exhibit the problems of long-term treatment, namely, dyskinesia and end-of-dose deterioration with the 'on-off' phenomenon. After 10 years virtually 100% of patients are affected.
Dyskinesia comprises involuntary writhing movement of the face and limbs that may be biphasic (occurring at the start and end of motor response) or develop at the time of the maximum plasma levodopa concentration. They respond initially to reducing the dose of levodopa but at the cost of bradykinesia and as time passes there is progressively less scope to obtain benefit without unwanted effects.
End-of-dose deterioration is managed by increasing the frequency of dosing with levodopa (e.g. to 2-3-hourly), but this tends to result in the appearance, or worsening of the dyskinesia. The motor response then becomes more brittle with abrupt swings between hyper- and hypomobility (the on-off phenomenon). Despite their unpredicatable nature over the course of a single day, these changes are in fact dose-related, an effect that becomes apparent only when the response is related to total medication taken over a week.
Various strategies have been devised to overcome these problems. Controlled release preparations of levodopa tend to be associated with an inadequate initial response and disabling dyskinesia at the end of the dose. A more effective approach appears to be the use of a COMT inhibitor, e.g. entacapone, which can sometimes allay early end-of-dose deterioration without causing dyskinesia. This is now the main indication for its use. In any event, many patients with Parkinson's disease take at least two and sometimes more drugs at frequent intervals each day, an outcome that tends to rule their lives.
Continuous subcutaneous infusion of apomorphine can transform the quality of life of younger patients with severe motor fluctuations and dyskinesia, but this may lead to neuropsychiatric effects. If drug treatment fails in young non-demented patients, stereotactic subthalamotomy or bilateral stereotactic subthalamic stimulation can be very successful with only a small risk of surgical complications in experienced hands. Some 20% of patients with Parkinson's disease, notable the older ones, develop impairment of memory and speech with a fluctuating confusional state and hallucinations. As these symptoms are often aggravated by medication, it is preferable gradually to reduce the antiparkinsonian treatment, even at the expense of lessened mobility.
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