Sleep disorders and extrapyramidal diseases: an historical review

Sleep Medicine 5 (2004) 163–167 www.elsevier.com/locate/sleep

Udine Special Section

Sleep disorders and extrapyramidal diseases: an historical review G. Pauletto*, E. Belgrado, R. Marinig, P. Bergonzi Clinica Neurologica, Ospedale S. Michele, Piazza Rodolone, Universita` degli Studi di Udine, Gemona del Friuli, Udine, Italy Received 1 July 2002; received in revised form 1 August 2002; accepted 15 October 2003

Abstract Background and purpose: Sleep disorders have been mentioned since the first descriptions of extrapyramidal diseases in James Parkinson’s Essay on the Shaking Palsy, but only recently they have become the subject of attention, thanks to new acquisitions in clinical knowledge and electroencephalographic technology. In the late 1960s, the introduction of L-dopa permitted comparison of sleep patterns in drug-naive patients before and after therapy in conditions very similar to experimental ones. Historically, we can recognise two major lines of study, one dealing with descriptions of sleep behaviours modified by drugs and the other with polysomnographic sleep research carried out before and after treatment. Patients and methods: The data obtained from the first polysomnographic studies led to the definition of sleep macro- and microstructure in patients suffering from Parkinson’s disease, but the interpretation of drug-induced changes was not unequivocal. Results: According to some authors, the improvement in sleep architecture was due mainly to improvement of nocturnal motor impairment. Other researchers suggested a primary sleep dysfunction caused by specific neurodegenerative processes in the brain structures regulating the sleep – wake cycle. Conclusions: The latter hypothesis has recently been supported by the observation that distinct sleep disorders, such as REM behaviour disorder or restless legs syndrome, often herald extrapyramidal diseases or are a frequent adjunctive complaint for these patients. q 2004 Elsevier B.V. All rights reserved. Keywords: Sleep; Sleep disorders; Extrapyramidal diseases; L-dopa

1. Introduction: from clinical description to electroencephalographic recordings “In this stage, the sleep becomes much disturbed. The tremulous motion of the limbs occurs during sleep, and augments until it awakens the patient, and frequently with much agitation and alarm… As the debility increases and the influence of the will over the muscles fades away, the tremulous agitation becomes more vehement. It now seldom leaves him for a moment; but even when exhausted nature seizes a small portion of sleep, the motion becomes so violent as not only to shake the bed-hangings, but even the floor and sashes of the room… His attendants observed, that of late the trembling would sometimes begin in his sleep, and increase until it awakened him: when he always was in a state of agitation and alarm…” James Parkinson, ‘Essay on the Shaking Palsy’, 1817 * Corresponding author. Tel.: þ 39-432-989289; fax: þ 39-432-989336. E-mail addresses: [email protected] (G. Pauletto), paolo.bergonzi@ dpmsc.uniud.it (P. Bergonzi). 1389-9457/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2003.10.008

With these words, James Parkinson described for the first time sleep problems in extrapyramidal diseases (ED) [1]. Later, at the turn of the century, Charcot and his co-workers confirmed the observations of Sir Parkinson in their wellknown cahiers. Surprisingly, despite the attention paid to sleep disorders in these early descriptions, sleep has until recently been considered no more than a secondary problem in ED. An important milestone was the introduction of L-dopa, in late 1960s. Together with research in sleep neurophysiology, it promoted an increased and renewed interest in sleep characteristics in Parkinson’s disease (PD). The moment was favourable; new polygraphic techniques permitted detailed sleep studies, and the use of L-dopa among drugnaive patients allowed conditions comparable to experimental ones. The main question has been whether sleep abnormalities resulted only from nighttime motor disability or were the expression of lesions in sleep – wake regulatory centres. Some lines of research considered enhanced sleep quality to be an indicator of improvement in basal condition and linked it with clinical descriptions of pathological

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behaviours modified by the new therapy; this approach was comparable to Parkinson’s reports. Polysomnographic (PSG) studies, by contrast, lead to definitions of sleep micro- and macrostructure in PD patients, comparing sleep quality before and after the use of L-dopa in order to determine whether sleep architecture was primarily affected by the degenerative illness and if dopamine restoration could revert the dysfunction. The latter question arose from the experiments of Jouvet, who suggested the important role of brain amines in the regulation of the sleep –wake cycle [2]. The first results from whole-night PSG recordings were encouraging, but the interpretation of data was not unequivocal and remains far from definitive. What is the real role of ED in determining sleep pattern changes? How and how deeply does dopamine affect sleep?

2. Sleep architecture in Parkinson’s disease: age-related and illness-related changes PSG data obtained from PD patients before treatment with L-dopa have shown some sleep patterns similar to those of the aged: † † † † †

difficulty in falling asleep and in maintaining sleep superficial and fragmentary sleep increased wakefulness after sleep onset (WASO) reduction of total sleep time decreased percentage of slow wave sleep (SWS) and REM sleep † advanced sleep phase † poor sleep efficiency In patients with ED, however, sleep fragmentation, sleep onset and sleep maintenance insomnia are more marked and more frequent than in healthy age-matched controls [3]. The degree of sleep disturbance seems to correlate with the severity of illness. Moreover, REM sleep dysfunction is not common in healthy older people, but is somewhat of a hallmark of ED. REM sleep often appears to be reduced, but some cases of increased REM sleep have also been mentioned. The resulting sleep microstructure is affected by: † decreased amounts of spindles, especially in hypokinetic syndromes † poorly formed K-complexes † increased arousals † increase of muscular tone during light sleep (phase II) † persistence of muscular activity during REM sleep Similar sleep alterations have been described in ED patients with Gilles de la Tourette syndrome, neuroacanthocytosis and Huntington’s chorea, who have poor sleep efficiency with a high number of arousals and a high percentage of WASO. Reduction of REM sleep and SWS and increased

spindling occur in most patients [4]. In Multiple System Atrophy (MSA), sleep is scarcely organised, with reduction of total sleep time and REM sleep, prevalence of light sleep, increased arousals and persistence of muscular tone during whole-night recordings [5]. Comparable features have only recently been described in Cortico-basal Degeneration, Progressive Supranuclear Palsy, Lewy body disease and Parkinson ALS dementia [6 – 8].

3. Dopamine and sleep In 1970, many PSG studies recorded drug-naive PD patients before and after administration of L-dopa at various dosages (from 0.5 to 5 g). All were whole-night recordings of spontaneous sleep, performed in order to observe changes in sleep patterns. At an average dose of L-dopa (3 g), a reduction of wakefulness, REM latency, light sleep, number of awakenings and time needed to fall asleep was observed, along with a slight increase in SWS, a sharp increase in REM sleep and augmentation of sleep cycles. A higher dosage caused an alteration of sleep architecture comparable to the baseline, with a general increase of alertness and a reduction of SWS and REM sleep [9 – 12]. The normalising action seemed to be closely related to the dosage that restored physiological levels without exceeding that limit. Such modifications were not seen in healthy controls after administration of L-dopa, perhaps because the endogenous levels of dopamine and aminergic pathways were intact. The hypothesis that dopamine directly affects sleep has been a source of discussion, for a long time; some authors have considered the modification in sleep patterns after treatment with L-dopa purely an effect of its clinical benefit [13,14]. However, sleep can be disturbed by PD-specific motor symptoms such as rigidity, bradykinesia, nocturia, sleep-onset blepharospasm, early morning foot dystonia, eye blinking, painful leg cramps, tremor and dyskinesia, which are usually reduced during SWS but not completely suppressed in light sleep or phase shifts. Therapy with L-dopa and dopamine agonists, as well as a treatment such as high frequency stimulation of the subthalamic nucleus, reduces motor disability related to PD and improves sleep quality. Unfortunately, these treatments do not affect the sleep – wake pattern or specific sleep disorders such as REM behaviour disorder (RBD) or periodic limb movements (PLMs) [15]. These observations reinforce the results of much pharmacological and PSG research carried out in order to prove that the alterated sleep pattern in PD patients is due to primary dysfunction of nuclei involved in the control of the sleep – wake cycle [16 – 19]. In fact, the pathologic process that causes PD determines the depletion of striatal and mesencephalic dopaminergic neurones, serotoninergic neurones of the dorsal Raphe, noradrenergic neurones of the locus coeruleus and cholinergic neurones of

