. However, it is unclear how representative was the sample of controls. Given the severity of PSP, it is likely that all cases will eventually be referred for a neurological opinion, though not always to a tertiary specialist center. However, other neurological conditions, e.g., headaches, sciatica, etc., may be referred to a wide variety of other clinicians. Those reaching a tertiary center may be biased toward a higher educational level. Since smoking shows a negative association with Parkinson s disease, Vanacore and colleagues examined this factor among PSP patients (26). The study recruited 55 PSP and 134 control subjects. The control subjects were healthy relatives of patients with non-neurodegenerative diseases. Any further information about control selection was not given nor were the response rates reported. Since smokers are likely to be overrepresented in any randomly selected patient cohort, there is the possibility that controls were more likely to be relatives of patients who smoked. This bias would tend to show an inverse association with PSP but in fact there was little evidence of any association, though the wide 95% confidence intervals mean it is not possible to exclude even a halving of risk as seen with PD. Risk Factors for MSA Only two case-control studies have been reported for MSA. The first examined family history and specific occupational exposures. This noted significant odds ratios for organic solvents (2.4), metallic dusts (14.8), pesticides (5.8), and plastic monomers and additives (5.3) (27). Anecdotal case reports have also suggested pesticides (28), heavy metals (28), and organic solvents (28,29).

8 30 Zermansky and Ben-Shlomo Logistic regression analysis uncovered an increased risk of MSA with a positive family history of any neurological disease. No response rates were reported for cases and controls and the use of spouse, friends, and volunteer controls may have introduced substantial selection bias. In particular, as more male cases were ascertained, the use of female spouses will artifactually increase the risk of any occupationally related exposure found in male jobs. The increased odds ratio of having a family history of neurological disorders may have been spurious, since only 33 of the 60 MSA subjects family members participated, and attempts to recruit MSA-subject family members were made only if the MSA patients thought their relatives would be interested. Vanacore and colleagues in the same study mentioned earlier did find an inverse association between smoking and MSA. Although the odds rations for smoking were not significant at the 5% level, they did observe a dose response effect with decreasing odds as the number of pack-years increased. This may have been biased, owing to the control selection, however their results for PD are consistent with other studies suggesting that this may not have been a real problem. Implications From Case-Control Studies of PSP and MSA Summarizing the current published data, it appears that there is no evidence identifying any clear environmental risk factor for PSP, other than tropical fruit and herbal tea consumption for the PSPlike disorder in Guadeloupe. Evidence for environmental factors in MSA is mainly anecdotal, although the study by Nee and colleagues implicates various nonspecific occupational exposures. This does not, however, exclude the possibility of the role for an environmental factor in the etiology of either disorder. Furthermore, none of these studies recruited more than 100 cases. This means they are limited in statistical power with a high likelihood of a type II error, accepting the null hypothesis when the alternative hypothesis is true. Even with a study recruiting 100 cases and 200 controls, at a 5% level of significance and 90% power, one could only detect an odds ratio of 2.3 for a common exposure with 50% prevalence in the control group. For a rarer exposure with only 10% prevalence, this further deteriorates to an odds ratio of 3.0. CONCLUSIONS Remarkably little good-quality evidence exists on the epidemiology of PSP and MSA. Basic descriptive data on the variations of both diseases in time, place, and person are sparse. There is at this stage little evidence of widespread geographical variations, but many areas of the world have yet to report prevalence and incidence rates. Other than the possible rare exposure of benzyltetrahydoisoquinolones, we have little to go on for specific environmental clues. Positive findings with occupational exposures may reflect publication bias and negative studies may simply be underpowered to detect modest increased risks. Single centers are unlikely to be able to undertake sufficiently large and powerful studies so future research must either use a multicenter approach or use standardized methods to enable future meta-analysis of results. The challenges of undertaking highquality epidemiology of PSP and MSA are likely to remain well into the 21st century. FUTURE DIRECTIONS The future direction for PSP and MSA epidemiology will depend on various factors. Firstly, clinical anecdotes or natural experiments as occurred with MPTP and parkinsonism, will generate new hypotheses. Whilst many of these will be red herrings, true etiological insights can be gained by methodological sound exploration of such reports. Secondly, new developments in laboratory-based research may highlight etiological factors that have an analogous lifestyle exposure. This in turn can be tested using either questionnaires or, better still, with some plausible biomarker. Finally, well undertaken large case control studies will be necessary to refute or support plausible hypotheses.

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