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Keywords:

  • Parkinson's disease;
  • dopaminergic treatment;
  • resting tremor;
  • bradykinesia;
  • rigidity

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We aimed to evaluate the clinical factors predicting response to dopaminergic treatment for resting tremor in patients with Parkinson's disease (PD). Eighty-five PD patients with prominent resting tremor, defined as tremors of score greater than 3 in at least one limb on the Unified Parkinson's Disease Rating Scale (UPDRS), were divided into those responsive or nonresponsive to dopaminergic treatment. Responsiveness was defined as a reduction of at least two points for more than 3 months in the UPDRS tremor score. Of the 85 patients, 36 (42.4%) were responsive and 49 (57.6%) were nonresponsive to dopaminergic treatment. Initial UPDRS III score (P = 0.015) and Hoehn and Yahr stage (P = 0.010) were each significantly higher in the RG than in the NRG. UPDRS subscores for rigidity (P = 0.012), bradykinesia (P = 0.021) and postural impairment (P = 0.018) also correlated with responsiveness to dopaminergic treatment. Resting tremor in PD patients was more responsive to dopaminergic treatment when accompanied by moderate degrees of bradykinesia and rigidity than in patients without other prominent parkinsonian features. © 2007 Movement Disorder Society

Parkinson's disease (PD) is one of the most common neurodegenerative disorders of the elderly, but its etiology remains uncertain. PD is characterized by bradykinesia, rigidity, resting tremor, and postural instability.1, 2 Resting tremor is one of the cardinal motor features of PD, as well as one of the most readily identifiable signs of this disease.

Although bradykinesia and rigidity in PD have been associated with the degree of depletion of striatal dopamine caused by selective loss of dopaminergic neurons in the substantia nigra,3 the underlying pathophysiology of resting tremor remains unclear. A previous study with animal model has shown that focal lesions restricted to the substantia nigra pars compacta resulted in akinesia and rigidity without tremor.4 Using 18F-dopa positron emission tomography (18F-dopa PET) and [123I]-CIT (2β-carboxymethoxy-3β(4-iodophenyl tropane) single photon emission computed tomography (123I-β CIT SPECT), the reduced levels of striatal dopaminergic terminal function were shown to correlate consistently with the severity of rigidity and bradykinesia, but not with the degree of resting tremor.5, 6

Responsiveness of resting tremor to dopaminergic treatment is quite variable, such that physicians may have difficulty managing PD patients with severe resting tremor.7 We, therefore, sought to evaluate the clinical factors predicting responsiveness to dopaminergic treatment for resting tremor in patients with PD.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We tested responsiveness to dopaminergic treatment for resting tremor in 85 of the 104 PD patients with prominent resting tremor who visited Asan Medical Center between June 2004 and June 2005. A prominent resting tremor was defined as a tremor in at least one limb scoring higher than 3 on the Unified Parkinson's Disease Rating Scale Part III (UPDRS III).8 The clinical diagnosis of PD was established by experienced neurologists (S.J.C and M.C.L) using the United Kingdom Parkinson's Disease Society Brain Bank criteria.9 Patients with atypical parkinsonism, secondary parkinsonism, and family history of tremor were excluded.

Subjects were classified as responsive or nonresponsive according to the responsiveness of their resting tremors to dopaminergic treatment. Responsiveness was defined as a reduction of at least two points for more than 3 months in the UPDRS tremor score of the limb with prominent resting tremor. The evaluations of the UPDRS tremor score were performed during medication-“off” state at baseline and during medication-“on” state during follow-up period.

Medications used for the management of resting tremor were levodopa (standard form and/or slow release form) and dopamine agonists. Patients who were ≤60 years old were initially treated with dopamine agonists and were given supplementary L-dopa when patients were not adequately controlled by the therapeutic dose of dopamine agonists. Patients who were more than 60 years old were initially treated with L-dopa and were given supplementary dopamine agonists when patients were not adequately managed by the therapeutic dose of L-dopa. Thirty-nine patients were treated with only L-dopa, one with only dopamine agonist, and 45 with both L-dopa and dopamine agonists. Responsiveness to dopaminergic medications was evaluated in patients who were treated with therapeutic dosage of both L-dopa and dopamine agonists.

