**First Two-Year Observational Exploratory Real Life Clinical Phenotyping, and Societal Impact Study of Parkinson's Disease in Emiratis and Expatriate Population of United Arab Emirates 2019–2021: The EmPark Study**

**Vinod Metta 1,2,3,\* , Huzaifa Ibrahim <sup>4</sup> , Tom Loney <sup>5</sup> , Hani T. S. Benamer <sup>5</sup> , Ali Alhawai <sup>6</sup> , Dananir Almuhairi <sup>4</sup> , Abdulla Al Shamsi <sup>4</sup> , Sneha Mohan <sup>3</sup> , Kislyn Rodriguez <sup>3</sup> , Judith Mohan <sup>3</sup> , Margaret O'Sullivan <sup>3</sup> , Neha Muralidharan <sup>3</sup> , Sheikha Al Mazrooei <sup>7</sup> , Khadeeja Dar Mousa 8,9, Guy Chung-Faye 1,2,3, Rukmini Mrudula <sup>10</sup> , Cristian Falup-Pecurariu <sup>11</sup>, Carmen Rodriguez Bilazquez <sup>12</sup> , Maryam Matar <sup>13</sup>, Rupam Borgohain <sup>10</sup> and K. Ray Chaudhuri 1,2,3**


**Abstract:** Background: Phenotypic differences in Parkinson's Disease (PD) among locals (Emiratis) and Expatriates (Expats) living in United Arab Emirates have not been described and could be important to unravel local aspects of clinical heterogenicity of PD pointing towards genetic and epigenetic variations. Objective: To investigate the range and nature of motor and nonmotor clinical presentations of PD and its impact on time to diagnosis, local service provisions, and quality of life in Emiratis and Expats in UAE, as well as address the presence of current unmet needs on relation to care and etiopathogenesis of PD related to possible genetic and epigenetic factors. Methods: a cross-sectional one point in time prospective, observational real-life study of 171 patients recruited from PD and Neurology clinics across United Arab Emirates from 2019–2021. Primary outcomes were sociodemographic data, motor and nonmotor symptoms (NMS), including cognition and sleep, and quality of life (QOL) assessments, Results: A total of 171 PD patients (52 Emiratis 119 Expats) were included with mean age (Emiratis 48.5 (13.1) Expats 64.15 (13.1)) and mean disease duration (Emiratis 4.8 (3.2) Expats 6.1 (2.9)). In the Emiratis, there was a significant mean delay in initiating treatment after diagnosis (Emiratis 1.2 (0.9) Expats 1.6 (1.1)), while from a clinical phenotyping aspect, there is a high percentage of akinesia 25 (48.1) or tremor dominant (22 (42.3)) phenotypes as opposed to mixed subtype 67 (56.3) in Expat cohorts; double tremor dominant, especially Emirati females (25%), had a predominant lower limb onset PD. Both Emirati (27.9 (24.0)) and Expat 29.4 (15.6) showed moderate NMS burden and the NMS profile is dominated by Sleep, Fatigue, Mood, Emotional well-being 3.0 (1.1) and Social Stigma 3.5 (0.9) aspects of PDQ8 SI measurements are predicted worse QOL in Emiratis, while lack of social support 2.3 (1.3) impaired QOL in Expat population. Awareness for advanced therapies was low and only 25% of Emiratis were aware of deep brain surgery (DBS), compared to 69% Expats. Only 2% of Emiratis, compared to 32% of Expats, heard of Apomorphine infusion (CSAI), and no (0%) Emiratis were aware of intrajejunal levodopa

**Citation:** Metta, V.; Ibrahim, H.; Loney, T.; Benamer, H.T.S.; Alhawai, A.; Almuhairi, D.; Al Shamsi, A.; Mohan, S.; Rodriguez, K.; Mohan, J.; et al. First Two-Year Observational Exploratory Real Life Clinical Phenotyping, and Societal Impact Study of Parkinson's Disease in Emiratis and Expatriate Population of United Arab Emirates 2019–2021: The EmPark Study. *J. Pers. Med.* **2022**, *12*, 1300. https://doi.org/10.3390/ jpm12081300

Academic Editor: Enrique Santamaria Martinez

Received: 16 June 2022 Accepted: 2 August 2022 Published: 9 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

infusion (IJLI), compared to 13% of expats. Conclusion: Our pilot data suggest clinical phenotypic differences in presentation of PD in Emiratis population of UAE compared to expats. Worryingly, the data also show delayed treatment initiation, as well as widespread lack of knowledge of advanced therapies in the Emirati population.

**Keywords:** young onset Parkinson's (YOPD); Emiratis; expatriate; genetic; epigenetics; societal impact; device aided therapies; quality of life; non motor symptoms

#### **1. Background**

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with an increasing prevalence with age; according to a recent study by Post et al. [1], 1 in 10 people aged 45 to 100 are at risk of developing PD and 4 out of every 100 people are diagnosed with PD before the age of 50 (young onset PD) YOPD [1]. Whether or not the frequency of PD varies by race/ethnicity or gender, it is now the leading cause of disability worldwide. Unlike in European and United Kingdom Parkinson's cohorts, Arab families have a high rate of consanguineous marriages [2] which may increase the risk of genetic phenotypes (YOPD) albeit Familial PD accounts for less than 10% of all cases of PD [3]. Some studies show low prevalence of PD in some Arab communities, especially in the Al Thuqbah region of Saudi Arabia (27 per 100,000) [4], in contrast to relatively high prevalence in north African Arabs [5] (31.4–557.4 per 100,000), whereas varied genetically heterogenous patterns were reported in Tunisian study by Gouider-Khouja N [6].

A pilot study conducted by the Movement Disorders International task force [7] identified unmet needs in the Middle East, North Africa, South Asia (MENASA) region and recommended requirement and need for multidisciplinary care, increased movement disorders specialists, educational programs, accurate epidemiologic/genetic data, awareness and availability of more advanced therapies, and suitable infrastructure to provide care to the people with PD. However, no tangible developments in relation to the aforementioned unmet needs are currently obvious, and our study aimed to address the awareness and range and nature of PD in a granular manner in a local UAE population here a comparison with settled expat communities. There are also genetic aspects that have to be considered. For instance, the LRRK2, G2019S, autosomal dominant PD with inadequate penetrance and autosomal recessive inheritance patterns were discovered in a genomic analysis of familial PD in Tunisia [8] and are now known to be prevalent in North African Arabs in Gulf cooperation council countries (GCC) with Arabic population [8–10]. This could be due to ancestry disparities between Arabs from the Gulf Cooperation Council and Arabs from North Africa, with the latter being considerably more closely linked to Berber ancestry [11]. As an example, Al-Mubarak et al. [11] reported no LRRK2 G2019S mutations in the Saudi population they studied.

Furthermore, epidemiologic evidence suggests that ethnicity/race may play a significant impact on genetic, epigenetic, environmental, cultural, and socioeconomic factors, which may affect the pathophysiology and symptomatic expression in PD [12–14]. Given its multi- ethnic population, the United Arab Emirates (UAE), particularly the Dubai area, allows our study and comparison of endophenotypic variations in carefully selected locals and expats. The results may aid in the establishment of a biobanking share initiative with the local setup, specifically to study genetic and epigenetic aspects of diseases. Aside from a few anecdotal studies, as discussed above, no obvious robust prevalence or any endophenotypic studies have been reported or been described among UAE patient cohorts to date. Ours is possibly the first UAE real-life study seeking to understand any specific clinical phenotypic (motor and nonmotor, predictors of QOL) differences in the local Emirati population compared to a wider Expat group in addition to differences in perception of treatment and delivery of care.

#### **2. Methods**

#### *Study Design*

This was a cross-sectional one-point-in-time prospective, observational real-life study of 171 patients recruited from PD and Neurology clinics across United Arab Emirates from 2019 to 2021. Primary outcomes were sociodemographic data, motor and nonmotor symptoms (NMS), including cognition and sleep, and quality of life (QOL) assessments.

This study was carried out in accordance with local ethical committee guidelines. Prior to participating in the study, all patients provided written consent and all data were stored in an anonymized fashion in accordance with the ongoing UK portfolio adopted NILS longitudinal cohort study at the National Parkinson's Centre of Excellence at Kings College Hospital in London, Dubai, in accordance with the General Data Protection Regulation (GDPR UAE). The NILS (UK) study has been authorized by local ethics committees (NRES South-East London REC3, 10,084, 10/H0808/141).

#### **3. Informed Consent**

Informed consent was obtained from patients/carers/all participants involved in this study.

#### *3.1. Patient Selection*

Patients with a confirmed diagnosis of Parkinson's disease (PD) who met the UK PD Brain Bank criteria were recruited. Referrals to national Parkinson's Centre of Excellence Kings College Hospital, Dubai, from all around the UAE (mainly from Dubai, Abu Dhabi Sharjah, Al Ain, Ras Al Khaimah, and others) and self-referrals were included.

