211
Journal of Parkinson’s Disease 4 (2014) 211–221 DOI 10.3233/JPD-130301 IOS Press
Review
Sleep Disorders in Parkinson’s Disease Wiebke Schrempfa,b,∗ , Moritz D. Brandta,b , Alexander Storcha,b,c and Heinz Reichmannb a Division
of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany b Department of Neurology, Dresden University of Technology, Dresden, Germany c German Center for Neurodegenerative Diseases (DZNE), Research Site Dresden, Dresden, Germany
Abstract. Sleep disorders in patients with Parkinson’s disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD. Keywords: Parkinson’s disease, non-motor symptoms, sleep, REM sleep behaviour disorder (RBD), restless legs syndrome (RLS), insomnia
INTRODUCTION Parkinson’s disease (PD) is a neurodegenerative disease characterized by neuropathological changes with deposits containing alpha-synuclein and ubiquitin called Lewy inclusion bodies [1]. Characteristic clinical motor symptoms are bradykinesia, tremor, rigidity and impaired postural reflexes. After Alzheimer’s disease, PD is the most common neurodegenerative disease in the Western countries [2]. The prevalence is about 0.3% in the general population and rises with ∗ Correspondence
to: Wiebke Schrempf, MD, Division of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, 01307 Dresden, Germany. Tel.: +49 351 458 3876; Fax: +49 351 458 5802; E-mail: Wiebke.schrempf@ uniklinikum-dresden.de.
age [1, 3]. PD is suspected to follow a defined course with progressive cell degeneration of the olfactory bulb and gastrointestinal tract followed by an ascending degeneration of the brainstem first involving the medulla and pons and then progressing to dopaminergic neurons in the substantia nigra pars compacta, resulting in motor symptoms e.g., akinesia, tremor and rigidity, and finally involving cortical structures [4]. In the last few years, the importance of non-motor symptoms (e.g., depression, olfactory dysfunction, autonomic dysfunction such as constipation and sleep disorders with a special focus on REM-sleep behaviour disorder) has been stressed as evidence rose that these symptoms precede motor symptoms and may be helpful in identifying patients with increased risk
ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
212
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
of developing a neurodegenerative disorder especially dementia with Lewy bodies (DLB) or PD [5–9]. Although patients suffer from non-motor-symptoms (e.g., sleep disorders, autonomic dysfunction, cognitive decline) throughout, during the moderate to advanced stages of PD non-motor-complications such as dementia, psychosis as well as increasing sleep-wake dysregulation or mood instability gain importance. As novel therapeutic options with potentially disease-modifying potential emerge (e.g., nicotine, rasagiline – a MAO-inhibitor), it becomes increasingly important to identify the pre-motor-stages (characterized by olfactory dysfunction, depression, anxiety and REM-sleep-behaviour disorder) or even pre-symptomatic stages (characterized by gene abnormalities, preexisting imaging pathologies or potential existing biochemical abnormalities such as changes of alpha-synuclein levels). Therefore, strategies to identify patients with an increased risk of developing a neurodegenerative disorder have become one of the main topics in research in the field of neurodegeneration. Sleep disturbances are very common in the general population and also in PD with an incidence of about 60–70% [10, 11]. Causes for sleep disorders in PD are varied and can have an immensely negative impact on the quality of life of these patients [12]. Most patients complain about difficulties falling or staying asleep, sleep fragmentation and daytime sleepiness with involuntarily daytime naps. Also patients report disturbed sleep resulting from vivid, violent dreams and dream enactment behaviour, known as REM-sleep behaviour disorder (RBD). In addition patients with PD are commonly affected by primary sleep disorders also existing in the general population – particularly restless-legssyndrome (RLS, also known as Willis-Ekbom Disease) or periodic leg movements in sleep and sleep disordered breathing, notably obstructive sleep apnea [13]. Other comorbidities such as depression or dementia, hallucinations and psychosis may also affect sleep adversely [14]. In addition, changes occur with age. Older persons complain about shorter total sleep time, early awakenings and also problems to remain asleep. Diagnosis and effective treatment and management of these problems are essential for improving the quality of life and reducing institutionalization of these patients [15].
