Forms of Sleep Disturbances Increase as Parkinson's Progresses

Daniel M. Keller, PhD

October 12, 2018

Hong Kong — Various forms of sleep disturbances are common across the stages of Parkinson's disease (PD), and the different forms may have different etiologic mechanisms, a study shows.

"Parkinson's disease patients can have any number of sleep disorders, and it is increasingly recognized that sleep disorders could be a prodromal symptom," Zheyu Xu, MB BChir, of the National Neuroscience Institute in Singapore, told delegates here at the International Congress of Parkinson's Disease and Movement Disorders (MDS) 2018.

"But what has not been explored in the Parkinson's population is what is the manifestation of expression of the different sleep disorders in each individual patient," she said.

Using 5 years of questionnaire data from the Parkinson's Progression Markers Initiative (PPMI) observational clinical study, the researchers compared longitudinal measures of changes in excessive daytime sleepiness (EDS), insomnia, and probable rapid eye movement (REM) sleep behavior disorder (pRBD) among 218 early PD patients and 102 healthy control participants (HCs).

The conditions were defined by scores on the RBD Screening Questionnaire (>5), the Epworth Sleepiness Scale (≥10), and the Unified Parkinson's Disease Rating Scale (UPDRS) Part 1.7 (≥2).

Medication logs revealed demographic data and information regarding use of PD medications and sleep-related sedatives. Clinical motor assessments included Hoehn and Yahr stage and the Movement Disorder Society (MDS)–UPDRS Part III.

At baseline, PD patients and HCs were similar in age, body mass index, and use of sleep-related medications. PD patients had higher MDS-UPDRS scores and Hoehn and Yahr ratings. The proportion of men was higher in the PD group than in the HC group (68.8% vs 56.9%, respectively; P = .05).

For PD patients, the prevalence of insomnia increased from 21% at baseline to 56% at 5 years. The prevalence of EDS increased from 17% to 32%; pRBC showed the least increase in prevalence, going from 22% to 30%. Whereas 2 years from baseline, the increases in EDS and pRBD mainly leveled off, insomnia steadily increased yearly from baseline to year 5.

For HCs, insomnia increased slightly between baseline and years 2 and 3 (at 22%) but then dropped slightly at years 4 and 5. The amount of EDS was mainly constant from baseline to year 5 (the highest prevalence was 14% at year 4). There was no pRBD among HCs at any time point.

"What is real striking is that...at the end of this 5-year period, about one third of patients do remain free of any sleep complaints, and surprisingly, there was only a very, very small percentage of patients who had all three sleep complaints," Xu said. There was little overlap even among two forms of sleep disturbance.

Table. Prevalence of Sleep Disturbances Among Parkinson ' s Patients

Sleep Disturbance Baseline (%) 5 Years (%)
pRBD 10.6 11.0
EDS 8.3 8.7
Insomnia 12.8 19.3
pRBD + EDS 5.0 5.5
pRBD + Insomnia 4.1 7.3
EDS + Insomnia 2.3 10.6
pRBD + EDS + Insomnia 1.4 7.3
None 55.5 30.3

 

When there was a co-occurrence of insomnia and EDS, the questionnaire data only documented the overlap; it could not inform the question of whether insomnia resulted in EDS or vice versa.

The proportions of patients with multiple sleep disturbances increased over time but were still relatively small, and the researchers therefore suggested that the different forms of sleep disturbances may have different pathogeneses.

At baseline, 31.7% of PD patients reported one form of sleep disturbance, 11.5% reported two types, and 1.4% reported all three types. At 5 years, 39.0% reported one type, 23.4% two types, and 7.3% reported all three types.

Xu noted that these results, which are based on responses to questionnaires, correspond to those obtained by polysomnography performed on populations of Parkinson's patients with respect to the general lack of overlap of sleep disorders.

Senior author Nicola Pavese, MD, PhD, of Newcastle University in the United Kingdom, told Medscape Medical News that the fact that there is not much overlap in the forms of sleep disturbance in individual patients as the disease progresses indicates that the forms may not have the same etiologies.

"Our impression is that there are different mechanisms," he said. "People who have clusters of sleep disorders probably are caused by different mechanisms.... So there are probably different substrates for each one of these different mechanisms."

Xu reported that the only statistically significant difference found between the PD patients was that for those with three types of sleep disturbances, the mean L-dopa equivalent daily dose was higher (P = .001).

Some lively discussion among Parkinson's experts followed Xu's presentation, with questions, proposed explanations for the findings, and suggestions for further research.

Claudia Trenkwalder, MD, of the University Medical Center of Goettingen, Germany, said that when the PPMI was developed, it was not known that the REM sleep behavior disorder screening questionnaire was not particularly valid, especially for de novo Parkinson's patients. She said she published a validation study in which the RBD screening questionnaire was compared with polysomnography, and "this does not fit, so it's not really significant."

Regarding the insomnia found by Xu and coworkers, she said, "I think...that's a very valid finding, because insomnia often increases when treatment starts because of the dopamine agonists. They have increased nighttime insomnia...and many have the daytime sleepiness."

She suggested that, because the PPMI contains treatment data on individuals, the researchers could see whether there was a correlation between kinds of treatments of insomnia and daytime sleepiness, "so that you can get a better picture what are the drivers to these problems."

She suggested seeing whether patients were taking high doses of pramipexole (Mirapex, Boehringer Ingelheim), "as this is the most likely cause of the EDS."

Trenkwalder noted that the patients in the PPMI were "a peculiar population," because they were mostly younger, were highly motivated to fill out the questionnaires, and "are the ones who most likely take high doses of dopaminergic drugs."

Ray Chaudhuri, MD, DSc, of the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom, noted that dopamine agonist drugs in low doses can be sedative but in high doses can be alerting.

Finally, Stephen Reich, MD, of the University of Maryland in Baltimore, cautioned that people tend to underestimate daytime sleepiness and overestimate insomnia.

There was no commercial funding for the study. Dr Xu and Dr Pavese have disclosed no relevant financial relationships. Dr Trenkwalder receives royalties for the Parkinson's Disease Sleep Scale-2 (PDSS-2). Dr Chaudhuri has consulted and served on advisory boards for Britannia, AbbVie, Neuronova, Mundipharma, UCB, Synapsus, and Medtronic. He has received honoraria from Boehringer Ingelheim, GlaxoSmithKline, AbbVie, Britannia, UCB, Mundipharma, Otsuka, and Zambon and has received grants from Boehringer Ingelheim, GlaxoSmithKline, Britannia, AbbVie, UCB and Neuronova. He holds intellectual property rights for the KPP scale and the PDSS and receives royalties for the books Non-Motor Symptoms of Parkinson's Disease and Fastfacts: Parkinson's Disease. Dr Reich has consulted for Enterin, has acted as a peer reviewer for UpToDate, and receives royalties from Informa for Movement Disorders: 100 Instructive Cases.

International Congress of Parkinson's Disease and Movement Disorders (MDS) 2018. Abstract 1641, presented October 9, 2018.

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