Patients administered amantadine, selegiline, anticholinergics, and β-blockers in combination with L-dopa or dopamine agonists were excluded. The equivalent dose of medications was calculated according to the following conversion formula: standard L-dopa dose × 1 '2b slow release L-dopa × 0.75 + bromocriptine × 10 + ropinirole × 20 + pergolide × 100 + pramipexole × 100.10

Patients visited clinic every month and their medications were optimally adjusted. Each patient was evaluated by a detailed medical history and a complete neurological examination, including the UPDRS and Hoehn and Yahr stage.

Two-sided t-test and χ2 test were used to analyze differences in demographic features, L-dopa dosage, UPDRS scores, and Hoehn and Yahr stage between in the responding and nonresponding groups. Logistic regression analysis was used to assess the clinical factors predictive of L-dopa responsiveness. All statistical analyses were performed using SPSS for Windows (version 12.0, SPSS). A P value <0.05 was regarded as statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The demographic and clinical characteristics of the 85 patients are summarized in Table 1. Thirty-six patients (42.4%) were in the responsive group (RG), and 49 (57.6%) in the nonresponsive group (NRG). There were 13 men and 23 women in the RG and 22 men and 27 women in the NRG. Mean age of the RG (70 ± 9.9 years) was higher than that of the NRG (64 ± 11.3 years; P = 0.016), but age at onset and duration of disease did not differ significantly. In the RG, the mean total L-dopa dosage was 743 ± 437 mg/day and the mean L-dopa equivalent dosage was 728 ± 437 mg/day, whereas in the NRG, the mean L-dopa dosage was 693 ± 405 mg/day and the mean L-dopa equivalent dosage was 713 ± 399 mg/day; neither of these differences was significant (Table 1).

Table 1. Demographic characteristics of patients with Parkinson's disease
 Total (n = 85)RG (n = 36)NRG (n = 49)P value
  1. Values are mean ± SD.

  2. RG, patients responsive to dopaminergic medications; NRG, patients nonresponsive to dopaminergic medications; LDED, levodopa equivalent dose.

Age (year)67 ± 1170 ± 9.964 ± 11.30.016
Gender (M/F)35/5013/2322/270.5
Age at onset (year)61.7 ± 12.863.5 ± 13.360.3 ± 12.30.262
Disease duration (year)5.3 ± 4.46.8 ± 5.94.2 ± 3.50.064
Levodopa dose (mg/day)715 ± 417743 ± 437693 ± 4050.59
LDED (mg/day)719 ± 413728 ± 437713 ± 3990.87

The Parkinsonian features of these two groups, including their UPDRS III subscores and Hoehn and Yahr stage are shown in Table 2. The scores for rigidity (P = 0.012) and bradykinesia, including hand movement (P = 0.002), leg agility (P = 0.041), body bradykinesia (P = 0.021) and finger tap (P = 0.004), and postural instability (P = 0.018) were significantly higher in the RG than in the NRG, as were total UPDRS III scores and median Hoehn and Yahr stage.

Table 2. Parkinsonian features of patients with Parkinson's disease
Parkinsonian featuresRange of possible scoresTotal (n = 85)RG (n = 36)NRG (n = 49)P value
  1. Values are mean ± SD.

