Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Sleep Disorders in Parkinson's Disease

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Chapter 21Sleep Disorders in Parkinson’s Disease

Friederike Sixel-Doring & Claudia TrenkwalderParacelsus-Elena-Klinik, Center for Parkinsonism and Movement Disorders, Kassel, Germany

Introduction

Patients suffering from Parkinson’s disease (PD) fre-quently report a variety of nighttime problems includ-ing poor sleep quality [1]. In recent years, excessive day-time sleepiness and so-called paroxysmal sleep – an unex-pected dozing-off – were associated with dopaminergicmedication, and this resulted in transient restrictions inthe use of non-ergot dopamine agonists for those patientswho wanted to continue driving. However, James Parkin-son in his first report on Parkinson’s disease in 1817already described an increase in disturbed sleep, day-time somnolence with mild confusion, and other signsof intense fatigue in advanced stages of the illness [2].Today it is generally acknowledged that disordered sleepnot only appears in advanced stages of the disease, butcan also be an early symptom. Prior to the evolution ofmotor symptoms, patients may prodromally present withdisruptions of dream sleep, thereby indicating that thisfeature could be highly significant for preclinical diag-nosis. It has been recognized that the specific patho-physiology of PD per se will lead to disordered sleepand thus have an additional negative impact on daytimeperformance. A number of neurodegenerative, psycho-logic and pharmacologic factors may be involved in thesomnopathy of parkinsonian patients, calling for specialattention to be paid to diagnosis and treatment of theirdyssomnia. The presence of sleep disorders can be estab-lished through an interview with the patient and his/herbed partner. Video-supported polysomnography (PSG) isrecommended for clarifying sleep diagnosis, identifyingthe specific nocturnal problem, and choosing the righttreatment.

Pathophysiologic aspects

Serotonergic neurons in the dorsal raphe nucleus, nora-drenergic neurons in the locus coeruleus, and choliner-gic neurons in the pedunculo-pontine region are regarded

as crucial for sleep. Disturbances in these neural areascan lead to disruption of the sleep–wake rhythm. Like-wise, alterations in the mesocorticolimbic system mayproduce sleep-wake abnormalities [3]. We also know thatdopamine D1 receptor agonists are particularly likelyto provoke electroencephalogram (EEG) desynchroniza-tions and arousal reactions [4], whereas low doses ofdopamine D1 and D2 receptor agonists work in a sleep-inducing fashion. This seems to be a function of thedopamine D2 autoreceptors, which play an importantrole in sleep mediation and indirectly take part in theregulation of sleep by influencing the firing rate of theventral tegmental dopaminergic neurons [5]. The regu-lation of rapid eye movement (REM) sleep and, moreimportantly, its disruption, which manifests as REM sleepbehavior disorder (RBD), has not yet been elucidated inhumans (see Chapter 22). Recent experimental data froma rat model propose a putative on–off switch for the con-trol of REM sleep [6]. According to this model, REM-off is activated by the ventrolateral part of the periaque-ductal gray matter and the lateral pontine tegmentum.These regions are inhibited by GABAergic and galanin-ergic projections from the forebrain ventrolateral preop-tic nucleus, thus inducing REM-on. The REM-off neuronsin turn are activated by noradrenergic projections fromlocus coeruleus, serotonergic raphe nucleus, and hypocre-tinergic pathways from the lateral hypothalamus, therebyending the period of REM sleep. REM-on and -off areasare mutually inhibitory with reciprocal interactions witheach other. In the rat, projections from the sublaterodor-sal nucleus to the medulla and the spinal cord with acti-vation of inhibitory interneurons that hyperpolarize ante-rior horn motor neurons are held responsible for atoniaduring REM sleep. Braak et al. showed a characteristicascension pattern of Lewy bodies and Lewy neurites asthe specific pathologic–anatomic hallmarks of PD, affect-ing sleep-sensitive areas of the brainstem at the earliest“preclinical” stage [7], thereby explaining why sleep dis-orders such as RBD might precede the typical motor man-ifestation of the disease. It is therefore essential for sleep

Parkinson’s Disease: Non-Motor and Non-Dopaminergic Features, First Edition. Edited by C. Warren Olanow, Fabrizio Stocchi, and Anthony E. Lang.c© 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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disorders to be recognized as an important non-motor fea-ture of PD that can be present at all stages of the illnessranging from the preclinical to the advanced state.

