The Ever-Changing Management of Dyskinesia in Parkinson Disease

Participating in the panel are, from top left, Rajesh Pahwa, MD; Daniel E. Kremens, MD, JD; Robert A. Hauser, MD, MBA; William G. Ondo, MD; and Fernando L. Pagan, MD.

PARKINSON DISEASE (PD) is one of the most common neurologic disorders, projected to affect at least 12 million people worldwide by 2040.¹ Despite the lack of approved disease-modifying therapies, there are several relatively effective medications for PD. Most of these treatments are aimed at increasing dopaminergic tone, with levodopa considered the gold standard. Over the years, there have been several preparations developed to try to extend the half-life of levodopa, including extended-release (ER) tablets and an immediate-release (IR) combination.

Motor fluctuations and dyskinesias frequently affect patients living with PD as the disease progresses. The mean time to develop dyskinesia is 5.81 years from diagnosis, and a study suggests 95% of individuals with PD will experience motor fluctuations by 10 years.² Consequently, there is a vast need for improved treatments to address these motor symptoms.

With this in mind, NeurologyLive^® brought together a panel of experts from institutions across the United States to offer perspectives on the diagnosis and treatment of dyskinesias in this patient population. Moderated by Daniel E. Kremens, MD, JD, vice chair for education in the Department of Neurology and codirector of the Movement Disorders Program at Thomas Jefferson University, in Philadelphia, Pennsylvania, the group discussed challenges in treating dyskinesia and finding a balance between OFF episodes and ON time and highlighted the current and emerging treatment options available for dyskinesia treatment.

Available PD Treatments and Identifying OFF Episodes

William G. Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute, kicked off the discussion with an overview of the currently available treatments and pharmacokinetic properties of different drugs for PD. He noted that levodopa has been at the forefront of treatment but that other advances, such as duodenal pumps, have made their way forward as well.

“There have been several other pharmacologic strategies to try to prolong the effects of levodopa. For example, COMT [catechol-O-methyltransferase] inhibitors, opicapone and entacapone being the 2 that are widely available in the United States, prevent the metabolism of levodopa and can extend the effective duration that you get out of levodopa tablets,” Ondo said. “They are used only in conjunction with levodopa, never as monotherapy.”

Although type-B monoamine oxidase (MAO-B) inhibitors have shown a modest impact in symptoms of PD, these therapies can be used as adjuncts to levodopa to try to extend the duration of ON time patients might receive. Dopamine agonists, which are independent mimickers of dopamine, tend to have a longer duration of effect; however, the main disadvantage is that they tend to have more adverse events compared with pure levodopa therapy.

The panel discussed the various formulations of carbidopa/ levodopa, including controlled release (CR) and ER, which can be confusing to patients. ER carbidopa/levodopa is a capsule in which one-third of the beads are an instant-release preparation and the other two-thirds are a proprietary extended-release formulation. “One thing we’ve seen in our clinic is that often carbidopa/ levodopa CR is mislabeled on the bottles as carbidopa/levodopa ER, or extended release, and that creates a lot of confusion,” said Robert A. Hauser, MD, MBA, director of the Parkinson’s Disease and Movement Disorders Center at USF Health, said. “We’ve talked about the difference, but this labeling adds to confusion, so patients and clinicians need to be aware of that.”

Panelist Fernando L. Pagan, MD, professor and vice chairman of the Department of Neurology at MedStar Georgetown University Hospital, similarly commented that it can be challenging to treat patients as the disease progresses. “This is where you may think of more advanced therapies like deep brain stimulation that can reduce the OFF time or the time of dyskinesia, but also reduce the overall need for levodopa medication. You could also think about more continuous delivery of carbidopa/levodopa,” he said.

Pathophysiology and Risk Factors of Dyskinesia in PD

Ondo moved the conversation to dyskinesia in PD by providing an overview on dyskinesia, noting 2 key clinical features. As for its association with dopaminergic medications, a preponderance of evidence suggests that the fluctuations and levels of levodopa and dopamine in the brain are a risk factor for drug-induced dyskinesia.

