[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.
Cumulative occurrence over time of all motor complications, motor fluctuations before dyskinesia, dyskinesia before motor fluctuations, and both at the same time for the 189 subjects who experienced motor complications.

Cumulative occurrence over time of all motor complications, motor fluctuations before dyskinesia, dyskinesia before motor fluctuations, and both at the same time for the 189 subjects who experienced motor complications.

Table 1.  
Incidence of Dyskinesias and Motor Fluctuations and Order of Appearance in Patients Randomized in the CALM-PD Study
Incidence of Dyskinesias and Motor Fluctuations and Order of Appearance in Patients Randomized in the CALM-PD Study
Table 2.  
Associations Between Baseline Characteristics and Order of Appearance of Motor Fluctuations and Dyskinesias
Associations Between Baseline Characteristics and Order of Appearance of Motor Fluctuations and Dyskinesias
Table 3.  
Associations Between Patient Characteristics and Time to First Occurrence of Dyskinesias*
Associations Between Patient Characteristics and Time to First Occurrence of Dyskinesias*
Table 4.  
Multiple Regression Model for Time to First Occurrence of Dyskinesias*
Multiple Regression Model for Time to First Occurrence of Dyskinesias*
Table 5.  
Associations Between Patient Characteristics and Time to First Occurrence of Motor Fluctuations (Wearing Off or On-Off)*
Associations Between Patient Characteristics and Time to First Occurrence of Motor Fluctuations (Wearing Off or On-Off)*
Table 6.  
Multiple Regression Model for Time to First Occurrence of Motor Fluctuations (Wearing Off or On-Off)*
Multiple Regression Model for Time to First Occurrence of Motor Fluctuations (Wearing Off or On-Off)*
1.
Chapuis  SOuchchane  LMetz  OGerbaud  LDurif  F Impact of the motor complications of Parkinson's disease on the quality of life.  Mov Disord 2005;20224- 230PubMedArticle
2.
Damiano  AMMcGrath  MMWillian  MK  et al.  Evaluation of a measurement strategy for Parkinson's disease.  Qual Life Res 2000;987- 100PubMedArticle
3.
Marras  CLang  AKrahn  MTomlinson  GNaglie  GParkinson Study Group, Quality of life in early Parkinson's disease.  Mov Disord 2004;1922- 28PubMedArticle
4.
Ahlskog  JEMuenter  MD Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.  Mov Disord 2001;16448- 458PubMedArticle
5.
Rascol  OBrooks  DJKorczyn  ADDe Deyn  PPClarke  CELang  AE A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa: 056 Study Group.  N Engl J Med 2000;3421484- 1491PubMedArticle
6.
Oertel  WHWolters  ESampaio  C  et al.  Pergolide versus levodopa monotherapy in early Parkinson's disease patients.  Mov Disord 2006;21343- 353PubMedArticle
7.
Lees  AJKatzenschlager  RHead  JBen-Shlomo  Y Ten-year follow-up of three different initial treatments in de-novo PD.  Neurology 2001;571687- 1694PubMedArticle
8.
Parkinson Study Group, Pramipexole vs. levodopa as initial treatment for Parkinson disease: a randomized controlled trial.  JAMA 2000;2841931- 1938PubMedArticle
9.
The Parkinson Study Group, Pramipexole vs. levodopa as initial treatment for Parkinson disease.  Arch Neurol 2004;611044- 1053PubMed
10.
Miller  AJ Subset Selection in Regression. 2nd ed. Boca Raton, Fla: Chapman & Hall/CRC; 2002
11.
Hosmer  DW  JrLemeshow  S Applied Survival Analysis.  New York, NY: John Wiley & Sons; 1999
12.
Hobson  DELang  AEMartin  WRRazmy  ARivest  JFleming  J Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group.  JAMA 2002;287455- 463PubMedArticle
13.
Mazzella  LYahr  MDMarinelli  LHuang  NMoshier  EDi Rocco  A Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy.  Parkinsonism Relat Disord 2005;11151- 155PubMedArticle
14.
Rajput  AHFenton  MEBirdi  S  et al.  Clinical-pathological study of levodopa complications.  Mov Disord 2002;17289- 296PubMedArticle
Original Contribution
December 2006

Factors Associated With the Development of Motor Fluctuations and Dyskinesias in Parkinson Disease

Author Affiliations

Author Affiliations: Departments of Neurology, Pharmacology, and Experimental Therapeutics, University of South Florida, and Tampa General Healthcare, National Parkinson Foundation Center of Excellence, Tampa (Dr Hauser); and Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY (Dr McDermott and Ms Messing).

