Dyskinesia refers to uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body. Dyskinesia is common in Parkinson’s disease patients and is associated with long-term use of levodopa, a medication that increases levels of dopamine in the brain.
What causes dyskinesia in Parkinson’s disease?
In Parkinson’s disease, there is a significant loss of dopaminergic (dopamine-producing) nerve cells in the brain. Dopaminergic neurons control voluntary movements and behavioral processes such as mood, reward, addiction, and stress. The loss of dopaminergic neurons affects regular body movements and results in symptoms such as involuntary shaking of hands, arms, legs, jaw, and the tongue, slowness of body movement (bradykinesia), stiffness in the arms and legs, and gait and balance problems.
Levodopa is one of the most potent medications available for Parkinson’s disease. It is a precursor of dopamine, or a molecule that is converted to dopamine in the body. Unlike dopamine, levodopa can cross the blood-brain barrier and replenish dopamine levels in the brain, relieving symptoms of Parkinson’s disease. However, because levodopa is taken intermittently during the day, its levels in the blood fluctuate. Dyskinesia usually begins after two to three years of levodopa treatment and becomes progressively worse. Nearly half of levodopa-treated patients display some form of dyskinesia after levodopa treatment for five years.
There are two kinds of dyskinesia: peak dyskinesia and diphasic dyskinesia. Peak dyskinesia occurs when the concentration of levodopa in the body is at a maximum. Diphasic dyskinesia occurs when the levels of levodopa are rising or falling. This type of dyskinesia is generally associated with low-dose levodopa treatment.
The severity of dyskinesia can vary widely among different individuals and younger patients have a greater risk of developing dyskinesia.
Risk factors for developing dyskinesia
A study published in 2018 assessed the risk factors of levodopa-related dyskinesia in a group of Parkinson’s disease patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI). The study identified seven independent risk factors associated with the development of levodopa-related dyskinesia. These factors were: female sex, greater exposure to levodopa treatment, severe motor and functional impairment, lack of tremors, a higher genetic risk score — which is based on the analysis of the presence or absence of variations in multiple genetic locations that are associated with the disease, anxiety — and marked asymmetric or non-uniform distribution of a domapine transporter protein in an area of the brain called the caudate region.
Treatment, management of dyskinesia in Parkinson’s disease
Treatment of dyskinesia is challenging. Several treatment strategies have been developed that strike the right balance between dyskinesia and improved mobility. Summaries of those strategies follow:
- Using the controlled release form of levodopa (Rytary)
- Dividing the total daily dose of levodopa into more frequent, smaller doses
- Prolonging the action of levodopa by combining it with medications such as carbidopa, which slows the breakdown of levodopa
- Replacing levodopa wholly or significantly with dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Neupro (rotigotine) or Apokyn (apomorphine), which are approved by the U.S. Food and Drug Administration (FDA) to treat Parkinson’s disease.
- Treating Parkinson’s disease patients with mild symptoms with dopamine receptor agonists, and introducing levodopa when necessary.
- Treatment with Duodopa, a gel containing levodopa and carbidopa, which is absorbed continuously and evenly via a tube inserted into the upper part of the small intestine. This provides stable levels of levodopa in the blood, enabling smoother control of motor symptoms.
- Treatment with amantadine, a medication that down-regulates glutamate, the antagonist of dopamine. (An antagonist is a compound having the opposite effect). Amantadine can be given orally or infused into the bloodstream to reduce dyskinesia. It also reduces Parkinson’s symptoms. Multiple daily doses of Symmetrel, or the new extended-release formulation Gocovri, maintain a high level of amantadine in the body throughout the day.
- Use of deep brain stimulation (DBS), when all other methods of treating severe dyskinesia have failed. In DBS, thin electrodes are implanted into parts of the brain that control movement. The electrodes deliver tiny electrical pulses to these brain regions. This allows the brain to maintain normal movement activity with a lower dose of levodopa. A wire connects the electrodes to a pulse generator that is implanted under the skin in the chest.
- In some Parkinson’s disease patients, treatment with dopamine agonists, COMT (catechol-o-methyl transferase) inhibitors and MAO-B (monoamine oxidase-B) inhibitors can worsen levodopa-related dyskinesias. In such cases, the peak dyskinesia can be treated by withdrawing these medications, in addition to lowering the dose of levodopa to reduce the peak levels of dopamine.
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