ABSTRACT
OBJECTIVE: To determine whether neuropsychological measures differ between patients with idiopathic Parkinson's disease (PD) who acquire dementia within 10 years of disease onset versus those who acquire dementia later in the disease course, using data from the longitudinal Sydney Multicentre Study of PD. METHODS: The Sydney Multicentre Study of PD is a cohort of 149 community-living de novo patients with idiopathic PD studied over a 20-year period. Detailed clinical and neuropsychological tests were administered at baseline and at 3, 5, 10, 15 and 20 years, and the dementia status was assessed at each time point. For the present study, the pattern of longitudinal neuropsychological measures was compared between PD patients with the onset of dementia in the middle (5-10 years, mid-stage PD dementia, N = 20) or late (>10 years, late-stage PD dementia, N = 10) disease stages using analysis of variance and multiple linear regression modelling, and the relationship between age and dementia onset assessed using survival statistics. RESULTS: Mid-stage PD dementia patients were differentiated from late-stage PD dementia patients by having greater deficits in vocabulary skills prior to and at dementia onset. The pattern of cognitive deficits following dementia onset are similar, and there is no difference in the age of dementia onset between the different PD groups. CONCLUSIONS: These data suggest that the evolution of dementia within PD occurs at around 70 years of age, regardless of the time of PD onset, and affects cognitive domains in a similar way, although patients with earlier-onset PD have a preserved linguistic ability prior to dementia onset.
Subject(s)
Dementia/etiology , Dementia/psychology , Neuropsychological Tests , Parkinson Disease/complications , Parkinson Disease/psychology , Age Factors , Age of Onset , Aged , Antiparkinson Agents/therapeutic use , Bromocriptine/therapeutic use , Cognition/physiology , Cohort Studies , Disease Progression , Female , Humans , Levodopa/therapeutic use , Longitudinal Studies , Male , Memory/physiology , Middle Aged , Neurologic Examination , New South Wales , Survival AnalysisABSTRACT
A patient with PD who exhibited disabling tremor and prominent dyskinesia underwent deep brain stimulation (DBS) of the left thalamic ventral intermediate nucleus. The electrode migrated and was replaced but with suboptimal clinical response. Two years later, postmortem analysis found the second electrode tip had entered the thalamic centromedian-parafascicular complex. There was a small thalamotomy and cell loss exceeding that found in PD. Thalamic damage may occur in association with DBS for PD.
Subject(s)
Electric Stimulation Therapy/adverse effects , Electrodes, Implanted/adverse effects , Intralaminar Thalamic Nuclei/pathology , Parkinson Disease/pathology , Chronic Disease , Fatal Outcome , Foreign-Body Migration/pathology , Humans , Male , Middle AgedABSTRACT
We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause.
Subject(s)
Parkinson Disease/complications , Pick Disease of the Brain/complications , Activities of Daily Living , Age Factors , Aphasia/diagnosis , Aphasia/etiology , Atrophy/pathology , Brain/metabolism , Brain/pathology , Cognition Disorders/diagnosis , Disability Evaluation , Fatal Outcome , Female , Follow-Up Studies , Humans , Immunohistochemistry , Lewy Bodies/metabolism , Lewy Bodies/pathology , Mental Disorders/diagnosis , Mental Disorders/etiology , Middle Aged , Nerve Tissue Proteins/metabolism , Neuropsychological Tests , Parkinson Disease/diagnosis , Pick Disease of the Brain/diagnosis , Reaction Time , Severity of Illness Index , Synucleins , tau Proteins/metabolismABSTRACT
The aim of current treatment of Parkinson's disease is to ameliorate the symptoms while seeking to lessen the potential development of late levodopa complications. To this end, there is ample evidence that the early use of dopamine agonists is beneficial in younger Parkinsonian patients but monotherapy with dopamine agonists is for only a select few. Nonergot dopamine agonists offer the potential for fewer side effects. Lower dose levodopa therapy delays the onset and reduces severity of dyskinesia and end of dose failure. However levodopa remains the treatment of choice in Parkinson's disease and should not be restricted unnecessarily in patients with disability. There is no evidence that levodopa is toxic to dopaminergic neurons in people with Parkinson's disease. As yet, no drugs are of proven neuroprotective value. Dopamine agonists, catechol-o-methyltransferase inhibitors, amantadine and apomorphine have differing but beneficial roles in the management of levodopa side effects. Ablative surgery and deep brain stimulation of thalamus, globus pallidus and subthalamic nucleus are increasingly available but choice of procedure depends not just on patient symptomatology, but also on local experience and results. Ideally, deep brain stimulation is the treatment of choice as it offers less morbidity than bilateral ablative surgery, the possibility of postoperative adjustments and the potential for reversibility if better treatments become available.
