Sleep in Parkinson syndromes

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 15

Sleep in Parkinson syndromes ¨ GL2 CLAUDIA TRENKWALDER1* AND BIRGIT HO 1

Paracelsus Elena-Klinik, Kassel and University of Go¨ttingen, Germany 2

Department of Neurology, Medical University of Innsbruck, Austria

15.1. Introduction and pathophysiology of sleep in Parkinson syndromes Sleep complaints are frequent and substantially impair quality of life in patients with Parkinson’s disease (PD). Listening to PD patients, it is soon revealed that fatigue and sleepiness are major complaints independent of any medication and motor disability. Although previous research on sleep and daytime sleepiness in PD primarily focused on nocturnal sleep disturbance and pharmacological therapy, recent neuropathological publications demonstrate that neurodegeneration involves sleep regulation and daytime alertness to a large degree (Braak et al., 2003). Severely disrupted sleep and rapid-eye movement (REM) sleep disturbances are early signs of neurodegeneration with involvement of the brainstem with Lewy bodies. First, the neurodegenerative process starts in the lower brainstem areas, according to the six progressive stages described by Braak and collaborators (Del Tredici et al., 2002; Braak et al., 2003). REM sleep behavior disorder (RBD) may be a preclinical and premotor sign of PD or other Parkinson syndromes. Therefore the observation of early changes in sleep may be of particular importance, especially if neuroprotective agents may be available in the future. Second, the behavioral, respiratory and motor system phenomena accompanying the disease may produce nocturnal symptoms. Third, the medications used as treatment may induce new symptoms, such as nightmares, nocturnal movements or increased wakefulness. In addition to the primary cause of PD, the loss of dopaminergic neurons in the substantia nigra, serotonergic neurons originating in the dorsal raphe nuclei

are reduced in number, as are noradrenergic neurons originating in the region of the locus ceruleus (Jellinger, 1986). Cholinergic neurons of the pedunculopontine nucleus, implicated in control of REM sleep, are also reduced in number (Zweig et al., 1989). Because the noradrenergic, serotonergic and cholinergic systems have all been implicated in the control and regulation of sleep, abnormalities in these systems may account for some of the sleep disturbances that occur in patients with parkinsonism. Abnormalities of the mesocorticolimbic dopamine system, as well as the mesostriatal system, are apparent in PD and may contribute to sleep–wake disturbances (Javoy-Agid and Agid, 1980). The administration of a dopamine D1-receptor agonist produces electroencephalographic (EEG) desynchronization and behavioral arousal (Ongini et al., 1985). High doses of dopamine D1- and D2-receptor agonists, such as apomorphine (Chianchetti, 1985), reduce total sleep time; the dopamine D1- and D2-agonist pergolide decreases the amount of slow-wave sleep (Tagaya et al., 2002). Very low doses, however, induce sleep and increase the amount of slow-wave sleep. Low doses of apomorphine also induce sleep when injected into the ventral tegmental area, an effect that is blocked by dopamine receptor autoantagonists, suggesting that dopamine D2 autoreceptors play a role in the mediation of sleep through autoinhibition of the firing rate of ventral tegmental dopaminergic neurons (Svensson et al., 1987; Bagetta et al., 1988). It is not surprising, therefore, that levodopa and dopamine agonists induce yawning, sleepiness or even irrestistible onset of sleep in some patients (Ho¨gl et al., 2001b). The arousing effects of higher doses of dopamine D2-receptor agonists may be due to effects at postsynaptic receptors. This may also explain the

*Correspondence to: Claudia Trenkwalder, MD, Paracelsus Elena-Klinik, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, D-34128 Kassel, Germany. E-mail: [email protected], Tel: þ49/561-6009-200, Fax: þ49/561-6009-126.

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arousal effects that occur when high dosages of dopamine agonists are applied during the day. In normal individuals, levodopa reduces the amount of REM sleep, an effect that may be due to increased activity of dopamine, norepinephrine, or both. The effects of levodopa on sleep may be due in part to effects on serotonergic neurons. RBD is an important and characteristic sleep problem in PD, as it requires a neurodegenerative process, if it is not pharmacologically induced (Schenck et al., 1992). It differentiates sleep disturbance in PD from a severely disruptive sleep of any other origin, as RBD is not associated with any other sleep problems, such as periodic limb movements during sleep (PLMS), insomnia, restless-legs syndrome (RLS) or sleep with increased number of awakenings. RBD can be induced by antidepressants, such as mirtazapine or serotonine reuptake inhibitors (Onofrj et al., 2003; Winkelman and James, 2004).

15.2. Diagnosis of Parkinson syndrome sleep disorders To determine which factors are most important, the patient’s clinical history and that of partners or caregivers is used, as well as examination and polysomnographic evaluation. Sleep disturbance is rarely the presenting complaint in a patient with previously undiagnosed parkinsonism, with the exception of RBD, which presents with violent behavior in only a few cases. More commonly, the diagnosis of PD has been established, and the patient complains about nocturnal problems, i.e. insomnia, daytime sleepiness, or both. The history of sleep problems should include all the features the physician would obtain from any patient with a sleep complaint. It must include disease-specific questions on nocturnal akinesia, daytime fatigue in relation to medication intake and psychiatric symptoms. The use of a disease-specific questionnaire, such as the Parkinson Disease Sleep Scale (PDSS) may be helpful (Chaudhuri et al., 2002), as the Unified Parkinson’s Disease Rating Scale (UPDRS: see Ch. 13) comprises only one question related to sleep. A careful history given by the bed partner is essential to determine the occurrence of movements, sleeptalking, the frequency of awakenings and probable difficulties in getting up and moving at night. The medication schedule is significant. If dopaminergic medications are not prescribed in the evening, nocturnal rigidity may often contribute to the sleep disturbance; on the other hand, excessive evening doses of dopamine agonists may induce sleep-onset insomnia. For the majority of patients a history

of nocturnal problems is sufficient to establish a treatment regimen. Some patients, however, require a polysomnogram to diagnose the sleep disorder correctly. These patients may be characterized by severe daytime sleepiness and sudden onset of sleep during the daytime. They should be screened for sleep apnea syndrome or severe PLMS syndrome and may then require respiratory polysomnography. Patients who present with probable RBD or hallucinations may need a polysomnogram to evaluate whether both syndromes are present or either one, as the treatment options are different. Simultaneous closed-circuit television monitoring and surface electromyographic monitoring of all four extremities are often helpful to decide whether nocturnal myoclonic movements or the RBD is contributing to the sleep disturbance. If daytime sleepiness is a prominent complaint, or suspected from the care-giver’s reports, several tests or scales can be used, such as the Multiple Sleep Latency Test (MSLT) (Carskadon et al., 1986), the Maintenance of Wakefulness Test (MWT) (Mitler et al., 1982; Doghramji et al., 1997), the seven-point Stanford Sleepiness Scale (SSS) (Hoddes et al., 1973), the nine-point Karolinska Sleepiness Scale (KSS) (Gillberg et al., 1994) and the eight-question Epworth Sleepiness Scale (ESS) (Johns, 1991). Whereas the SSS and KSS are appropriate to assess momentaneous sleepiness at a single time point, the eight questions of the ESS cover a time span of 2 weeks. The best-established polygraphic test for daytime sleepiness is the MSLT (Richardson et al., 1978). In this test, the subject is put to bed in a sleep-conducive environment for 30 minutes on five occasions distributed throughout the day (usually 9 a.m.; recording time is 20 or 30 minutes). The latency to sleep onset is measured, as well as the latency to onset of REM sleep. Normative values are well established for the MSLT. Another possibility is the MWT (Mitler et al., 1982, 2000). In contrast to the MSLT, the instruction to the patient in the MWT is ‘not to fall asleep’. The MWT therefore measures the ability to maintain wakefulness in monotonous situations. Because the MWT trial is interrupted as soon as the patient falls asleep, the MWT does not measure REM latencies. Therefore, the MSLT is more appropriate to get wellestablished mean sleep latencies, and to evaluate sleep-onset REM periods. In contrast, the MWT is better able to assess the capacity to remain awake in monotonous situations, which may be relevant for everyday life such as driving. In both tests, the individual sleep latency at any given time point of the test will also permit information on the circadian variation of the patient’s sleepiness.

SLEEP IN PARKINSON SYNDROMES

15.3. Clinical features of sleep in Parkinson’s disease 15.3.1. Sleep fragmentation The most consistent abnormality in PD sleep is sleep fragmentation. Sleep studies show sleep disruption caused by many, often short, motor events, not even fulfilling the criteria for PLMS, tremor or dyskinesias. Sometimes arousals without any motor event may also induce an awakening that may lead to prolonged wakefulness (Kales et al., 1971; Bergonzi et al., 1975). Increased amount of stage 1 sleep and reduced amount of stage 3 and 4 sleep and REM sleep are also common; in some patients deep sleep is completely absent. The number of sleep spindles during slow-wave sleep is reduced (Bergonzi et al., 1975; Friedman, 1980). In de novo patients or milder cases, sleep architecture may still be normal (Ferini-Strambi, 1992). Untreated PD patients show a significant decrease of stage 3 and 4 sleep and increased periodic limb movements (Wetter et al., 2000). EEG alpha activity may be prominent during REM sleep (Mouret, 1975; Brunner et al., 2002). In other Parkinson syndromes, such as progressive supranuclear palsy (PSP), patients had a shorter total sleep time, lower sleep efficiency, a significant reduction in sleep spindles, an atonic slow-wave sleep, and a lower percentage of REM sleep, although the frequencies of REM sleep muscle tone abnormalities are controverse (Arnulf et al., 2005). 15.3.2. Characteristic parkinsonian motor signs: hyperkinesia and akinesia The predominant motor symptoms of PD – tremor and dyskinesias – mainly occur during wakefulness but may also arise during non-REM sleep stages. Parkinson rest tremor usually disappears with the onset of stage 1 sleep, in some cases before EEG alpha activity is entirely gone (April, 1966; Stern et al., 1968), stops in stage 3–4 sleep but may reappear in stages 1 and 2 and with awakenings, arousals and body movements (Fish et al., 1991). Tremor is not associated with spindles or K-complexes. Tremor may also appear, with various amplitudes, for a few seconds during sleep stage changes, during bursts of REM and shortly before or after a REM period (Stern et al., 1968). In contrast to the quiet sleep in normal persons, a variety of motor activity, short jerks or increased muscle tone, abnormal simple and complex movements are common and predominate in the picture of a Parkinson polysomnogram. Sometimes scoring following the system of Rechtschaffen and Kales (1968) is difficult as sleep stages cannot be defined unequivocally. One

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study examined the interrater reliability of sleep scoring in patients with Parkinson’s disease with three experienced scorers. A good interrater reliability was found for distinguishing REM from non-REM sleep, but a reliable differentiation of non-REM sleep stages was much more difficult (Bliwise et al., 2000). Patterns of simple motor activity during sleep include repeated blinking at the onset of sleep, blepharospasm at the onset of REM sleep and prolonged tonic contractions of limb extensor or flexor muscles during non-REM sleep (Mouret, 1975). Abnormal muscle tone in REM sleep has been described in early studies (Traczynska-Kubin et al., 1969; Mouret, 1975). Fragmentary myoclonus in surface EMG and jerks of the extremities may be recorded in stage 1 and 2 Parkinson sleep (Broughton and Tolentino, 1984). Painful dystonia in the limb primarily affected by the disease may result in an extension of the great toe (‘striatal toe’), as a sign for off dystonia. Early-morning foot dystonia may occur just before waking or soon thereafter and may reflect the low concentration of dopamine in the basal ganglia after the last intake of medication at night. It usually starts as a sign of motor response fluctuations that occur almost exclusively in idiopathic PD patients, but not in other Parkinson syndromes. Early-morning akinesia and painful off dystonia are frequent complaints of advanced PD patients and require adequate nocturnal treatment strategies (Lees et al., 1988). Nocturnal akinesia, the most frequent complaint of PD patients at night, is characterized by a lack of dopamine and disables PD patients significantly more than dyskinetic stages. Patients complain about being unable to turn in bed or stand up at night without help, and of painful muscle cramps. In the polysomnogram sleep fragmentation and increased muscle tone predominate during nocturnal akinesia. 15.3.3. Sleep-associated motor phenomena PLMS (Atlas Task Force of the American Sleep Disorders Association, 1993), previously known as ‘nocturnal myoclonus’, occur in sleep and are usually associated with a variety of sleep disorders, such as RLS, narcolepsy, Parkinson syndromes or sleep apnea. New criteria have been published for scoring PLMS more appropriately in research projects (Zucconi et al., 2006). Periodic limb movements are defined as at least four movements in a row with a defined intermovement interval and periodicity. An index of more than 5 PLM per hour of sleep (PLMS index >5) is estimated as a pathological value and occurs in up to one-third of patients with untreated PD, but is even more common in elderly controls (Wetter et al., 2000). PLMS may

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often be associated with arousals (Ondo et al., 2002) and therefore lead to sleep disruption. Some authors doubt that isolated PLMS have any pathological relevance for sleep disorders (Mendelson, 1996) and question if they should be treated at all (Leissner and Sandelin, 2002). The association of RLS in PD is still incompletely understood (Poewe and Ho¨gl, 2004). The frequency of RLS in PD is controversial (Ondo et al., 2002).

Reist et al., 1995), these results were not confirmed in a later study (Ho¨gl et al., 2001a). Baseline UPDRS motor score, tapping rates and motor function after the usual medication did not show a global difference after total or partial sleep deprivation compared to a night of normal sleep (Ho¨gl et al., 2001a).

15.4. Rapid-eye movement sleep behavior disorder

15.3.4. Sleep benefit The term ‘sleep benefit’ has been coined to describe the phenomenon of subjective fluent mobility on awakening from a night sleep (Marsden, 1980; Marsden et al., 1981), even prior to drug intake. Sleep benefit has been estimated or reported from questionnaires to occur in around one-third to one-half of patients with PD (Merello et al., 1997). It has been suggested that accumulation and storage of dopamine in remain dopaminergic nerve terminals underlie sleep benefit (Marsden, 1980; Marsden et al., 1981). About onethird of PD patients report a ‘sleep benefit’ (Currie et al., 1997). Only one study has investigated the phenomenon of sleep benefit using polysomnography (Ho¨gl et al., 1998). Ten patients with clear-cut sleep benefit were matched pairwise to 10 patients without sleep benefit. Patients with sleep benefit showed a distinctive response profile to levodopa, with more severe interdose ‘off’, indicating pharmacodynamic differences between patients with and without sleep benefit. However, polysomnography did not show any significant differences between both groups; there was even a non-significant trend towards more fragmented sleep in patients with sleep benefit (Ho¨gl et al., 1998). 15.3.5. Sleep deprivation in Parkinson’s disease An increased motor response to apomorphine has been found in normal rats after selective REM sleep deprivation (Tufik, 1981) and was also demonstrated in a parkinsonian rat model (Drucker-Colin et al., 1996). Selective REM sleep deprivation per se also produced a significant increase in ambulatory behavior and rearing in another parkinsonian rat model (Andrade et al., 1987). In humans, dopamine D2-receptor binding was modified after total sleep deprivation in patients with major depression (Ebert et al., 1994). The question whether sleep deprivation is able to improve motor performance in patients with PD was addressed by several authors (Bertolucci et al., 1987; Levin, 1991; Reist et al., 1995; Ho¨gl et al., 2001a). Whereas significant motor improvements were reported in the earlier studies (Bertolucci et al., 1987; Levin, 1991;

First described by Schenck and collaborators (1987, 1992), the criteria for RBD are now modified in the new International Classification of Sleep Disorders, ICSD-2 (American Sleep Disorders Association, 2005). To make a diagnosis of RBD, both polysomnographic abnormalities and abnormal behaviors are now required. The criteria require: (1) the presence of REM sleep without atonia in polysomnography; and (2) the presence of sleep-related (potentially) injurious behaviors by history and/or documented during PSG. In contrast to previous criteria, polysomnography is now obligatory to make the diagnosis of RBD (American Sleep Disorders Association, 2005) and includes complex behaviors during REM sleep with a loss of skeletal muscle atonia. Sleep-talking, screaming, dream mentation or nightmares are associated with a variety of movements that may disrupt sleep continuity. The motor activity in RBD may consist of small jerky movements of the extremities – finger or hand twitches – but can also lead to abrupt violent body movements; some patients commonly fall out of bed. Comella and coworkers (1998) found 15% clinically diagnosed RBD in a cohort of PD patients; other data show higher numbers (Gagnon et al., 2002). Our own group found abnormalities of REM sleep in 40% of 45 patients with PD; 24% had REM sleep without atonia, and 16% had full-blown RBD (Wetter et al., 2001). More than one-third of an unselected population of PD patients revealed RBD diagnosed in the sleep laboratory. Depending on the diagnostic criteria of RBD, the prevalence of RBD may vary substantially. When RBD is diagnosed polysomnographically without clinical criteria, those numbers may even increase to up to 60% of Parkinson syndrome patients (Fantini et al., 2005). In atypical Parkinson syndromes such as multiple system atrophy (MSA), RBD is detected polysomnographically in up to 100% of patients (Plazzi et al., 1997; Vetrugno et al., 2004), similar to up to 80% RBD in advanced PD patients (authors’ own observations). Only 50% of polysomnographically diagnosed patients would have been detected by history alone (Eisensehr et al., 2001; Gagnon et al., 2002). However, recent

SLEEP IN PARKINSON SYNDROMES questionnaires or interviews for diagnosing RBD according to ICSD criteria by sleep specialists still lack sufficient interrater reliability (Vignatelli et al., 2005). RBD most likely reflects dysfunction in the brainstem circuitry and the dorsolateral pontine tegmentum, where REM sleep without atonia can be induced in animal experiments. RBD may represent a preclinical marker of a neurodegenerative process in synucleinopathies such as PD and MSA and may precede motor symptoms by years (Schenck, et al., 1996; Iranzo et al., 2006). Neuroimaging studies of patients with characteristic complaints of RBD revealed a marked reduction of presynaptic dopamine transporter binding, indicating early PD or MSA (Eisensehr et al., 2000). Subclinical RBD correlates with the extent of presynaptic dopamine transporter binding in idiopathic RBD (Eisensehr et al., 2003). The duration of REM sleep correlated with fluorodopa uptake as measured by positron emission tomography (PET) in PD patients with RBD (Hilker et al., 2003). RBD as an early sign of PD could be confirmed in a recent study relating olfactory dysfunction to RBD as a possible indicator for a-synucleinopathy measured by dopamine transporter FP-CIT single photon emission computed tomography (SPECT) (Stiasny-Kolster et al., 2005). The distribution of cerebral metabolism assessed with whole brain function perfusion using (99m) Tc-ethylene cysteinate dimer (ECD) SPECT showed hypoperfusion in idiopathic RBD patients consistent with anatomic metabolic profile in PD (Mazza et al., 2006). Controversy exists, however, as to whether RBD and psychosis share a common pathway. Sleep disorders in general seem to be more frequent in PD patients with nocturnal hallucinations (Arnulf et al., 2000) and sometimes difficult to distinguish by clinical history alone. Other authors found that sleep disturbances in PD do not occur as early as olfactory deficits but during the first years of PD (Henderson et al., 2003). In the long term, sleep disorders and RBD are similarly frequent in the PD population with and without hallucinations. Sleep alterations are not necessarily harbingers of hallucinations (Goetz et al., 2005). Experimental studies point to the role of different regulatory centers in the brainstem responsible for either the duration of REM sleep or REM atonia. An excessive GABAergic output from the basal ganglia to the peduncolopontine tegmental nucleus in parkinsonian patients may induce sleep disturbances, including a reduction of REM sleep periods and RBD (REM without atonia) (Takakusaki et al., 2004). RBD may occur in treated or non-treated PD patients and may disturb the patient’s sleep by disagreeable dreams or awakenings, affecting sleep continuity.

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Features of violent or injurious behavior during sleep should be treated for the safety of both patient and bed partner. Some bed partners, however, are anxious and severely confused by the patient’s bizarre nocturnal behavior. RBD may disrupt the relationship between the patient and care-giver and may be the main reason for admittance to a nursing home (Comella et al., 1998). As RBD can be easily treated in most patients with small dosages of clonazepam (0.5–1 mg), the condition should be diagnosed and treated adequately and early (Schenck and Mahowald, 1990).

15.5. Respiratory disorders of sleep in parkinsonism Results of studies on respiration during sleep in PD patients have yielded inconsistent results. In 26 patients with untreated PD and short disease duration, respiration during sleep was found to be normal (Ferini-Strambi et al., 1992). ‘Disorganized’ respiration with frequent central and obstructive apneas was found in patients with parkinsonism and autonomic disturbance (Apps et al., 1985). Some authors reported that apneas were predominantly central (Emser et al., 1987), whereas others mainly observed obstructive apneas (Hardie et al., 1986). More recent studies have demonstrated that obstructive sleep-disordered breathing is present in around 20% of patients with PD (Arnulf et al., 2002). Another study found increased apnea/hypopnea indices mostly without significant oxygen desaturation in 43% of PD patients (Diederich et al., 2005). An abnormal tone of the muscles surrounding the upper airway has been suggested as contributing to sleep-disordered breathing in PD (Vincken et al., 1984). These patients are characterized with upper-airway obstruction during wakefulness and decreased effective muscle strength in pulmonary function testing (Hovestadt et al., 1989). In some patients, upper-airway endoscopy has shown intermittent airway closure due to dyskinetic movements of glottic and supraglottic structures caused by either the disease itself or dopaminergic medications (Vincken et al., 1984). A questionnaire survey found that severe snoring was associated with increased daytime sleepiness in PD, as it is in controls (Ho¨gl et al., 2003b). Upper-airway dysfunction has been reported to be partially responsive to levodopa treatment (Vincken et al., 1989). In patients with advanced parkinsonism, stridor was observed during off dystonia (Corbin and Williams, 1987). Stridor, however, is much more characteristic of MSA. It has been recognized as an adverse prognostic sign regarding survival (Silber and Levine, 2000).

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Stridor may occur during the nighttime only, or extend into daytime. In a study of 10 patients with MSA, all MSA patients displayed snoring, 42% stridor, and 37% obstructive sleep apnea. Breathing and motor abnormalities are often concomitant in the same patient, indicating a diffuse impairment of sleep homeostatic integration that should be included within the diagnostic features of MSA (Vetrugno et al., 2004). Pathophysiologically, a vocal cord paralysis (Isozaki et al., 1996; Kakitsuba et al., 1997; Maurer et al., 1999) which may be uni- or bilateral (Maurer et al., 1999; Silber and Levine, 2000), has been reported to underlie stridor. It has been recognized that mostly vocal cord abductor function is impaired (Blumin and Berke, 2002). In contrast, other authors found that not paralysis, but rather dystonia with persistent tonic EMG activity, is underlying stridor (Merlo et al., 2002). Stridor, which is produced by vibration of the vocal cords (Kakitsuba et al., 1997; Maurer et al., 1999), must be differentiated from ordinary palate snoring (Kakitsuba et al., 1997). Although stridor produces a very characteristic high-pitched sound, care-givers often cannot differentiate between snoring and stridor (Kakitsuba et al., 1997). In some of these patients, specifically in those with MSA, further respiratory abnormalities are present, including reduced ventilatory responses to hypercapnia and hypoxia (Chokroverty et al., 1978; McNicholas et al., 1983; Tsuda et al., 2002; Vetrugno et al., 2004). Tracheostomy (Munschauer et al., 1990) and nocturnal continuous positive-airways pressure (CPAP) therapy have been proposed for the treatment of stridor (Iranzo et al., 2000; Isono et al., 2001). Although positive results with long-term nocturnal CPAP therapy have been reported in MSA (Iranzo et al., 2004), adherence and practicability are still debated in these patients.

15.6. Daytime sleepiness in Parkinson’s disease Excessive daytime sleepiness, not resulting from respiratory problems in PD, is a well-known phenomenon in PD patients. Studies have described an increased risk for causing motor vehicle accidents by sudden sleep onset, so-called ‘sleep attacks’ (Frucht et al., 1999). Those episodes were primarily attributed to the intake of non-ergot dopamine agonists and therefore a variety of studies investigated the effect of dopaminergic drugs on daytime performance and sleepiness in PD patients, leading to controversial results. One study showed an association of daytime sleepiness with more advanced stages of PD, longer disease duration and male sex (Ondo et al., 2001). Other studies could not confirm these results: Higher daily levodopa dosages were predictors of sleep

episodes while driving, whereas gender, age, disease severity and individual dopaminergic agents were not (Brodsky et al., 2003). Patients with PD preselected for sleepiness, however, did not meet those criteria, and sleepiness did not result from pharmacotherapy or sleep abnormalities but was related to the pathology of disease (Arnulf et al., 2002). Dopaminomimetics may exacerbate sleepiness in a small subset of patients, but the primary pathology seems to contribute largely to the development of daytime sleepiness. These patients may benefit from wake-promoting agents such as bupropion, modafinil or traditional psychostimulants (Rye, 2003). An interesting observation reveals that PD patients are not aware of their sleepiness compared to elderly controls. Therefore the patient’s history or excessive daytime sleepiness (EDS) scores may not be helpful; only observation or objective measurements of sleepiness, such as PSG, may solve the question of sleepiness in individual PD patients (Merino-Andreu et al., 2003). The most serious consequence of daytime sleepiness in PD is whether PD patients are allowed to drive and if there should be special tests for sleepiness. As there are different laws in different countries, it is necessary to advise PD patients that sudden sleepiness may occur in the course of the disease and may be attributed to specific dopaminergic drugs. Finally, the patients themselves are responsible for their ability to drive and need to decide individually.

15.7. Treatment of disturbed sleep or impaired wakefulness in Parkinson’s disease Treatment of disturbed sleep and impaired wakefulness in PD principally aims to eradicate possible causes. For instance, if nocturnal akinesia, earlymorning dystonia or painful off periods are causing the sleep problem, optimizing the dopaminergic treatment during the night is the most important step. Optimizing the motor state in general has been shown to improve sleep (Askenasy and Yahr, 1985; Ho¨gl et al., 2003a). In mild cases, nocturnal motor symptoms may disappear with adequate dopaminergic treatment during the day (Askenasy and Yahr, 1985). A number of patients benefit from a bedtime dose of a controlled-release formulation containing 100–200 mg levodopa/25–50 mg dopamine decarboxylate inhibitor (DDCI) (Jansen and Meerwaldt, 1990; Koller et al., 1999). In this context, the advantage of long-acting dopamine agonists, such as cabergoline, become obvious (Ho¨gl et al., 2003a). However, higher dosages of dopamine agonists per se tend to disrupt sleep (Saletu et al., 2001; Happe et al., 2003; Ho¨gl et al., 2003a). Subjectively, this is

SLEEP IN PARKINSON SYNDROMES not necessarily associated with a subjective impairment of sleep because the benefit of dopaminergic treatment predominates over this effect (Ho¨gl et al., 2003a). If causal treatment of the sleep disturbance is not possible, i.e. because of side-effects of dopaminergic treatment or other reasons, treatment should at least be tailored to be as specific as possible (Askenasy, 2001). As has been discussed earlier, sleep-disordered breathing is very frequent in patients with PD. Basically, treatment modes are similar to those for patients without PD. In patients with obstructive apneas and hypopneas, nasal CPAP offers the best chance of success and can be used effectively by most patients with parkinsonism, until the advanced stages of the disease are reached (Askenasy, 2001). For patients with MSA and severe vocal cord dysfunction, tracheostomy is sometimes necessary. Patients with bilateral vocal fold paresis, a life threatening condition, should be treated for their glottic obstruction with CPAP at night or tracheotomy (Blumin and Berke, 2002). Appropriate nasal CPAP therapy may improve the condition of a PD patient substantially, also normalizing nocturnal blood pressure and neuropsychiatric symptoms. Although nasal CPAP therapy is first-line treatment for obstructive sleep apnea (Loube et al., 1999), handling of the CPAP device and the mask is sometimes complicated by impaired mobility and craniofacial dyskinesia. If sleep-disordered breathing is milder, or nasal CPAP cannot be used, intraoral mandibular advancement devices can be a useful alternative (Thorpy et al., 1995; Mohsenin et al., 2003). The improvement achieved with such devices (apnea– hypopnea index reduction) is usually smaller than with CPAP treatment. Some authors have noted that mild snoring or sleep-disordered breathing improves with levodopa therapy (Scha¨fer, 2001; Yoshida et al., 2003), but may not be sufficient to restore sleep in Parkinson syndromes. For REM sleep behavior disorder, clonazepam 0.5–2 mg has been reported to be the treatment of choice (Schenck and Mahowald, 1990). Treatment should be started to avoid these episodes of abnormal sleep behavior interfering with the relationship between patient and care-giver (Comella et al., 1998). If clonazepam is insufficient, melatonin can be tried as an alternative (Kunz and Bes, 1999). Some authors have reported improvement of RBD with dopaminergic therapy, e.g. levodopa (Tan et al., 1996) or pramipexole (Fantini et al., 2003). Quetiapin and clozapin may be useful alternatives, but this has not been formally evaluated. Importantly, RBD may worsen after

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subthalamic nucleus stimulation, possibly due to increased mobility, and may then require additional treatment (Arnulf et al., 2000). As in patients with idiopathic RLS, in PD RLS should first be treated by establishing full body iron stores, because this seems to be an important modulator of RLS severity, not only in the idiopathic form (Allen and Earley, 2001), but also in patients with RLS and PD (Ondo et al., 2002). Ferritin should be elevated above 45 mg/l in patients without inflammatory disease (Allen and Earley, 2001). Tricyclic antidepressants or serotonin reuptake inhibitors may manifest or worsen symptoms of RLS and eventually may have to be stopped in PD patients. Treatment of RLS includes dopaminergic substances, such as treatment of nocturnal akinesia in PD. Long-acting dopamine agonists such as cabergoline or transdermal application may be preferred. Treatment studies are not available. If a nocturnal dopaminergic treatment is not tolerable or insufficient, antiepileptics, such as gabapentin, clonazepam or opiates, are treatment options for RLS in Parkinson syndrome. It is unclear if augmentation, a well-known phenomenon of dopaminergic treatment in idiopathic RLS, occurs in PD patients with RLS. Augmentation is characterized by earlier onset of symptoms throughout the day, or an increase of RLS symptoms despite increase in the drug dose (Allen et al., 2003). Conceivably, these features are difficult to disentangle in patients with PD. Opiates can be used for treating RLS in PD, but the development of sleep apnea (Walters et al., 2001) needs to be closely monitored. Specifically in patients with PD or parkinsonian syndromes, constipation may be a contraindication for opiate treatment. Nocturia has been identified as another cause for sleep fragmentation in patients with PD. In cases of detrusor hyperreflexia, oxybutinin or tolterodine may be tried, but the anticholinergic side-effects must be kept in mind. Intranasal application of desmopressin has been recommended to combat nocturia (Suchowersky et al., 1995), but electrolytes need to be closely monitored to prevent low sodium and related seizures. High doses of dopaminergic treatment in advanced stages of PD may lead to insomnia and require further medication. Tricyclic antidepressants with sedating properties, such as amitryptiline (25–50 mg) or mirtazapine (15 mg) (Gordon et al., 2002), are frequently helpful for sleep-onset insomnia. The anticholinergic effects of tricyclic antidepressants may have therapeutic benefits for daytime parkinsonian symptoms in addition to depression, but they can induce nocturnal delirium in patients with cognitive impairment.

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Symptomatic treatment of sleep disorders in PD implies hypnotics and other sleep-promoting substances. Low-dose short-acting benzodiazepines or benzodiazepine receptor agonists such as low doses of triazolam, flunitrazepam or zolpidem may be tried. A possible worsening of pre-existing sleep-disordered breathing must be taken into account (Schuld et al., 1999). In patients with severe PD and insomnia, sleep fragmentation, akathisia and nocturnal hallucinations, clozapine has been found to improve sleep in general (Trosch et al., 1998). Quetiapin has also been reported to improve sleep, in both PD patients and care-givers (Gimenez-Roldan et al., 2003). Although insomnia complaints are extremely frequent (Tandberg et al., 1998) in patients with PD, there is a severe lack of controlled trials on the efficacy of hypnotics in these patients. The treatment of daytime sleepiness has long been neglected in patients with PD. This may relate to the fact that the increased daytime sleepiness is often unnoticed, even by patients themselves (MerinoAndreu et al., 2003). However, increased daytime sleepiness severely impairs quality of life assessed in patients with narcolepsy (Broughton et al., 1984). The capacity to remain awake is most important for social functioning, and increased daytime sleepiness is associated with increased risk for accidents in patients with PD (Comella, 2002; Hobson et al., 2002). Treatment of daytime sleepiness will first aim to identify causes that can be eliminated, such as sleep-disordered breathing, or sleepiness associated with a certain dopamine agonist. If those causes are absent or cannot be modified, symptomatic treatment comes into the discussion. First-line substance is modafinil, which has been demonstrated to improve subjective sleepiness in placebo-controlled studies (Ho¨gl et al., 2002; Adler et al., 2003). However, the improvements were small and data on long-term efficacy are not available. Methylphenidate is another stimulant which has been used for a long time in narcolepsy. It has been shown to improve apathia in an elderly patient with PD and cognitive impairment (Chatterjee and Fahn, 2002). Stimulants like amphetamines act on the dopamine system, and have previously been investigated for their effects on mobility in PD (Parkes et al., 1975), but possible motor side-effects must be taken into account. For instance, methylphenidate treatment in combination with levodopa has led to an increase in dyskinesia (Camicioli et al., 2001). Bupropion has also been recommended for the treatment of daytime sleepiness in PD (Rye, 2003), based on the reversal of daytime sleepiness in MPTP-lesioned primates (Rye, 2003). The effect of adenosine agonists such as caffeine has not been specifically investigated in PD but the

interaction between adenosine and the dopaminergic system is well recognized (Solinas et al., 2002). In clinical practice, however, the use of stimulants is not a relevant treatment option in PD patients, as the effects are small and side effects have to be considered. Dopaminergic medication may induce visual hallucinations, frequently starting at night, in up to 30% of PD patients (Sharf et al., 1978). PD patients with dementia are at high risk of developing psychiatric side-effects of dopaminergic therapy, and may require a reduced dopaminergic dosage in the afternoon or evening. Nocturnal hallucinations, mostly characterized by a reduction in sleep efficiency, slow-wave sleep and REM sleep, should be treated with low dosages of clozapine (Parkinson Study Group, 1999) that should be slowly increased until a complete remission is achieved. Patients who do not tolerate clozapine may be switched to low-dose quetiapine (12.5–50 mg) that is also appropriate for treatment of PD patients because of its side-effect profile (Fernandez et al., 1999; Reddy et al., 2002). Low dosages of benzodiazepines may be an alternative or additional treatment option in mild psychosis or nocturnal confusion, but no studies in patients with PD are yet available.

References Adler CH, Caviness JN, Hentz JG et al. (2003). Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 18: 287–293. Allen RP, Earley CJ (2001). Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol 18: 128–147. Allen RP, Picchietti D, Hening WA et al. (2003). Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health and the International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4: 101–119. American Sleep Disorders Association (2005). International classification of sleep disorders, ICSD-2, revised: diagnostic and coding manual. American Academy of Sleep Medicine, Westchester, Illinois. Andrade LA, Lima JG, Tufik S et al. (1987). REM sleep deprivation in an experimental model of Parkinson’s disease. Arq Neuropsiquiatr 45: 217–223. Apps MC, Sheaff PC, Ingram DA et al. (1985). Respiration and sleep in Parkinson’s disease. J Neurol Neurosurg Psychiatry 48: 1240–1245. April RS (1966). Observations on parkinsonian tremor in allnight sleep. Neurology 16: 720–724. Arnulf I, Bonnet AM, Damier P et al. (2000). Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 55: 281–288.

SLEEP IN PARKINSON SYNDROMES Arnulf I, Konofal E, Merino-Andreu M et al. (2002). Parkinson’s disease and sleepiness: an integral part of PD. Neurology 58: 1019–1024. Arnulf I, Merino-Andreu M, Bloch F et al. (2005). REM sleep behavior disorder and REM sleep without atonia in patients with progressive supranuclear palsy. Sleep 28: 349–354. Askenasy J (2001). Approaching disturbed sleep in late Parkinson’s Disease: first step toward a proposal for a revised UPDRS. Parkinsonism Relat Disord 8: 123–131. Askenasy JJ, Yahr MD (1985). Reversal of sleep disturbance in Parkinson’s disease by antiparkinsonian therapy: a preliminary study. Neurology 35: 527–532. Atlas Task Force of the American Sleep Disorders Association, Guilleminault C, chairman (1993). Recording and scoring leg movements. Sleep 16: 748–759. Bagetta G, De Sarro G, Priolo E et al. (1988). Ventral tegmental area site through which dopamine D2-receptor agonists evoke behavioural and electrocortical sleep in rats. Br J Pharmacol 95: 860–866. Bergonzi P, Chiurulla C, Gambi D et al. (1975). L-dopa plus dopa-decarboxylase inhibitor: sleep organization in Parkinson’s syndrome before and after treatment. Acta Neurol Belg 75: 5–10. Bertolucci PH, Andrade LA, Lima JG et al. (1987). Total sleep deprivation and Parkinson disease. Arq Neuropsiquiatr 45: 224–230. Bliwise DL, Willians ML, Irbe D et al. (2000). Inter-rater reliability for identification of REM sleep in Parkinson’s disease. Sleep 23: 671–676. Blumin JH, Berke GS (2002). Bilateral vocal fold paresis and multiple system atrophy. Arch Otolaryngol Head Neck Surg 128: 1404–1407. Braak H, Ru¨b U, Gai WP et al. (2003). Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517–536. Brodsky MA, Godbold J, Roth T et al. (2003). Sleepiness in Parkinson’s disease: a controlled study. Mov Disord 18: 668–672. Broughton R, Tolentino MA (1984). Fragmentary pathological myoclonus in NREM sleep. Electroencephalogr Clin Neurophysiol 57: 303–309. Broughton RJ, Guberman A, Roberts J (1984). Comparison of the psychosocial effects of epilepsy and narcolepsy/ cataplexy: a controlled study. Epilepsia 25: 423–433. Brunner H, Wetter TC, Hogl B et al. (2002). Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson’s disease: effects of dopaminergic treatment. Mov Disord 17: 928–933. Camicioli R, Lea E, Nutt JG et al. (2001). Methylphenidate increases the motor effects of L-dopa in Parkinson’s disease: a pilot study. Clin Neuropharmacol 24: 208–213. Carskadon MA, Dement WC, Mitler MM et al. (1986). Guidelines for the multiple sleep latency test (MSLT): a standard measure for sleepiness. Sleep 9: 519–524. Chatterjee A, Fahn S (2002). Methylphenidate treats apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 14: 461–462. Chaudhuri KR, Pal S, DiMarco A et al. (2002). The Parkinson’s disease sleep scale: a new instrument for assessing

373

sleep and nocturnal disability in Parkinson’s disease. J Neurol Neurosurg Psychiatry 73: 629–633. Chianchetti C (1985). Dopamine agonists and sleep in man. In: A Wauquier, JM Gaillard, JM Monti et al. (Eds.), Sleep: Neurotransmitters and Neuromodulators. Raven Press, New York, pp. 121–134. Chokroverty S, Sharp JT, Barron KD (1978). Periodic respiration in erect posture in Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 41: 980–986. Comella CL (2002). Daytime sleepiness, agonist therapy, and driving in Parkinson’s disease. JAMA 287: 455–463. Comella CL, Nardine TM, Diederich NJ et al. (1998). Sleeprelated violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 51: 526–529. Corbin D, Williams A (1987). Stridor during dystonic phases of Parkinson’s disease. J Neurol Neurosurg Psychiatry 50: 821–822. Currie LJ, Bennett JP Jr., Harrison MB et al. (1997). Clinical correlates of sleep benefit in Parkinson’s disease. Neurology 48: 1115–1117. Del Tredici K, Rub U, De Vos RA et al. (2002). Where does Parkinson’s disease pathology begin in the brain? Neuropathol Exp Neurol 61: 413–426. Diederich NJ, Vaillant M, Leischen M et al. (2005). Sleep apnea syndrome in Parkinson’s disease. A case-control study in 49 patients. Mov Disord 20: 1413–1418. Doghramji K, Mitler MM, Sangal RB et al. (1997). A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 103: 554–562. Drucker-Colin R, Duran-Vazquez A, Salin-Pascual RJ et al. (1996). A rapid eye movement (REM) sleep deprivation in 6-OHDA nigro-striatal lesioned rats with and without transplants of dissociated chromaffin cells. Brain Res 729: 170–175. Ebert D, Feistel H, Kaschka W et al. (1994). Single photon emission computerized tomography assessment of cerebral dopamine D2 receptor blockade in depression before and after sleep deprivation—preliminary results. Biol Psychiatry 35: 880–885. Eisensehr I, Linke R, Noachtar S et al. (2000). Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behavior disorder. Comparison with Parkinson’s disease and controls. Brain 123: 1155–1160. Eisensehr I, Linke R, Tatsch K et al. (2003). Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 26: 507–512. Eisensehr I, v Lindeiner H, Jager M et al. (2001). REM sleep behavior disorder in sleep-disordered patients with versus without Parkinson’s disease: is there a need for polysomnography? J Neurol Sci 186: 7–11. Emser W, Hoffmann K, Stolz T et al. (1987). Sleep disorders in diseases of the basal ganglia. Interdiscpl Topics Gerontol 22: 144–157. Fantini ML, Gagnon JF, Filipini D et al. (2003). The effects of pramipexole in REM sleep behaviour disorder. Neurology 61: 1328–1329.