Arch Neurol. 2006;63(12):1756-1760. doi:10.1001/archneur.63.12.1756
Abstract

Background  Motor fluctuations and dyskinesias can cause disability and reduce quality of life for patients with Parkinson disease (PD).

Objectives  To evaluate factors associated with the development of motor fluctuations and dyskinesias and to assess the sequence in which they occur in individual patients.

Design  We performed a retrospective analysis of data from a randomized clinical trial comparing pramipexole dihydrochloride and levodopa as initial treatment for PD. Subjects were followed up for 48 to 58 months and evaluated at 3-month intervals for the presence of motor fluctuations and dyskinesias.

Setting  Academic and private practices.

Patients  Three hundred one patients with early Parkinson disease were enrolled in this study between October 2, 1996, and August 21, 1997, and were observed through August 24, 2001, when the last patient enrolled completed 4 years of follow-up.

Main Outcome Measures  Order of appearance of motor fluctuations and dyskinesias, time to the first occurrence of motor fluctuations, and time to the first occurrence of dyskinesias.

Results  One hundred eighty-nine subjects (62.8%) developed motor complications. Of these, 71 (37.6%) developed fluctuations but not dyskinesias, 23 (12.2%) developed dyskinesias but not fluctuations, 48 (25.4%) developed fluctuations before dyskinesias, 33 (17.5%) developed dyskinesias before fluctuations, and 14 (7.4%) developed both at the same time. Factors significantly associated with earlier occurrence of dyskinesia were Hoehn and Yahr stage of 2 or higher, cumulative levodopa dose, cumulative levodopa equivalent dose (levodopa plus pramipexole), and occurrence of motor fluctuations. Pramipexole treatment was associated with later occurrence of dyskinesias. Factors associated with earlier occurrence of motor fluctuations were cumulative levodopa dose, cumulative levodopa equivalent dose, and occurrence of dyskinesias. Factors associated with later occurrence of motor fluctuations were age at onset of 65 years or older and pramipexole treatment.

Conclusions  Higher cumulative levodopa doses and higher cumulative levodopa equivalent doses (levodopa plus pramipexole) were associated with the earlier occurrence of motor complications. Motor fluctuations and dyskinesias appear to be interrelated because the presence of one is associated with the earlier development of the other.

In Parkinson disease (PD), long-term therapy with levodopa is associated with the development of motor fluctuations and dyskinesias. These motor complications limit the effectiveness of medication treatment and can cause disability and lower quality of life for some patients.13 In the modern era, the incidence of motor fluctuations after 4 to 6 years of levodopa therapy has been reported as 12% to 60% and for dyskinesias 8% to 64%.4

Recently, several studies59 have reported that compared with initial treatment with levodopa, initial treatment with a dopamine agonist causes a lower incidence of motor complications. The Parkinson Study Group8,9 reported that initial treatment with pramipexole dihydrochloride was associated with lower incidences of dyskinesia and wearing off than initial treatment with levodopa. This study (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease [CALM-PD]) also provides an ideal opportunity to evaluate other factors that might affect the emergence of motor complications because the patient sample was well characterized, followed up prospectively from before the initiation of dopamine replacement therapy, randomized to 1 of 2 widely used treatment strategies, and evaluated over time using standardized operational definitions of clinical events. Whereas the CALM-PD study focused on comparing the development of motor complications in subjects assigned to initial treatment with levodopa vs pramipexole, in the present study, we retrospectively analyzed data from this trial to evaluate additional factors associated with the development of motor fluctuations and dyskinesias and assessed the sequence in which they occurred in individual patients.

Methods
Study design

We performed a retrospective analysis of the CALM-PD database. The CALM-PD study was a prospective randomized clinical trial that compared pramipexole with levodopa as initial treatment for PD.8,9 Three hundred one subjects were enrolled between October 2, 1996, and August 21, 1997, and observed through August 24, 2001, when the last subject completed 4 years of follow-up. Eligible subjects had had PD for less than 7 years, were at least 30 years old, had Hoehn and Yahr stage 1 through 3 disease, and required dopaminergic therapy at the time of enrollment. Stable dosages of selegiline hydrochloride, amantadine hydrochloride, and anticholinergics were permitted.