Separation of Emirati and Expat groups were carried out following established local methodology. Emirates were UAE nationals and Expats were carefully selected to provide for a comparator group and only included subjects from outside Asia and settled in UAE.

#### *3.2. Assessments*

During the consultation, as a part of good clinical practice, standardized assessment protocols such as the demographics of (Emirati vs. Expat), age, gender, disease duration, were used, Levodopa Equivalent Daily Dose Calculation (LEDD) [15]. other scales like Hoehn and Yahr Staging (H&Y) [16], and Non-Motor Symptoms Scale (NMSS) [17], Parkinson's Disease Questionnaire-8 (PDQ-8) [18], Kings Parkinson's Pain Scale (KPPS) [19], PDSS (Parkinson's Disease Sleep Scale) [20], MMSE (Mini-Mental State Examination) [21], PFS 16 (Parkinson's Fatigue Scale) [22], and the Hospital Anxiety Depression Scale (HADS) [23] were applied. Details of these validated scales have been published elsewhere and the assessments were performed in line with the NILS assessment; a national study by the National Institute of Health Research in the UK (UKCRN No: 10,084) currently containing data for over 1600 PD patients.

#### **4. Statistical Methods**

Data did not fit normal distribution; thus, non-parametric statistics were applied. Descriptive statistics (frequencies and percentages, mean, standard deviation—SD-, median, and inter-quartile range—IQR) were calculated for socio-demographic and clinical variables and scale scores. Differences in scores between Emiratis and Expats were explored using Mann–Whitney and chi-square tests (significance, *p* < 0.05).

#### **5. Results**

In total, 171 patients of all ages and HY stages of Parkinson's disease from across the UAE (primarily from Dubai, Abu Dhabi Sharjah, Ain, Abu Dhabi, Ras Al Khaimah, etc.) were recruited during the period 2019–2021. A total of 171 PD patients (52 Emiratis 119 Expats) were included, with mean age (Emiratis 48.5 (13.1), Expats 64.15 (13.1)) and mean disease duration (Emiratis 4.8 (3.2), Expats 6.1 (2.9)), respectively, regardless of their origin, similar to other European and Caucasian cohorts. Male preponderance (73.1%) compared to females (26.9%) is observed in both Emiratis and Expat patients, whereas

disease duration in Expats cohorts 6.1 (2.9) was longer than Emiratis 4.8 (3.2) in years (Table 1).


**Table 1.** Demographic and clinical variables by origin of the patients.

All values are expressed as mean (standard deviation), except <sup>a</sup> median (inter-quartile range) and <sup>b</sup> frequency (percentage). \* Mann-Whitney test; \*\* chi-square test.

There was a 1.5 (1.06) delay in starting PD treatment after formal diagnosis with an average delay of 1.2 (0.9) years in Emiratis and 1.6 (1.1) years in Expats, and, interestingly, we discovered at least three neurologists 3.6 (1.1) were seen by Emiratis compared to expats 2.5 (0.9) consulted after onset of symptoms, before diagnosis and initiation of PD treatment (Table 1). Surprisingly, 37% of Emirati patients were not on any treatment even after 2–5 years of diagnosis.

Emiratis appeared to have a higher rate of young onset Parkinson's disease (PD onset below 50 years) (YOPD) and while from a clinical phenotyping aspect, there is a high percentage of akinesia 25 (48.1) or tremor dominant 22 (42.3) phenotypes as opposed to mixed subtype 67 (56.3), in Expat cohorts, double tremor dominant especially Emirati females (25%) had a predominant lower limb onset PD (Table 1).

In Table 2, the differences in the applied rating scales between Emiratis and Expats are displayed.


**Table 2.** Scales scores and differences by origin of the patients.


**Table 2.** *Cont.*

\* Mann-Whitney test.

Based on NMSS score and staging, both Emirati (27.9) (24.0) and Expats 29.4 (15.6) had moderate NMS burden. NMS profile is dominated by Sleep, Fatigue, Mood, Emotional wellbeing 3.0 (1.1), and Social Stigma 3.5 (0.9) aspects of PDQ8 measurements are predicted worse QOL in Emiratis, while lack of social support 2.3 (1.3) impaired QOL in Expat population. Nocturnal pain 2.7 (1.7) dominates in Emiratis, whereas both nocturnal and radicular pain, 3.3 (1.8) and 2.3 (1.3), respectively, dominates in Expat population.

#### **6. Discussion**

Our study reports some key findings highlighting differences in PD presentation and delivery of Parkinson's care among local Emirati population versus a comparator Expat PD population in UAE.

These are: Emirati PD patients tended to have young onset Parkinson's (YOPD) 48.5 (13.1) which is lower than a global average, Khalil et al. [7]. This may underpin a genetic causation or predisposition possibly contributed to by consanguinity in Arab population, although this was not specifically studied and is certainly worthy of further larger suitable powered clinical genetic cohort studies. Moreover, 93.8% of Emiratis presented to our clinics were YOPD within 1–5 years' duration. It is also considered that the general age of the Emirate population tends to be lower and as such there may be a bias to this observation.

The occurrence of higher proportion of Lower limb tremor (LLT) in emirate female PD is of interest. LLT has been specifically described to occur in some genetic variants of PD such as in Parkin mutation [24], as well as in those with LRRK2 [25] and the data, therefore, need more specific observation, and genetic and biomarker analysis, as well as clinical follow up of this specific cohort. There was a higher representation of nocturnal, fluctuation, and radicular pain in the LLT group. This is a preliminary finding and needs to be investigated in more granular detail. Lower back pain and shoulder pain (variants of musculoskeletal and radicular pain) have been reported in PINK1 and GBA mutation related PD cases [26]. Fluctuation is often seen at a greater level in YOPD and parkin positive cases. These factors, therefore, need exploring as Emirati patients, who were either on low levodopa doses or those who were eligible or unaware of advanced device aided therapies (DAT), respond very well either to escalating dopaminergic regime or DAT therapies.

When data on the Emirate PD are examined in a more granular fashion, it emerges that the Emirate PD, in spite of lower disease duration, have similar HY stage compared to the expat group and similar burden of overall NMS scores. Moreover, 29.0 (18.5) was seen in both Emiratis and Expats and NMS profile is dominated by Sleep, Fatigue, Mood. On the whole the overall NMS burden were similar cross both groups, and given that the emirate PD group had a significantly lower disease duration, this may mean that the clinical PD phenotype in this group may have a greater representation of the recently described

therapies

NMS endophenotypes [27]. Greater understanding and clarity around this pattern of endophenotype would be important to assign sub type specific treatment and delivery of personalized medicine [28] in this group. A faster disease progression in this group, therefore, could be proposed on the basis of this observation although lower LED intake in the Emirate group could be a confounder. scribed NMS endophenotypes [27]. Greater understanding and clarity around this pattern of endophenotype would be important to assign sub type specific treatment and delivery of personalized medicine [28] in this group. A faster disease progression in this group, therefore, could be proposed on the basis of this observation although lower LED intake in the Emirate group could be a confounder.

fluctuation, and radicular pain in the LLT group. This is a preliminary finding and needs to be investigated in more granular detail. Lower back pain and shoulder pain (variants of musculoskeletal and radicular pain) have been reported in PINK1 and GBA mutation related PD cases [26]. Fluctuation is often seen at a greater level in YOPD and parkin positive cases. These factors, therefore, need exploring as Emirati patients, who were either on low levodopa doses or those who were eligible or unaware of advanced device aided therapies (DAT), respond very well either to escalating dopaminergic regime. Or DAT

When data on the Emirate PD are examined in a more granular fashion, it emerges that the Emirate PD, in spite of lower disease duration, have similar HY stage compared to the expat group and similar burden of overall NMS scores. Moreover, 29.0 (18.5) was seen in both Emiratis and Expats and NMS profile is dominated by Sleep, Fatigue, Mood. On the whole the overall NMS burden were similar cross both groups, and given that the emirate PD group had a significantly lower disease duration, this may mean that the clinical PD phenotype in this group may have a greater representation of the recently de-

*J. Pers. Med.* **2022**, *12*, x FOR PEER REVIEW 6 of 13

Another striking feature of our study we would like to highlight is Emotional wellbeing and Social Stigma aspects of PDQ8 SI measurements, which were predicted worse QOL in Emiratis, while lack of social support impaired QOL in Expat population Pain in Parkinson's is independent of disease severity so is with disease duration. Nocturnal pain Predominates in Emiratis, whereas both nocturnal and radicular pain dominate in Expat population (Figure 1). Another striking feature of our study we would like to highlight is Emotional wellbeing and Social Stigma aspects of PDQ8 SI measurements, which were predicted worse QOL in Emiratis, while lack of social support impaired QOL in Expat population Pain in Parkinson's is independent of disease severity so is with disease duration. Nocturnal pain Predominates in Emiratis, whereas both nocturnal and radicular pain dominate in Expat population (Figure 1).