374

¨ GL C. TRENKWALDER AND B. HO

Fantini ML, Ferini-Strambi L, Montplaisir J (2005). Idiopathic REM sleep behavior disorder: toward a better nosologic definition. Neurology 64: 780–786. Ferini-Strambi L, Franceschi M, Pinto P et al. (1992). Respiration and heart rate variability during sleep in untreated Parkinson patients. Gerontology 38: 92–98. Fernandez HH, Friedman JH, Jacques C et al. (1999). Quetiapine for the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 14: 484–487. Fish DR, Sawyers D, Allen PJ et al. (1991). The effect of sleep on the dyskinetic movements of Parkinson’s disease, Gille de la Tourette syndrome, Huntington’s disease, and torsion dystonia. Arch Neurol 48: 210–214. Friedman A (1980). Sleep pattern in Parkinson’s disease. Acta Med Pol 21: 193–199. Frucht S, Rogers JD, Greene PE et al. (1999). Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 52: 1908–1910. Gagnon JF, Bedard MA, Fantini ML et al. (2002). REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 59: 585–589. Gillberg M, Kecklund G, Akerstedt T (1994). Relations between performance and subjective ratings of sleepiness during a night awake. Sleep 17: 236–241. Gimenez-Roldan S, Navarro E, Mateo D (2003). Effects of quetiapine at low doses on psychosis motor disabilitiy and stress of the caregiver in patients with Parkinson’s disease. Rev Neurol 36: 401–404. Goetz CG, Wuu J, Curgian LM et al. (2005). Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 64: 81–86. Gordon PH, Pullman SL, Louis ED et al. (2002). Mirtazapine in parkinsonian tremor. Parkinsonism Relat Disord 9: 125–126. Happe S, Sauter C, Klosch G et al. (2003). Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology 48: 82–86. Hardie RJ, Efthimiou J, Stern GM (1986). Respiration and sleep in Parkinson’s disease. J Neurol Neurosurg Psychiatry 49: 1326. Henderson JM, Lu Y, Wang S et al. (2003). Olfactory deficits and sleep disturbances in Parkinson’s disease: a case-control survey. J Neurol Neurosurg Psychiatry 74: 956–958. Hilker R, Razai N, Ghaemi M et al. (2003). [18F]fluorodopa uptake in the upper brainstem measured with positron emission tomography correlates with decreased REM sleep duration in early Parkinson’s disease. Clin Neurol Neurosurg 105: 262–269. Hobson DE, Lang AE, Martin WR et al. (2002). Excessive daytime sleepiness and sudden-onset sleep in Parkinson’s disease: a survey by the Canadian Movement Disorders Group. JAMA 287: 455–463. Hoddes E, Zarcone V, Smythe H et al. (1973). Quantification of sleepiness: a new approach. Psychophysiology 10: 431–436. Ho¨gl BE, Gomez-Arevalo G, Garcia S et al. (1998). A clinical, pharmacologic, and polysomnographic study of sleep benefit in Parkinson’s disease. Neurology 50: 1332–1339. Ho¨gl B, Peralta C, Wetter TC et al. (2001a). Effect of sleep deprivation on motor performance in patients with Parkinson’s disease. Mov Disord 16: 616–621.

Ho¨gl B, Seppi K, Brandauer E et al. (2001b). Irresistible onset of sleep during acute levodopa challenge in a patient with multiple system atrophy (MSA): placebocontrolled, polysomnographic case report. Mov Disord 16: 1177–1179. Ho¨gl B, Saletu M, Brandauer E et al. (2002). Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 25: 905–909. Ho¨gl B, Rothdach A, Wetter TC et al. (2003a). The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor function in patients with Parkinson’s disease. Neuropsychopharmacology 28: 1866–1870. Ho¨gl B, Seppi K, Brandauer E et al. (2003b). Increased daytime sleepiness in Parkinson’s disease: a questionnaire survey. Mov Disord 18: 319–323. Hovestadt A, Bogaard JM, Meerwaldt JD et al. (1989). Pulmonary function in Parkinson’s disease. J Neurol Neurosurg Psychiatry 52: 329–333. Iranzo A, Santamaria J, Tolosa E et al. (2000), the Barcelona Multiple System Atrophy Study Group. Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy. Lancet 356: 1329–1330. Iranzo A, Santamaria J, Tolosa E et al. (2004). Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 63: 930–932. Iranzo A, Molinuevo JL, Santamaria J et al. (2006). Rapideye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 5: 572–577. Isono S, Shiba K, Yamaguchi M et al. (2001). Pathogenesis of laryngeal narrowing in patients with multiple system atrophy. J Physiol 536: 237–249. Isozaki E, Naito A, Horiguchi S et al. (1996). Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 60: 399–402. Jansen EN, Meerwaldt JD (1990). Madopar HBS in nocturnal symptoms of Parkinson’s disease. Adv Neurol 53: 527–531. Javoy-Agid F, Agid Y (1980). Is the mesocortical dopaminergic system involved in Parkinson’s disease? Neurology 30: 1326–1330. Jellinger K (1986). Pathology of parkinsonism. In: S Fahn, CD Marsden, P Jenner et al. (Eds.), Recent Developments in Parkinson’s Disease. Raven Press, New York, pp. 33–66. Johns MW (1991). A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Kakitsuba N, Sadaoka T, Kanal R et al. (1997). Peculiar snoring in patients with multiple system atrophy: its sound source, acoustic characteristics, and diagnostic significance. Ann Otol Rhinol Laryngol 106: 380–384. Kales A, Ansel RD, Markham CH et al. (1971). Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration. Clin Pharmacol Ther 12: 397–406. Koller WC, Hutton JT, Tolosa E et al. (1999). Carbidopa/ Levodopa Study Group. Immediate-release and controlledrelease carbidopa/levodopa in PD: a 5-year randomized multicenter study. Neurology 53: 1012–1019.

SLEEP IN PARKINSON SYNDROMES Kunz D, Bes F (1999). Melatonin as a therapy in REM sleep behaviour disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov Disord 14: 507–511. Lees AJ, Blackburn NA, Campbell VL (1988). The nighttime problems of Parkinson’s disease. Clin Neuropharmacol 11: 512–519. Leissner L, Sandelin M (2002). Periodic limb movements in sleep: to treat or not to treat? Sleep Med 3 (Suppl): S27–S30. Levin IaI (1991). Effects of sleep deprivation in parkinsonism. Sov Med 11: 9–11. Loube DI, Gay PC, Strohl KP et al. (1999). Indications for positive airway pressure treatment of adult obstructive sleep apnea patients: a consensus statement. Chest 115: 863–866. Marsden CD (1980). “On–off” phenomena in Parkinson’s disease. In: UK Rinne, M Klinger, G Stamm (Eds.), Parkinson’s Disease: Current, Progress, Problems and Management. Elsevier, Amsterdam, pp. 241–254. Marsden CD, Parkes JD, Quinn N (1981). Fluctuations of disability in Parkinson’s disease—clinical aspects. In: CD Marsden, S Fahn (Eds.), Movement Disorders. Butterworth Scientific, London, pp. 96–122. Maurer JT, Juncker C, Baker-Schreyer A et al. (1999). Sleep apnoea syndromes in multiple system atrophy. HNO 47: 117–121. Mazza S, Soucy JP, Gravel P et al. (2006). Assessing whole brain perfusion changes in patients with REM sleep behavior disorder. Neurology 67: 1618–1622. McNicholas WT, Rutherford R, Grossman R et al. (1983). Abnormal respiratory pattern generation during sleep in patients with autonomic dysfunction. Am Rev Respir Dis 128: 429–433. Mendelson WB (1996). Periodic leg movements associated with clinical sleep disturbance? Sleep 19: 219–223. Merello M, Hughes A, Colocimo C et al. (1997). Sleep benefit in Parkinson’s disease. Mov Disord 12: 506–508. Merino-Andreu M, Arnulf I, Konofal E et al. (2003). Unawareness of naps in Parkinson’s disease and in disorders with excessive daytime sleepiness. Neurology 60: 1553–1554. Merlo IM, Occhini A, Pacchetti C et al. (2002). Not paralysis, but distonia causes stridor in multiple system atrophy. Neurology 58: 649–652. Mitler MM, Gujavarty KS, Browman CP (1982). Maintenance of wakefulness test: a polysomnographic technique for evaluation treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 53: 658–661. Mitler MM, Doghramji K, Shapiro C (2000). The maintenance of wakefulness test: normative data by age. J Psychosom Res 49: 363–365. Mohsenin N, Mostofi MT, Mohsenin V (2003). The role of oral appliances in treating obstructive sleep apnea. J Am Dent Assoc 134: 442–449. Mouret J (1975). Differences in sleep in patients with Parkinson’s disease. Electroencephalogr Clin Neurophysiol 38: 653–657. Munschauer FE, Lob L, Dannister R et al. (1990). Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 40: 677–679.

