0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contributions |

Resting Tremor in Parkinson Disease:  A Negative Predictor of Levodopa-Induced Dyskinesia FREE

Stefan Kipfer, MD; Marianne A. Stephan, PhD; W. M. Michael Schüpbach, MD; Pietro Ballinari, MA; Alain Kaelin-Lang, MD, PhD
[+] Author Affiliations

Author Affiliations: Movement Disorders Center, Department of Neurology (Drs Kipfer, Stephan, Schüpbach, and Kaelin-Lang), and Departments of Psychiatric Neurophysiology and Psychiatry (Mr Ballinari), “Inselspital” Berne University Hospital, University of Berne, Berne, Switzerland. Dr Stephan is now with the Human Cortical Physiology and Stroke Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.


Arch Neurol. 2011;68(8):1037-1039. doi:10.1001/archneurol.2011.147.
Text Size: A A A
Published online

Background It is unclear whether patients with different clinical subtypes of Parkinson disease (PD) differ in their risk of developing levodopa-induced dyskinesia (LID) and whether resting tremor is negatively correlated with this risk.

Objectives To determine whether resting tremor as an initial manifestation of PD negatively correlated with subsequent occurrence and severity of LID and to study the correlations between LID and other epidemiological factors (eg, age at onset of PD and duration of PD).

Design Logistic regression analysis was used to determine predictive factors of LID. Spearman rank correlations between LID and epidemiological factors and motor signs (including tremor) were calculated.

Setting Institutional tertiary referral center for movement disorders.

Patients Cohort of 85 patients with PD.

Main Outcome Measure Occurrence of LID according to the Unified Parkinson Disease Rating Scale part IV.

Results Resting tremor as an initial manifestation of PD was associated with reduced risk of developing LID independent of other predictors of LID (duration of PD, axial signs, and levodopa dose).

Conclusion Resting tremor as an initial manifestation of PD predicts lower probability of developing LID under levodopa treatment.

Levodopa-induced dyskinesia (LID) is a common and disabling long-term complication of dopaminergic therapy for Parkinson disease (PD). For example, the ELLDOPA (Earlier vs Later Levodopa Therapy in Parkinson Disease) study showed that as many as 16.5% of patients experience dyskinesia within 9 months after initiating levodopa treatment.1 Several clinical factors are known to increase the risk of developing LID, such as more advanced Hoehn and Yahr2 stage (H&Y stage), higher cumulative levodopa dose, and longer duration of PD.35

However, it is unclear whether patients with different clinical subtypes of PD differ in their risk of developing LID. Patients with PD having so-called benign tremulous parkinsonism were reported to have a benign clinical course with slowly progressive disease.6 Yet, it remains unknown whether resting tremor is negatively correlated with the risk of developing LID.

In this cohort study, we aimed to determine whether resting tremor as an initial manifestation of PD is negatively correlated with subsequent occurrence and severity of LID. Furthermore, the Spearman rank correlations between LID and other epidemiological factors (eg, age at onset of PD and duration of PD) were studied.

Using the database at our Movement Disorders Center in Berne, Switzerland, we studied 85 consecutively seen patients with PD. For each patient, data were used from 1 single assessment. Inclusion criteria were clinically diagnosed PD according to the United Kingdom Brain Bank guidelines,7 no deep brain stimulation surgery, and a complete medical record with available data on the following: duration of PD, actual treatment regimen, clinical assessment scores (described herein), disease stage (H&Y stage and Schwab and England Disability Scale8 score [S&E score]), and onset and nature of initial symptoms (according to medical history or predominant symptoms at the initial visit).

Eighty-five patients (57 men and 28 women) had a mean (SD) age of 64.6 (8.4) years. Their mean (SD) age at onset of PD was 55.3 (10.6) years, and they had had PD for a mean (SD) of 9.5 (6.4) years; 48 patients had resting tremor as an initial manifestation of PD. Seventeen patients were examined in the off-medication state (ie, not taking their current dopaminergic therapeutic regimen); all others were examined in the on-medication state (ie, taking their current dopaminergic therapeutic regimen). Patients were assessed using the Unified Parkinson Disease Rating Scale (UPDRS) part III (motor function),9 H&Y disease staging scale,7 and Schwab and England (S&E) scale.8 Occurrence and severity of LID were quantified using the UPDRS IV-A, a calculated subscore of the UPDRS IV (anamnestic information on dyskinesia duration, disability, early morning dystonia, and painful dyskinesia during the preceding week). We also used the following motor subscores based on the UPDRS III: rigidity subscore, resting tremor and action tremor subscores, axial subscore (voice, rising from a chair, posture, gait, and postural stability), and bradykinesia subscore (finger tapping, hand movements, hand pronation and supination, and leg agility).10