Clinical symptoms

Parkinsonian patients often complain of difficulties infalling asleep and maintaining sleep, and also noctur-nal immobility and RBD, as reported by bed partners.Sleep disorders undeniably worsen with the progressionof PD. Up to 15% of PD patients show daytime sleepi-ness and paroxysmal sleep, which become more obvi-ous during the course of the illness. Severe sleep disor-ders are primarily seen in elderly patients who alreadysuffer from motor fluctuations and/or hallucinations [8].See Table 21.1 and Figure 21.1 for aspects of PD that con-tribute to sleep–wake disturbances.

Disorders of initiating andmaintaining sleep

Problems in falling asleep are likely related to anincreased dosage of mainly dopamine agonists, andrarely to levodopa therapy. Fragmented sleep with loss ofslow wave sleep and a subsequent increase in sleep stages1 and 2, as well as an increase of arousals [9,10], are usu-ally not predominant in early stages of the disease, butescalate with advancing neurodegeneration [11]. Patients

will experience this as a problem of sleep maintenance,which can be further aggravated by dopaminergic over-stimulation.

Nocturnal akinesia

Many patients complain about being unable to turn overat night, and have difficulties in getting up to go to thetoilet. This nighttime immobility as a motor fluctuation isalso a classic symptom of advanced PD. It is often associ-ated with recurrent nocturnal tremor, periodic and non-periodic leg movements, and feelings of rigidity [1,12].Nocturnal tremor typically occurs during sleep stage 1or in waking phases at night; it can be very bothersomefor the patient as it prevents him/her from going backto sleep. Simple or complex movements, such as blink-ing when falling asleep, blepharospasm, increased mus-cle contractility of the extremities during non-REM sleep,and so-called fragmented myoclonus of an extremity, areobserved at varied intensity and frequency in parkinso-nian patients while asleep.

Periodic leg movements in sleep(PLMS)

PLMS, like restless legs syndrome (RLS), is a frequentdisorder that can, in severe cases, have a periodic limbmovement index (PLMI) (the number of periodic limb

Table 21.1 Aspects of Parkinson’s disease that contribute to sleep–wake disturbances (modified from Happe and Trenkwalder [12].

Reason Predominant impairments

Neurochemical alterations of cholinergic, serotonergic, andnoradrenergic systems and the neuropathologic changes of PD

Impaired sleep–wake control, reduced REM sleep

Alterations of REM sleep control, “flip-flop” switch of REM sleep

Bradykinesia and rigidity Reduction of normal body shifts during sleep with problem turning over inbed, leading to discomfort and awakenings; impaired ability to use thebathroom at night, and respiratory muscle dysfunction

Periodic and non-periodic movements Increased motor activity – disturbs sleep continuity

PLMS, tremor, dystonia, drug-induced myoclonus Arousals, pain with discomfort during lying down

Restless legs syndrome Sleep onset problems, discrepancy between wish to move and immobility

REM sleep behavior disorder Disrupted REM sleep, arousals, anxiety

Abnormal motor activity affecting respiratory and upper airwaymuscles

Breathing abnormalities during sleep such as sleep apnea syndrome,obstructive and/or central sleep apnea

Drug-related effects Dopamine agonists: reduced total sleep time with increased time awakeAnti-depressants: reduced REM sleep

Various agents: reduced slow-wave sleep, nightmares, psychosis,hallucinosis

Depression and anxiety Difficulty falling asleep, arousals, early morning awakening

Dementia and psychosis Nocturnal episodes of confusion, “sundowning” with disturbedday-and-night rhythm

Nocturia Increased time awake, problems of falling asleep again, nocturnal falls,discomfort