Subjects were randomized to blinded treatment with pramipexole or levodopa using a double-dummy design. During a 10-week dose escalation phase, subjects were initially treated with pramipexole dihydrochloride, 1.5 mg/d, or carbidopa/levodopa, 75 and 300 mg/d, divided into 3 daily doses (level 1). Subjects who required additional therapy could escalate to pramipexole dihydrochloride, 3.0 mg/d, or carbidopa/levodopa, 112.5 and 450 mg/d (level 2), or pramipexole dihydrochloride, 4.5 mg/d, or carbidopa/levodopa, 150 and 600 mg/d (level 3). Open-label, immediate-release carbidopa/levodopa could be added as necessary to treat emerging disability. Additional medication adjustments were permitted once subjects experienced motor complications.9

Evaluations

The presence of motor complications (dyskinesia, wearing off, and on-off) was assessed by blinded raters every 3 months until month 58. Dyskinesias were defined as an abnormal involuntary movement, including chorea, dystonia, myoclonus, or tics, that could be either peak dose or end of dose. Dyskinesias did not include early morning or other off dystonias. Wearing off was defined as a perception of loss of mobility or dexterity, usually taking place gradually over minutes and usually bearing close relationship to the timing of antiparkinsonian medications. On-off was defined as an unpredictable and generally sudden (seconds to minutes) shift between on (mobility) and off (immobility) not apparently related to the timing of antiparkinsonian medications.

Statistical analysis

Logistic regression analyses were used to examine the relationships between order of appearance of motor fluctuations and dyskinesias (motor fluctuations first or dyskinesias first) and each of the following independent variables determined at the baseline visit (with the exception of dosage level): sex, age at onset (<65 or ≥65 years), time since PD diagnosis (<2 or ≥2 years), total Unified Parkinson's Disease Rating Scale (UPDRS) score (≤30 or >30), Hoehn and Yahr stage (1, 2, or 3), original treatment assignment (pramipexole or levodopa), dosage level after the 10-week dose escalation phase (level 1, level 2, or level 3), selegiline hydrochloride use, and amantadine hydrochloride use. Cutoff points for the independent variables were determined before data analysis. Results are presented in terms of odds ratios (ORs) and corresponding 95% confidence intervals (CIs), with ORs greater than 1 indicating increased odds of motor fluctuations occurring before dyskinesias. A multiple regression model was constructed using the best-subsets model selection technique.10,11 Clinical judgment was used to select a parsimonious model for outcome from the candidate models identified by this procedure.

Cox proportional hazards models were used to examine the relationships between time to the first occurrence of dyskinesias and the independent variables listed herein. We also considered the following time-dependent covariates in the analyses: cumulative levodopa dose (expressed in 300 mg-years), cumulative levodopa-equivalent dose (with 1 mg of pramipexole treated as 67 mg of levodopa),12 and occurrence of motor fluctuations. Study site was included as a stratification factor in the statistical models. Similar analyses were performed for the outcome of time to the first occurrence of motor fluctuations, except that occurrence of dyskinesias replaced occurrence of motor fluctuations as a time-dependent covariate. Multiple regression models were developed for each of the 2 end points (dyskinesias and motor fluctuations) using a best-subsets model selection technique combined with clinical judgment.

Results

Three hundred one subjects were randomized in the CALM-PD study: 151 allocated to pramipexole and 150 allocated to levodopa. Mean  ±SD age at entry was 61.1 ± 10.4 years. Eighty-three (55.0%) of the pramipexole-assigned subjects and 100 (66.7%) of the levodopa-assigned subjects remained in the study until the planned final visit.9

One hundred eighty-nine subjects (62.8%) developed motor complications (Table 1). Of these, 71 (37.6%) developed fluctuations but not dyskinesias and 23 (12.2%) developed dyskinesias but not fluctuations. Forty-eight (25.4%) developed fluctuations before dyskinesias, 33 (17.5%) developed dyskinesias before fluctuations, and 14 (7.4%) developed both at the same time. The timing of the first event for the 189 subjects who developed motor complications is depicted in Figure 1. For subjects who developed dyskinesia first, dyskinesia usually occurred within the first 15 months. For subjects who developed fluctuations first, fluctuations generally occurred after 20 months.

