SECTION EDITOR: DAVID E. PLEASURE, MD Predicting Motor Decline and Disability in Parkinson Disease A Systematic Review NEUROLOGICAL REVIEW Connie Marras, MD; Paula Rochon, MD, MPH; Anthony E. Lang, MD Context: The clinical course of Parkinson disease (PD) varies from patient to patient. A number of studies investigating predictors of prognosis in patients with PD have been performed. Objective: To summarize evidence on predicting the rate of motor decline and increasing disability in early PD. Data Sources: English-language and French-language literature cited in the MEDLINE database (1966-2002). Study Selection: Cohort and case-control studies investigating associations between clinical features and subsequent motor impairment or disability were selected. Data Extraction: Study methods and results were abstracted by a single reviewer. Data Synthesis: The results of 13 studies were summarized qualitatively. Study methods were highly variable, particularly regarding the choice of outcome measure. Baseline motor impairment and cognitive impairment are probable predictors of more rapid motor decline and disability. A lack of tremor at onset and older age both appear to be predictive of increasing disability, but conflicting results exist for their association with the rate of change of motor impairment. Family history of PD does not appear to be prognostically important. The prognostic value of many other factors studied is uncertain owing to conflicting or unconfirmed results. Conclusions: Uncertainty remains about the prognostic importance of many baseline clinical features in PD. Greater baseline impairment, early cognitive disturbance, older age, and lack of tremor at onset appear to be adverse prognostic factors. Arch Neurol. 2002;59:1724-1728 From the Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, University Health Network, University of Toronto (Drs Marras and Lang), the Kunin-Lunenfeld Applied Research Unit, Baycrest Center for Geriatric Care, University of Toronto (Dr Rochon), and the Institute for Clinical and Evaluative Sciences (Dr Rochon), Toronto, Ontario. THE CLINICAL course of Parkinson disease (PD) varies from patient to patient, and this variability has led to a number of studies investigating predictors of prognosis in PD. Predicting the clinical course of PD is important for several reasons. It helps patients recently diagnosed with a progressive disorder make social and occupational decisions that take into account their likely future physical functioning. Understanding the variables associated with disease progression also guides the design and interpretation of clinical trials of neuroprotective and symptomatic therapy. It would be important, for example, to ensure balance between groups on the basis of important prognostic factors. The heterogeneity of PD has been noted by many authors. For example, in their 1999 report of the Sydney, Australia, multicenter study of PD, Hely et al 1 showed that despite the wide availability of current treatment strategies and excluding patients developing signs and symptoms atypical for PD in follow-up, during 10 years of observation, 9 of 126 patients progressed to confinement to bed or a wheelchair unless aided, whereas 13 patients remained without significant functional restriction. Such variability leaves us with the challenge of predicting the future course of PD in individuals and groups of patients. We conducted a systematic review to identify predictors of motor decline and disability in patients with PD. We focused on motor impairment and disability because motor impairment is the defining feature of this illness and it affects patients largely through increasing physical disability. METHODS DATA SOURCE Using the MEDLINE database, we searched the English-language and French-language literature published from 1966 through January 31, 1724
