Complications Of Long-Term Therapy In Parkinson's Disease

Patients usually experience good control of parkinsonian features when symptomatic therapy is first introduced. This is maintained for approximately three to five years into levodopa therapy. Patients initially experience a stable response through the day. Despite levodopa therapy, disability continues to progress. Over the years there is a tendency to administer increasing amounts of dopaminergic medication in order to minimize the progression of functional disability.

Between approximately four and eight years, many patients experience motor fluctuations and dyskinesia. Patients begin to notice that whereas they used to be able to take standard levodopa/PDI three or four times a day and still maintain a stable response, the benefit now lasts a few hours and then wears off. Patients may initially notice a short duration levodopa response of four to five hours. Over the next few years, the short duration response becomes more fleeting and benefit lasts only two to three hours. Over time, clinical status more and more closely fluctuates in concert with peripheral levodopa concentration .

During this time, many patients also develop peak-dose dyskinesia consisting of choreiform twisting, turning movements that occur when central dopamine levels are peaking. This marks an important milestone in the treatment of Parkinson's disease because it limits the amount of dopaminergic therapy that can be provided. At this point, higher doses of dopaminergic therapy are likely to increase peak-dose dyskinesia. This "hypersensitivity" may result from exposing post-synaptic receptors to rapidly fluctuating levodopa-derived dopamine levels.

From five to ten years into symptomatic therapy, much of the management of Parkinson's disease centers on titrating therapy to maximize "on" time without dyskinesia. Too much dopaminergic therapy exacerbates peak- dose dyskinesia and too little dopaminergic therapy fails to bring about sufficient benefit. Despite optimal titration, many patients eight or more years into symptomatic therapy suffer with troublesome or disabling motor fluctuations and dyskinesia.

Some patients develop dementia as the disease progresses. As antiparkinsonian therapy can worsen confusion and hallucinations, the presence of cognitive dysfunction can also limit administration of medication to improve motor symptoms.

By ten to twelve years into therapy, many patients have developed balance difficulty. This is another important milestone. True postural imbalance is not improved by any current antiparkinsonian therapy. Patients are then at risk for morbidity and mortality from falls. immobility may place a patient at increased risk for infections and swallowing difficulty may increase the risk of aspiration and malnutrition.

Individual progression varies greatly. Some patients maintain relatively good function fifteen years into the disease and others experience meaningful disability within a few years.

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