We performed nonparametric Spearman rank correlations between severity of LID, as assessed by the UPDRS IV-A, and the following variables: duration of PD, age at onset of PD, S&E score, H&Y stage, motor signs (UPDRS III subscores), and current levodopa-equivalent daily dose (LEDD).11

We performed univariate and multivariate logistic regression analyses (separately calculated for anamnestic and clinical predictors) to assess the contribution of each of the following variables to the presence or absence of LID: sex, LEDD, duration of PD, age at onset of PD, UPDRS III subscores, S&E score, H&Y stage, and initial manifestations of PD (tremor or other manifestations). For these analyses, patients were divided into dyskinetic and nondyskinetic groups according to their UPDRS IV-A subscores (patients in the dyskinetic group had a nonzero UPDRS IV-A subscore). A forward stepwise multivariate logistic regression analysis was then performed to identify independent predictors.12 To avoid potential systematic bias, we excluded 17 patients who were examined in the off-medication state from all analyses correlating the UPDRS III subscores and H&Y stage with the UPDRS IV-A subscores and from the multivariate logistic regression analyses. Therefore, we avoided correlating clinical off-medication signs with the UPDRS IV-A subscores, which reflect the on-medication state during the past week. Nevertheless, small therapeutic differences between groups (tremor or other manifestations) are possible because cumulative LEDD was not recorded. Only small proportions of both groups were receiving amantadine sulfate treatment.

P <.05 was considered statistically significant. Statistical analyses were performed using commercially available statistical software (SPSS, version 17.0; SPSS, Inc, Chicago, Illinois).

Thirty-nine of 85 patients had LID (a nonzero UPDRS IV-A subscore). Correlations between severity of LID and the various clinical variables are given in Table 1.

Table Graphic Jump LocationTable 1. Spearman Rank Correlation Coefficients Among Patients in the Dyskinetic Groupa

Univariate logistic regression analysis identified 8 of 12 variables as significant predictors of LID (eTable). Patients in the dyskinetic group had longer duration of PD, were younger at onset of PD, had a higher UPDRS III axial subscore, and less frequently had resting tremor as an initial manifestation of PD; however, they had higher LEDD, lower S&E score, higher H&Y stage,2 and lower tremor subscore.

Because patients in the dyskinetic group had significantly longer duration of PD, a multivariate logistic regression analysis (Table 2) was performed among all prognostic variables in the statistical model. Identified as independent predictors of LID were LEDD, duration of PD, UPDRS III axial subscore, and type of initial motor manifestation of PD (tremor or other manifestations). The absence of resting tremor among initial manifestations of PD was a strong predictor of LID (odds ratio, 8.67) independent of the duration of PD.

Table Graphic Jump LocationTable 2. Multivariate Logistic Regression Analysisa

About 50% of patients with PD have resting tremor as an initial manifestation of the disease.13 The disease course depends on the PD subtype.14 Josephs et al6 described a subgroup of 16 patients with PD having predominant resting tremor whose motor manifestations other than tremor progressed more slowly. Only 2 of these patients developed dyskinesia; however, not all patients in this cohort were treated with levodopa. We observed that the absence of resting tremor at onset of PD is an important independent predictor of the development of LID during the course of PD. This agrees with the observation of a more benign course of PD in tremor-dominant forms.6 Moreover, we found a positive correlation between the severity of LID and axial motor signs, which may best be explained by the fact that both reflect advanced disease.

Multivariate logistic regression analyses revealed that LID was independently predicted by LEDD, duration of PD, and the presence or absence of resting tremor as an initial manifestation of PD. Most important, the duration of PD was a weaker predictor than the type of initial manifestation. Therefore, our findings suggest that resting tremor as an initial manifestation of PD is a negative predictor of LID (presence and severity) during the course of PD independent of LEDD and the duration of PD.