**Figure 1.** Graphical representation of PD subtype vs. pain domains (KPPS) in Emiratis. In this graph it can be seen that Nocturnal pain (NP) is found to be higher in all the PD Subtypes where as Radicular pain scores high in Tremor Dominant Subtype. **Figure 1.** Graphical representation of PD subtype vs. pain domains (KPPS) in Emiratis. In this graph it can be seen that Nocturnal pain (NP) is found to be higher in all the PD Subtypes where as Radicular pain scores high in Tremor Dominant Subtype.

Finally, we consider vignettes of care delivery of PD across both groups. The Emirates saw more neurologists, and, in spite of seeing at least three neurologists, there was a significant delay in initiation of treatment, even after diagnosis in general UAE PD patients (both Emiratis and Expats). Surprisingly, 33% Emiratis were not on any treatment, even after 2–5 years of diagnosis, and this observation is in conflict with the wider consensus that treatment in PD ought to be started at diagnosis as patients otherwise report progressive deterioration in QoL [29]. Finally, we consider vignettes of care delivery of PD across both groups. The Emirates saw more neurologists, and, in spite of seeing at least three neurologists, there was a significant delay in initiation of treatment, even after diagnosis in general UAE PD patients (both Emiratis and Expats). Surprisingly, 33% Emiratis were not on any treatment, even after 2–5 years of diagnosis, and this observation is in conflict with the wider consensus that treatment in PD ought to be started at diagnosis as patients otherwise report progressive deterioration in QoL [29].

Delivery of care in PD is also underpinned by successful provision of advanced infusion (apo IJLI) and surgical treatments. Here, awareness of patient about these treatments Delivery of care in PD is also underpinned by successful provision of advanced infusion (apo IJLI) and surgical treatments. Here, awareness of patient about these treatments is paramount and our data suggest (Figure 2) that only 25% of Emiratis are aware of the deep brain stimulation surgery (DBS), compared to 69% of Expats. Interestingly only 2% of Emiratis are aware of Apomorphine infusion treatment (CSAI), compared with 32% of Expats. Surprisingly, no (0%) Emiratis, compared to 13% of expats, were aware of intrajejunal levodopa infusion (IJLI). Out of 171 (our study sample), only 8% were treated with device aided therapies, despite the fact that nearly 50% were eligible based on Delphi 5-2-1 criteria [30]. This may be due to lack of awareness, or specialist skills or experience or advanced device aided therapy (DAT) treatment guidelines to implement these therapies. Some of the Arabic patients and care givers struggled with clinical scales/questionnaires being in English; perhaps Arabic translated ones would be beneficial.

**Figure 2.** Graphical representation of the awareness of novel therapies in PD treatment among the Emiratis and Expats. This graph shows only 25% of Emirates are aware of deep brain stimulation test compared to 69% Expats and 2% of Emirates are aware of Apomorphine pump treatment compared to 32% of Expats. Whereas Not even a single ( 0%) Emirati is aware of Ileo-jejunal levodopa infusion compared to 13% of expats. **Figure 2.** Graphical representation of the awareness of novel therapies in PD treatment among the Emiratis and Expats. This graph shows only 25% of Emirates are aware of deep brain stimulation test compared to 69% Expats and 2% of Emirates are aware of Apomorphine pump treatment compared to 32% of Expats. Whereas Not even a single ( 0%) Emirati is aware of Ileo-jejunal levodopa infusion compared to 13% of expats.

is paramount and our data suggest (Figure 2) that only 25% of Emiratis are aware of the deep brain stimulation surgery (DBS), compared to 69% of Expats. Interestingly only 2% of Emiratis are aware of Apomorphine infusion treatment (CSAI), compared with 32% of Expats. Surprisingly, no (0%) Emiratis, compared to 13% of expats, were aware of intrajejunal levodopa infusion (IJLI). Out of 171 (our study sample), only 8% were treated with device aided therapies, despite the fact that nearly 50% were eligible based on Delphi 5-2- 1 criteria [30]. This may be due to lack of awareness, or specialist skills or experience or advanced device aided therapy (DAT) treatment guidelines to implement these therapies. Some of the Arabic patients and care givers struggled with clinical scales/questionnaires

being in English; perhaps Arabic translated ones would be beneficial.

The findings consolidate several key unmet needs related to MENASA countries as articulated in the 2020 paper by Khalil et al. [7]. In the Emirate PD, well controlled longitudinal cohort studies need to be undertaken seeking genotype phenotype correlations from a care perspective; awareness for advanced therapies needs to be improved and this needs to be a multilevel educational exercise related to both patients and health care professionals. Such access to therapies can be improved by implementation of a culturally bespoke local clinical guideline for pharmacological as well as non-pharmacological therapies for PD. The findings consolidate several key unmet needs related to MENASA countries as articulated in the 2020 paper by Khalil et al. [7]. In the Emirate PD, well controlled longitudinal cohort studies need to be undertaken seeking genotype phenotype correlations from a care perspective; awareness for advanced therapies needs to be improved and this needs to be a multilevel educational exercise related to both patients and health care professionals. Such access to therapies can be improved by implementation of a culturally bespoke local clinical guideline for pharmacological as well as non-pharmacological therapies for PD.

#### *6.1. Why Early Diagnosis and Treatment Important in PD?*

*6.1. Why Early Diagnosis and Treatment Important in PD?*  Parkinson's disease is a progressive neurodegenerative condition attributed to progressive loss of dopaminergic neurons emerging evidence supports early intervention may help preserving the functioning of neurons helps in slowing disease progression and improving overall quality of life [31]. Early treatment depends and relies on early diagnosis; a UK autopsy study of 100 subjects who had been diagnosed with PD found a misdiagnosis rate of 24% [32], while another study [33] showed nearly 47% of PD diagnosis are incorrect when performed in primary care setting and by non-movement disorder specialists. It is necessary that the required skill set and resources are refined as early detec-Parkinson's disease is a progressive neurodegenerative condition attributed to progressive loss of dopaminergic neurons emerging evidence supports early intervention may help preserving the functioning of neurons helps in slowing disease progression and improving overall quality of life [31]. Early treatment depends and relies on early diagnosis; a UK autopsy study of 100 subjects who had been diagnosed with PD found a misdiagnosis rate of 24% [32], while another study [33] showed nearly 47% of PD diagnosis are incorrect when performed in primary care setting and by non-movement disorder specialists. It is necessary that the required skill set and resources are refined as early detection and treatment have potential to improve the experience and quality of life [34].

#### tion and treatment have potential to improve the experience and quality of life [34]. *6.2. Clinical Benefits of Early Diagnosis and Treatment in PD?*

Several studies demonstrated clinical benefit of early treatment. A multicenter controlled clinical trial of Selegiline for 24 months' follow-up on 800 patients in 1987 demonstrated a delayed onset of disability and reduction in motor function (UPDRS) and requirement of Ldopa [35]. Early Parkinson's disease can be managed successfully for up to five years with the use of Ropinirole alone and supplementing it with levodopa if necessary. This result is observed in a 5-year follow up study comparing the role of Ropinirole vs. L-DOPA and Benserazide [36]. In another study, Rasagiline treatment demonstrated significant improvement in motor (UPDRS) and no change in onset/frequency of adverse events in a 26-week follow-up study comparing Rasagiline vs. Placebo [37]. A 46-month SPECT study of individuals treated with Pramipexole and Carbidopa Levodopa revealed

that the Pramipexole-treated group had less dopaminergic neuron degeneration than the Carbidopa-treated group, with identical UPDRS scores in both groups [38]. After a 24-month follow-up, in a PET study of patients treated with Ropinirole and Carbidopa Levodopa, the Ropinirole-treated group showed decreased dopaminergic neuron degeneration, with equivalent UPDRS ratings in both groups [39]. A 42-week follow-up study of varied multiple doses of carbidopa levodopa revealed a dose-related improvement in motor UPDRS scores [40]. With Pramipexole, there was a reduction in dyskinesia and wear-off, but the L-dopa group had a better overall score and motor score, as well as fewer side effects (freezing, somnolence, and edema) [41]. In a meta-analysis of 5247 individuals treated with dopamine agonists and levodopa, patients treated with dopamine agonists had fewer motor problems (dyskinesias or dystonia) than patients treated with levodopa [42]. Individuals treated with MAO B inhibitors had improvements in both motor scores and activities of daily living in a meta-analysis study of 3525 patients treated with MAO B inhibitors and levodopa [43]. Rasagiline 1 mg and 2 mg were compared to placebo in a 72-week follow-up study. With Rasagiline 1 mg, but not with 2 mg dosage, the early-start group had better UPDRS scores than the delayed-start group [44]. The 6.5-year extension of the TEMPO research confirmed that the early treated group had less UPDRS score degradation than the delayed onset group [45]. The intervention group experienced a slow onset of dyskinesia and had a higher frequency of dyskinesia [46]. L-dopa improves mobility and gives higher quality of life than dopamine agonists (DA) and monoamine oxidase type B inhibitors, according to a 36-month follow-up study of 1620 patients comparing levodopa and dopamine agonists and MAOB inhibitors [47] all these studies (randomized clinical trials and meta-analysis) summarized in (Table 3) supports treatment should be initiated at the time of diagnosis, delaying the treatment has worst prognostic implications (Table 3).


**Table 3.** Studies showing clinical benefits of early diagnosis of Parkinson's disease.


**Table 3.** *Cont.*

#### *6.3. Economical Benefits of Early Diagnosis and Treatment in PD?*

Early intervention is likely to have a significant impact on healthcare costs, as well as societal impact; several studies showed the impact of social healthcare burden and economic costs and quality of life is severe in the later stages of the disease, when symptoms are at their most severe, necessitating more healthcare services or caregiver support [34,35,48,49]. Motor difficulties (motor fluctuations, dyskinesias, and dystonia, which manifests as uncontrollable and sometimes painful muscular spasms) have been recognized as variables contributing to the rise in PD-related expenditures. Social, healthcare burden, and economic costs impact quality of life in patients with advanced Parkinson's disease (APD) [48–50].

Patients with Parkinson's disease (PwP) experience more unpredictable and troublesome motor and non-motor fluctuations as they progress through advanced stages, with the emergence of severe motor (progressive disability) and non-motor symptoms, such as mood, cognitive, and behavioral problems, causing a severe impact on QoL and necessitating more healthcare services or caregivers [48–50].

According to a study by Schrag et al. [48], the overall burden of Parkinson's disease and healthcare resource consumption expenses grew dramatically as the disease progressed with advanced Parkinson's disease (APD). Annual costs for early Parkinson's disease were €2110, but for advanced Parkinson's disease, they were about twenty times higher (€38,625), and majority of patients with advanced disease not on any device aided therapies (DAT) elderly over 70 years old [48]. A Spanish study by Zecchinelli et al. [51] revealed roughly 30% of Parkinson's patients are in advanced stages, and the cost of illness rose sharply, primarily due to costs linked with in-patient treatment and nursing homes because advanced-stage patients are bedridden, wheelchair-bound, or hospitalized [52,53]. The primary drivers and determinants of the socio-economic burden of PD were hospitalization, nursing care, drug costs, indirect costs (loss of work, etc.), predictors of quality of life, societal socio-economic impact healthcare burden, and QOL in PwP [54–56] (Figure 3).

A study by Popov et al. [57] looked at costs of PD illness and societal burden in a cohort of 100 patients showed over all annual burden of 1 billion euros with direct costs accounting to 67% and indirect costs accounting 33% and main drivers of the burden being informal care and drugs [58]. Another UK study by McCrone [59] et al. showed the informal care compared to formal (80% vs. 20%) impact on societal burden and the main predictors being male gender, level of disability and non-motor symptoms like depression [59], as well as adherence to oral medications, especially in elderly patients with advanced disease where they have to take several pills multiple times

tating more healthcare services or caregivers [48–50].

**Figure 3.** highlighting socio-economic burden increases as disease progress (yellow). **Figure 3.** highlighting socio-economic burden increases as disease progress (yellow).

A study by Popov et al. [57] looked at costs of PD illness and societal burden in a cohort of 100 patients showed over all annual burden of 1 billion euros with direct costs accounting to 67% and indirect costs accounting 33% and main drivers of the burden being informal care and drugs [58]. Another UK study by McCrone [59] et al. showed the informal care compared to formal (80% vs. 20%) impact on societal burden and the main predictors being male gender, level of disability and non-motor symptoms like depression [59], as well as adherence to oral medications, especially in elderly patients with advanced Strong predictors of socio-economic burden 61% of PD patients were non-adherent to oral therapy and medical costs were significantly higher among non-adherent versus adherent (\$15,826 vs. \$9228) [60]. A multicenter (France, Germany, and UK) observational study by Pechevis et al. [61] showed dyskinesia (motor complications measured using UPDRS scale) was associated with significant socio-economic and societal burden and increasing total healthcare costs with each unit increase in dyskinesia score led to 562 euros additional costs per patient over a 6-month period [61].

Patients with Parkinson's disease (PwP) experience more unpredictable and troublesome motor and non-motor fluctuations as they progress through advanced stages, with the emergence of severe motor (progressive disability) and non-motor symptoms, such as mood, cognitive, and behavioral problems, causing a severe impact on QoL and necessi-

According to a study by Schrag et al. [48], the overall burden of Parkinson's disease and healthcare resource consumption expenses grew dramatically as the disease progressed with advanced Parkinson's disease (APD). Annual costs for early Parkinson's disease were €2110, but for advanced Parkinson's disease, they were about twenty times higher (€38,625), and majority of patients with advanced disease not on any device aided therapies (DAT) elderly over 70 years old [48]. A Spanish study by Zecchinelli et al. [51] revealed roughly 30% of Parkinson's patients are in advanced stages, and the cost of illness rose sharply, primarily due to costs linked with in-patient treatment and nursing homes because advanced-stage patients are bedridden, wheelchair-bound, or hospitalized [52,53]. The primary drivers and determinants of the socio-economic burden of PD were hospitalization, nursing care, drug costs, indirect costs (loss of work, etc.), predictors of quality of life, societal socio-economic impact healthcare burden, and QOL in PwP [54–

disease where they have to take several pills multiple times Strong predictors of socio-economic burden 61% of PD patients were non-adherent to oral therapy and medical costs were significantly higher among non-adherent versus adherent (\$15,826 vs. \$9228) [60]. A multicenter (France, Germany, and UK) observational study by Pechevis et al. [61] showed dyskinesia (motor complications measured using UPDRS scale) was associated with significant socio-economic and societal burden and increasing total healthcare costs with each unit increase in dyskinesia score led to 562 euros additional costs per patient over a 6-month period [61]. The economic and clinical evidence gathered in the literature shows and confirms The economic and clinical evidence gathered in the literature shows and confirms that early diagnosis and initiation of treatment is crucial, halts risk of disease progression, and reduces the effects on QOL. This can potentially reduce treatment costs if possible non-oral therapeutic device aided therapies are offered to patients as they progress to an advanced stage before significant deterioration has occurred. Patients' QOL and well-being are improved when the Multidisciplinary care approach and timely referrals to a movement disorders specialist with expertise in PD, as selection of patients for advanced device aided therapies (IJLI, CSAI, DBS) are likely to be most effective and patients are likely to be more complaint with these therapies.

#### that early diagnosis and initiation of treatment is crucial, halts risk of disease progression, **7. Conclusions**

56] (Figure 3).

Our study highlights heterogenetic and endophenotype variations of Parkinson's disease in UAE population comparing local Emirati and Expat populations. Our study identifies the importance of early diagnosis, prompt treatment initiation, which has huge societal socio-economic impact, and healthcare burden. Moreover, timely implementation of advanced therapies help delay PD disease progression. A bio banking share initiative with the local setup specifically to study genetic and epigenetic aspects focusing on: GBA, LRRK2, Parkin gene mutation. Screening of Emirati patients with young onset Lower limb tremor dependent Parkinson's disease would be beneficial, identifying these endophenotypes is paramount as these patients will respond very well to dopaminergic dose escalation or to advanced device aided therapies and also helps to formulate gene-targeted therapies. Setting up a local expert committee panel, implementation of national treatment protocols involving patients and care giver groups (expert patient panel) will help empower patients and caregivers.

**Author Contributions:** V.M., H.I., T.L., H.T.S.B., A.A., D.A., A.A.S., S.M., K.R., J.M., M.O., N.M., S.A.M., K.D.M., G.C.-F., R.M., C.F.-P., C.R.B., M.M., R.B. and K.R.C. contributed to the designing, drafting, and revision of the manuscript for intellectual content; V.M. and K.R.C. oversaw the

entire writing and editing process. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This study was carried out in accordance with local ethical committee guidelines. Prior to participating in the study, all patients provided written consent and all data were stored in an anonymized fashion in accordance with the ongoing UK portfolio adopted NILS longitudinal cohort study at the National Parkinson's Centre of Excellence at Kings College Hospital in London, Dubai, in accordance with the General Data Protection Regulation (GDPR UAE). The NILS (UK) study has been authorized by local ethics committees (NRES South-East London REC3, 10,084, 10/H0808/141).

**Informed Consent Statement:** Informed consent was obtained from patients/carers/all participants involved in this study.

**Data Availability Statement:** Raw data were generated at Kings College hospital London, Dubai. Derived data supporting the findings of this study are available from the corresponding author VM on request.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**¸Stefania Diaconu <sup>1</sup> and Cristian Falup-Pecurariu 1,2,\***


**Abstract:** Sleep disturbances are more common in patients with Parkinson's disease (PD) than in the general population and are considered one of the most troublesome symptoms by these patients. Insomnia represents one of the most common sleep disturbances in PD, and it correlates significantly with poor quality of life. There are several known causes of insomnia in the general population, but the complex manifestations that might be associated with PD may also induce insomnia and impact the quality of sleep. The treatment of insomnia and the strategies needed to improve sleep quality may therefore represent a challenge for the neurologist. A personalized approach to the PD patient with insomnia may help the clinician to identify the factors and comorbidities that should also be considered in order to establish a better individualized therapeutic plan. This review will focus on the main characteristics and correlations of insomnia, the most common risk factors, and the main subjective and objective methods indicated for the assessment of insomnia and sleep quality in order to offer a concise guide containing the main steps needed to approach the PD patient with chronic insomnia in a personalized manner.

**Keywords:** Parkinson's disease; insomnia; sleep quality; assessment; personalized medicine

**Citation:** Diaconu, ¸S.;

Falup-Pecurariu, C. Personalized Assessment of Insomnia and Sleep Quality in Patients with Parkinson's Disease. *J. Pers. Med.* **2022**, *12*, 322. https://doi.org/10.3390/jpm12020322

Academic Editor: Niels Bergsland

Received: 24 January 2022 Accepted: 17 February 2022 Published: 21 February 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Several non-motor symptoms are known to affect the quality of life in patients with Parkinson's disease (PD), both in the early and advanced stages. Sleep disorders are found in all stages of PD, including in the pre-motor ones. Neurodegenerative processes that affect the normal functioning of neurotransmitters and the various effects of antiparkinsonian drugs could be involved in the pathogenesis of sleep disorders in PD [1]. Insomnia is reported by almost half of PD patients, and it is significantly related to motor fluctuations and other non-motor features [2].

The diagnosis of insomnia is based on the definition criteria established by the International Classification of Sleep Disorders, 3rd edition: difficulties to initiate and/or to maintain sleep and/or early morning awakenings [3]. For chronic insomnia, the above symptoms should be experienced by the patient at least 3 times a week for a minimum of 3 months. The association of daytime symptoms as consequences of insomnia is usually mandatory to establish the diagnosis [3]. Insomnia is commonly reported by PD patients, regardless of the severity of the disease, with a reported prevalence of 37–83% [4,5]. Polysomnographic studies revealed that PD patients have a shorter total sleep time and lower sleep efficiency compared to controls [6]. A polysomnographic analysis of 50 PD patients showed prolonged sleep latencies in almost half of the patients (mean duration: approximate 22 min) and a mean total sleep time of approximately 5 h/night [7]. Regarding the duration of sleep during the daytime, a study that objectively measured napping using wrist actigraphy in 85 PD patients showed a mean nap time of 39.2 ± 35.2 min/day [8]. All subtypes of insomnia (derived from the main definition) can be identified in PD, with variations across PD stages [9]. According to the results of a study performed on 689 PD

patients, sleep maintenance insomnia due to disrupted sleep was the most commonly encountered (81.54%), followed by early morning awakenings (40.4%) [10]. Sleep disturbances, especially insomnia and reduced sleep quality, affect the quality of life [11]. Moreover, worsening of sleep disturbances and other neuropsychiatric complaints may contribute to the progression of other non-motor symptoms [12]. Some of the motor and non-motor symptoms are interrelated; for instance, gastrointestinal dysfunction may lead to poor absorption of antiparkinsonian drugs and to worsening motor symptoms [13]. Certain sleep disturbances might influence disease-related disability as well [14]. A proper and careful assessment of insomnia and other comorbidities is therefore mandatory in order to choose the right therapeutic intervention for each patient. Depending on the main causes of insomnia, the therapeutic options may vary from recommending sleep hygiene or cognitive behavioral therapy to pharmacological options such as benzodiazepine and nonbenzodiazepine hypnotics [15].

#### **2. Assessment**

#### *2.1. Clinical Interview*

A thorough history taking is essential when evaluating a patient with complaints suggestive of insomnia. The anamnesis should be obtained from the patient but also from the bed partner or caregiver. It is important to highlight the most important subjective symptoms, the time of the night when these complaints occur (first part of the night or after the patient falls asleep) and information regarding sleep patterns and habits. Regarding this aspect, the physician should be interested in the consistency or not of a sleep schedule, naps during the day, the consumption of alcohol, caffeine or other energizing products, as well as the type of physical activity performed by the patient. The patient's medication should be reviewed in search of insomnia as a side effect. Even if dopaminergic medication is known to induce daytime sleepiness, it can also be associated with insomnia [16]. According to a meta-analysis, levodopa, dopamine agonists, acetyl-cholinesterase inhibitors, and certain antidepressants may cause insomnia as an adverse effect [17]. Therefore, the medication regimen of the patient and the effects of polypharmacy should be carefully evaluated. Additionally, the medication and personal strategies used to alleviate insomnia should be assessed.

The clinician should search for the associated non-motor symptoms that can impair sleep quality and might sustain insomnia (an easy method in this regard is to use the Non-Motor Symptoms Questionnaire [18], which is described below) and also for the motor features that might interfere with satisfactory nighttime sleep (tremor, rigidity, dystonia). It is also essential to assess the consequences of insomnia that are experienced by the patient (e.g., headache, fatigue, daytime sleepiness, depression, anxiety) and the effects of insomnia on daily life activities. As daytime sleepiness frequently occurs in PD patients and is associated with episodes of sudden onset of sleep that might potentially be dangerous [19], it is important to ask PD patients with chronic insomnia if they feel sleepy during the day. A quick evaluation method of this symptom is to use the Epworth Sleepiness Scale (ESS) [20], which is one of the most commonly used scales for the evaluation of daytime sleepiness in the general population and also in PD. The Movement Disorders Society (MDS) Task Force considers the ESS a "recommended" instrument to screen for daytime sleepiness in the PD population [21]. Cognitive decline might also be considered as a negative consequence of sleep disorders, including insomnia [22]. For further assessment of cognitive function, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) [23] are among the tools most commonly used in the general population. The MoCA has been shown to be more sensitive than the MMSE in detecting cognitive impairment in patients with PD [24] and other neurodegenerative disorders, such as progressive supranuclear palsy or multiple system atrophy [25]. The MDS Task Force recommends the following scales for cognitive screening in PD: MoCA, Mattis Dementia Rating Scale 2nd Edition (DRS-2) [26] and Parkinson's Disease-Cognitive Rating Scale (PD-CRS) [27].

A sleep diary is an easy method of assessing patients' sleep patterns that is used in the general population [28] and in PD patients for clinical evaluation [29], for comparison with other evaluation methods or for monitoring therapeutic effects [30]. There are several designs of sleep logs, but generally, the following information should be recorded by the patient: the bedtime hour, the estimated time of sleep onset, total sleep duration, wake-up time and awakenings overnight, sleep quality and the presence of naps/physical exercises/medication/alcohol or caffeine intake during daytime [28]. The sleep diary could also be used in association with other objective measurements.

#### *2.2. The Assessment of Specific Risk Factors for Insomnia Associated with PD*

Risk factors that lead to insomnia or are known to aggravate insomnia in the general population (e.g., age, stress, mood, maladaptive lifestyle, behavioral and environmental factors [31]) may also be found in PD. According to recent studies, overall sleep disturbances in PD were associated with napping during the day, watching the clock repeatedly and staying in bed when not able to fall asleep [32], or other inadequate sleep habits [33]. In addition to these factors, there are some specific symptoms in PD patients that contribute to insomnia and should be carefully assessed by the clinician.

#### 2.2.1. Motor Symptoms

Motor features that are persistent or worsen during the night are associated with frequent awakenings and therefore, with sleep-maintenance insomnia. Nocturnal hypokinesia and rigidity might impair mobility and turning in bed and, therefore, might lead to sleep disturbances such as insomnia and reduced sleep quality and efficiency [34,35]. The persistence of tremors or dyskinesia during nighttime may also contribute to sleep fragmentation and poor sleep quality [36]. Motor symptoms may interfere with sleep maintenance even in the early stages; nocturnal dystonia, cramps and tremor were the motor features most commonly associated with sleep dysfunction in drug-naïve PD patients [37]. These motor symptoms, increased muscular tension, sleep apnea, age and disease duration may contribute to the concept of sleep fragmentation [38]. According to recent polysomnographic research, sleep fragmentation has a high rate in PD patients and might be considered a promising marker of PD progression [39].

#### 2.2.2. Non-Motor Symptoms

Urinary dysfunction, especially nocturia, is a common symptom in the general elderly population and is a major factor that contributes to sleep disturbances [40]. Nocturia is a commonly encountered dysautonomic feature in PD patients, and it may correlate with subjective insomnia [41], frequent awakenings and insufficient total sleep time [2].