Subject(s)
Antiparkinson Agents/therapeutic use , Catechol O-Methyltransferase Inhibitors , Dopamine Agonists/therapeutic use , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Age Factors , Animals , Anxiety/etiology , Depression/etiology , Dyskinesia, Drug-Induced , Dystonia/chemically induced , Humans , Parkinson Disease/complications , Parkinson Disease/surgeryABSTRACT
There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.
Subject(s)
Brain/pathology , Cerebral Cortex/pathology , Lewy Body Disease/pathology , Parkinson Disease/pathology , Supranuclear Palsy, Progressive/pathology , Aged , Amygdala/pathology , Atrophy , Autopsy , Basal Ganglia/pathology , Female , Hippocampus/pathology , Humans , Male , Patient Selection , Regression Analysis , Thalamus/pathologyABSTRACT
We examined the topography and degree of cell loss within basal ganglia structures commonly involved in progressive supranuclear palsy in order to identify any relationship between degeneration in these nuclei and gaze palsy. Serial section analyses and unbiased quantitative techniques were applied to brain tissue from six cases with progressive supranuclear palsy (four with gaze palsy and two without) and six controls with no neurological or neuropathological abnormalities. The total number of nucleolated neurons within the substantia nigra pars compacta (SNc) and reticulata (SNr), the subthalamic nucleus, and the internal and external segments of the globus pallidus was determined for all subjects and the data expressed as percentages of control values to compare degeneration across these basal ganglia structures. The density of neurofibrillary tangles was also evaluated within these structures. Despite significant subcortical neurofibrillary tangle formation in all cases, there was considerable variability in the degree of neuronal cell loss in all basal ganglia regions, except the SNc which was consistently affected. There was no correlation between the ranked density of neurofibrillary tangles and the degree of neuronal cell loss in any basal ganglia region. Comparisons between cases with and without gaze palsy revealed a 40% greater decrease in the number of SNr neurons in cases with gaze palsy (75 +/- 8% loss) compared with those without (35 +/- 14% loss). This was the largest difference between these cases. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in progressive supranuclear palsy.
Subject(s)
Ocular Motility Disorders/physiopathology , Substantia Nigra/physiopathology , Supranuclear Palsy, Progressive/physiopathology , Aged , Basal Ganglia/pathology , Cell Death , Female , Humans , Male , Middle Aged , Nerve Degeneration/pathology , Neurofibrillary Tangles/pathology , Ocular Motility Disorders/pathology , Prospective Studies , Supranuclear Palsy, Progressive/pathologyABSTRACT
OBJECTIVES: To report on a 10 year follow up of patients with idiopathic Parkinson's disease, particularly with respect to mortality and the effect of early treatment with bromocriptine. METHODS: The patients are from the 149 new patients recruited for a double blind, randomised study of low dose levodopa-carbidopa versus low dose bromocriptine. Patients were examined neurologically at least yearly. Neuropsychological examinations were performed at 0, 3, 5, and 10 years. Mortality and cause of death in these patients were compared with the Australian population using standardised mortality ratios (SMRs). Mortality and disease progression were compared by sex and treatment group. Predictors of death within 10 years, nursing home admission, and progression in Columbia score of >/=20 points were examined by logistic regression analysis. RESULTS: Thirteen patients were excluded as having atypical Parkinsonism and six were lost to follow up. All available patients have been followed up for 10 years. Fifty patients (38%) were dead by 10 years and 63 by the last follow up. The SMR was 1.58 for all patients (p<0. 001). There was no significant difference in SMRs between the sexes. The mean duration of disease until death was 9.1 years. Parkinson's disease was thought to have contributed substantially to the death of 30 patients. The most common cause of death was pneumonia. Women progressed at a similar rate to men until 8 years, when the severity of their disease as measured by Hoehn and Yahr stage became greater (p<0.05). Older age of onset correlated with increased risk of death but the SMR was increased even in those aged <70 years (SMR 1.80, p=0.03). Early use of bromocriptine did not reduce mortality or slow progression of disease. One quarter of all patients had been admitted to nursing homes by 10 years. Only four patients were still employed. CONCLUSIONS: Mortality in Parkinson's disease remains increased despite low dose levodopa-carbidopa therapy and no additional benefit was gained from early use of bromocriptine. Duration of disease was similar to that in the era before levodopa.