However, the pathophysiological mechanisms of resting tremor are not completely understood and cannot be fully explained as the result of a dopaminergic deficit. Functional imaging studies, including positron emission tomography and single-photon emission computed tomography, show poor correlation between resting tremor and dopaminergic deficiency, while bradykinesia and rigidity are highly correlated with the degree of dopaminergic denervation.15 The relative resistance of resting tremor to levodopa, as well as the effectiveness of nondopaminergic drugs like clozapine16 or the glutamate antagonist budipine17,18 against resting tremor, implies that the pathogenesis of resting tremor may involve nondopaminergic, possibly compensatory, mechanisms. Therefore, the negative association between LID and resting tremor as an initial manifestation of PD might be caused by differing patterns of neurodegeneration in these subgroups of patients. It has also been proposed that resting tremor may be linked with secondary compensatory mechanisms that might prevent LID, despite levodopa treatment.13

Aside from the known clinical predictors of LID, occurrence of resting tremor as an initial manifestation of PD may predict not only slower progression of the disease but also lower probability of developing LID. However, selection bias owing to the referral of more severe cases to our tertiary care center cannot be excluded. Nevertheless, it is unlikely that a referral bias falsified our findings because no systematic selection of patients occurred. Prospective studies are desirable to correlate occurrence of LID with cumulative levodopa dose in subgroups of patients with PD.

Correspondence: Marianne A. Stephan, PhD, Human Cortical Physiology and Stroke Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 10, Room 7D50-52, Bethesda, MD 20892 (marianne.stephan@alumni.ethz.ch).

Accepted for Publication: April 22, 2011.

Author Contributions:Study concept and design: Stephan, Schüpbach, and Kaelin-Lang. Acquisition of data: Kipfer, Stephan, and Schüpbach. Analysis and interpretation of data: Kipfer, Schüpbach, Ballinari, and Kaelin-Lang. Drafting of the manuscript: Kipfer. Critical revision of the manuscript for important intellectual content: Stephan, Schüpbach, Ballinari, and Kaelin-Lang. Statistical analysis: Kipfer, Schüpbach, Ballinari, and Kaelin-Lang. Obtained funding: Kaelin-Lang. Administrative, technical, and material support: Kipfer and Stephan. Study supervision: Stephan, Schüpbach, and Kaelin-Lang.

Financial Disclosure: Dr Stephan received a fellowship from the Swiss National Science Foundation to perform scientific studies at the National Institutes of Health, Bethesda, Maryland. Dr Schüpbach received speaker's honoraria and travel reimbursement from Medtronic and UCB Pharma; he received research grants from Parkinson Switzerland and Mach-Gaensslen Stiftung Switzerland. Dr Kaelin-Lang received speaker's and advisory board honoraria and travel reimbursement from UCB Pharma, Boehringer Ingelheim, Novartis, and Allergan Inc; he received research grants from Parkinson Switzerland.

Funding/Support: This work was supported by a grant from Swiss Parkinson Association (Dr Kaelin-Lang).

Additional Contributions: Ethan Taub, MD, performed text editing.

Fahn S, Oakes D, Shoulson I,  et al; Parkinson Study Group.  Levodopa and the progression of Parkinson's disease.  N Engl J Med. 2004;351(24):2498-2508
PubMed   |  Link to Article
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality.  Neurology. 1967;17(5):427-442
PubMed   |  Link to Article
Hauser RA, McDermott MP, Messing S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease.  Arch Neurol. 2006;63(12):1756-1760
PubMed   |  Link to Article
Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism.  Lancet Neurol. 2006;5(4):355-363
PubMed   |  Link to Article
Fahn S. The spectrum of levodopa-induced dyskinesias.  Ann Neurol. 2000;47(4):(suppl 1)  S2-S11
PubMed
Josephs KA, Matsumoto JY, Ahlskog JE. Benign tremulous parkinsonism.  Arch Neurol. 2006;63(3):354-357
PubMed   |  Link to Article
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.  J Neurol Neurosurg Psychiatry. 1992;55(3):181-184
PubMed   |  Link to Article
Schwab R, England A. Projection technique for evaluating surgery in Parkinson's disease. In: Gillingham FJ, Donaldson IML, eds. Third Symposium on Parkinson's Disease. Edinburgh, Scotland: Livingstone; 1969:152-158
Fahn S, Elton RL. The Unified Parkinson's Disease Rating Scale. Vol 2. Florham Park, NY: Macmillan Health Care Information; 1987
Schüpbach WM, Chastan N, Welter ML,  et al.  Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up.  J Neurol Neurosurg Psychiatry. 2005;76(12):1640-1644
PubMed   |  Link to Article
Esselink RA, de Bie RM, de Haan RJ,  et al.  Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.  Neurology. 2004;62(2):201-207
PubMed   |  Link to Article
Hosmer DW, Lemeshow S. Applied Logistic Regression. 2nd ed. New York, NY: John Wiley & Sons Inc; 2000
Fishman PS. Paradoxical aspects of parkinsonian tremor.  Mov Disord. 2008;23(2):168-173
PubMed   |  Link to Article
Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Parkinson disease subtypes: a 39-year clinicopathologic study.  Neurology. 2009;73(3):206-212
PubMed   |  Link to Article
Pirker W. Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it?  Mov Disord. 2003;18:(suppl 7)  S43-S51
PubMed   |  Link to Article
Jansen EN. Clozapine in the treatment of tremor in Parkinson's disease.  Acta Neurol Scand. 1994;89(4):262-265
PubMed   |  Link to Article
Reichmann H. Budipine in Parkinson's tremor.  J Neurol Sci. 2006;248(1-2):53-55
PubMed   |  Link to Article
Blahak C, Wöhrle JC, Capelle HH,  et al.  Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson's disease.  J Neurol. 2007;254(2):169-178
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Spearman Rank Correlation Coefficients Among Patients in the Dyskinetic Groupa
Table Graphic Jump LocationTable 2. Multivariate Logistic Regression Analysisa