Another non-motor symptom that is significantly associated with sleep disturbances is pain. This symptom was found in almost half of PD patients, and the most reported type of pain was musculoskeletal pain [42]. Martinez-Martin et al. reported that any type of pain, but mostly the musculoskeletal subtype, was significantly correlated with overall sleep disorders [43]. Polysomnographic (PSG) studies demonstrated sleep fragmentation and modifications of sleep architecture in patients with PD and pain, characteristics which were less prominent in PD patients without pain [42]. An easy and robust method to assess pain is to use the King's Parkinson's Disease Pain Scale, which was demonstrated to be reliable and valid for the evaluation of this complex symptom in PD patients [44].

Among psychiatric non-motor symptoms, depression and anxiety were the most associated with sleep disturbances and reduced sleep quality. The severity of insomnia is correlated with the severity of depression in PD patients [45]. Moreover, an interconnection between depression, anxiety and pain may be found in conjunction with sleep disturbances and poor sleep quality in PD patients [46,47].

#### 2.2.3. Other Associated Sleep Disorders

Restless legs syndrome (RLS), defined as discomfort in lower limbs that induces the need for movement and occurs during the night and during periods of immobility, is found in higher rates among PD patients compared to the general population [48]. RLS in association with periodic limb movements may induce arousal and disrupt normal sleep continuity, contributing to chronic insomnia [48,49]. The clinical diagnosis of RLS is based on the International Restless Legs Syndrome Study Group (IRLSSG) criteria [50]. There are various screening scales that can help the clinician to better assess these symptoms [51].

Sleep-disordered breathing (SDB) and mainly obstructive sleep apnea (OSA) may contribute to a reduced quality of sleep. Difficulties maintaining sleep are more common in patients with OSA than in healthy controls [52], and there is evidence that more than half of OSA patients without treatment have chronic insomnia [53]. In PD patients, the prevalence of OSA is approximately 62% [54]. Sobreira-Neto et al. found that PD patients with OSA may present lower rates of chronic insomnia (probably due to their reduced insight of sleep onset latency caused by sleep deprivation), but they also show reduced time spent in the N3 sleep stage and higher numbers of arousals compared to PD patients without OSA [55].

REM sleep behavior disorder (RBD), a parasomnia with "dream enacting", expressed by abnormal movements instead of muscular atonia during the REM sleep stage, is commonly associated with PD and with other neurodegenerative disorders. Longitudinal studies, including patients with idiopathic RBD, show significant correlations with neurodegenerative disorders and even high rates of phenoconversion [56]. RBD in PD patients causes reduced quality of sleep and also induces other consequences, such as cognitive impairment and autonomic dysfunctions [57,58]. RBD is associated with disrupted sleep architecture, explained by lower percentages of N2 and N3 sleep and a high periodic limb movement index [59].

#### *2.3. Rating Scales and Objective Assessment of Insomnia and Quality of Sleep in PD Patients* 2.3.1. Multidomain Scales or Questionnaires Designed to Evaluate Non-Motor Symptoms in PD, including Insomnia

Many of these scales contain items for screening and/or assessment of the severity of sleep disturbances.

*The Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)* is one of the most commonly used scales for the complex evaluation of various features of PD. It contains four parts, and part I is designed for the assessment of non-motor complaints. There is one question regarding insomnia and one question about daytime sleepiness. For all the items in this first part of the scale, the answers can be chosen between "0 = normal" and "4 = severe" [60].

*The Non-Motor Symptoms Questionnaire (NMSQ)* [18] has proven its efficiency in screening non-motor features of patients with PD. It contains 30 questions with simple answer choices ("yes"/"not"), and five of them are dedicated to the assessment of sleep: the difficulty of staying awake in certain circumstances, the difficulty of falling asleep and maintaining sleep, vivid dreams or nightmares, speaking or having abnormal movements during sleep and unpleasant sensations in the lower limbs during nighttime or rest associated with the need to move. This questionnaire is very easy for the patient to complete. It offers an accurate overview of the main symptoms, but it does not offer any information regarding the severity or the frequency of these symptoms. There are no items addressing SDB.

*The Non-Motor Symptoms Scale (NMSS)* [61] was created to complete and deepen the information obtained with the NMSQ. It is completed by the examiner. It takes a longer time for scoring than the NMSQ, but it provides data regarding symptom frequency and severity. For all the 30 items, the severity of the symptoms is evaluated from "0 = none" to "3 = severe", and the frequency is scored from "1 = rarely" to "4 = very frequent". The total score for each item is obtained by multiplying its severity by its frequency. The

sleep/fatigue domain is comprised of items about insomnia, daytime sleepiness, RLS and fatigue.

*The International Parkinson and Movement Disorder Society Non-Motor Rating Scale (MDS-NMSS)* [62] is a reviewed version of the NMSS. It is administered by the examiner; it contains 52 items about non-motor symptoms, and the scoring process is similar to the NMSS: the frequency of the symptom is rated from "0 = never" to "4 = majority of time" and the severity is chosen between "0 = never" to "4 = severe". The product (frequency × severity) is calculated for each question. The "sleep and wakefulness" domain contains six questions about insomnia, RBD, excessive daytime sleepiness (EDS), restlessness, periodic limb movements and SDB.

#### 2.3.2. Specific Scales or Questionnaires Designed to Evaluate Insomnia and Sleep Quality

*The Parkinson's Disease Sleep Scale (PDSS)* [63] is a self-assessment rating scale encompassing 15 questions which assess general aspects of sleep/daytime symptoms within one (previous) week: items related to insomnia, restlessness, hallucinations, bladder dysfunctions, tremor, dystonia, overall quality of sleep, and EDS. It was designed to assess sleep disturbances in the PD population, with each item being evaluated based on a visual analogue scale (VAS) ranging from 0 (never/excellent) to 10 (always/awful). A cutoff of 82/83 is considered suggestive for sleep disturbances, and the maximum score is 150 points, representing the worse clinical picture [64].

Regarding the psychometric properties of the PDSS, in the original study, the PDSS was applied on 280 adults (143 PD patients in different stages of severity and 137 healthy controls). Test-retest reliability was very high; good internal consistency (Cronbach's alpha, 0.77) and high repeatability were also observed [63]. Floor and ceiling responses were low (1%) [58,60]. High scores on the PDSS regarding EDS correlated with low scores on the ESS, which is the main scale used to assess EDS [63]. The PDSS showed a good correlation with SCOPA-S scores as well [64].

Regarding the strengths of the PDSS, it was developed as a brief, easy-to-use, reliable bedside instrument to screen for sleep symptoms in PD patients. Based on the results, the clinician may have insights regarding the severity of the sleep complaints. The items addressing insomnia might help discriminate between the types of insomnia or the possible causes (e.g., nocturia, tremor). The MDS Task Force classified the PDSS as a "recommended" tool to assess the existence and the severity of sleep disorders in PD [21]. It was shown that the PDSS could discriminate between PD and controls and also within PD severity levels and duration [64].

The PDSS is in the public domain and has been validated in several languages (Spanish, Japanese, Portuguese), with good clinimetric properties [65–67]. It was also widely used in several clinical trials in the PD population—e.g., evaluating the effectiveness of rotigotine [68]).

Regarding the weaknesses of the PDSS, even if the VAS is considered a simple method of assessing the level of severity of symptoms, it may be necessary to first inform the patient or caregiver how to apply this scoring system correctly.

The scale has only one question regarding EDS; therefore, it does not represent a proper tool to assess daytime symptoms. There are no questions related to other sleep disturbances, like sleep apnea or RBD; regarding RLS, there is only one question about "restlessness" of the arms or legs that might be related to RLS symptoms, but the mandatory criteria for RLS diagnosis are not fulfilled. The proposed timeframe is the previous week.

Based on the experience gathered from the administration of the PDSS, a revised version, the *Parkinson's Disease Sleep Scale (PDSS-2),* was designed with the intention of exploring several aspects of sleep in the PD population that were not evaluated in the first version. It was also intended to be a useful tool to assess the effects of treatment on sleep disturbances [69].

The PDSS-2 includes 15 questions for the self-evaluation of sleep symptoms, addressing sleep quality, insomnia, restlessness, nightmares/hallucinations, bladder problems, motor features like rigidity or tremor, pain and breathing difficulties. The VAS scoring system was replaced with a grading system of symptom severity from 0 (never) to 4 (very frequent), with a maximum score of 60, indicating severe nocturnal sleep disturbances [69]. A score of 15 or above was considered the cutoff for poor sleepers [69,70].