375

Ondo WG, Dat Vuong K, Khan H et al. (2001). Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 57: 1392–1396. Ondo WG, Vuong KD, Jankovic J (2002). Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 59: 421–424. Ongini E, Caporali MG, Massotti M (1985). Stimulation of dopamine-D-1 receptors by SKF 38393 induces EEG desynchronization and behavioural arousal. Life Sci 37: 2327–2333. Onofrj M, Luciano AL, Thomas A et al. (2003). Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism. Neurology 60: 113–115. Parkes JD, Tarsy D, Marsden CD et al. (1975). Amphetamines in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 38: 232–237. Parkinson Study Group (1999). Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 340: 757–763. Plazzi G, Corsini R, Provini F et al. (1997). REM sleep behavior disorders in multiple system atrophy. Neurology 48: 1094–1097. Poewe W, Hogl B (2004). Akathisia, restless legs and periodic limb movements in sleep in Parkinson’s disease. Neurology 63 (Suppl): S12–S16. Rechtschaffen A, Kales A (1968). A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Brain Information Service/ Brain Research Institute, Los Angeles. Reddy S, Factor SA, Molho ES et al. (2002). The effect of quetiapine on psychosis and motor function in parkinsonian patients with and without dementia. Mov Disord 17: 676–681. Reist C, Sokolski KN, Chen CC et al. (1995). The effect of sleep deprivation on motor impairment and retinal adaptation in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 19: 445–454. Richardson GS, Carskadon MA, Flagg W et al. (1978). Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 45: 621–627. Rye D (2003). Sleepiness and unintended sleep in Parkinson’s disease. Curr Treat Options Neurol 5: 231–239. Saletu M, Anderer P, Saletu B et al. (2001). Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as compared with normals and acute effects of ropinirole. Hum Psychopharmacol 16: 177–187. Scha¨fer D (2001). Sleep related breathing disorders in parkinsonism: frequency, nature and therapeutical approaches. Somnologie 5: 103–114. Schenck CH, Mahowald M (1990). A polysomnographic, neurologic, psychiatric and clinical outcome report on 70 consecutive cases with REM sleep behavior disorder (RBD): sustained clonazepam efficacy in 89.5% of 57 treated patients. Cleve Clin J Med 57: 10–24. Schenck CH, Bundlie SR, Patterson AL et al. (1987). Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA 257: 1786–1789. Schenck CH, Mahowald MW, Kim SW et al. (1992). Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder. Sleep 15: 226–235.

376

¨ GL C. TRENKWALDER AND B. HO

Schenck CH, Bundlie SR, Mahowald MW (1996). Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46: 388–393. (Erratum in Neurology (1996) 46: 1787.) Schuld A, Kraus T, Haack M et al. (1999). Obstructive sleep apnea syndrome induced by clonazepam in a narcotic patient with REM-sleep-behavior disorder. J Sleep Res 8: 321–322. Sharf B, Moskovitz C, Lupton MD et al. (1978). Dream phenomena induced by chronic levodopa therapy. J Neural Transm 43: 143–151. Silber MH, Levine S (2000). Stridor and death in multiple system atrophy. Mov Disord 15: 699–704. Solinas M, Ferre S, You ZB et al. (2002). Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 22: 6321–6324. Stern M, Roffwarg H, Duvoisin R (1968). The parkinsonian tremor in sleep. J Nerv Ment Dis 147: 202–210. Stiasny-Kolster K, Doerr Y, Moller JC et al. (2005). Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alphasynucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128: 126–137. Suchowersky O, Furtado S, Rohs G (1995). Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 10: 337–340. Svensson K, Alfoldi P, Hajos M et al. (1987). Dopamine autoreceptor antagonists: effects of sleep–wake activity in the rat. Pharmacol Biochem Behav 26: 123–129. Tagaya H, Wetter TC, Winkelmann J et al. (2002). Pergolide restores sleep maintenance but impairs sleep EEG synchronization in patients with restless legs syndrome. Sleep Med 3: 49–54. Takakusaki K, Saitoh K, Harada H et al. (2004). Evidence for a role of basal ganglia in the regulation of rapid eye movement sleep by electrical and chemical stimulation for the pedunculopontine tegmental nucleus and the substantia nigra pars reticulata in decerebrate cats. Neuroscience 124: 207–220. Tan A, Salgado M, Fahn S (1996). Rapid eye movement sleep behaviour disorder preceding Parkinson’s disease with therapeutic response to levodopa. Mov Disord 11: 214–216. Tandberg E, Larsen JP, Karlsen K (1998). A communitybased study of sleep disorders in patients with Parkinson’s disease. Mov Disord 13: 895–899. Thorpy M, Chesson A, Derderian S et al. (1995). Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances. Sleep 18: 511–513. Traczynska-Kubin D, Atzef E, Petre-Quadens O (1969). Sleep in parkinsonism. Acta Neurol Psychiatr Belg 69: 727–733. Trosch RM, Friedman JH, Lannon MC et al. (1998). Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentered clinical experience. Mov Disord 13: 377–382. Tsuda T, Onodera H, Okabe S et al. (2002). Impaired chemosensitivity to hypoxia is a marker of multiple system atrophy. Ann Neurol 52: 367–371.

Tufik S (1981). Increased responsiveness to apomorphine after REM sleep deprivation: supersensitivity of dopamine receptors or increase in dopamine turnover? J Pharm Pharmacol 33: 732–733. Vetrugno R, Provini F, Cortelli P et al. (2004). Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med 5: 21–30. Vignatelli L, Bisulli F, Zaniboni A et al. (2005). Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias. J Neurol 252 (6), 712–717. Vincken WG, Gauthier SG, Dollfuss RE et al. (1984). Involvement of upper-airway muscles in extrapyramidal disorders. A cause of airflow limitation. N Engl J Med 311: 438–442. Vincken WG, Derauay CM, Cosio MG (1989). Reversibility of upper airway obstruction after levodopa therapy in Parkinson’s disease. Chest 96: 210–212. Walters AS, Winkelmann J, Trenkwalder C et al. (2001). Longterm follow-up on restless legs syndrome patients treated with opioids. Mov Disord 16: 1105–1109. Wetter TC, Collado-Seidel V, Pollmacher T et al. (2000). Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep 23: 361–367. Wetter TC, Trenkwalder C, Gershanik O et al. (2001). Polysomnographic measures in Parkinson’s disease: a comparison between patients with and without REM sleep disturbances. Wien Klin Wochenschr 113: 249–253. Winkelman JW, James L (2004). Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27: 317–321. Yoshida T, Kono I, Yoshikawa K et al. (2003). Improvement of sleep hypopnea by antiparkinsonian drugs in a patient with Parkinson’s disease: a polysomnographic study. Intern Med 42: 1135–1138. Zucconi M, Ferri R, Allen R et al. (2006). The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 7: 175–183. Zweig RM, Jankel WR, Hedreen JC et al. (1989). The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26: 41–46.

Further Reading Kumru H, Santamaria J, Tolosa E et al. (2004). Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations. Ann Neurol 56: 599–603. Montplaisir J, Petit D, Decary A et al. (1997). Sleep and quantitative EEG in patients with progressive supranuclear palsy. Neurology 49: 999–1003. Olson EJ, Boeve BF, Silber MH (2000). Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123: 331–339. Schenck CH, Milner DM, Hurwitz, TD et al. (1989). A polysomnographic and clinical report on sleep-related injury in 100 adult patients. Am J Psychiatry 146: 1166–1173.