DIAGNOSIS OF SLEEP DISORDERS To identify sleep abnormalities in patients with PD, patients as well as spouses and caregivers should
be interviewed carefully regarding symptoms and features of sleeping disorders. Symptoms of sleep disruption, difficulties in falling or remaining asleep (“do you have trouble to fall asleep or trouble to fall asleep again after you have woken up?”), daytime sleepiness (“do you have trouble staying awake?”), morning tiredness (“do you feel rested in the morning?”) or sudden onset of naps (“sleep attacks”) should be evaluated (“do you take naps (5 min or longer) during the daytime”?). Excessive daytime sleepiness can also be evaluated by using the Epworth Sleepiness Scale (ESS), a brief self-questionnaire which is commonly used in routine diagnosis and especially in diagnosis of sleep disordered breathing[16]. For rating daytime sleepiness and sleep attacks also the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS) can be used which are both suggested to measure severity of sleepiness with the SSS being more useful in measuring severity of daytime sleepiness at a specific time [17]. Easy to administer self-questionnaires which can be used in clinical routine and which help to differentiate sleep disturbances are the Pittsburgh Sleep Quality Index (PSQI) [18] or the Medical Outcomes Study Sleep Scale (MOS) [19]. The PSQI is recommended for rating overall sleep problems and to screen and to measure severity, The SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity and for rating daytime sleepiness [17]. In addition, patients and caregivers should be asked about excessive dreaming or nighttime activities such as shouting or laughing as well as involuntary movements (e.g., kicking, boxing, falling out of bed, sleep wandering, dream-enactment behaviour). Self-questionnaires which are helpful in diagnosing REM-sleep behaviour disorder are the Mayo Sleep Questionnaire [20] and also the REM sleep behaviour disorder screening questionnaire (RBDSQ) [21]. Patients should be additionally interviewed concerning symptoms of primary RLS (e.g., an irresistible urge to move the legs, usually accompanied by dysaesthesias, which are usually relieved by movement and exacerbated by rest and follow circadian rhythms (they are worse in the evenings and at nights)) and also sleep disordered breathing (snoring, apnea, morning headaches, daytime sleepiness with involuntarily naps). Sometimes sleep diaries can be helpful especially regarding insomnia or evaluation of parasomnia (frequency and time of appearance, which can be helpful in differentiating NREM from REM-associated parasomnia).
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
Depressive symptoms should be evaluated by taking medical history and questionnaires (e.g., BDI, MADRS) and by interviewing spouses or caregivers carefully. To determine other non-motor symptoms in PD the NMSQuest might be helpful although this tool is quite detailed and therefore not applicable for routine diagnosis. It might be helpful to diagnose other confounding factors leading to disruption of sleep (e.g., hallucinations, nocturia) [22]. The PDSS-2 [23] was designed to specifically evaluate sleep quality in PD, it is used more often in clinical trials. The amount and timing of nicotine and alcohol intake as well as consumption of other drugs and also dosage and time of medication intake and changes of medication at the time of onset of the sleeping difficulties should be determined. Laboratory tests should be conducted to rule out other organic causes for sleep disorders especially thyroid dysfunction or iron deficiency (particularly relevant in RLS). If features of sleep disordered breathing, parasomnia, excessive daytime sleepiness or RLS are present, referral to a sleep specialist or sleep laboratory should be considered. Sleep is evaluated by polysomnography using electroencephalograpy, electromyography and electrooculography. 