Sleep Disorders in Parkinson’s Disease 235

Disease specificmotor symptoms• Nocturnal akinesia• Tremor, rigidity• Fragmentary myoclonus

Restless legs syndromePeriodic limb movements

Psychiatric complications• Depression• Nocturnal hallucinations• Confusion

Dopaminergic therapyduring daytime/evening• L-DOPA• Dopamine agonists• Anticholinergics

Sleep apnea syndrome

Insomnia• At sleep onset• Sleep continuity• Early awakening

REM sleep behaviordisorder (RBD)

Subjectivesleep disturbance

Sleepinessduring daytime

Figure 21.1 Sleep disturbance inparkinsonism.

movements per hour) of >100, thus considerably inter-fering with the course of sleep. PLMS can also causearousals (PLMSA). PLMS in abundance, however, do notproduce any EEG alterations. The debate is still openabout the clinical relevance of PLMS in sleep disorders inPD patients. It is possible that PLMS-induced autonomicchanges, such as heart rate alterations and blood pressurevariations, are the only clinically significant parameters.

Sleep benefit

Although most PD patients with motor fluctuations wakein the “off” state, some patients experience sleep bene-fit and wake in the “on” state. Sleep benefit is character-ized by a clear improvement in motor performance and inthe general condition of the patient without a prior intakeof dopaminergic agents. It lasts approximately 15–30 minand then gradually wears off. About one-third of PDpatients experience this sleep-related symptom ameliora-tion. The reasons for this improvement are not clear. Apossible explanation could be a recovery of the dopamin-ergic system during the night [13].

REM sleep behavior disorder (RBD)

In the 1990s, Schenck and Mahowald described a so-called idiopathic RBD which was subsequently dis-covered to be predominantly associated with neurode-generative diseases [14]. RBD is currently defined, inaccordance with the International Classification of SleepDisorders [15], as an increased tonicity of the chin mus-cles evidenced on PSG during REM sleep, along withclinical features such as movements (e.g., of the limbs)in REM sleep, and dream-related vocalizations (scream-ing, laughing, or singing while asleep) (Plate 21.1). Thesedream-enacting behaviors can result in patients harm-ing themselves or others, and can cause them to fall outof bed without being able to recollect the incident after-wards [16,17]. The prevalence of RBD is higher than pre-

viously imagined: up to 90% of patients with multiplesystem atrophy [18] and up to 60% of patients with PD[19] are affected. Up to two-thirds of patients with idio-pathic RBD may develop parkinsonism within 10 yearsof diagnosis [14]. As striatal dopamine transporters havebeen found to be reduced in idiopathic RBD, it has beensuggested that RBD can in fact be a very early manifes-tation of a synucleinopathy that precedes the develop-ment of the more classic motor features of the particulardisease [20]. Recent studies suggest that RBD in PD maybe associated with cognitive impairment [21], and occurspredominantly in patients with the akinetic rigid form ofthe disease, suggesting the possibility of different under-lying patterns of neurodegeneration in PD with and with-out RBD [22].

It is important to differentiate RBD from nocturnal psy-chosis or confused states since these disturbances are dis-tinctly different in nature and pathogenesis, and requiredifferent therapeutic approaches [23]. It has so far beenimpossible to diagnose RBD reliably through the use ofvalidated questionnaires. Therefore, it is important care-fully to take the patient’s sleep history through interviewswith the patient and his/her bed partner, and to performa video-supported PSG to establish the correct diagnosis.As RBD may be an early symptom of neurodegeneration,a timely diagnosis may allow the identification of preclin-ical PD patients prior to the development of motor dis-turbances [24,25]. This could permit the early introduc-tion of neuroprotective therapies – should they becomeavailable – and perhaps prevent the emergence of motorsymptoms.