Subject(s)
Parkinson Disease/mortality , Parkinson Disease/physiopathology , Age Distribution , Aged , Aged, 80 and over , Australia , Cause of Death , Female , Follow-Up Studies , Humans , Male , Nursing Homes , Sex Distribution , Survival Analysis , Time FactorsABSTRACT
This study measured brain atrophy in patients with idiopathic Parkinson's disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimer's disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimer's disease and is likely to be the anatomical substrate for the memory deficits found in each of these patients groups. Frontal lobe atrophy was a feature of both late-onset Parkinson's disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopammergic deafferentation, frontal atrophy and dementia.
Subject(s)
Brain/pathology , Parkinson Disease/pathology , Aged , Aged, 80 and over , Atrophy , Female , Frontal Lobe/pathology , Humans , Male , Middle Aged , Movement , Organ Size , Parkinson Disease/physiopathology , Reference Values , Temporal Lobe/pathologyABSTRACT
Neuropsychological assessments were performed in ninety-one de novo patients participating in the Sydney Multicentre Study of Parkinson's disease. Assessments were made at baseline and after 3 and 5 years. Performance at baseline and after 5 years was compared with controls. At baseline 37% of patients whose symptoms of Parkinson's disease had begun after the age of 70 years were demented. This compared with a prevalence of dementia of 8.8% in patients whose symptoms had begun before the age of 70 years. By 5 years the prevalence of dementia in the two groups had risen to 62.3% and 17.3% respectively. The death rate was higher over the 5 year period in the demented patients. Demented patients had more symmetrical signs, higher disability and bradykinesia scores and more impairment of gait and balance at baseline than non-demented patients. The presence of dementia at baseline predicted a poor response to treatment. The dementia at baseline had features of a subcortical dementia. Subsequently, aphasia, apraxia and agnosia emerged, making the dementia indistinguishable from that of Alzheimer's disease. Patients with well preserved cognitive function at baseline had a good response to levodopa and were more likely to develop levodopa induced dyskinesia. These results show that the clinical features of Parkinson's disease and response to treatment are influenced by the age of onset of symptoms and by the presence of dementia.
ABSTRACT
Although theoretical reasons exist for believing that selegiline slows the progression of Parkinson's disease, this has not been shown in clinical trials. Selegiline improves the symptoms of Parkinson's disease, allowing the introduction of levodopa to be delayed in de-novo patients and, later, for levodopa to be used at a lower dose. It does not lessen the long-term problems of dyskinesia and fluctuations associated with levodopa therapy. The report of an increased mortality associated with selegiline therapy awaits further evaluation. Of the dopamine agonists, pergolide appears to be more potent than bromocriptine; cabergoline looks promising. The catechol-O-methyltransferase inhibitors, tolcapone and entacopone, prolong the duration of action of levodopa and also show promise. The main objective in the drug treatment of Parkinson's disease remains the optimization of the dose and frequency of levodopa administration.
Subject(s)
Antiparkinson Agents/therapeutic use , Parkinson Disease/drug therapy , Antiparkinson Agents/adverse effects , Dopamine Agonists/adverse effects , Dopamine Agonists/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , Neurologic Examination/drug effects , Parkinson Disease/mortality , Randomized Controlled Trials as Topic , Selegiline/adverse effects , Selegiline/therapeutic use , Treatment OutcomeABSTRACT
The efficacy and side effects of pergolide, a D(1) and D(2) dopamine agonist, were assessed in an open label study in 39 patients with long standing Parkinson's disease complicated by end of dose failure and/or dyskinesia. 27 patients completed 28 weeks of the study. The mean dose of pergolide was 2.26 mg/day (0.15-5.0mg/day). Levodopa was reduced by a mean of 273 mg/day (range 0-1950mg/day) from the initial mean dose of 920 mg/day (range 150-2950mg/day). Hours in which the drug was efficacious significantly increased. Dyskinesia and dystonia were significantly reduced. The scores on an abbreviated Parkinson's disease rating scale significantly improved in both the 'on' and 'off' periods. 11 patients withdrew due to early side effects but the majority of patients tolerated pergolide well. In these patients pergolide was an effective adjunct to levodopa.