Regarding the psychometric properties of the PDSS-2, the total score was evaluated, as were the scores for the three subscales (motor problems at night; PD symptoms at night; sleep specific disturbances) in order to establish the clinimetric characteristics. The PDSS-2 was validated in order to investigate nighttime impairments for the PD population, with findings demonstrating satisfactory reliability (Cronbach's alpha coefficient of 0.73 for the total score and few variations for the sub-scores), good internal consistency for most of the items (>0.30), and high test-retest reliability within 1–3 days (ICC of 0.80 for the total score) [69]. The test-retest reliability for a longer timeframe (1 month) was evaluated in another study, and it was considered acceptable (ICC of 0.799 for the total score) [71].

Regarding the strengths of the PDSS-2, it was shown that the PDSS-2 is a brief, easyto-use and easy-to-administer self-rating scale useful for both screening the existence of sleep symptoms and grading their severity. Compared to the previous version, it is easier for patients with PD to understand and complete the PDSS-2 scale due to its Likert scoring system. It has good discriminative power between the grades of disease severity as evaluated with the Hoehn and Yahr scale. PDSS-2 is an assessment tool belonging to the public domain, which was validated and translated into several languages (German [69], Spanish [72], Italian [73], and Chinese [74]). It has been widely used in prevalence studies to assess sleep symptoms and their associations with several other symptoms or objective investigations (e.g., the presence of sleep disturbances and their correlations with brain MRI morphometry [75]), and it was used in clinical trials to evaluate the efficiency of medication on sleep [76].

Regarding the weaknesses of the PDSS-2, it focuses on the existence and severity of nighttime symptoms and therefore is not a proper tool to investigate their diurnal consequences, such as EDS. Unlike the previous version, the PDSS-2 has more clear questions related to RLS, and it also assesses the existence of breathing disturbances, but these items are not precise enough to diagnose RLS or OSA. A caregiver might improve the accuracy of the answers for some of the items, like for those related to awakenings during the night or difficulties turning in bed (as the patient might underestimate the existence/severity of these issues). The proposed timeframe is the previous week.

*The Scales for Outcomes in Parkinson's Disease—Sleep (SCOPA—Sleep)* is a 12-item selfrating scale designed to specifically evaluate nighttime sleep and daytime consequences in PD patients [77]. The questionnaire is structured in three parts. The first part consists of five items representing nighttime-specific (NS) disturbances that the patient might have experienced in the previous month (most of them concerning different types of insomnia). To answer these 5 questions, the patient chooses the answer which fits best from 0 (not at all) to 3 (a lot). The maximum score for this part is 15, indicating severe nighttime impairments (cutoff: 6/7) [64,77]. The second part is composed of only one question regarding the quality of sleep during the night; there are seven response options, ranging from "very well" to "very badly". There is no numeric scoring for this part. The last part contains six items to evaluate the daytime symptoms (DS) in the previous month, including EDS and the existence of sudden onset of sleep. The scoring for each item varies from 0 "not at all" to 3 "very much", with a maximum of 18 and a cutoff of 4/5 indicating daytime disturbances [77].

Regarding the psychometric properties of SCOPA-sleep, it shows high internal consistency for both the NS and DS subscales (Cronbach's alpha: 0.88 and 0.91, respectively) and good test-retest reliability (ICC: 0.94 for the NS subscale and 0.89 for the DS subscale). There were robust correlations between the DS subscore and ESS; the subscores of the NS part correlated with the PDSS and PSQI [77]. The floor and ceiling effects are absent [64].

Regarding the strengths, this scale is a brief, easy-to-administer rating tool with good internal consistency and reproducibility which can be used for screening and quantifying nighttime and daytime symptoms (like sudden onset of sleep) in PD patients. The MDS task force indicated SCOPA-sleep as a "recommended" scale for the aforementioned purposes [16]. The scale has been translated into several languages, taking part of the public domain. Like other scales designed to assess sleep in PD, SCOPA-sleep was useful to analyze the effect of various therapeutic options on sleep [78], and it was also used for monitoring symptoms in longitudinal studies [2].

Regarding weaknesses, even if the scale is designed to screen for possible nighttime symptoms, SCOPA-sleep lacks questions addressing nocturia, RBD, RLS or OSA. There are no questions addressed to the caregiver.

*The Pittsburgh Sleep Quality Index (PSQI)* [79] represents a self-rating tool designed to assess sleep in the general population, with the timeframe being the previous month. The first four items are dedicated to sleep habits (like usual bedtime, the perceived sleep latency, and number of hours of sleep per night). This is followed by questions related to possible causes of sleep disturbances (e.g., insomnia, breathing difficulties, pain) and questions about sleep quality, use of sleep medication, difficulties staying awake during daytime activities, and difficulties maintaining enthusiasm in daily activities. The PSQI has an additional five informative questions for the bed partner, which do not accumulate to the final score. For each item, the answers can be scored from 0 to 3 (no impairment/severe impairment). Based on the type of sleep problem addressed, the results can be grouped into seven compounds. The total score reaches a maximum of 21 points (indicating severe sleep disturbances), and a score of more than 5 points (for the total items) was considered an indicator for "bad" sleepers [79]. For PD patients, a more appropriate cutoff was considered 8/9 [77].

Regarding the psychometric properties of the PSQI, in the original study published in 1989, it was demonstrated to have high internal consistency and homogeneity (Cronbach's alpha: 0.83) [79]. Test-retest reliability was high for a short interval (2 days apart), and it remained high for a longer timeframe considering the majority of the subscores and the total score (overall test-retest correlation coefficient: 0.87) [80]. The PSQI showed correlations with PSG only regarding sleep latency, but it has strong correlations with the SCOPA-Sleep scale [81].

Regarding its strengths, the PSQI is in the public domain, and it is used to assess sleep in the general population and in PD patients [54,82]. Even if not specifically validated for PD, the PSQI is considered by the MDS Task Force to be a "recommended" tool to investigate sleep in the PD population [21]. Furthermore, it is a commonly used scale to evaluate the occurrence of sleep disturbances in primary insomnia, dementia and other movement disorders [81]. It has been largely translated into several languages, and it is also useful for monitoring the impact of various interventional strategies on sleep parameters [83,84].

Regarding its weaknesses, even if it covers a large spectrum of sleep disturbances that might occur, the PSQI has limited power to assess some conditions, such as OSA or RBD, and has no items designed to evaluate RLS. The questions addressed to the bed partner can help the investigator to complete the picture of the patient's overall sleep disturbances, but the data is not included in the total score; consequently, the global severity may be underestimated. The scoring system is complex, and some additional time should be considered for this aspect; the investigator has a guide with instructions for scoring.

A summary of the main scales used to assess insomnia and sleep quality in PD patients is presented in Table 1.


**Table 1.** Main characteristics of the most commonly used scales for the assessment of insomnia and sleep quality.

EDS, excessive daytime sleepiness; PD, Parkinson's disease; PDSS, Parkinson Disease Sleep Scale; PSQI, Pittsburg Sleep Quality Index; RBD, REM sleep behavior disorder; RLS, restless legs syndrome; SCOPA, Scales for outcomes in PD; SDB, sleep-disordered breathing, VAS, Visual Analogue Scale.

#### *2.4. Objective Methods to Assess Insomnia*

*Actigraphy* is a non-invasive method that is able to investigate several sleep parameters based on recording limb activity via accelerometers [85]. The device is worn on the nondominant hand for a minimum of one week, and the results are interpreted together with a sleep log. Actigraphy is a useful method for the assessment of insomnia in the general population, as patients have the tendency to overestimate their sleep onset latency and to have a lower perception regarding the total sleep time [86]. On the other hand, some studies have demonstrated that PD patients might actually have a more accurate perception of their sleep problems [87]. Actigraphy was validated in patients with insomnia in the general population [88–91] and also demonstrated accurate results in evaluating sleep quality in PD patients compared to other subjective measures [29]. Actigraphy has several limits, though, as it cannot offer information about sleep stages, and it may overestimate the total sleep time if the patient remains still in bed without moving, as the recorder misinterprets immobility as sleep [91]. Therefore, actigraphy is best indicated for characterizing sleep disruptions and not to certify sleep initiation insomnia [85].

*The Parkinson's KinetiGraph (PKG)* is a device using wearable sensors (accelerometers) to record movements in order to offer data regarding several motor parameters in PD. It can also provide relative information regarding sleep parameters, as a period of immobility detected for at least 14 min is considered as an episode of sleep. The presence of interruptions of immobility during the night might be interpreted as awakenings or abnormal movements caused by sleep disturbances (RLS, RBD, etc.) [92]. Klingelhoefer et al. reported that the immobility and mobility states recorded by the PKG might correspond to sleep/awakening periods during nighttime, and the recorded sleep parameters correlate with other subjective measures of sleep [92]. The information obtained with the PKG changed the therapeutic decision in almost one-third of PD patients and improved communication with the neurologist in the majority of cases [93]. Comparative studies with polysomnography indicated that the periods of immobility that were identified with PKG during daytime correspond in approximately 85% with sleep periods confirmed with PSG [94]. Considering this, PKG might be a useful tool to investigate sleep onset and maintenance insomnia [92] and to integrate the information with the concomitant objective measures of the motor symptoms (bradykinesia, tremor, dyskinesia and fluctuations) [95,96]. PKG might also provide information regarding sleep quantity and quality, with significant correlations with subjective measures, but it cannot establish the sleep stages only based on the immobility data recorded [92], nor can it establish other events such as OSA or periodic limb movements [97]. It is a reliable tool that should be used together with a thorough history and clinical examination [93].