Nocturnal respiratory disorders

As with all patients with disturbed sleep, PD patientscan suffer from nocturnal breathing disorders that sub-sequently increase daytime sleepiness. Upper airwayobstruction, possibly due to altered muscle tone inthe oropharyngeal region, is thought to be most often



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responsible [26]. Nocturnal breathing disorders withcentral apneas, obstructive apneas, and hypoventilationepisodes can be observed. PD patients appear to experi-ence consequent autonomic disturbances more frequentlythan non-parkinsonian age-matched individuals. Further-more, an akinetically fixed nocturnal posture with thepatient lying on the back, as is often present in PDpatients, will encourage upper airway obstruction. Stri-dor and laryngeal stenosis can also develop as a mani-festation of a dystonic syndrome, particularly in patientswith multiple system atrophy.

Excessive daytime sleepiness (EDS)

Excessive daytime sleepiness (EDS) is a well-known phe-nomenon in PD patients. After 20 years of disease dura-tion, 70% of PD patients have EDS [27]. Although EDSmay arise as a primary manifestation of PD reflectingthe anatomic structures affected by the neurodegenera-tive process, nocturnal breathing disorders, nocturnal legmovements, fragmented sleep, and dopaminergic drugscan also each contribute to or exacerbate this problem[28]. Patients complain mainly of increasing tiredness, forexample, and describe, that they nod off while eating orreading. Sudden onset “sleep attacks,” that were formerlyassociated with the use of the non-ergot dopamine ago-nists pramipexole and ropinirole, have been proven to bea class effect attributable to all dopamine agonists cur-rently employed in the management of PD [29]. A recentstudy using continuous sleep EEG monitoring showedthat even patients without a history of sleep attacks alsohad microsleep episodes in the form of non-REM stage1 and 2 intrusions into wakefulness during the day. Fur-thermore, the majority of these microsleep episodes werenot perceived by the patients [30]. Recent studies showthat daytime somnolence is further enhanced by seda-tive medications taken at night [31,32]. EDS can mani-fest as simply falling asleep while reading or watchingTV but can also occur in more dangerous situations suchas while the patient is driving. The issue of sleepinessshould be addressed routinely in all PD patients, assistedby the use of appropriate scales such as the EpworthSleepiness Scale (ESS) or the Parkinson’s Disease SleepScale (PDSS) [33]. Individual counseling is recommended.Patients obviously need to be informed that they mustrefrain from driving if they suffer from daytime somno-lence or episodes of paroxysmal sleep [34]. This may be apotential conflict with the patient for whom the ability todrive may be an important issue for maintaining quality-of-life and independence.

Diagnostic work-up

Experience shows that sleep problems rarely represent themain complaint of PD patients. However, up to 90% of

patients will report sleep difficulties at some point dur-ing the course of their disease and it can be a trouble-some problem. Since a variety of factors contribute tosleep disorders in PD patients, individual case historieswith an assessment of sleep perception, assessment ofsleep habits, and medication status should all be carefullyreviewed. An interview with bed partners and/or fam-ily members and caregivers could yield important addi-tional information. Specific questionnaires, such as thePDSS, can be used to provide a more accurate clinicalpicture [33].

Video-based polysomnography andmultiple sleep latency (MSLT)

If the physician is unable to come to a clear diagnosisthrough clinical examination and by eliciting the patient’ssleep history, the patient should be referred to a sleeplaboratory for further examination. Synchronized videorecording is specifically necessary to recognize and ade-quately assess RBD. MSLT can be useful in providing anobjective measure of excess sleepiness in a patient whereit is not clear from history by recording the length of timeit takes for the person to fall asleep.

Treatment of sleep disorders

The aim of a thorough diagnostic work-up should bea specific treatment for the PD patient’s sleep distur-bance. It is necessary to establish whether disturbedsleep is mainly due to parkinsonian akinesia and motorsymptoms, which generally require increased doses ofdopaminergic medication, or alternatively whether theproblems are due to increased fragmentation of sleepwith insomnia and increased waking phases or noctur-nal confusion with abnormal behaviors which are oftencaused by medications such as high-dose dopamine ago-nists, amantadine, anti-cholinergics, or selegiline and arebest treated by a reduction in medication. RBD needs tobe differentiated from nocturnal hallucinations, and treat-able conditions such as RLS and sleep-disordered breath-ing (sleep apnea) should be identified.