ABSTRACT
OBJECTIVE: To further elucidate the relation between diffuse Lewy body disease and Parkinson's disease. METHODS AND RESULTS: The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer's neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson's disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson's disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. CONCLUSIONS: Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson's disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson's disease.
Subject(s)
Alzheimer Disease/pathology , Parkinson Disease/pathology , Aged , Alzheimer Disease/psychology , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/psychologyABSTRACT
We have quantified midbrain cell loss in idiopathic Parkinson's disease (PD) compared with controls; six patients had PD with onset before 70 years, five patients had late onset PD (>70 years) and nine patients had diffuse Lewy body disease. The pattern of cell loss in these last two groups has not been previously described. No age associated neuronal loss was seen in controls. There was cell loss and reduced area of the pars compacta in all cases but no difference in the pattern of cell loss, which was predominantly ventral. The amount of cell loss in the dorsolateral cluster correlated with the duration of Parkinsonian symptoms, while greater cell loss in the dorsomedial cluster correlated with the presence of tremor and the absence of early dementia. These results suggest that the topography of midbrain pathology does not assist in differentiating these overlapping syndromes.
ABSTRACT
Factors at presentation which influenced the course of the disease and response to treatment were assessed in 125 de novo patients with Parkinson's disease. Ninety-eight patients were available for re-assessment at 5 years. Older patients presented earlier after the onset of symptoms, deteriorated more rapidly, and were significantly more likely to develop dementia and impairment of balance. Increasing age and symmetrical disease predicted the new appearance of imbalance. Age of onset did not predict dyskinesia or end of dose failure. A low tremor score at baseline and female gender were predictive of the early appearance of dyskinesia. Patients who experienced end of dose failure were taking a significantly higher dose of levodopa. Once dose and duration of treatment were corrected for, no baseline features were predictive of end of dose failure. The dose of levodopa at 5 years was positively correlated to baseline disease severity as measured by the Columbia score. We conclude that the age of onset of symptoms of Parkinson's disease is a major determinant of the course of the disease and response to treatment.
Subject(s)
Age of Onset , Antiparkinson Agents/therapeutic use , Bromocriptine/therapeutic use , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Adult , Aged , Antiparkinson Agents/administration & dosage , Bromocriptine/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Levodopa/administration & dosage , Male , Middle Aged , Movement Disorders/complications , Parkinson Disease/complications , Postural Balance , Treatment Outcome , Tremor/complicationsABSTRACT
149 previously untreated patients with Parkinson's disease were recruited over a three year period and randomly allocated to either low dose levodopa-carbidopa (< or = 600/150 mg/day) or low dose bromocriptine (< or = 30 mg/day). A five year follow up is reported on the 126 patients who completed the dose titration and who have not developed features of atypical Parkinsonism. Levodopa-carbidopa in low dosage adequately controlled symptoms in most patients and delayed the appearance of dyskinesia and end of dose failure for about two years longer than conventional doses. Only a few patients could be managed for more than one year on low dose bromocriptine alone; these patients had mild disease and asymmetric signs. Patients randomised to bromocriptine did not develop dyskinesia or troublesome end of dose failure until levodopa-carbidopa was added. The prevalence of dyskinesia in this group was lower than in patients given levodopa-carbidopa alone. The prevalence of end of dose failure was similar in the two randomisation groups once levodopa was introduced.
Subject(s)
Bromocriptine/therapeutic use , Carbidopa/therapeutic use , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Adult , Aged , Double-Blind Method , Drug Combinations , Female , Follow-Up Studies , Humans , Male , Middle Aged , Movement Disorders/epidemiology , Movement Disorders/etiology , Parkinson Disease/complications , Prevalence , Prospective Studies , Severity of Illness Index , Survival Analysis , Treatment FailureABSTRACT
Inter- and intrarater reliability in scoring the signs of Parkinson's disease using the original Columbia scale and a modified version of this, the Sydney scale, were assessed in five neurologists participating in a long-term study of Parkinson's disease. Scoring was done on video recordings of 41 patients whose disability ranged from mild to severe. Although all the neurologists were familiar with the scales and had received training designed to produce uniformity of scoring, interrater reliability was poor. The mean score for the Columbia scale varied from 18.6 to 30 and for the Sydney scale from 15.2 to 23.2. By contrast, intrarater reliability was good. This study highlights the limitations of clinical rating scales in Parkinson's disease when more than one rater is used. In designing clinical trials, every effort should be made to ensure that the same patient is always assessed by the same rater.