4 different stages (NREM 1–3, REM) are recognized according to AASM (American Academy of Sleep Medicine) criteria. Normal sleep follows a defined sleep cycle with alternating NREM and REM stages with predominating slow wave sleep (NREM 3) during the first part of the night and REM sleep during the second part of the night. To assess daytime sleepiness either multiple sleep latency tests (MSLT) measuring the ability to fall asleep during daytime in defined conditions (patient is instructed to try to fall asleep every 2 hours in a darkened room) or pupillography [24] might be considered. Insomnia can be assessed using sleep diary and a wrist-worn actigraph- a portable rest and activity monitor which can be used to indirectly measure sleeping periods. Sleep disordered breathing can be positively diagnosed using polysomnography in a sleep laboratory or an appropriate home sleep study (polygraphy). Also REM Sleep behaviour disorder needs confirmation by polysomnography. Other parasomnias (e.g., night-terror) are more common in children but may also persist throughout adulthood and differentiation from REM Sleep behavior disorders or other conditions (e.g., frontal lobe epilepsy) may some-
213
times also require polysomnography or video-EEGmonitoring. Other sleep-disrupting disorders may only be diagnosed using polysomnography. For example, motor disturbances of sleep like periodic limb movements in sleep (PLMS) might be detected which may cause disruption of sleep. In addition, the diagnosis of RLS might be supported by showing periodic limb movements in most (up to 80%) of the affected patients. Diagnosis of RBD requires complex motor behaviour with a loss of muscle atonia during REM sleep as shown by polysomnography. Questionnaires might be helpful to identify patients with RBD (e.g., REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) [21]; or single question questionnaire [25]). Recently, Frauscher and colleagues tried to come to a better definition of polysomnographic diagnostic criteria of RBD [26–28], but these new criteria have not yet been approved by the American Academy of Sleep Medicine.
EFFECTS OF MEDICATION Sleep disturbances are more likely in advanced PD and are positively correlated with higher doses of medication [29]. Drug treatment itself may have either negative or positive impact on sleep quality: Lower doses of levodopa or dopamine agonists are able to improve sleep quality partly by reducing motor symptoms such as nighttime hypokinesia, dyskinesia or tremor [30, 31] which interfere with normal sleep [32–34]. However, the same drugs may cause insomnia (particularly in higher doses) and excessive daytime sleepiness with sudden onset of “sleep attacks” [35]. These dose-dependent effects are partly explained by the involvement of different receptor types (particularly dopamine D1, D2 and D3 receptors). Dosage, duration of treatment and timing of application all seem to cause different effects – with insomnia and daytime sleepiness at the opposite ends of the spectrum [36]. It has been suspected that especially the application of those dopamine agonists which predominantly act via dopamine D3 receptors lead to excessive daytime sleepiness. In contrast, agonists mediated via dopamine D1 receptors seem to reduce sleep efficacy by increasing arousals, whereas stimulation of dopamine D2 receptors leads to controversial effects depending on the dosage [37, 38]. Different studies showed contradictory results regarding the impact of MAO-inhibitors on sleep. Patients treated with selegiline, which is a non-
214
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
selective MAO-B-inhibitor, frequently complained about sleep disruption and daytime sleepiness [39]. Polysomnographic studies showed a decrease in REM sleep and increase in sleep fragmentation. These side effects of selegiline might be caused by its amphetamine-like metabolites. Treatment with rasagiline, a selective MAO-B-inhibitor not metabolized to amphetamine derivatives, did not impair sleep significantly compared to placebo [40]. Together, influence of medication on sleep in PD is complex and studies show contradictory results, partly resulting from methodological differences. Drug effects seem to be specific to the substance class, and exhibit a dependence on dosage and time of application. A direct influence of dopamine agonists on excessive daytime sleepiness is still an area of debate and effects of the neurodegenerative process itself should not be underestimated.
INSOMNIA Insomnia is one of the most common symptoms of sleep disorders in the general population and frequently observed in PD. Insomnia is even more frequent in patients with PD compared to age matched controls [41]. In a cross-sectional survey with face-to-face interview, 50% of PD patients complained about insomnia [42]. In an observational, multicenter, cross-sectional study insomnia was one of the most common nonmotor-symptoms with 40–50% of 545 PD patients affected [43]. The main complaints are difficulty in falling and remaining asleep and early awakening. Coexisting depression might partly be responsible for insomnia but patients without depression experience similar difficulties which leads to the assumption that also other factors such as the neurodegeneration itself and/or the influence of drugs but also other coexisting conditions like fatigue or cognitive impairment contribute to these sleep disorders [44]. In sleep laboratory studies, polysomnography showed sleep fragmentation with reduced sleep efficiency (ratio of total sleep time/ total recording time (TRT) in %), elevated proportion of wake after sleep onset (WASO), increased arousals and also reduced REM- and slow wave-sleep [36, 45]. Impaired sleep efficiency and total sleep time was documented even in untreated de novo PD patients [46]. Potential causes for the disruption of sleep-wake rhythms in PD are the neurodegeneration of the regulatory brainstem and thalamo-cortical networks. In addition, biochemical alterations of monoaminergic (e.g., serotonin, noradrenaline) and cholinergic sys-
tems which are involved in sleep-wake regulation are discussed as causative factors for sleep disruption in PD: A decline of serotonergic neurons in the dorsal raphe nuclei and also of noradrenergic neurons in the locus coeruleus as well as cholinergic neurons of the pedunculopontine nucleus, which are involved in REM sleep regulation, have been described [47]. Furthermore, the loss of dopaminergic neurons might have a negative impact on sleep quality in PD patients [48]. Degeneration of the ventral tegmental area in the midbrain which seems to be involved in sleep-wake regulation and regulation of arousals via dopamine D1 receptors is supposed to have a substantial impact on sleep disorders in PD [49]. Insomnia in PD may be aggravated by discomfort resulting from nighttime hypokinesia, particularly if turning in bed is impaired. Pain and other sensations or other comorbidities (e.g., coexisting polyneuropathy) may also influence sleep negatively. Patients also complain about nocturia, which is very common in PD and is responsible for sleep disruption [22, 50, 51]. Furthermore, hallucinations or psychosis and other sleep disorders e.g., RLS, PLMS and sleep disordered breathing could have a negative impact on sleep quality. Drug treatment for PD may lead to insomnia, in particular if dopamine-agonists or levodopa are administered late in the day or at high doses during the evening or at nighttime. It is assumed that therapy with other drugs known to impair sleep quality (e.g., activating antidepressants, antihypertensives) further increases sleep problems in patients with PD. Treatment of insomnia depends on the underlying pathology. The first priority should be to optimize control of motor symptoms while carefully evaluating (antiparkinsonian) medication regarding potentially negative impact on sleep. If necessary, medication should be redistributed and if necessary doses of dopamine agonists should be reduced to minimize negative impact on sleep quality. If necessary, the prescription of sedating antidepressants or hypnotics (for short-term use only) should be considered. As a second priority, other sleep disorders like RLS or sleep disordered breathing should be excluded by medical history, history taken from bed partners and other measurements such as polysomnography, portable sleep study or actigraphy if necessary and if present treated as efficiently as possible according to the appropriate guidelines. Insomnia caused or partly caused by depression could be treated by psychological and pharmacological interventions with sedating antidepressants (e.g., mirtazapine). Nonpharmacological treatments include the introduction of
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
sleep hygiene rules (e.g., abandoning daytime naps), cognitive behavioural therapy for insomnia (CBTI) and relaxation training. In disorders of circadian rhythm application of bright light as well as melatonin therapy might be helpful to reset circadian rhythm [52].