For subjects who developed dyskinesias before or at the same time as fluctuations (including those who developed dyskinesias only) (n = 70), the median time from onset of dyskinesias to onset of fluctuations was 17.2 months (interquartile range, 2.8-29.8 months). For subjects who developed fluctuations before or at the same time as dyskinesias (including those who developed fluctuations only) (n = 133), the median time to onset of dyskinesias was 27.2 months (25th percentile, 6.3 months; 75th percentile could not be estimated).

Order of appearance of motor fluctuations and dyskinesias

The ORs that describe the associations between subject characteristics and order of appearance of motor fluctuations and dyskinesias are presented in Table 2. Pramipexole treatment assignment was significantly associated with the development of fluctuations before dyskinesias (OR, 2.69; 95% CI, 1.34-5.37; P = .005). Time since PD diagnosis of 2 years or more was significantly inversely associated with the development of fluctuations before dyskinesias (OR, 0.37; 95% CI, 0.19-0.71; P = .003). The selected multiple regression model also included only these 2 factors (pramipexole treatment assignment: OR, 2.59; 95% CI, 1.28-5.26; P = .008; time since PD diagnosis of ≥2 years: OR, 0.38; 95% CI, 0.19-0.75; P = .005).

Time to first occurrence of dyskinesias

Hazard ratios (HRs) that describe the associations between subject characteristics and the time to first occurrence of dyskinesias are presented in Table 3. Characteristics significantly associated with earlier occurrence of dyskinesias were selegiline use (HR, 1.73; 95% CI, 1.08-2.76; P = .02), total UPDRS score greater than 30 (HR, 1.69; 95% CI, 1.10-2.62; P = .02), Hoehn and Yahr stage of 2 or higher (HR, 1.82; 95% CI, 1.09-3.03; P = .02), cumulative levodopa dose (HR, 1.19; 95% CI, 1.08-1.31; P<.001), cumulative levodopa equivalent dose (HR, 1.21; 95% CI, 1.09-1.34; P<.001), and occurrence of motor fluctuations (HR, 2.46; 95% CI, 1.53-3.95; P < .001). Pramipexole treatment assignment was significantly associated with later occurrence of dyskinesias (HR, 0.37; 95% CI, 0.25-0.56; P<.001), as has previously been reported.8 The selected multiple regression model included sex, selegiline use, amantadine use, Hoehn and Yahr stage of 2 or higher, treatment assignment, and occurrence of motor fluctuations (Table 4). In this model, Hoehn and Yahr stage of 2 or higher (HR, 2.04; 95% CI, 1.18-3.51; P = .01) and occurrence of motor fluctuations (HR, 2.36; 95% CI, 1.48-3.77; P<.001) were significantly associated with earlier occurrence of dyskinesias, and pramipexole treatment assignment (HR, 0.36; 95% CI, 0.23-0.54; P<.001) was significantly associated with a longer time to occurrence of dyskinesias.

Time to first occurrence of motor fluctuations

The HRs that describe the associations between subject characteristics and the time to first occurrence of motor fluctuations appear in Table 5. Characteristics significantly associated with earlier occurrence of motor fluctuations were cumulative levodopa dose (HR, 1.10; 95% CI, 1.00-1.21; P = .04), cumulative levodopa equivalent dose (HR, 1.13; 95% CI, 1.01-1.27; P = .03), and occurrence of dyskinesias (HR, 1.66; 95% CI, 1.06-2.59; P = .03). Characteristics significantly associated with later occurrence of motor fluctuations were age at onset of 65 years or older (HR, 0.67; 95% CI, 0.47-0.94; P = .02), amantadine use (HR, 0.58; 95% CI, 0.35-0.96; P = .04), and pramipexole treatment assignment (HR, 0.64; 95% CI, 0.47-0.89; P = .007). The selected multiple regression model included sex, age at onset of 65 years or older, selegiline use, amantadine use, time since PD diagnosis of 2 years or more, treatment assignment, and cumulative levodopa equivalent dose (Table 6). Selegiline use (HR, 1.53; 95% CI, 1.06-2.21; P = .02) and cumulative levodopa equivalent dose (HR, 1.16; 95% CI, 1.01-1.32; P = .04) were significantly associated with earlier occurrence of motor fluctuations, and age at onset of 65 years or older (HR, 0.63; 95% CI, 0.44-0.91; P = .01), time since PD diagnosis of 2 years or more (HR, 0.63; 95% CI, 0.43-0.92; P = .02), and pramipexole treatment assignment (HR, 0.68; 95% CI, 0.47-0.98; P = .04) were significantly associated with a longer time to occurrence of motor fluctuations.

