We sought to determine the continued benefit and the pattern of motor complications of long-term levodopa treatment in Parkinson's disease. Patients were evaluated between 1968 and 1996. Only those who had an adequate levodopa trial and in whom autopsy revealed Lewy body Parkinson's disease were included. Total levodopa and mean daily dose were calculated in each case. Dyskinesia, wearing-off and on-off were collectively classified as motor adverse effects and reported as cumulative incidence. Forty-two patients (male, 30; female, 12) with mean 15.9 years of illness and 9.1 years follow-up received on average 500-mg levodopa daily over 9.8 years. Seventeen of 21 patients assessed during the last 18 months of life reported some motor benefit. Adverse effects were seen in 71.4% of patients. The most common was dyskinesia, in 61.9%; wearing-off in 35.7%; and on-off in 16.7% of patients. The earliest adverse effect was dyskinesia and the last to emerge was on-off. Isolated dyskinesia was seen in 35.7% and wearing-off in 7.1% of patients; 15.5% of patients developed dyskinesia after 2.6 years and 31% after 6.4 years on levodopa. We concluded that levodopa benefit declined and adverse effects increased with time. Dyskinesia was the earliest and the most common isolated adverse effect.

We evaluated 16 (15 men, 1 woman) autopsy-verified progressive supranuclear palsy (PSP) cases during 31 years (1969-2000) for clinical diagnosis and the course of the disease. The onset was gait difficulty or postural instability in 9 (56.3%), general motor slowing in 3 (18.8%), and tremor in 2. One case had onset with cognitive decline and 1 as hemidystonia. Four cases had supranuclear ophthalmoplegia (SNO) at the first assessment and were diagnosed as PSP. By last assessment, PSP diagnosis was made in 4 additional cases, but in 8 (50%) who never manifested ophthalmoplegia (mean 9.8 years after onset), PSP diagnosis was not made. Other manifestations included bulbar symptoms in 13 (81.3%), and cognitive impairment in 10 (62.5%) during the course of illness. Fifteen cases received levodopa, amantadine, anticholinergics, dopamine agonists, and selegiline in different combinations with symptomatic benefit in 9 of 15 (60%). Five had some improvement on levodopa alone and 3 showed more improvement when a dopamine agonist was added to levodopa. In general, the benefit was minimal and occurred only early in the course of illness. The mean age at onset was 63.7 (range, 53-85) years. Mean duration at PSP diagnosis was 4.8 (range, 2-11) years. Mean survival was 8.6 (range, 3-24) years and mean age at death was 72.3 (range, 60-89) years. When the different diagnostic criteria recommended in the literature were used, the accuracy of clinical diagnosis did not improve substantially.

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The expression of preproenkephalin messenger RNA was studied in the brain of Parkinson disease (PD) patients using in situ hybridization. All these patients were treated with levodopa (LD) and the development of motor complications was recorded. Eleven normal controls and 14 PD patients were used, of which 4 developed dyskinesias, 3 developed wearing-off, 3 developed both dyskinesias and wearing-off, and 4 developed no adverse effect following dopaminomimetic therapy. Nigrostriatal denervation was similar between the subgroups of PD patients as assessed using 125I-RTI-specific binding to the dopamine transporter and measures of catecholamine concentrations by HPLC. A significant increase of preproenkephalin messenger RNA levels was observed in the lateral putamen of dyskinetic patients in comparison to controls (+210%; p < 0.01) and in comparison to nondyskinetic patients (+112%; p < 0.05). No change was observed in medial parts of the putamen or in the caudate nucleus. No relationship between preproenkephalin messenger RNA levels and other clinical variables such as development of wearing-off, age of death, duration of disease, or duration of LD therapy was found. These findings suggest that increase synthesis of preproenkephalin in the medium spiny output neurons of the striatopallidal pathway play a role in the development of dyskinesias following long-term LD therapy in Parkinson disease.

Levodopa (LD) is the most effective drug for symptomatic control of Parkinson's disease, but has been suspected to be toxic to substantia nigra (SN) dopaminergic neurons. Tissue culture and animal studies of LD toxicity have produced contradictory evidence, and one study reported that a human subject exposed to a large cumulative dose (cd) of LD over 4 years had no evidence of SN damage. We report the cases of five patients, each of whom received a large cd of LD over a long period. Fluorodopa positron-emission tomography performed in one case indicated parkinsonism. Autopsies in two cases indicated a normal SN in one and a hypopigmented SN with normal cell complement in the other. Three patients had essential tremor, one had nonprogressive parkinsonism, and one had dopa-responsive dystonia. LD (without decarboxylase inhibitor) was administered over 21 years (cd = 21.99 kg), 9 years (cd = 6.6 kg), 26 years (cd = 18.7 kg), 11 years (cd = 3 kg), and 26 years (cd = 23.93 kg), respectively. None of the patients with essential tremor developed clinical features of parkinsonism that indicated significant SN damage, and one had a normal SN at autopsy. The parkinsonian patient displayed no detectable acceleration of disease process, and the patient with dopa-responsive dystonia had a normal complement of SN neurons at autopsy. We conclude that LD, administered at a dose commonly used for treating Parkinson's disease, was not toxic to SN neurons in these cases.

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