Table 1. Cohort and Case-Control Studies of Motor Prognosis in Patients With Parkinson Disease* Source, Year Setting/Inclusion Criteria No. of Patients/Total Follow-up, y Outcome Measures Diamond et al, 8 1989 Trial cohort followed since starting 54/54 6 Change in UCLA scale score levodopa Diamond et al, 7 1990 Trial cohort followed since starting 70/70 2-6 Change in UCLA scale score levodopa Ferraz et al, 11 1996 Tertiary care/follow-up 6 mo 63/118 1.7 (mean) HY stage: better, worse, or same Tertiary care/hy stage 1-2, 31/NS 2 (mean) Progression to HY stage 3 untreated throughout Goetz et al, 16 2000 Tertiary care/follow-up 4 y 221/434 4 Change in UPDRS motor score Chastang, 10 1978 Tertiary care/follow-up 4 y 164/164 4-8 Time to motor decline and moderate to severe deterioration Guillard et al, 9 1986 Tertiary care/treated with levodopa 356/356 NS Time to loss of independence Hely et al, 6 1995 Trial cohort/hy stage 1-3, untreated 76/125 5 Change in CURS 10 points Hely et al, 1 1999 Trial cohort/hy stage 1-3, untreated 130/132 10 Change in CURS 20 points Tertiary care/disease duration 2 y 218/229 NS Percentage of patients disabled Tertiary care/follow-up 3 y 297/NS 6.4 (mean) Change in UPDRS ADL and motor scores Tertiary care/follow-up 1 y 237/NS 3.3 (mean) Change in UPDRS motor score Starkstein et al, 5 1992 Consecutive patients/tertiary care 92/106 1 Change in NWUDS, HY stage, tremor, rigidity, and bradykinesia scores *HY indicates Hoehn and Yahr; UCLA, University of California, Los Angeles; UPDRS, Unified Parkinson s Disease Rating Scale; CURS, Columbia University Rating Scale; ADL, activities of daily living; NWUDS, Northwestern University Disability Scale; and NS, not stated. Data are given as the number of patients reported on in the series/the total number of patients prior to exclusion for insufficient baseline data or loss to follow-up. Of 221 patients, 100 were randomly selected. 2002. The medical subject headings Parkinson disease and prognosis were combined with either of the text words progression or natural history, and we limited the search to clinical trials or cohort studies. STUDY SELECTION We reviewed 457 titles and abstracts for reports investigating the association between progression of motor features or disability and patient or disease-related factors (as opposed to the effect of an intervention). These articles and relevant articles from their reference lists were obtained for review. Reports published only in abstract form and reports of predictive factors for dyskinesias or motor fluctuations were excluded. We included only studies that prospectively documented disease progression, whether this was within the context of the study (prospective cohort studies) or from medical records (retrospective cohort studies and case-control studies). Studies that made a single observation of outcome were considered to be cross-sectional and were excluded. DATA EXTRACTION Study methods and results were abstracted by one of us (C.M.). Studies were assessed for methodologic quality using 5 criteria adapted from the Evidence-Based Medicine Working Group s Users Guide to the Medical Literature criteria for appraising an article about prognosis 2 and from the methodologic and quality scoring instrument developed by Cho and Bero 3 (criterion 5 of our instrument). 1. Patients within 5 years of symptom onset at first observation. 2. Median or mean follow-up of at least 2 years. 3. Greater than 80% of patients followed up. 4. Clearly defined and reproducible outcome measures. 5. Known confounders accounted for in the design or analysis. When examining the prognostic significance of other variables, baseline status on the outcome of interest, disease duration, and treatment allocation (if applicable) should be adjusted for statistically or should be balanced between groups. OUTCOME MEASURES Studies were grouped by category of outcome measure, either disability or motor impairment. RESULTS DATA SYNTHESIS Of the studies assessed, 41 articles were identified that investigated factors (other than treatment) associated with outcome in PD; 27 of these were excluded from our review: 13 were cross-sectional studies, 10 studies investigated only nonmotor outcomes (cognitive dysfunction, 8 studies; mortality or institutionalization, 2 studies), 1 study investigated factors associated with time to requiring therapy with levodopa, and 3 were review articles. One cohort study was excluded because the source of subjects (inpatients having had a computed tomographic scan of the head) was felt to significantly limit the external validity of the study. 4 One prospective cohort study, 5 11 retrospective cohort studies, 1,4,6-15 and 1 case-control study 16 were retained for review. Table 1 provides a summary of their methods. PREDICTING DISABILITY Variables investigated for their association with increasing disability are presented in Table 2. Presentation without tremor (bradykinesia/rigidity type) was found to be a marker of poor prognosis in 2 studies by Guillard et al 9 and Chastang, 10 and a trend toward this result was noted in 2 other studies. 13,15 Guillard et al 9 and 1725