  2. RG, patients responsive to dopaminergic medications; NRG, patients nonresponsive to dopaminergic medications.

Resting tremor0–286.2 ± 2.76.5 ± 2.75.9 ± 2.80.37
Rigidity0–204.3 ± 3.45.4 ± 3.33.5 ± 3.20.012
Finger tap0–82.6 ± 1.53.1 ± 1.52.2 ± 1.40.004
Hand movement0–82.0 ± 1.32.5 ± 1.31.6 ± 1.30.002
Alternative hand movement0–82.2 ± 1.22.5 ± 1.12.0 ± 1.30.088
Leg agility0–82.1 ± 1.62.5 ± 1.51.8 ± 1.60.041
Body bradykinesia0–41.1 ± 0.81.4 ± 0.71.0 ± 0.80.021
Postural instability0–40.6 ± 0.70.8 ± 0.70.4 ± 0.60.018
Total motor UPDRS0–10826.9 ± 13.431 ± 11.623.9 ± 140.015
Hoehn and Yahr stage0–52.1 ± 0.62.3 ± 0.51.9 ± 0.60.01

When we performed logistic regression analysis to evaluate the factors predicting response of resting tremor to dopaminergic treatment, we found that both age and hand movement subscore of the UPDRS III were significantly associated with responsiveness. Each 1 year increase in age increased the probability of responsiveness 1.051-fold (P = 0.04), and each 1 point increase in the hand movement subscore of the UPDRS III increased the probability of responsiveness 1.636-fold (P = 0.008).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We found that resting tremor in patients with PD was more responsive to dopaminergic treatment when accompanied by a moderate degree of bradykinesia and rigidity than when it presented without prominent accompanying parkinsonian features. These findings suggest that resting tremor accompanying rigidity and bradykinesia in RG involving predominantly dopaminergic system may respond more favorably to dopaminergic treatment. In contrast, resting tremor without prominent other parkinsonian features in NRG may implicate other nondopaminergic neurotransmitter dysfunctions and this may explain why patients in NRG showed no responsiveness to dopaminergic medications.

Our results further suggest that the anatomical basis of the resting tremor may differ from the classic neuropathology of PD. In a previous study using 18F-dopa PET, decreases of 18F-fluorodopa uptake in the striatum correlated with the degree of bradykinesia and rigidity, but not with the degree of tremor.11 Recently, other studies have investigated the association between resting tremor in PD and the deficit of nondopaminergic neurotransmitters, especially serotonin.12, 13

There is also evidence that resting tremor in some PD patients may be partly or entirely caused by dopaminergic dysfunction. Although the responsiveness of resting tremor to dopaminergic treatment is highly variable, these tremors may respond dramatically.14 In addition, resting tremor typical of PD can be produced by neuroleptics or other dopamine receptor blocking agents such as prochlorperazine and metoclopramide,15, 16 or by destruction of the substantia nigra pars compacta with intracarotid injections of MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine).17

It is currently unclear what mechanisms underlie more favorable dopaminergic response of the resting tremor in elderly advanced PD patients. One possible explanation is that age-related decrease in dopaminergic neurons in the substantia nigra may contribute to the development of resting tremor by more severe dopaminergic dysfunction and more favorable response to dopaminergic medications in elderly PD patients in RG compared with patients in NRG.

Our study has significant clinical implications. Although resting tremor is the major symptom of PD, the optimal pharmacologic treatment has not yet been established. The results presented here suggest that dopaminergic medications may be more effective on resting tremor in PD patients with a moderate degree of bradykinesia and rigidity than in those who have disproportionately prominent resting tremor compared with other parkinsonian features. In contrast, tremor dominant relatively young PD patients may have little therapeutic benefit from dopaminergic medications; in these latter individuals, anticholinergics or amantadine may be needed to control severe resting tremor.

The present study had limitations, including the small number of patients. In addition, the maximum tolerable dosage of dopaminergic medications was not administered to each patient. Additional large-scale studies with functional brain imaging, such as PET study with markers of the dopaminergic and nondopaminergic systems, are needed to confirm the significance of our findings.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

This study was supported by a grant (2006–416) from the Asan Institute for Life Sciences, Seoul, Korea.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES