There is a loss of 50% to 60% of nigrostriatal neurons or a reduction in striatal dopamine concentrations of approximately 70% associated with the onset of clinical symptoms of PD (24). The surviving neurons can initially compensate with increased dopamine synthesis, but subsequently, with continued disease progression and neuronal loss, these mechanisms fail. What follows is the loss of the ability of nigrostri-atal neurons to store and release dopamine appropriately, followed by postsynaptic changes, both of which lead to a fluctuating response to levodopa (25). Glial cells can also convert levodopa to dopamine, but they lack the machinery for appropriate regulation (23). Hence, levodopa therapy leads to a substantial release of dopamine in the synapse in a pulsatile fashion. The levels of dopamine have been shown to be four-fold higher in the striatum of lesioned animals compared to normal, suggesting that a large pulse occurs in the synapse with oral medications in advanced disease (26). In PD, the loss of nigrostriatal innervation initially leads to putaminal D2 receptor upregulation, but a subsequent decline follows due to medical therapy (27).
Presynaptic and postsynaptic changes are important not only for responsiveness to levodopa but also the occurrence of motor fluctuations (wearing-off, dyski-nesia, and unpredictable responses). Historical literature suggests that the rate is approximately 50% for motor fluctuations and dyskinesia after five years of disease duration, and as high as 90% for patients with PD onset under age 40 (28). Ahlskog and Muenter (29) compared more recent literature to older studies and found that the rate is 35% to 40% after four to six years of disease with an increased frequency of 10% per year so that nearly 90% of patients experience these complications to some extent after a decade.
Motor fluctuations have several facets. Muenter and Tyce defined the long-duration response (LDR) as the gradual motor improvement seen after repeated dosing and subsequent decline over days upon levodopa withdrawal. This effect remains present even after long-term chronic therapy (30). The short-duration response (SDR) is defined as that which parallels the plasma concentrations of levodopa and seems to be present to some extent from the beginning of therapy. Nutt et al. showed that after a three-day withdrawal of levodopa, a patient receiving a single dose would have a full SDR, without a LDR. It has been suggested that the LDR may relate to storage capacity of dopaminergic neurons, although that is not the entire story since it occurs with levodopa and dopamine agonists (31) It may be that the LDR leads to the early and prolonged responsiveness to levodopa. Its loss results in the subsequent emergence and dependency on the SDR for symptomatic relief (32,33). A negative or inhibitory response has also been described; it is a worsening of motor function occurring prior to the SDR. It can last minutes to hours and has been termed a "super-off " (34). These three responses are imposed on a diurnal pattern of motor function (better performance in the morning with subsequent decline throughout the day) and on top of the continued endogenous dopamine activity (35,36). Nutt et al. (32) proposed that the residual endogenous dopamine activity as well as the LDR essentially determine the off-time patients experience.
Several patterns of motor fluctuations have been described (37-41). They progress from simple predictable patterns early to more complicated unpredictable ones. The earliest type is the wearing-off effect. With this pattern, the antiparkin-sonian effect of levodopa wears off toward the end of a dose in a predictable fashion. This has also been referred to as end-of-dose failure. This is followed by complicated wearing-off, where the duration of response of levodopa becomes more variable and the timing of wearing-off becomes less predictable but is still attributable to timing of doses. Patients may also begin to experience delayed-on (a delay in onset of effect of levodopa) and dose failures (no-on). The on-off effect is when levodopa response varies in an unpredictable manner unrelated to timing of the dose. This often happens suddenly like a light switch being turned on and off (38-40).
Dyskinesia can also occur in various patterns. The most common is peak-dose dyskinesia where choreic movements occur when plasma levodopa levels are at their peak. Diphasic dyskinesia is when mainly choreic or dystonic movements occur as plasma levels rise and at the end of the dose as plasma levels fall. Some patients have dyskinesia the entire time they are on, which is called square-wave dyskinesia. Dystonia may occur in the on or off states and includes early morning dystonia. Finally, patients may fluctuate abruptly from severe immobility to severe dyskinesia, which is referred to as yo-yoing (41).
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