Table 2. Variables Investigated for Association With Increasing Disability in Patients With Parkinson Disease* Variable Bradykinesia/rigidity type (vs tremor at onset or tremor dominant) Predictive Cognitive disturbance in the first year Initial lack of independence Babinski response at baseline Older age at onset Diamond et al, 8 1989 Male sex Depression Starkstein et al, 5 1992 Source Not Predictive Diamond et al, 7 1990 Living in a rural area Ferraz et al, 11 1996 Family history of Parkinson disease Smoking history Early dyskinesias or fluctuations Birth trauma Environmental exposures Physical and emotional stress Vitamin intake *Includes Hoehn and Yahr stage as an outcome. Chastang, 10 1978, and Guillard et al, 9 1986, used overlapping samples of patients. There was a trend toward a worse prognosis in patients without tremor at onset. Measles prior to age 18 years and chemical, herbicide, or well water exposure were analyzed separately. Chastang 10 did not report their results quantitatively. Hoehn and Yahr 13 reported that at the end of their follow-up period, 19% of patients with tremor at onset were disabled vs 24% of patients without tremor at onset. Goetz et al 15 found an odds ratio of 0.43 for progression to Hoehn and Yahr stage 3 when tremor was the first symptom. In a fifth study investigating the dominant symptom type of PD (postural instability gait disorder vs tremor), Kapadia 14 found that subjects with a tremor-dominant subtype (they did not classify patients by initial symptom) experienced slower worsening of Unified Parkinson s Disease Rating Scale (UPDRS) activities of daily living (ADL) scores. Early lack of physical independence, a positive Babinski sign, and cognitive disturbance within the first year of symptoms were found to be poor prognostic factors by Chastang, 10 again with a subjectively defined outcome and no quantitative result given. A positive Babinski sign and cognitive disturbance within the first year would be unusual for patients with PD, raising the possibility that these signs are markers of alternative diagnoses with a worse prognosis. Older patients had a poorer prognosis in 4 of 5 studies. 8,9,13-15 Diamond et al 8 found that older patients had poorer outcomes after 6 years of levodopa therapy. Patients older than 60 years experienced little net change in UCLA (University of California, Los Angeles) scale scores (99 to 92) compared with a net score change of 39 points (92 to 53) in those younger than 50 years (ie, younger patients maintained their improvement with levodopa; higher scores indicate greater disease severity). Goetz et al 15 found that patients who progressed to Hoehn and Yahr stage 3 during 2 years of observation were older (mean age, 65 years) than a group of patients matched for disease duration and initial Hoehn and Yahr stage who did not progress beyond stage 2 (mean age, 52 years). Older age at onset was reported to predict earlier loss of independence by Guillard et al 9 and a more rapid worsening of UPDRS ADL scores by Kapadia. 14 Hoehn and Yahr 13 did not find an association between increasing age and disability. Three studies generated differing results regarding the prognostic importance of depression in patients with PD. 5,9,10 Using a prospective design, Starkstein et al 5 found depression at baseline to predict greater decline in Northwestern University Disability Scale score (2.7 point deterioration in patients with depression vs 0.1 point mean improvement in individuals without depression during 1 year). This contrasts with 2 retrospective studies that did not detect an association between depression and future disability (disability not defined). 9,10 A family history of PD had no significant prognostic value in 4 studies. 9,10,13,15 Other variables investigated for their association with increasing disability with conflicting or negative results are presented in Table 2. PREDICTING MOTOR IMPAIRMENT Factors investigated for association with motor impairment are shown in Table 3. Dementia at baseline was found to be associated with faster motor decline in 2 studies 6,12 ; however, in only one did this remain significant after adjusting for other baseline factors. 12 Louis et al 12 found that the UPDRS motor scores of patients with dementia were, on average, 7.9 points higher (higher scores represent greater severity) at each annual visit than in those without dementia at baseline. Although there was adjustment for several baseline factors, there was no adjustment made for initial motor score. The degree of baseline motor impairment was found to be positively correlated with later impairment in 2 studies. Louis et al 12 found that a baseline Schwab and England ADL score of 70 or less (lower scores indicate greater disability) was associated with mean UPDRS motor scores 11.7 points higher at each annual visit over a mean follow-up of 3.3 years compared with those with ADL scores greater than 70. 1726
