Parkinson’s Study Analyzes Levodopa‐induced Dyskinesia’s Effect on Sleep

When a person is awake, brain circuit activity is constantly “on.” This activity needs to be normalized during sleep. Researchers now report that neuronal activity in Parkinson’s disease patients with levodopa-induced dyskinesia fails to decrease during sleep.

The study, “Levodopa-induced dyskinesia in Parkinson’s disease: sleep matters,” was published in Annals of Neurology.

The brain’s structure and functional networks are constantly changing/evolving in a biological process scientists call “neuronal plasticity,” which affects the brain’s learning and memory abilities.

Levodopa (L-Dopa), one of the main therapies used to treat Parkinson’s symptoms, “successfully controls motor symptoms for several years and then induces motor fluctuation and abnormal involuntary movements, i.e. levodopa-induced dyskinesias (LIDs),” researchers wrote.

This long-term, therapy-related complication results in important functional disability, often requiring complex pharmacological or surgical interventions.

Although LDIs are believed to be associated with changes in neuronal plasticity in the striatum — a brain area involved in multiple aspects of cognition — studies have demonstrated abnormal motor cortex plasticity in LID patients. The motor cortex is the brain area involved in the planning, control, and execution of voluntary movements.

In addition, changes in cortical slow wave activity (SWA) — the major characteristic of deep sleep key for both cortical restructuring and functioning, which, in turn, supports cognition — have been described in animal models of Parkinson’s disease with LID.

SWA increases with wake duration, peaks in early sleep, and declines in late sleep. Animal studies have shown that “rodents exposed to combined levodopa treatment and sleep deprivation developed earlier and more severe LID than animals that were not sleep deprived,” authors noted.

The team at Neurocenter of Southern Switzerland investigated if sleep could influence clinical presentation of Parkinson’s in humans, as previously observed in animals.

A total of 27 Parkinson’s patients (50-65 years old) were divided into three groups:

• de novo: seven recently diagnosed patients who had received only azilect (rasagiline, by Teva) as dopaminergic therapy;
• advanced: nine subjects without LID using their usual therapy, but demonstrating the end-of-dose or wearing-off phenomenon;
• dyskinetic: 11 advanced patients with LID.

Seven healthy and age-matched participants also were recruited as controls.

Researchers evaluated subjects’ mood and sleep complaints as well as their Parkinson’s motor symptoms, using a series of rating scales, and asked them to maintain regular sleep-wake schedules.

A wristwatch-like device was attached to individuals’ non-dominant wrist to monitor their sleep/wake cycles for one week. This method is known as actigraphy. Because of technical failure, one patient from each of the Parkinson’s groups could not undergo rest/activity cycles monitoring.

Additionally, participants were submitted to whole night video polysomnography-high-density electroencephalogram (EEG) recording, meaning those studied had their brain waves, blood oxygen level, heart rate, breathing patterns, eye and leg movements monitored while they were asleep. Recording data was corrupted by artifacts in two de novo patients and one dyskinetic participant, and as a result was excluded from the SWA analysis.

Subjects were followed for at least six months.

Results showed there was a decline in SWA in the de novo, advanced and control groups, but not in dyskinetic patients, who had their SWA persistently elevated during the night.

In accordance, all groups except the dyskinetic one, manifested a significant decrease in SWA between early and late sleep, further supporting the investigators’ hypothesis that dyskinetic patients have their much-needed overnight brain activity normalization process compromised.

In all Parkinson’s patients, total sleep time and sleep efficiency were negatively correlated with disease duration, which is consistent with previous studies.

However, “while the correlation between [deep sleep] and disease duration was positive in both [de novo and advanced] patients, it was surprisingly negative in [dyskinetic] patients,” researchers wrote.

A possible explanation is there may be biological compensatory mechanisms in the de novo and advanced sample that can be compromised in the dyskinetic one, making dyskinetic patients unable to sleep efficiently as disease progresses.

Because levodopa dose influences dyskinesia onset, investigators performed a correlation analysis between sleep parameters and levodopa-equivaled daily dose.

A negative correlation of total sleep time and sleep efficiency with levodopa-equivalent daily dose was observed in all patients with motor fluctuations, i.e., in both advanced and dyskinetic groups. Importantly, slow wave (or deep) sleep was negatively correlated with levodopa-equivalent daily dose only in patients  experiencing LID.

“In conclusion, these results support our preclinical findings of a clear association between sleep and LID at the electrophysiological, behavioral, and biochemical levels,” researchers wrote.

“Although our findings do not imply a causative role for the lack of SWA reduction in the emergence of LID … they do suggest an association between sleep and some clinical [features] of PD and suggest a relationship between sleep disruption and LID,” they concluded.