EXCESSIVE DAYTIME SLEEPINESS Excessive daytime sleepiness and sleep attacks are one of the most common non-motor symptoms in PD, which highly impairs patients’ quality of life. As sleepiness and especially sudden sleep attacks are incompatible with driving a car or handling a machine, these symptoms could impose another dramatic restriction upon PD patients who are limited in their ambulation anyway. Approximately every other PD patient suffers from excessive daytime sleepiness with an ESS score >10 or a mean sleep latency in the MSLT
Journal of Parkinson’s Disease 4 (2014) 211–221 DOI 10.3233/JPD-130301 IOS Press
Review
Sleep Disorders in Parkinson’s Disease Wiebke Schrempfa,b,∗ , Moritz D. Brandta,b , Alexander Storcha,b,c and Heinz Reichmannb a Division
of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany b Department of Neurology, Dresden University of Technology, Dresden, Germany c German Center for Neurodegenerative Diseases (DZNE), Research Site Dresden, Dresden, Germany
Abstract. Sleep disorders in patients with Parkinson’s disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD. Keywords: Parkinson’s disease, non-motor symptoms, sleep, REM sleep behaviour disorder (RBD), restless legs syndrome (RLS), insomnia
INTRODUCTION Parkinson’s disease (PD) is a neurodegenerative disease characterized by neuropathological changes with deposits containing alpha-synuclein and ubiquitin called Lewy inclusion bodies [1]. Characteristic clinical motor symptoms are bradykinesia, tremor, rigidity and impaired postural reflexes. After Alzheimer’s disease, PD is the most common neurodegenerative disease in the Western countries [2]. The prevalence is about 0.3% in the general population and rises with ∗ Correspondence
to: Wiebke Schrempf, MD, Division of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, 01307 Dresden, Germany. Tel.: +49 351 458 3876; Fax: +49 351 458 5802; E-mail: Wiebke.schrempf@ uniklinikum-dresden.de.
age [1, 3]. PD is suspected to follow a defined course with progressive cell degeneration of the olfactory bulb and gastrointestinal tract followed by an ascending degeneration of the brainstem first involving the medulla and pons and then progressing to dopaminergic neurons in the substantia nigra pars compacta, resulting in motor symptoms e.g., akinesia, tremor and rigidity, and finally involving cortical structures [4]. In the last few years, the importance of non-motor symptoms (e.g., depression, olfactory dysfunction, autonomic dysfunction such as constipation and sleep disorders with a special focus on REM-sleep behaviour disorder) has been stressed as evidence rose that these symptoms precede motor symptoms and may be helpful in identifying patients with increased risk
ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
212
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
of developing a neurodegenerative disorder especially dementia with Lewy bodies (DLB) or PD [5–9]. Although patients suffer from non-motor-symptoms (e.g., sleep disorders, autonomic dysfunction, cognitive decline) throughout, during the moderate to advanced stages of PD non-motor-complications such as dementia, psychosis as well as increasing sleep-wake dysregulation or mood instability gain importance. As novel therapeutic options with potentially disease-modifying potential emerge (e.g., nicotine, rasagiline – a MAO-inhibitor), it becomes increasingly important to identify the pre-motor-stages (characterized by olfactory dysfunction, depression, anxiety and REM-sleep-behaviour disorder) or even pre-symptomatic stages (characterized by gene abnormalities, preexisting imaging pathologies or potential existing biochemical abnormalities such as changes of alpha-synuclein levels). Therefore, strategies to identify patients with an increased risk of developing a neurodegenerative disorder have become one of the main topics in research in the field of neurodegeneration. Sleep disturbances are very common in the general population and also in PD with an incidence of about 60–70% [10, 11]. Causes for sleep disorders in PD are varied and can have an immensely negative impact on the quality of life of these patients [12]. Most patients complain about difficulties falling or staying asleep, sleep fragmentation and daytime sleepiness with involuntarily daytime naps. Also patients report disturbed sleep resulting from vivid, violent dreams and dream enactment behaviour, known as REM-sleep behaviour disorder (RBD). In addition patients with PD are commonly affected by primary sleep disorders also existing in the general population – particularly restless-legssyndrome (RLS, also known as Willis-Ekbom Disease) or periodic leg movements in sleep and sleep disordered breathing, notably obstructive sleep apnea [13]. Other comorbidities such as depression or dementia, hallucinations and psychosis may also affect sleep adversely [14]. In addition, changes occur with age. Older persons complain about shorter total sleep time, early awakenings and also problems to remain asleep. Diagnosis and effective treatment and management of these problems are essential for improving the quality of life and reducing institutionalization of these patients [15].