Nocturnal akinesiaIncreasing the dose of dopaminergic medication at nightmay ameliorate nocturnal akinesia and other parkinso-nian features that interfere with sleep. Levodopa slow-release preparations in doses of 100–200 mg taken atbedtime are frequently recommended [35]. Long-actingdopamine receptor agonists [36] or continuous dopamin-ergic stimulation via transdermal application (ongoingtrial with rotigotine patch) may also be useful, if slow-release formulations of levodopa are not sufficient. Forpatients in advanced stages of the disease who have




severe motor fluctuations and dyskinesias, these mea-sures may not be sufficient and may result in further sleepdisruption with nocturnal exacerbation of PD symptomsand dyskinesia after the additional medication intake.For these patients, continuous dopaminergic stimulationvia duodenal levodopa instillation or subcutaneous apo-morphine infusion around the clock may prove beneficial[37], although here one must be concerned about the riskof developing tolerance with impaired motor responses.Deep brain stimulation of the subthalamic nucleus, whichhas been shown to reduce parkinsonian features effec-tively in advanced stages of PD, also can have a favorableimpact on sleep quality and sleep architecture [38]. Somepatients, however, complain about symptoms of noctur-nal RLS after DBS and reduced dopaminergic medication.Those complaints can easily be managed, however, withone dosage of a nocturnal dopaminergic or even opioider-gic medication (authors’ personal observation).

RLS and PLMSThe treatment of choice for PLMS is increased dosing ofdopaminergic agents. Interestingly, no case of augmenta-tion has been observed in patients with PD and RLS. Thismay be because PD patients typically receive dopamin-ergic therapy during the daytime, which may preventthe emergence of augmentation in PD RLS patients com-pared with patients with idiopathic RLS. Another expla-nation, that is perhaps more likely, is that RLS in PDdevelops by way of a different pathophysiologic mech-anism. In contrast to idiopathic RLS patients, PD patientshave a proven dopamine deficiency that prevents themfrom developing dopaminergic overstimulation duringthe daytime, which could be one reason for augmenta-tion in those with idiopathic RLS [39]. Clinical experi-ence shows that PLMS, like RLS, can also be relievedby opiates such as tilidine slow release; however, pub-lished randomized controlled studies are lacking. Thesymptoms of RLS – associated with particularly unpleas-ant sensory symptoms in PD patients, not only whenfalling asleep but also during the night – can be man-aged with dopaminergic agents or with opiates, prefer-ably in the slow-release form [36]. Aperiodic movementsand fragmentary myoclonus are best treated with ben-zodiazepines, and will often benefit from a reduction indopaminergic medication.

InsomniaAs mentioned above, insomnia in PD patients may bean adverse effect of PD medication. Administration latein the day of amantadine, anti-cholinergics, selegiline,and dopamine agonists can seriously impede the initia-tion of sleep and should then be avoided. Frightful hal-lucinations will add to this effect and also call for areduction of nighttime dopaminergic medication. Con-comitant depression is frequently found in PD patientsand may induce or enhance insomnia [40]. In these

cases, the administration of tricyclic anti-depressants ormirtazapine has been recommended [41,42]. It must beremembered, however, that the anti-cholinergic effects oftricyclic agents can contribute to nocturnal states of con-fusion in PD patients and their use should be restricted inpatients with cognitive impairment.

Treatment of insomnia in PD patients includes the eval-uation of psychosocial and behavioral issues as it wouldfor non-PD patients. Special attention should be paid tosleep hygiene: patients should be advised to have reg-ular bedtimes, and to avoid caffeine, alcohol, and phys-ical effort in the evening. Intermittent administrationof benzodiazepine receptor agonists such as zolpidemcan be helpful for severe sleep initiation difficulty thatcannot be addressed otherwise and that lead to addi-tional impairment of daytime functioning (personal clin-ical experience). It is also essential to reduce the fre-quency of nocturia to avoid subsequent awakenings atnight. Urologic agents can help to improve a patient’ssleep at night. Longstanding insomnia may sometimes belinked to a prior abuse of benzodiazepines or benzodi-azepine receptor agonists, prohibiting withdrawal of thismedication.