Chastang 10 found that the median time to significant motor impairment (not defined) was 6 years in patients with mild akinesia at baseline and 4 years in patients with more severe akinesia. In contrast, Goetz et al 16 found that baseline UPDRS scores showed a negative correlation (r= 0.25) with the change in scores during the subsequent 4 years. The correlation is modest, and this could represent a tendency for outlying observations to regress to the mean. Older age was associated with more rapid progression of motor impairment in 2 of 4 studies. 1,8 Hely et al 1 studied a cohort of patients followed prospectively for 10 years. Each increase in age of 10 years was associated with an odds ratio of 2.41 (95% confidence interval, 1.24-4.66) for an increase in Columbia University Rating Scale score by 20 or more points. Diamond et al 8 found a significant effect of age using the UCLA scale, as described previously. They noted that tremor and rigidity changed little and that the most decline occurred in gait, balance, rising from a chair, and rolling over in bed. In contrast, 2 other studies did not find age at onset to be associated with increasing UPDRS motor scores. 12,14 Sex was not found to be related to motor decline in 4 studies. 6,7,12,14 A fifth study by Hely et al 1 found that female sex was predictive of a deterioration in modified Columbia University Rating Scale score of more than 20 points in univariate (odds ratio not given) but not multivariate analysis. Conversely, men did more poorly in 2 studies using disability 9 and increasing UPDRS ADL scores 14 as outcome measures (Table 2). Two studies investigated the relationship between type of presentation (tremor vs bradykinesia/rigidity type) and progression of motor impairment. In contrast with the studies of disability, this was not found to be an important predictor of motor impairment in either study. 1,14 Other factors with contradictory or negative results can be seen in Table 3. METHODOLOGIC APPRAISAL Of 13 studies, 9 did not identify their cohort by duration of disease. 1,5,6,9-12,14,16 Two studies followed their cohort for less than 2 years, 5,11 and 2 studies did not achieve greater than 80% follow-up of their cohort. 11,16 Three studies did not objectively define the outcomes used, 9,10,13 and 6 studies did not account for potential confounders in their analysis. 9-14 COMMENT SUMMARY OF RESULTS Our systematic review identified trends for the prognostic importance of 4 baseline factors. First, those with more severe baseline impairment continue to be more impaired later in the disease course. Second, there is some inconsistent evidence that a presentation without tremor (predominant bradykinesia/rigidity or postural instability) and increasing age may be predictors of more rapidly increasing disability but not of more rapidly increasing motor impairment. Regarding age, this Table 3. Variables Investigated for Association With Increasing Motor Impairment in Patients With Parkinson Disease Source, Year Variable Predictive Not Predictive Bradykinesia/rigidity presentation Dementia Hely et al, 6 1995* Schwab and England score 70 Lack of independence Chastang, 10 1978 More severe rigidity Chastang, 10 1978 Greater tremor severity Hely et al, 1 1999* Baseline UPDRS score Goetz et al, 16 2000 Early (prestudy) disease progression Older age Diamond et al, 8 1989 Hely et al, 1 1999 Older age at onset Longer illness duration Goetz et al, 16 2000 Female sex Hely et al, 1 1999* Diamond et al, 7 1990 Depression Starkstein et al, 5 Starkstein et al, 5 1992 1992 Living in a rural area Ferraz et al, 11 1996 Balance disorder Goetz et al, 16 2000 Symmetry of disease Ethnicity Level of education *The variable was predictive in univariate but not multivariate analysis. Hely et al, 6 1995, and Hely et al, 1 1999, used the sample of patients at 5 and 10 years of follow-up, respectively. UPDRS indicates Unified Parkinson s Disease Rating Scale. Depression predicts a greater change in Hoehn and Yahr stage but not tremor, rigidity, or bradykinesia scores. raises the possibility that measures of disability are detecting an association between increasing age and non-pd related disability. Finally, cognitive impairment at baseline also appears to be associated with future disability and motor impairment. Sex does not appear to have prognostic importance for progression of motor impairment; for changes in disability, the evidence is conflicting. Family history of PD was consistently found not to be an important prognostic factor for motor impairment or disability. However, it is important to consider that family history may not be a significant prognostic factor for sporadic PD but rare familial forms may have distinct prognoses. For example, mutations in the parkin gene can cause a recessively inherited parkinsonism clinically indistinguishable from idiopathic PD other than by younger average age at onset and a relatively benign course. 17 Epidemiologic studies may not detect this association because of the rarity of these types of PD (especially in older cohorts 1727
in the case of parkin mutations 18 ) and their geographic clustering. Prognostic factors may also be different depending on the outcome being evaluated. We did not consider other important outcomes such as cognitive deterioration, mortality, institutionalization, or the development of dyskinesias and motor fluctuations. For example, younger age has been shown in several different studies to predispose to the development of drug-induced dyskinesias earlier in the disease course. 19,20 METHODOLOGIC VARIABILITY ACROSS STUDIES We noted conflicting results on many potential prognostic factors that have been investigated, and this may be due in part to variable methods used by the investigators. For example, defining a cohort by (mild) symptom severity or only by having the disease rather than by duration of disease favors the selection of patients with more slowly progressive PD who live longer and have more mild symptoms for a longer duration. Also, short duration of follow-up limits the ability to detect important prognostic factors in a disease that often lasts more than a decade. Of 13 studies, 6 did not indicate whether they excluded patients developing atypical symptoms during the follow-up period. 5,7-9,11,12 Patients with atypical symptoms may have distinct disorders with distinct prognostic factors, despite early clinical features entirely consistent with PD. Finally, outcome measures varied markedly across studies. The use of different outcome scales in different ways may further contribute to apparently conflicting results. It would be helpful for future research to make use of previously used outcome measures to build on the results of past studies. CONCLUSIONS Our review identified baseline severity of motor symptoms and possibly early cognitive impairment as factors influencing the progression of motor symptoms and disability. Increasing age and lack of rest tremor appear to predict more rapid accumulation of disability, but not necessarily motor impairment. Conflicting results were found concerning the prognostic importance of many other factors, and this may result, in part, from methodologic variability across studies. Accepted for publication June 14, 2002. Author contributions: Study concept and design (Drs Marras and Lang); acquisition of data (Dr Marras); analysis and interpretation of data (Drs Marras, Rochon, and Lang); drafting of the manuscript (Drs Marras and Rochon); critical revision of the manuscript for important intellectual content (Drs Marras and Lang); obtained funding (Dr Marras); administrative, technical, and material support (Dr Lang); study supervision (Drs Rochon and Lang). This study was supported by a Research Training Award (Dr Marras) and an Investigator Award (Dr Rochon) from the Canadian Institutes of Health Research, Ottawa, Ontario, and the University of Toronto Clinician Scientist Training Program, Toronto, Ontario (Dr Marras). Corresponding author and reprints: Anthony E. Lang, MD, Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital 11-MP, 399 Bathurst St, Toronto, Ontario M5G 2S8, Canada. REFERENCES 1. Hely MA, Morris JG, Traficante R, Reid WG, O Sullivan DJ, Williamson PM. The Sydney multicentre study of Parkinson s disease: progression and mortality at 10 years. J Neurol Neurosurg Psychiatry. 1999;67:300-307. 2. Laupacis A, Wells G, Richardson S, Tugwell P, for the Evidence-Based Medicine Working Group. Users guides to the medical literature, V: how to use an article about prognosis. JAMA. 1994;272:234-237. 3. Cho MK, Bero L. Instruments for assessing the quality of drug studies published in the medical literature. 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