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The Need for Enhanced Strategies to Manage Levodopa-Induced Dyskinesia in Parkinson’s Disease

The Need for Enhanced Strategies to Manage Levodopa-Induced Dyskinesia in Parkinson’s Disease

Levodopa-induced dyskinesia (LID)
LID is characterized by involuntary movements during the waking hours that are nonrhythmic, purposeless, and unpredictable. In some cases, and especially for patients, it is difficult to recognize the occurrence of dyskinesias as a side-effect of levodopa and not a symptom of the underlying PD.10 An increased risk of developing LID has been associated with different factors, including:
  • An early onset (<50 years) of PD11,12
  • A longer duration of PD12
  • Longer periods of treatment with levodopa12  
  • Higher-daily levodopa dosages13,14
Although the pathophysiologic changes are not completely understood, LID is most likely a consequence of progressive motor circuitry dysfunction in the parkinsonian brain and levodopa therapy.
In the non-disease state, purposeful movement is generated through the interplay of cortical and subcortical motor pathways. The motor cortex sends axonal projections to the subcortical structures collectively referred to as the basal ganglia. Cortical inputs to the basal ganglia are received in the area known as the striatum. Outputs from the basal ganglia are carried by way of 2 main pathways, the direct and indirect pathways. These 2 subcortical pathways work in opposing, but coordinated, fashion to regulate movement, the direct (or GO) pathway facilitating movement, and the indirect (or STOP) pathway inhibiting it.15 

The direct (GO) and indirect (STOP) pathways both receive excitatory drive via glutamate, a neurotransmitter that is released from cortical axon terminals within the striatum. The responsiveness of these 2 pathways to glutamatergic excitation is, however, differentially modulated by dopamine. Dopamine acting on the neurons of the direct (GO) pathway (expressing D-1 type dopamine receptors) facilitates glutamate-mediated neuronal activity, whereas dopamine acting on the neurons of the indirect pathway (expressing D-2 type dopamine receptors) inhibits glutamate-mediated neuronal activity.15,16

The striatum receives its dopaminergic innervation from axonal projections from the specialized neurons of the substantia nigra. In return, the activity of the substantia nigra is regulated by reciprocating pathways from the basal ganglia. Thus, it is the regulated release of dopamine from substantia nigra neurons that modulates the responsiveness of striatal neurons in both the direct (GO) and indirect (STOP) pathways to glutamatergic activation originating from the motor cortex.15

It is well-established that PD results from the progressive degeneration and loss of dopaminergic neurons in the substantia nigra. In PD, as dopamine is lost, the subcortical motor pathways become dysregulated, with the indirect (STOP) pathway becoming overactive and the direct (GO) pathway becoming under-active. Dopamine loss therefore shifts the balance of signaling in the key motor pathways of the basal ganglia in favor of STOP signals, leading to reduction and slowing of voluntary movement, cardinal symptoms of the disease.16

To offset the imbalance between the STOP and GO pathways, and thereby to reestablish voluntary movement, dopamine needs to be resupplied to the striatum of patients with PD. This is best achieved through the systemic (usually oral) administration of levodopa, a precursor of dopamine. When plasma levodopa levels are adequate to generate striatal dopamine levels capable of facilitating the GO and inhibiting the OFF pathways to the point where a PD patient can move voluntarily, the patient is said to be in the “ON” state; and when they are insufficient, and cardinal symptoms of PD return, the patient is said to be in the “OFF” state. Switching between ON states and OFF states is referred to as the “ON-OFF phenomenon.”17

Early in the course of PD, there is a sufficient number of surviving dopaminergic neurons (as many as 50%) to allow for the conversion of levodopa to dopamine by neurons that are still subject to physiologic regulation. When this is the case, OFF periods tend to occur predictably, as end-of-dose wearing-off, and ON periods are characterized by movement that approximate normal mobility.17
With continued loss of dopaminergic neurons, higher doses of levodopa are usually required to overcome the OFF state. Additionally, serotonergic neurons take over the processing of levodopa and release of dopamine, but they lack the appropriate regulatory mechanisms. This results in wide and often unpredictable fluctuations in striatal dopamine levels in response to levodopa administration.17 As a consequence, OFF periods may occur more frequently and less predictably. Moreover, ON periods may occur less frequently and be accompanied by the abnormal movements of LID.

While the progressive loss of levodopa to provide adequate and reliable levels of striatal dopamine is one of the major contributors to the development of levodopa-associated motor complications, another is the overactivation of glutamatergic motor pathways in response to dopamine dysregulation. This is particularly relevant to the development of LID.17
Evidence suggests that the overactivation of glutamatergic motor pathways involves excessive release of glutamate from the presynaptic terminals of cortical neurons projecting to the striatum. Further evidence suggests the involvement of postsynaptic mechanisms, including the up-regulation of glutamate receptors of the NMDA class on striatal neurons.17 Thus, in PD, levodopa administration can cause increased release of glutamate into the synaptic cleft, resulting in excessively high levels of glutamate receptor stimulation (Figure 2),15 and its clinical manifestation, LID.
The clinical manifestations of LID can be heterogeneous and include rapid, dance-like (choreic) movements, as well as slow twisting or writhing (dystonic) movements. The occurrence of LID can be related to the levodopa plasma levels and classified on this basis. The most common form of LID occurs when levodopa plasma levels are at their highest, ie, peak-dose dyskinesia. Manifestations of LID can, however, also occur between “on” and “off states,” so-called diphasic dyskinesia, the second most common form of LID. The least common manifestation of LID is the off-period form, which tends to be dystonic. (Figure 3)17-19

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