Nocturnal abnormal behaviorsIn the advanced stage of PD, nocturnal problems arepredominantly governed by hallucinations and psychoticstates at night. In the course of the illness up to 30%of patients will encounter vivid dreams and nightmareswith hallucinations, especially if they are treated withdopamine agonists. These conditions can be extremelybothersome for patients and caregivers, as nighttime restmay be disturbed for every household member. Video-based PSG will allow for the differentiation of noctur-nal psychotic states and RBD. For severe RBD the treat-ment of choice is clonazepam (0.5–2 mg). Clozapine asan anti-psychotic substance that does not induce adverseexrapyramidal side effects has been successfully studiedin a controlled setting for treating hallucinations and psy-chotic states in PD [43]. Quetiapine has also been found tobe efficient, although a double-blind, randomized studycould not show a beneficial effect on drug-induced psy-chosis in PD, probably owing to a large drop-out ratein the trial [44]. It is generally used as the first-choicedrug for the treatment of hallucinations and nocturnalpsychosis (starting with a dose of 12.5 or 25 mg HS) asit avoids the risk of hematologic side effects seen withclozapine [45–47]. Both drugs can also enhance night-time rest, as they induce sleepiness. Although no tri-als are available, low-dosage quetiapine is widely usedto treat insomnia in PD patients. It may particularly behelpful in patients who do not tolerate benzodiazepinesor anti-depressants, likely providing some anti-psychoticprophylaxis at the same time. In some cases, administra-tion of low-dose clomethiazole before retiring may be arelevant therapeutic supplement. However, one must be



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aware that all drugs with a sedative effect may worsensleep-disordered breathing.

Sleep-disordered breathing (SDB)Concomitant SDB may distinctly worsen pre-existingdaytime vigilance problems in PD patients. As a treat-able cause it should be identified and addressed withnighttime ventilation therapy as in non-PD patients. AsPD patients often have difficulties tolerating a mask forcontinuous positive airways pressure application, com-pliance may be a problem. Individual tailoring of ther-apy is necessary and much patience is required to adapttherapy to the individual patient. Adequate treatment ofsleep-disordered breathing is a prerequisite for treatingconcurrent RBD with clonazepam or RLS with opiates,as the administration of these substances may worsen anobstructive or central sleep apnea syndrome. Successfullyaddressing a sleep apnea syndrome in PD patients maybe of value in improving many tedious nocturnal prob-lems such as nocturia, nocturnal confusion, and sleep dis-ruption, with subsequent improvement in daytime per-formance.

Excessive daytime sleepiness (EDS)The first steps in managing EDS in PD patients are toidentify treatable causes and to improve sleep hygiene. Ifthese measures, including nocturnal ventilation therapyand the reduction of sedative medication in the evening[48], do not sufficiently improve the condition, a psycho-stimulating therapy such as modafinil can be tried. How-ever, not every patient benefits from this medication anddiffering results have been observed [49]. A recently pub-lished double-blind, placebo-controlled trial showed nosignificant positive effect of modafinil on EDS in PDpatients [50]. It is important that physicians seek out EDSin PD patients. Patients should be advised about the risks,and refrain from driving until the problem has been satis-factorily managed.

Conclusion

Sleep fragmentation, PLMS, RLS, and RBD are commondisease-related sleep disorders in PD and can be regardedas manifestations of Lewy body pathology in sleep-related areas of the brainstem. Nocturnal exacerbation ofPD symptoms and SDB, insomnia due to depression, andside-effects of the many drugs taken by these patientsmay furthermore severely disturb the initiation and main-tenance of sleep, enhancing EDS. Therefore, sleep dis-orders represent an important, multifactorial, non-motorsymptom of the disease. A thorough diagnostic work-upincluding interviews with the patient and his/her bedpartner and also video-supported PSG can establish thespecific sleep diagnosis and facilitate therapy.

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Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Sleep Disorders in Parkinson's Disease