Dyskinesia and Parkinson’s Disease
What is dyskinesia?
Dyskinesia is a type of involuntary movement. The movements can affect any part of the body and are usually random and purposeless. Dyskinesia can manifest as wiggling, twisting, tapping, shrugging, chewing, swaying, etc. As a result, a person with dyskinesia appears fidgety or restless. When dyskinesia is mild, the affected person may not notice the movements unless someone points them out. On the other hand, when dyskinesia is severe, the movements can be so large and persistent that they can interfere with basic activities like eating, drinking and walking.
There are two other types of involuntary movements that commonly affect people with Parkinson’s disease and can be confused with dyskinesia. Tremor is an involuntary movement, but unlike dyskinesia, tremor is a rhythmic back-and-forth shaking. Dystonia is another involuntary movement in Parkinsons’ disease that often causes abnormal neck posture or painful curling of the toes.
What causes dyskinesia?
In people with Parkinson’s disease, dyskinesia is most often caused by the medication levodopa. These are also referred to as levodopa-induced dyskinesia (LID). Levodopa is taken as a combination tablet, carbidopa + levodopa, and is the most common medication used in Parkinson’s disease. Dyskinesia can occur or worsen as a side effect when other medications are used to treat Parkinson’s disease, including rasagiline, selegiline, safinamide, ropinirole, pramipexole, rotigotine, apomorphine, entacapone, opicapone, tolcapone, and istradefylline are added to levodopa.
However, not everyone who is treated with levodopa has dyskinesia. There are a number of risk factors for LID, including younger age at the onset of Parkinson’s disease, higher doses of levodopa, women compared to men, and patients with lower weight. In addition, LID is more common among those who have more advanced Parkinson’s disease compared to those who are in the early stages of Parkinson’s disease. Estimates vary, but approximately 30-50% of people will develop dyskinesia by 5 years and approximately 60-75% by 10 years. Delaying the start of levodopa therapy does delay the onset of dyskinesia but does not prevent the development of dyskinesia. Due to advanced disease, by delaying levodopa, the onset of dyskinesia is much earlier as compared to starting levodopa in early disease.
Dyskinesia is related to medication dosing, and it tends to fluctuate during the day. Most often, dyskinesia coincides with the time that the levodopa concentration within the body reaches its peak, about 30-90 minutes after each dose of levodopa. This is called “peak-dose” dyskinesia. There is also a rare form of LID called diphasic dyskinesia. In diphasic dyskinesia, involuntary movements occur during both the rise and fall in levodopa concentration.
Dyskinesia are believed to occur due to the short half life of levodopa that causes pulsatile stimulation of the post synaptic dopaminergic neurons in the brain. This leads to changes in the post synaptic receptors along with increase in glutamate release.
How is dyskinesia diagnosed?
Dyskinesia is diagnosed by a healthcare provider based on medical history and observation of the involuntary movements in the clinic. Many rating scales exist that can be used to quantify the severity of the dyskinesia. There are also digital technologies that can be used to assess the severity of dyskinesia, but these are not necessary to establish the diagnosis.
What treatments are available for dyskinesia?
Physicians don’t always treat dyskinesia. If the dyskinesia are not causing difficulties in daily activities, no active treatment may be required. Treatment of LID can be challenging, since levodopa is increased to reduce OFF periods and this can result in dyskinesia and reducing levodopa often leads to worsening of PD symptoms. This often involves trying to balance the amount of daily levodopa the patient is taking without worsening the symptoms. For peak dose dyskinesia, reducing the individual dose of levodopa and giving the lower dose more often might help with reducing dyskinesia and not worsening OFF periods. Another option to consider might be using longer acting levodopa preparations namely carbidopa/levodopa extended release capsules. Some physicians try to reduce the dose of levodopa and use adjunctive medications like dopamine agonists, MAO-B inhibitors, etc. with the hope that reducing a more potent medication like levodopa with dopamine agonist may balance the OFF periods and dyskinesia.