*Polysomnography (PSG)* is considered the 'gold standard' assessment tool for sleep disorders, as it can evaluate in an objective manner the sleep stages, sleep architecture and the normal and abnormal events during sleep. Several studies have been conducted in order to evaluate the sleep differences between PD patients and healthy controls. In PD patients, most of the PSG studies revealed more awakenings in PD patients, but no differences in sleep stages 1, 2 and the slow-wave sleep stage were observed in comparison to controls [98]. Most of the PSG studies did not demonstrate an increased rate of periodic limb movements during sleep in PD patients, nor a certain association with obstructive sleep apnea [98]. The contribution of nocturia to disrupted sleep and poor sleep quality was also demonstrated objectively by PSG evaluation [99]. Regarding the suspicion of RBD in PD patients, the clinical interview of the patient and PD partner might underestimate the occurrence of the abnormal motor behavior during sleep; therefore, PSG is necessary for the correct diagnosis of RBD [100]. However, PSG does not take part in the routine assessment of insomnia, as it has several limits—it is laborious and it requires trained clinicians and special conditions for the assessment (sleep lab). It is neither useful nor recommended to diagnose insomnia, but it can be necessary to rule out other conditions that might induce and perpetuate insomnia, such as SDB, RBD, and periodic limb movements [101].

#### **3. Personalized Medicine and the Assessment of the PD Patient with Insomnia and Impaired Quality of Sleep**

The concept of personalized (precision) medicine emphasizes the need for multidimensional approaches to the PD patient considering the complexity of this disorder. Several factors should be reviewed in order to establish tailored management strategies: genomics, pharmacogenetics, personality, lifestyle, comorbidities, etc. [102]. For instance, the comorbidity of respiratory disorders/sleep apnea, which is related to excessive daytime sleepiness, sleep fragmentation, anxiety and memory difficulties, represents one of the interrelated clinical situations addressed by personalized medicine [103]. In that case, the proper assessment of sleep-maintenance insomnia could reveal an underlying respiratory problem and consultation with a pulmonologist would be necessary. Taking into account the various factors known to be associated with insomnia and the particularities of the sleep disturbances in PD, an individualized approach is therefore mandatory in order to better characterize sleep in PD and to develop adequate management strategies. We propose an algorithm for the personalized assessment of PD patients with insomnia and impaired sleep quality, which is shown in Figure 1. In this regard, the clinician should always approach the patient with sleep disturbances by asking for more details about the main complaints (the information obtained from a caregiver could be valuable). A full general and neurological exam should be performed; a proper examination of the motor symptoms should include assessment using the UPDRS part III & IV. As the non-motor symptoms have strong connections with insomnia and poor sleep quality, the NMSQ can be used as a screening tool that is brief and easy to apply. To better understand the patient's pre-sleep habits and symptoms, several aspects should be asked (for instance, sleep patterns during day and night, the intake of coffee or alcohol, if the patient leads a sedentary lifestyle, etc.). A sleep diary may bring valuable information in this regard, and the patient should be informed regarding how to overcome his or her bad sleep habits. The side effects of medications should be reviewed and changed accordingly. Once the clinician identifies certain symptoms that occur before sleep onset (for instance, RLS), the next step is to evaluate the severity of these symptoms and start a treatment (in this case, IRLS might be a useful tool for severity grading and monitoring). If the patient complaints about poor sleep quality, frequent awakenings during nighttime and difficulties falling back asleep, the neurologist should try to identify and treat the cause(s), considering the common association with motor symptoms (nocturnal cramps, tremor, dyskinesia, etc.), non-motor symptoms (e.g., pain, nocturia) and other comorbidities (RLS/ PLMS, SDB, RBD). In the context of a busy medical practice, we strongly recommend the use of standardized scales for non-motor evaluation (NMSQ) and for overall sleep assessment (considering their main indications, advantages, and disadvantages—see Table 1). Daytime consequences of insomnia and poor quality of sleep should be asked about in order to appreciate the magnitude of the sleep complaints. For instance, if the patient or the clinician suspects that poor quality of sleep may be associated with memory and attention problems, a cognitive screening test such as the MMSE or MoCA can offer supplementary information. In some cases, when the causes or the consequences of insomnia and poor sleep quality are difficult to identify or are resistant to the recommended treatment, further objective assessment should be indicated. Wearable devices might be more convenient for the patient. They are useful for obtaining objective measurements of sleep parameters and motor function and can record information for a longer time (at least 1 week). PSG, on the other hand, should be indicated only in particular circumstances, for instance, when the diagnosis is uncertain or when other associated conditions such as SBD or RBD are suspected. Considering the many interconnected aspects of sleep disorders in PD patients, we suggest that a comprehensive assessment of sleep parameters and associated factors may be the key to personalized and successful management of these disturbances.


**Figure 1.** Proposed clinical interview components and subjective and objective methods for the personalized assessment of insomnia and sleep quality in PD patients. ESS, Epworth Sleepiness Scale; IRLS, International Restless Legs Syndrome Study Group rating scale; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; NMSQ, Non-Motor Symptoms Questionnaire; PD, Parkinson's disease; PDSS, Parkinson Disease Sleep Scale; PKG, Parkinson's KinetiGraph; PLMS, periodic limb movements of sleep; PSG, polysomnography; PSQI, Pittsburg Sleep Quality Index; RBD, REM sleep behavior disorder; RLS, restless legs syndrome; SCOPA, Scales for outcomes in PD; SDB, sleep-disordered breathing; UPDRS, Unified Parkinson Disease Rating Scale. **Figure 1.** Proposed clinical interview components and subjective and objective methods for the personalized assessment of insomnia and sleep quality in PD patients. ESS, Epworth Sleepiness Scale; IRLS, International Restless Legs Syndrome Study Group rating scale; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; NMSQ, Non-Motor Symptoms Questionnaire; PD, Parkinson's disease; PDSS, Parkinson Disease Sleep Scale; PKG, Parkinson's KinetiGraph; PLMS, periodic limb movements of sleep; PSG, polysomnography; PSQI, Pittsburg Sleep Quality Index; RBD, REM sleep behavior disorder; RLS, restless legs syndrome; SCOPA, Scales for outcomes in PD; SDB, sleep-disordered breathing; UPDRS, Unified Parkinson Disease Rating Scale.

#### **4. Conclusions 4. Conclusions**

There are several aspects of sleep that should be carefully examined when investigating the PD patient with insomnia. Many behavioral factors, as well as the associated motor and non-motor symptoms, are interconnected with sleep disturbances and poor quality of life. An easy and methodical approach is to start from the main complaint and then assess the habits and symptoms before sleep, then the symptoms during sleep and the consequences during the day. There are several useful scales and questionnaires designed to help the clinician identify the main complaints and to grade their severity. When in doubt, further objective assessment methods should be recommended, such as actigraphy, the Parkinson KinetiGraph or polysomnography. A personalized approach to the PD patient with sleep disturbances would be therefore much effective in establishing the proper therapeutic strategies that can help improve the quality of life of these patients. There are several aspects of sleep that should be carefully examined when investigating the PD patient with insomnia. Many behavioral factors, as well as the associated motor and non-motor symptoms, are interconnected with sleep disturbances and poor quality of life. An easy and methodical approach is to start from the main complaint and then assess the habits and symptoms before sleep, then the symptoms during sleep and the consequences during the day. There are several useful scales and questionnaires designed to help the clinician identify the main complaints and to grade their severity. When in doubt, further objective assessment methods should be recommended, such as actigraphy, the Parkinson KinetiGraph or polysomnography. A personalized approach to the PD patient with sleep disturbances would be therefore much effective in establishing the proper therapeutic strategies that can help improve the quality of life of these patients.

**Author Contributions:** Conceptualization, Ș.D. and C.F.-P.; methodology, Ș.D. and C.F.-P.; writing—original draft preparation, Ș.D.; writing—review and editing, Ș.D. and C.F.-P. All authors have read and agreed to the published version of the manuscript. **Author Contributions:** Conceptualization, ¸S.D. and C.F.-P.; methodology, ¸S.D. and C.F.-P.; writing original draft preparation, ¸S.D.; writing—review and editing, ¸S.D. and C.F.-P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding. **Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable. **Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable. **Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable. **Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest. **Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