Subject(s)
Neurologic Examination , Parkinson Disease/diagnosis , Reproducibility of Results , Analysis of Variance , Female , Humans , Male , Videotape RecordingABSTRACT
One hundred de novo patients with Parkinson's disease (PD) were classified into two groups according to age of onset of symptoms. Seventy two patients were under 70 years and 28 were 70 years and over. All patients were given neurological and neuropsychological assessments, and the severity of the signs was rated on a modified Columbia scale. The neuropsychological assessment was also administered to 50 age-and-education-matched controls. The neuropsychological test battery included tests of verbal learning, visual memory, verbal fluency, visuospatial skill, simple and choice reaction time, language and maze learning. The late-onset patients had significant impairment in nonverbal reasoning, auditory verbal learning, visual memory and choice reaction time in contrast to early-onset patients and controls. A relationship was found between bradykinesia and widespread cognitive impairment. Severity of tremor was found to be significantly correlated with impairment in auditory verbal learning, visual memory and increased choice reaction time, while rigidity was found to be associated with cognitive impairment in verbal fluency and visuospatial skill. Using DSM II criteria, 39% of the late-onset and 8% of the early-onset group were classified as demented. Dementia was more common in patients with bilateral symmetrical disease and in those patients with marked tremor and bradykinesia. The pattern of cognitive impairment in PD was consistent with that associated with a subcortical dementia. This study confirms that the expression of PD is markedly influenced by the age of onset.
Subject(s)
Dementia/etiology , Parkinson Disease, Secondary/physiopathology , Age Factors , Aged , Humans , Neuropsychological Tests , Parkinson Disease, Secondary/psychologyABSTRACT
One hundred and twenty nine de novo patients with idiopathic Parkinson's disease are being followed over a 5 year period in a double-blind multicentre study comparing low-dose bromocriptine (less than 30 mg/day) with low-dose levodopa-carbidopa (less than 600/150 mg/day). Sixty six patients have been randomised to bromocriptine and 63 patients to levodopa-carbidopa. Improvement has been greater in the levodopa-carbidopa group than in the bromocriptine group. Involuntary movements have so far only occurred in patients on levodopa-carbidopa, the incidence being much lower than is usually described with conventional doses. Mild, end-of-dose failure has occurred in both treatment groups; however, no patient has developed the "on-off" phenomenon. Low-dose levodopa-carbidopa appears to be a more effective anti-Parkinsonian treatment than low-dose bromocriptine but more prone to cause dyskinesia.
Subject(s)
Bromocriptine/administration & dosage , Carbidopa/administration & dosage , Levodopa/administration & dosage , Parkinson Disease/drug therapy , Adult , Aged , Bromocriptine/adverse effects , Carbidopa/adverse effects , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Levodopa/adverse effects , Male , Middle Aged , Random AllocationABSTRACT
Low-dose bromocriptine therapy and low-dose levodopa-carbidopa therapy are being compared in a double-blind study over a five-year period as treatment for newly-diagnosed patients with Parkinson's disease. Ninety-four patients had entered the study by January 1986 and of these, 50 had been followed for six months or more. Preliminary results confirm that many patients with Parkinson's disease can be managed satisfactorily in the early stages of the disease with low-dose therapy. Three patients, all of whom were receiving levodopa-carbidopa therapy, developed dyskinesia. Twelve patients who had received bromocriptine had an inadequate response or developed confusion or postural hypotension. Of these patients, six had a poor response to subsequent levodopa-carbidopa therapy. While the initial improvement that results from low-dose bromocriptine therapy and low-dose levodopa-carbidopa therapy is less than one would expect with conventional doses of these agents, it is hoped that this approach will reduce the incidence of long-term side-effects such as dyskinesia and fluctuations.