Comment

Our results for order of appearance of motor complications in individual patients are strikingly different from those of the only other study, to our knowledge, to systematically evaluate it. In that study,13 records were reviewed for 116 patients with disease duration of more than 7 years who were treated with levodopa monotherapy for at least 5 years at Mount Sinai School of Medicine between 1965 and 1992. Fifty-four patients (47%) developed both motor fluctuations and dyskinesias. Of these, 49 (91%) developed dyskinesias before fluctuations and only 5 (9%) developed fluctuations before dyskinesia. In our study of 301 subjects, 95 (31.6%) developed both motor fluctuations and dyskinesias. Of these, 33 (34.7%) developed dyskinesias before fluctuations, 48 (50.5%) developed fluctuations before dyskinesias, and 14 (14.7%) developed both at the same time. In part, these results may differ because of the distinct treatment regimens used in the 2 populations. The Mount Sinai sample was treated with levodopa monotherapy, whereas half of our sample was initially treated with pramipexole. This potential explanation is consistent with our observation that initial pramipexole treatment is associated with the appearance of motor fluctuations before dyskinesias. However, even in our levodopa group, we still found that more subjects developed motor fluctuations before dyskinesias (30; 46.2%) than dyskinesias before motor fluctuations (25; 38.5%). These differences between studies may be related to our finding that longer time from diagnosis to treatment is associated with the development of dyskinesias before motor fluctuations. In our study, the mean time from diagnosis to treatment was 1.4 years in the pramipexole group and 1.8 years in the levodopa group, whereas in the Mount Sinai study, the time to initiation of treatment was 6.2 years. Similarly, in another study14 that evaluated 42 autopsy-proven cases of patients treated between 1968 and 1996, dyskinesia was the most frequent and earliest motor complication, and the mean time from PD symptoms to levodopa initiation was 6.1 years. Levodopa dosage may not be an important factor in the differences observed across these studies because our levodopa group's mean daily dose was higher than that in one of these studies14 and lower than that in the other.13

In our analysis of factors associated with the development of motor fluctuations and dyskinesias, the results of univariate analyses contrasted with those of multiple regression analyses in some cases, mainly because of the interrelationships among the independent variables (total UPDRS score and Hoehn and Yahr stage). Our interpretation of which independent variables appear to be the most important risk factors for motor complications was based on the selected multiple regression models. Important exceptions are treatment-related variables (original treatment assignment, cumulative levodopa dose, and cumulative levodopa-equivalent dose). We interpreted all of these as important risk factors because they are strongly interrelated and the overall fit of the multiple regression model was similar regardless of which of these (single) treatment-related variables was included. Both original treatment assignment and cumulative levodopa-equivalent dose appeared to provide incremental contributions to the model for time to the first occurrence of motor fluctuations.

In considering controllable factors, we found that initial treatment with pramipexole is associated with a longer time to the occurrence of both motor fluctuations and dyskinesias, as previously reported.8,9 Higher cumulative levodopa doses and higher cumulative levodopa equivalent doses (levodopa plus pramipexole) were associated with the earlier occurrence of both motor fluctuations and dyskinesias. This suggests that higher doses of dopaminergic medications than necessary to effectively control parkinsonian symptoms should be avoided. However, a causal relationship has not been proved, and patients with worse disease may be at greater risk for the development of motor complications and require higher doses of dopaminergic medication. In addition, motor complications do not necessarily cause meaningful functional impairment and can potentially be managed medically or surgically.

The occurrence of motor fluctuations was associated with the earlier onset of dyskinesias, and the occurrence of dyskinesias was associated with the earlier onset of motor fluctuations. This observation emphasizes the interrelatedness of these motor complications and suggests they may be caused by similar or related mechanisms.

In conclusion, for subjects who developed motor complications, most experienced fluctuations before dyskinesias. Factors significantly associated with earlier occurrence of dyskinesia were Hoehn and Yahr stage of 2 or higher, cumulative levodopa dose, cumulative levodopa equivalent dose (levodopa plus pramipexole), and occurrence of motor fluctuations. Pramipexole treatment was associated with later occurrence of dyskinesias. Factors associated with earlier occurrence of motor fluctuations were cumulative levodopa dose, cumulative levodopa equivalent dose, and occurrence of dyskinesias. Factors associated with later occurrence of motor fluctuations were age at onset of 65 years or older and pramipexole treatment.

Back to top
Article Information

Correspondence: Robert A. Hauser, MD, Parkinson's Disease and Movement Disorders Center, Neuroscience Research Signature Program, University of South Florida, National Parkinson Foundation Center of Excellence, 4 Columbia Dr, Suite 410, Tampa, FL 33606 (rhauser@hsc.usf.edu).

Accepted for Publication: May 25, 2006.

Author Contributions:Study concept and design: Hauser and McDermott. Analysis and interpretation of data: Hauser, McDermott, and Messing. Drafting of the manuscript: Hauser, McDermott, and Messing. Critical revision of the manuscript for important intellectual content: Hauser and McDermott. Statistical analysis: McDermott and Messing. Study supervision: Hauser.

Financial Disclosure: Dr Hauser has received consulting fees or honoraria from Boehringer Ingelheim, Allergan, Bertek Pharmaceuticals, Eisai Medical Research, Inc, GlaxoSmithKline, Inc, Impax Pharmaceuticals, Merck KGaA, Novartis Pharmaceuticals, Ortho-McNeill, Pfizer Pharmaceutical Company, Prestwick Pharmaceuticals, Schering AG, Solvay Pharmaceuticals, Schwarz Pharma, Teva Pharmaceuticals, and Valeant Pharmaceuticals International.

References
1.
Chapuis  SOuchchane  LMetz  OGerbaud  LDurif  F Impact of the motor complications of Parkinson's disease on the quality of life.  Mov Disord 2005;20224- 230PubMedArticle
2.
Damiano  AMMcGrath  MMWillian  MK  et al.  Evaluation of a measurement strategy for Parkinson's disease.  Qual Life Res 2000;987- 100PubMedArticle
3.
Marras  CLang  AKrahn  MTomlinson  GNaglie  GParkinson Study Group, Quality of life in early Parkinson's disease.  Mov Disord 2004;1922- 28PubMedArticle
4.
Ahlskog  JEMuenter  MD Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.  Mov Disord 2001;16448- 458PubMedArticle
5.
Rascol  OBrooks  DJKorczyn  ADDe Deyn  PPClarke  CELang  AE A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa: 056 Study Group.  N Engl J Med 2000;3421484- 1491PubMedArticle
6.
Oertel  WHWolters  ESampaio  C  et al.  Pergolide versus levodopa monotherapy in early Parkinson's disease patients.  Mov Disord 2006;21343- 353PubMedArticle
7.
Lees  AJKatzenschlager  RHead  JBen-Shlomo  Y Ten-year follow-up of three different initial treatments in de-novo PD.  Neurology 2001;571687- 1694PubMedArticle
8.
Parkinson Study Group, Pramipexole vs. levodopa as initial treatment for Parkinson disease: a randomized controlled trial.  JAMA 2000;2841931- 1938PubMedArticle
9.
The Parkinson Study Group, Pramipexole vs. levodopa as initial treatment for Parkinson disease.  Arch Neurol 2004;611044- 1053PubMed
10.
Miller  AJ Subset Selection in Regression. 2nd ed. Boca Raton, Fla: Chapman & Hall/CRC; 2002
11.
Hosmer  DW  JrLemeshow  S Applied Survival Analysis.  New York, NY: John Wiley & Sons; 1999
12.
Hobson  DELang  AEMartin  WRRazmy  ARivest  JFleming  J Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group.  JAMA 2002;287455- 463PubMedArticle
13.
Mazzella  LYahr  MDMarinelli  LHuang  NMoshier  EDi Rocco  A Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy.  Parkinsonism Relat Disord 2005;11151- 155PubMedArticle
14.
Rajput  AHFenton  MEBirdi  S  et al.  Clinical-pathological study of levodopa complications.  Mov Disord 2002;17289- 296PubMedArticle
×