References

Fahn S, Oakes D, Shoulson I,  et al; Parkinson Study Group.  Levodopa and the progression of Parkinson's disease.  N Engl J Med. 2004;351(24):2498-2508
PubMed   |  Link to Article
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality.  Neurology. 1967;17(5):427-442
PubMed   |  Link to Article
Hauser RA, McDermott MP, Messing S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease.  Arch Neurol. 2006;63(12):1756-1760
PubMed   |  Link to Article
Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism.  Lancet Neurol. 2006;5(4):355-363
PubMed   |  Link to Article
Fahn S. The spectrum of levodopa-induced dyskinesias.  Ann Neurol. 2000;47(4):(suppl 1)  S2-S11
PubMed
Josephs KA, Matsumoto JY, Ahlskog JE. Benign tremulous parkinsonism.  Arch Neurol. 2006;63(3):354-357
PubMed   |  Link to Article
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.  J Neurol Neurosurg Psychiatry. 1992;55(3):181-184
PubMed   |  Link to Article
Schwab R, England A. Projection technique for evaluating surgery in Parkinson's disease. In: Gillingham FJ, Donaldson IML, eds. Third Symposium on Parkinson's Disease. Edinburgh, Scotland: Livingstone; 1969:152-158
Fahn S, Elton RL. The Unified Parkinson's Disease Rating Scale. Vol 2. Florham Park, NY: Macmillan Health Care Information; 1987
Schüpbach WM, Chastan N, Welter ML,  et al.  Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up.  J Neurol Neurosurg Psychiatry. 2005;76(12):1640-1644
PubMed   |  Link to Article
Esselink RA, de Bie RM, de Haan RJ,  et al.  Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.  Neurology. 2004;62(2):201-207
PubMed   |  Link to Article
Hosmer DW, Lemeshow S. Applied Logistic Regression. 2nd ed. New York, NY: John Wiley & Sons Inc; 2000
Fishman PS. Paradoxical aspects of parkinsonian tremor.  Mov Disord. 2008;23(2):168-173
PubMed   |  Link to Article
Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Parkinson disease subtypes: a 39-year clinicopathologic study.  Neurology. 2009;73(3):206-212
PubMed   |  Link to Article
Pirker W. Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it?  Mov Disord. 2003;18:(suppl 7)  S43-S51
PubMed   |  Link to Article
Jansen EN. Clozapine in the treatment of tremor in Parkinson's disease.  Acta Neurol Scand. 1994;89(4):262-265
PubMed   |  Link to Article
Reichmann H. Budipine in Parkinson's tremor.  J Neurol Sci. 2006;248(1-2):53-55
PubMed   |  Link to Article
Blahak C, Wöhrle JC, Capelle HH,  et al.  Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson's disease.  J Neurol. 2007;254(2):169-178
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Resting Tremor in Parkinson Disease: A Negative Predictor of Levodopa-Induced Dyskinesia
Arch Neurol.2011;68(8):1037-1039.eTable

eTable -Download PDF (19 KB). This file requires Adobe Reader®.

eTable. Univariate Logistic Regression Analysis
Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 3

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Make the Diagnosis: Parkinsonism

The Rational Clinical Examination
Original Article: Does This Patient Have Parkinson Disease?