Insomnia and Excessive Daytime Sleepiness in Parkinson’s Disease Patient—A Review Article

Sleep-wake disorders play an important role among non-motor symptoms in Parkinson’s Disease, being a constant subject of research in recent years. There are a multitude of sleep-wake disturbances that worsen the patient’s quality of life, insomnia and excessive daytime sleepiness being two of the most frequent complaints. The aim of this review is to highlight the most relevant clinical trials conducted during the last 5 years, focusing on the problematic of insomnia and daytime sleepiness correlated with Parkinson’s Disease and its treatment. Three electronic databases (Pubmed, Science Direct and Google Scholar) were searched during March and April 2020 for articles on this topic, finally selecting 21 most relevant articles that we have included in this review. Interesting aspects regarding correlation between sleep-wake disorders and Parkinson’s disease were found, showing that non-motor symptoms may be independent of the disease itself. We discussed the most recent advances in treatment opportunities and the adverse effects, with insomnia and daytime sleepiness among the most common complaints. Besides newly developed pharmacological therapy, consisting in mostly dopaminergic agonists or levodopa adjuvant drugs. Other possibly effective therapies on sleep-wake disorders such as deep brain stimulation, dietary changes, bright light therapy and alternative medicine protocols are also reviewed. Insomnia and excessive daytime sleepiness are common complaints in Parkinson’s disease patients, being either self-standing non-motor symptoms or adverse effects of the antiparkinsonian medication, diminishing patient’s quality of life. The efferves-cence of research on this topic shows promising results, with new clinical trials still to come in the near future.


Introduction
Non-motor symptoms (NMS) in Parkinson's disease are a broadly discussed topic nowadays, besides ameliorating the motor symptoms (tremor, dyskinesia, postural rigidity), researchers and neurologists focusing on the management of NMS [1] [2] [3]. Among NMS, sleep-wake disturbances are frequently encountered symptoms by the patient, having negative impact also on the motor symptoms management and on patient's quality of life (QoL) [4]. There are many sleep-wake disorders ( Table 1) that may occur during daytime such as excessive daytime sleepiness (EDS), fatigue, restless legs syndrome and circadian sleep-wake disorders. However, most disorders are related to sleep: insomnia, rapid eye movement (REM) sleep behavior disorder, non-REM parasomnias, and sleep apnea syndromes [5] [6].
As the spectrum of sleep-wake disorders is too broad to be thoroughly reviewed in one single article, two of the most common patient's complains, i.e.
insomnia and EDS will be presented here.
Insomnia, one of the most common complaints in PD patients, can be broadly defined as a quantitative and qualitative discomfort of sleep. Usually, the insomniac has the following symptoms: difficulty to fall asleep, difficulty to maintain a relaxing sleep, waking up many times during the night, and early awakening in the morning with the inability to return to sleep [7]. There are multiple causes for insomnia in parkinsonians, motor impairment as the main condition of the disease and antiparkinsonian medication playing important roles. Firstly, impairment of mobility during night due to elimination of dopamine intake during the night and the addition of neuropsychiatric symptoms (anxiety, depression) have a certainly negative impact on sleep quality, generating insomnia. Moreover, the majority of parkinsonian drugs have important side effects, being potential causes for insomnia, as the studies reviewed here will also demonstrate.
Two different diagnostic modalities for insomnia are used by neurologists nowadays. A detailed anamnesis of the patient and their relatives or caregivers is a good first step to begin with, as long as the clinician asks question-related to duration of sleep, habits of sleep initiating and morning awakenings, and numbers of  [10]. Another important, more sensitive and specific tool for evaluating sleep is polysomnography. Used extensively in studies but also in everyday practice, this method offers the possibility to diagnose several sleep disturbances, being preferred in monitoring REM sleep disorders or sleep apnea.
Lastly, actigraphy is more and more used by sleep specialists in diagnosing different sleep-wake disturbances. This method implies recording of the occurrence and degree of limb movement activity. For sleep measurements, actigraphic devices, usually worn over wrists and ankles are helpful to quantify insomnia also in PD patients.
Regarding the treatment, aspects related further in this article, during the last years numerous studies were conducted, researchers probing various pharmacological and non-pharmacological therapies in order to improve the patients QoL.
EDS, the increased tendency to fall asleep during daytime, is a common symptom in PD patients, affecting more than 55% of patients [11], contributing to poor QoL and increased risk of harm. This condition must be differentiated from fatigue, a vaguer symptom that reflects lack of energy, physical and mental exhaustion, and apathy, but no sleeping risk [12] [13].
The causes of EDS are multiple, different directions being studied in the literature. Firstly, according to some trials, the disease itself may contribute to sleepiness, as PD duration and severity are related to EDS [14]. However, more recent results show that EDS is not correlated to deterioration of motor symptoms in PD or substantia nigra degeneration [15]. Medication plays also an essential role in EDS, as in insomnia and other sleep-wake disturbances. Dopamine agonists, as shown also in trails reviewed in this work, have a significant contribution to EDS in PD patients, regardless the duration of disease.
The diagnosis of EDS follows the same pathway as in the case of insomnia, validated questionnaires translated in multiple languages such as the Epworth sleepiness scale are used by neurologists in order to diagnose EDS. The treatment remains a challenge for the clinician, numerous trials being conducting as researchers are trying to find effective remedies for this complaint.
In this context, this study aims to be a narrative review of the literature regarding the problematic of insomnia and EDS in Parkinson's disease patients, focusing on the most relevant studies conducted during the last 5 years and presenting some introspects on possible efficient treatments for this two sleep-wake disturbances.

Material and Methods
In order to achieve the aim of this article, three electronic databases (Pubmed, The following combination of terms was used to search for Parkinson's disease associated with insomnia or EDS: ("Parkinson disease" OR "primary parkinsonism") AND ("sleeplessness" OR "insomnia") AND ("somnolence" OR "sleepiness" OR "excessive daytime sleepiness"). The following exclusion criteria were used: non-English language, abstract only articles, animal researches, review articles, opinion-based letters-to-the-editors, and non-PD trials. The identification and selection process is presented in Figure 1.
After the search, application of exclusion criteria, and selection of the most relevant trials, a total of 21 articles were included in this review.

Results and Discussion
Improvement of treatment for PD is a constant concern for neurologist nowadays, proof being the multitude of clinical trial conducted in order to find the right medication in right doses and administration forms for specific parkinsonian patient's groups. Although the classical motor symptoms such as dyskinesia or freezing were major concerns for researchers, focus on sleep-wake disturbances is growing. As a result, our search revealed 6 studies that discussed the correlation between PD and insomnia ( Table 2), while another 15 recent studies reported on the problematic of EDS in PD patients (Table 3).    [18]. Another important class of therapeutics in PD with encouraging results is dopamine agonists (DA). Opposite to levodopa, having a less potent efficacy on motor symptoms but concomitantly also less motor adverse reactions, DA is used as first-line therapy in younger patients. The study conducted by Kasamo et al. comes to complete the actual knowledge on DA use in young-onset Parkinson's disease. As the authors mentioned, among the most frequent comorbidities, insomnia was the second most frequent, 30 out of 131 patients (22.9%) complaining about this particular sleep disorder. The nature of NMS remains an elusive problematic also in this study on the Japanese cohort, as the exact cause for insomnia could not be determined. The young age and short disease duration suggests that insomnia is also a comorbidity found in early PD stage, possibly preceding the appearance of motor symptoms, thus being considered a potential clinical marker for PD. Moreover, the study did not differentiate insomnia by categories of DA, being hard to draw a conclusion among effects of different dopamine agonists on sleep-wake rhythm [19].
In search to determine if there is a correlation between sleep disorders as NMS and a future risk of PD, Postuma and colleagues wanted to assess if idiopathic REM sleep behavior disorder could facilitate the development of PD or dementia. Besides REM sleep disorders, insomnia and daytime somnolence were also studied, but no significant predictive value was found [20]. According to the studies mentioned above [17] [18] [19] [20], it seems that insomnia found in PD patients is correlated with the antiparkinsonian medication, being a significant accuse regardless the drug therapy.
As neurologists are trying to find ways to counteract insomnia, non-conventional methods are gaining popularity. As a result, two recent protocols regarding use of alternative medicines were also reviewed. In one article, Shi and colleagues are planning a multicenter trial to test the effects of SQJZ herbal mixtures (used in traditional Chinese medicine) on non-motor symptoms, hoping to ameliorate them, including insomnia [21]. Another trial in preparation and conducted by Jang et al. will be focusing on another herbal medicine utilized in traditional Chinese medicine, Yokukansan [22]. As this traditional herb is thought to improve sleep disturbances, this randomized, double blind, placebo-controlled pilot trial will bring measurable evidence of the mechanism of action of the substance and the real impact, if any, on NMS in PD patients.
Daytime sleepiness and PD The research conducted to assess EDS outnumbers the studies on insomnia and somnolence were registered as medication side-effects, in line with other antiparkinsonian treatments. Somnolence was found in 8 out of 128 patients (6.3%) compared to 2.3% in the placebo group, while insomnia was as frequently found in the placebo group as in the testing groups [27].
While standard pharmacologic therapy reaches its limits regarding efficacy of symptom management in PD, motor fluctuations being unsatisfactorily controlled, new forms of medication are continually emerging. This is the case of Hauser et al. work, the first study of a new sublingual apomorphine formulation in PD patients. It was shown that apomorphine administered sublingually appeared to provide a convenient, rapid and reliable method for treating OFF episodes. However, this came at a certain cost, patient complaining of significant adverse effects: dizziness (7 of 19 patients, 36.8%) and somnolence (6 of 19 patients, 31.6%) were the two most common complaints [28]. This study is also important because it reveals the reciprocal association between nighttime sleep and EDS [29].
Offering a different approach, another study to be mentioned is the trail conducted by Uchino and his Japanese team. In that study, patient's turnover movements, a frequent symptom encountered in PD, were recorded during sleep, however, showing no direct correlation to EDS or sleep disturbances. On the other hand, use of anti-psychotic drugs and higher UPDRS score were significantly associated with daytime sleepiness [30].
Besides pharmacological therapies, more invasive therapeutic measures are tested in order to alleviate NMS. One of the methods used as complementary therapy in order to reduce the burden of NMS is transcranial direct current stimulation, a technique that uses a weak direct electrical current to stimulate different areas of the brain. Use mainly to stimulate the prefrontal cortex in order  Moreover, both bright and dim-red light therapy were associated with improvements in sleep quality [38].
Alternative medicine will always be a valid option in treating unpleasant symptoms, EDS making no exception. Kong and his colleagues searched on the implications of acupuncture on fatigue, demonstrating the safety of the methods [39]. Because there is no satisfactory therapy for daytime sleepiness, acupuncture may play an adjuvant role in alleviating sleep-wake symptoms in PD patients, the exact physiological mechanism remaining to be elucidated.

Conclusions
Along with motor symptoms, PD researchers are focusing more intensively on the non-motor symptoms. There are still questions regarding the pathophysiology of the NMS, recent studies showing that sleep-wake disturbances may not be related to the advanced stages of PD, being also found in early disease patients and premotor stages [15] [23], however more studies should be done to reveal the etiology of NMS.
As new therapeutic modalities, both pharmacologic and non-pharmacologic, appear, their impact on NMS is now regarded as important as their influence on the motor fluctuations. In all the above-mentioned studies [17] [18] [19] [20] [24]- [29], scientists were concerned about the side effects of the medication, with respect to sleep-wake symptoms. As demonstrated, most of the antiparkinsonian medication utilized nowadays provokes insomnia and EDS to patients, these side effects being among the most frequently encountered by PD patients. In the attempt to ameliorate sleep-wake status, alternative methods are implemented, from dietary changes such as ketogenic diet, low-fat diet, and homotaurine intake to invasive pedunculopontine nucleus stimulation, bright light therapy and traditional Chinese medicine remedies (acupuncture, traditional herbs).
There is a continuous need to improve PD patient's quality of life by ameliorating the treatment, finding new therapeutic methods and diminishing the adverse effects. By gathering the most important clinical trials of the last 5 years on PD with respect to insomnia and EDS, this review is a valuable starting point for future research.

Limitations of This Study
As stated already in the methodology, only English-language articles (human clinical trial type) published during the last 5 years were included in this review.
Thus, non-English articles, other review-type articles, research articles conducted on animals, and opinion-based letters-to-the-editors were omitted. Moreover, as sleep-wake disorders found in PD patients include a wide range of symptoms, because of space and time limitations, only insomnia and EDS were mentioned here. Sleep apnea syndromes, fatigue and rapid eye movement (REM) disorders are topics that will be addressed in future articles.