DIAGNOSIS OF SLEEP DISORDERS To identify sleep abnormalities in patients with PD, patients as well as spouses and caregivers should
be interviewed carefully regarding symptoms and features of sleeping disorders. Symptoms of sleep disruption, difficulties in falling or remaining asleep (“do you have trouble to fall asleep or trouble to fall asleep again after you have woken up?”), daytime sleepiness (“do you have trouble staying awake?”), morning tiredness (“do you feel rested in the morning?”) or sudden onset of naps (“sleep attacks”) should be evaluated (“do you take naps (5 min or longer) during the daytime”?). Excessive daytime sleepiness can also be evaluated by using the Epworth Sleepiness Scale (ESS), a brief self-questionnaire which is commonly used in routine diagnosis and especially in diagnosis of sleep disordered breathing[16]. For rating daytime sleepiness and sleep attacks also the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS) can be used which are both suggested to measure severity of sleepiness with the SSS being more useful in measuring severity of daytime sleepiness at a specific time [17]. Easy to administer self-questionnaires which can be used in clinical routine and which help to differentiate sleep disturbances are the Pittsburgh Sleep Quality Index (PSQI) [18] or the Medical Outcomes Study Sleep Scale (MOS) [19]. The PSQI is recommended for rating overall sleep problems and to screen and to measure severity, The SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity and for rating daytime sleepiness [17]. In addition, patients and caregivers should be asked about excessive dreaming or nighttime activities such as shouting or laughing as well as involuntary movements (e.g., kicking, boxing, falling out of bed, sleep wandering, dream-enactment behaviour). Self-questionnaires which are helpful in diagnosing REM-sleep behaviour disorder are the Mayo Sleep Questionnaire [20] and also the REM sleep behaviour disorder screening questionnaire (RBDSQ) [21]. Patients should be additionally interviewed concerning symptoms of primary RLS (e.g., an irresistible urge to move the legs, usually accompanied by dysaesthesias, which are usually relieved by movement and exacerbated by rest and follow circadian rhythms (they are worse in the evenings and at nights)) and also sleep disordered breathing (snoring, apnea, morning headaches, daytime sleepiness with involuntarily naps). Sometimes sleep diaries can be helpful especially regarding insomnia or evaluation of parasomnia (frequency and time of appearance, which can be helpful in differentiating NREM from REM-associated parasomnia).
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
Depressive symptoms should be evaluated by taking medical history and questionnaires (e.g., BDI, MADRS) and by interviewing spouses or caregivers carefully. To determine other non-motor symptoms in PD the NMSQuest might be helpful although this tool is quite detailed and therefore not applicable for routine diagnosis. It might be helpful to diagnose other confounding factors leading to disruption of sleep (e.g., hallucinations, nocturia) [22]. The PDSS-2 [23] was designed to specifically evaluate sleep quality in PD, it is used more often in clinical trials. The amount and timing of nicotine and alcohol intake as well as consumption of other drugs and also dosage and time of medication intake and changes of medication at the time of onset of the sleeping difficulties should be determined. Laboratory tests should be conducted to rule out other organic causes for sleep disorders especially thyroid dysfunction or iron deficiency (particularly relevant in RLS). If features of sleep disordered breathing, parasomnia, excessive daytime sleepiness or RLS are present, referral to a sleep specialist or sleep laboratory should be considered. Sleep is evaluated by polysomnography using electroencephalograpy, electromyography and electrooculography. 