Amantadine delayed release/extended release (DR/ER) (Gocovri) is the only FDA approved medication for OFF periods and dyskinesia. In PD patients with LID, the use of amantadine DR/ER reduces dyskinesia without worsening PD symptoms; in fact, it also reduces OFF periods. Amantadine DR/ER is taken once at bedtime, so the levels of the medication increase during sleep and are at its peak when the patient wakes up in the morning providing control of dyskinesia during the day. In patients with renal impairment, especially in elderly patients who usually have some degree of renal impairment, amantadine DR/ER should be used at lower doses to get similar benefit without side effects.
Amantadine immediate release (IR) although not approved for LID is often used to treat dyskinesia. Amantadine IR is used multiple times (2-3 times/day) during the day. Using it in the evenings can lead to nighttime disturbances including nightmares with its use. Similar to amantadine DR/ER, the dose should be adjusted in patients with renal impairment.
Although there are no head-to-head studies of amantadine IR vs amantadine DR/ER, the potential benefits of amantadine DR/ER include once at night use, better clinical data regarding the benefits with dyskinesia and OFF periods, FDA approval, and better blood level of amantadine during the day. In an open label study, when patients were switched from amantadine IR to DR/ER, patients reported better improvement in dyskinesia and OFF periods with amantadine DR/ER. This suggests if the patient is not getting benefit with amantadine IR, one should give a trial with amantadine DR/ER.
If dyskinesia are not managed with amantadine, surgical treatment options like carbidopa/levodopa enteral suspension or deep brain stimulation should be considered.
The carbidopa-levodopa enteral suspension involves surgically implanting a tube in the jejunum that delivers levodopa by a portable external pump. The pump provides CLES at a steady dose throughout the day. The use of the pump prevents peak levodopa concentrations and hence avoids peak dose dyskinesia and, similarly, the lack of troughs in levodopa concentration avoids OFF periods.
Deep Brain Stimulation (DBS) of the subthalamic nucleus or the globus pallidus is another surgical technique that is effective for the management of dyskinesia and OFF periods. The surgery involves the placement of tiny electrical rods into the brain in the operating room by a neurosurgeon. Electrical stimulation is then delivered to the brain by a battery that sits under the skin in the person’s chest. The use of electricity instead of medications is another form of therapy that improves dyskinesia without worsening OFF periods.
Key Takeaways
· Dyskinesia is a type of abnormal involuntary movement seen in people with Parkinson’s disease.
· Dyskinesia is a side effect of levodopa.
· The longer the patient has PD, the more likely they will have LID
· Every patient with dyskinesia does not need to be treated
· Amantadine DR/ER is the only medication approved for dyskinesia and OFF periods, although amantadine IR is also used for dyskinesia.
References
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Heumann R, Moratalla R, Herrero MT, Chakrabarty K, Drucker-Colín R, Garcia-Montes JR, Simola N, Morelli M. Dyskinesia in Parkinson's disease: mechanisms and current non-pharmacological interventions. J Neurochem. 2014 Aug;130(4):472-89. doi: 10.1111/jnc.12751. Epub 2014 Jun 7. PMID: 24773031.
Leta V, Jenner P, Chaudhuri KR, Antonini A. Can therapeutic strategies prevent and manage dyskinesia in Parkinson's disease? An update. Expert Opin Drug Saf. 2019 Dec;18(12):1203-1218. doi: 10.1080/14740338.2019.1681966. Epub 2019 Nov 5. PMID: 31619083.
Wang R, Shih LC. Parkinson's disease - current treatment. Curr Opin Neurol. 2023 Aug 1;36(4):302-308. doi: 10.1097/WCO.0000000000001166. Epub 2023 May 29. PMID: 37366218.
Tyler Okelberry, MD is a movement disorders fellow at the Parkinson and Movement Disorder Division of the University of Kansas Medical Center in Kansas, USA.
Rajesh Pahwa, MD is a member of the World Parkinson Coalition Board of Directors. He has been involved with the WPC for nearly 10 years in a variety of leadership and faculty roles. He is currently the Laverne & Joyce Rider Professor of Neurology, Chief of the Parkinson and Movement Disorder Division and Director of the Parkinson’s Foundation Center of Excellence at University of Kansas Medical Center in Kansas, USA.
𝕏: @Pahwa_KHSPD
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®