Moderator Daniel E. Kremens, MD, JD, poses a question to the panel during the discussion on dyskinesia management.

“The other important feature about dyskinesia is the patient component,” he said. “When patients develop symptoms of Parkinson disease, they’ve lost roughly 50% or 60% of their dopaminergic neurons, but you still have 40% or 50% left. When you take these dopaminergic medicines, it’s thought that they are taken up into those residual neurons and buffered, and then released in a physiologic manner the way it’s supposed to be.” Dyskinesia can emerge quite early, and this increases over time such that 60% to 70% of patients develop it after about 10 years. Rajesh Pahwa, MD, director of the Parkinson’s Disease and Movement Disorder Center at the University of Kansas, provided insight on who might be more at risk for dyskinesia, saying those who are getting 600 mg per day of levodopa are much more likely to be at risk than those receiving 300 mg. In addition, he said women are more likely to have dyskinesia, although the reasons for this are still not completely understood.

In mild cases, patients may need more monitoring than treatment for their dyskinesia. Kremens added that past studies indicate that lisuride, dopamine agonists, and carbidopa/ levodopa gel have potential to address this symptom. For nondopaminergic medications, also used as adjunctive medicines, keeping the dopamine as continuous as possible is key, Pagan noted. “We can sometimes do that by adding a COMT inhibitor, MAO-B inhibitors, and A2A inhibitors to try to enhance the action of the dopaminergic products that we may be using, like levodopa,” he said.

Use of Amantadine and Surgical Options

Amantadine-delayed release (DR)/ER is the only medication FDA-approved for both dyskinesia and OFF episodes in levodopa-treated patients. It is presumably the longest-acting version of amantadine and has by far the most data available.

“We also need to keep in mind that even though we have the most robust data, the challenge with the data out there is that amantadine-IR, yes, it has shown to reduce dyskinesia, but it has not had data showing reduction in OFF,” Pahwa said. “Similarly, amantadine-IR/ER shows that it reduces dyskinesia but not OFF, even though they did a well-designed, well-controlled study.”

Kremens and Pahwa led a discussion on the safety of amantadine, noting several common adverse events in studies including dry mouth, nausea, decreased appetite, insomnia, orthostatic hypotension, hallucinations, and peripheral edema, which is rare. If patients are older than 70 years, clinicians should start amantadine-DR/ER doses at 68.5 mg and go up slowly from there. The panelists noted that some patients around that age are able to tolerate the 274-mg dose, but “it still takes time to get there.”

Pagan said that with any oral therapy, clinicians can reduce the dyskinesia by about 40%, or an additional 2.6 hours of ON time without troublesome dyskinesia. For patients with more severe cases, deep brain stimulation (DBS) and other surgical procedures may be considered. DBS targeting the subthalamic nucleus (STN) or globus pallidus internus (GPI) are 2 main surgical choices for individuals with persistent motor fluctuations. In cases with more dystonia and dyskinesia, Pagan noted that clinicians might choose to target GPI, whereas STN might be used to allow for a greater reduction of oral levodopa dosing.

“There are some studies being done using MRI-guided, focused ultrasound. Most of that has been for tremor, but there’s some work being done looking at the GPI as a potential target,” Pagan said. “Most of the previous studies have been unilaterally using the VIM [ventral intermediate nucleus thalamotomy], which is a target for essential tremor and Parkinson disease, but the GPI is being looked at as a potential target with focus ultrasound.”

REFERENCES
1. Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of Parkinson pandemic. J Parkinsons Dis. 2018;8(s1):S3-S8. doi:10.3233/JPD-181474
2. Lopez IC, Ruiz PJ, Del Pozo SV, Bernardos VS. Motor complications in Parkinson’s disease: ten year follow-up study. Mov Disord. 2010;25(16):2735-2739. doi:10.1002/mds.23219