4 different stages (NREM 1–3, REM) are recognized according to AASM (American Academy of Sleep Medicine) criteria. Normal sleep follows a defined sleep cycle with alternating NREM and REM stages with predominating slow wave sleep (NREM 3) during the first part of the night and REM sleep during the second part of the night. To assess daytime sleepiness either multiple sleep latency tests (MSLT) measuring the ability to fall asleep during daytime in defined conditions (patient is instructed to try to fall asleep every 2 hours in a darkened room) or pupillography [24] might be considered. Insomnia can be assessed using sleep diary and a wrist-worn actigraph- a portable rest and activity monitor which can be used to indirectly measure sleeping periods. Sleep disordered breathing can be positively diagnosed using polysomnography in a sleep laboratory or an appropriate home sleep study (polygraphy). Also REM Sleep behaviour disorder needs confirmation by polysomnography. Other parasomnias (e.g., night-terror) are more common in children but may also persist throughout adulthood and differentiation from REM Sleep behavior disorders or other conditions (e.g., frontal lobe epilepsy) may some-
213
times also require polysomnography or video-EEGmonitoring. Other sleep-disrupting disorders may only be diagnosed using polysomnography. For example, motor disturbances of sleep like periodic limb movements in sleep (PLMS) might be detected which may cause disruption of sleep. In addition, the diagnosis of RLS might be supported by showing periodic limb movements in most (up to 80%) of the affected patients. Diagnosis of RBD requires complex motor behaviour with a loss of muscle atonia during REM sleep as shown by polysomnography. Questionnaires might be helpful to identify patients with RBD (e.g., REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) [21]; or single question questionnaire [25]). Recently, Frauscher and colleagues tried to come to a better definition of polysomnographic diagnostic criteria of RBD [26–28], but these new criteria have not yet been approved by the American Academy of Sleep Medicine.
EFFECTS OF MEDICATION Sleep disturbances are more likely in advanced PD and are positively correlated with higher doses of medication [29]. Drug treatment itself may have either negative or positive impact on sleep quality: Lower doses of levodopa or dopamine agonists are able to improve sleep quality partly by reducing motor symptoms such as nighttime hypokinesia, dyskinesia or tremor [30, 31] which interfere with normal sleep [32–34]. However, the same drugs may cause insomnia (particularly in higher doses) and excessive daytime sleepiness with sudden onset of “sleep attacks” [35]. These dose-dependent effects are partly explained by the involvement of different receptor types (particularly dopamine D1, D2 and D3 receptors). Dosage, duration of treatment and timing of application all seem to cause different effects – with insomnia and daytime sleepiness at the opposite ends of the spectrum [36]. It has been suspected that especially the application of those dopamine agonists which predominantly act via dopamine D3 receptors lead to excessive daytime sleepiness. In contrast, agonists mediated via dopamine D1 receptors seem to reduce sleep efficacy by increasing arousals, whereas stimulation of dopamine D2 receptors leads to controversial effects depending on the dosage [37, 38]. Different studies showed contradictory results regarding the impact of MAO-inhibitors on sleep. Patients treated with selegiline, which is a non-
214
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
selective MAO-B-inhibitor, frequently complained about sleep disruption and daytime sleepiness [39]. Polysomnographic studies showed a decrease in REM sleep and increase in sleep fragmentation. These side effects of selegiline might be caused by its amphetamine-like metabolites. Treatment with rasagiline, a selective MAO-B-inhibitor not metabolized to amphetamine derivatives, did not impair sleep significantly compared to placebo [40]. Together, influence of medication on sleep in PD is complex and studies show contradictory results, partly resulting from methodological differences. Drug effects seem to be specific to the substance class, and exhibit a dependence on dosage and time of application. A direct influence of dopamine agonists on excessive daytime sleepiness is still an area of debate and effects of the neurodegenerative process itself should not be underestimated.
INSOMNIA Insomnia is one of the most common symptoms of sleep disorders in the general population and frequently observed in PD. Insomnia is even more frequent in patients with PD compared to age matched controls [41]. In a cross-sectional survey with face-to-face interview, 50% of PD patients complained about insomnia [42]. In an observational, multicenter, cross-sectional study insomnia was one of the most common nonmotor-symptoms with 40–50% of 545 PD patients affected [43]. The main complaints are difficulty in falling and remaining asleep and early awakening. Coexisting depression might partly be responsible for insomnia but patients without depression experience similar difficulties which leads to the assumption that also other factors such as the neurodegeneration itself and/or the influence of drugs but also other coexisting conditions like fatigue or cognitive impairment contribute to these sleep disorders [44]. In sleep laboratory studies, polysomnography showed sleep fragmentation with reduced sleep efficiency (ratio of total sleep time/ total recording time (TRT) in %), elevated proportion of wake after sleep onset (WASO), increased arousals and also reduced REM- and slow wave-sleep [36, 45]. Impaired sleep efficiency and total sleep time was documented even in untreated de novo PD patients [46]. Potential causes for the disruption of sleep-wake rhythms in PD are the neurodegeneration of the regulatory brainstem and thalamo-cortical networks. In addition, biochemical alterations of monoaminergic (e.g., serotonin, noradrenaline) and cholinergic sys-
tems which are involved in sleep-wake regulation are discussed as causative factors for sleep disruption in PD: A decline of serotonergic neurons in the dorsal raphe nuclei and also of noradrenergic neurons in the locus coeruleus as well as cholinergic neurons of the pedunculopontine nucleus, which are involved in REM sleep regulation, have been described [47]. Furthermore, the loss of dopaminergic neurons might have a negative impact on sleep quality in PD patients [48]. Degeneration of the ventral tegmental area in the midbrain which seems to be involved in sleep-wake regulation and regulation of arousals via dopamine D1 receptors is supposed to have a substantial impact on sleep disorders in PD [49]. Insomnia in PD may be aggravated by discomfort resulting from nighttime hypokinesia, particularly if turning in bed is impaired. Pain and other sensations or other comorbidities (e.g., coexisting polyneuropathy) may also influence sleep negatively. Patients also complain about nocturia, which is very common in PD and is responsible for sleep disruption [22, 50, 51]. Furthermore, hallucinations or psychosis and other sleep disorders e.g., RLS, PLMS and sleep disordered breathing could have a negative impact on sleep quality. Drug treatment for PD may lead to insomnia, in particular if dopamine-agonists or levodopa are administered late in the day or at high doses during the evening or at nighttime. It is assumed that therapy with other drugs known to impair sleep quality (e.g., activating antidepressants, antihypertensives) further increases sleep problems in patients with PD. Treatment of insomnia depends on the underlying pathology. The first priority should be to optimize control of motor symptoms while carefully evaluating (antiparkinsonian) medication regarding potentially negative impact on sleep. If necessary, medication should be redistributed and if necessary doses of dopamine agonists should be reduced to minimize negative impact on sleep quality. If necessary, the prescription of sedating antidepressants or hypnotics (for short-term use only) should be considered. As a second priority, other sleep disorders like RLS or sleep disordered breathing should be excluded by medical history, history taken from bed partners and other measurements such as polysomnography, portable sleep study or actigraphy if necessary and if present treated as efficiently as possible according to the appropriate guidelines. Insomnia caused or partly caused by depression could be treated by psychological and pharmacological interventions with sedating antidepressants (e.g., mirtazapine). Nonpharmacological treatments include the introduction of
W. Schrempf et al. / Sleep Disorders in Parkinson’s Disease
sleep hygiene rules (e.g., abandoning daytime naps), cognitive behavioural therapy for insomnia (CBTI) and relaxation training. In disorders of circadian rhythm application of bright light as well as melatonin therapy might be helpful to reset circadian rhythm [52].
EXCESSIVE DAYTIME SLEEPINESS Excessive daytime sleepiness and sleep attacks are one of the most common non-motor symptoms in PD, which highly impairs patients’ quality of life. As sleepiness and especially sudden sleep attacks are incompatible with driving a car or handling a machine, these symptoms could impose another dramatic restriction upon PD patients who are limited in their ambulation anyway. Approximately every other PD patient suffers from excessive daytime sleepiness with an ESS score >10 or a mean sleep latency in the MSLT