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the pedunculo-pontine nucleus [3,20]. Mesocorticolimbic, nigrostriatal and brainstem aminergic pathways appear to be important in regulating the sleep – wake cycle and in modulating behavioural state [21 – 23]. Major evidence comes from animal studies, in which results do not always correspond to those obtained in man. Lesional experiments in cats performed by Jouvet and co-workers belong to history; they demonstrated that lesions on the locus coeruleus in the dorsolateral pontine tegmentum caused REM without atonia (RWA) and oneiric behaviour [2,24]. The extent of lesions determined the clinical importance of the symptoms. More recent studies on cats suggest that dopaminergic neurons of the ventral tegmental area (VTA) and Substantia Nigra facilitate arousals through their projections to the striatum and cortex [25]. In narcoleptic dogs, an interaction between mesencephalic dopaminergic nuclei and the hypocretin system is probably implicated in the control of wakefulness, and pharmacological studies suggest that dopaminergic pathways could be responsible for the wakefulness-promoting effect of amphetamines and modafinil [3]. It is a common clinical experience that drugs enhancing dopaminergic transmission can increase alertness [26,27]. Conversely, patients using L-dopa and dopaminergic agonists often complain of excessive daytime sleepiness, with a prevalence that varies widely from 84 to 11.4% [28]. REM sleep appears to be the most affected by the administration of these drugs; some authors describe a suppression of REM sleep, others an increase, sometimes with REM sleep intrusion into waking hours [29 – 32]. In narcoleptic dogs, the infusion of D3 agonists in VTA induces sedation. Frucht and co-workers speculated that the D3 activity of some dopamine agonists could be responsible for sleep attacks in PD patients [31]. It is important to mention that the term ‘sleep attack’ was subjectively defined, without any mention of previous sleep disorders, other medications, PSG data or genetic features. Thanks to the information collected from animal experiments, pharmacological trials and clinical evidence, we can summarize that neuronal degeneration in ED involves centres responsible for the sleep –wake cycle, thus causing sleep disorders. However, the effect of L-dopa and dopamine agonists on sleep is controversial and complex; in animals, D1 and D2 agonists have shown biphasic effects depending on the dose. Small doses decrease wakefulness, enhancing SWS and REM sleep, while higher doses have the opposite effect [3]. The decrease in wakefulness may be related to inhibition of dopaminergic actions via stimulation of pre-synaptic D2 auto receptors in VTA. Higher dosages promote arousals via stimulation of post-synaptic receptors [30].

4. Extrapyramidal disease and primary sleep disorders Primary sleep disorders are common in ED patients and some can heralds the clinical appearance of the diseases

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themselves. These observations are quite recent, beginning with the description of RBD as a distinct syndrome by Schenck and co-workers in 1986 [33]. The association between ED and primary sleep disorders is further evidence that pathological processes are affecting regulatory aminergic pathways. RBD is a dissociated state characterised by violent, dream-enacting behaviours with preservation of muscular tone, during REM sleep [8,34,35]. Some years later, the same group reported a delayed and selective emergence of parkinsonian disorders in patients initially diagnosed as idiopathic RBD [36]. Other reports described RBD as a prodrome of MSA, Lewy body disease and Cortico-basal degeneration [7,37 – 40]. Pedunculopontine nucleus (PPN), which is strictly connected with the substantia nigra, is a likely site of pathology in combined RBD and PD [36]. PPN has a strong connection with the REM atonia circuitry and the REM phasic generator circuitry [41]. Furthermore, the substantia nigra itself has a strong connection with that circuitry. The neuropathology of PD includes neuronal loss within the PPN. The retrorubral nucleus, possibly connected with REM atonia, is located near the substantia nigra and could be involved in the degenerative process too. Another hypothesis comes from Rye’s studies: the gabaergic output of the basal ganglia targets the glutamatergic retrorubral field and/or neurons of the midbrain extrapyramidal area, which activates the ventromedial medullary zone by promoting REM atonia [23]. Heightened phasic discharges of the internal segment of the globus pallidus, secondary to dopamine cell loss in the substantia nigra, inhibit the midbrain extrapyramidal area excessively, allowing the expression of movement that overcomes REM atonia. In PD, there is additional degeneration of brainstem neurons that play a significant role in the control of behavioural state, particularly the monoaminergic nuclei. There are two glutamatergic receptors in the dorsolateral pons and the nucleus magnocellularis; one promotes RWA and the other REM atonia [42,43]. In PD, additional degeneration of the nucleus that promotes RWA can hide the effect of phasic discharge within the globus pallidus, which may explain why RBD is not present in all PD patients. Restless legs syndrome (RLS), another common sleep disorder in patients suffering from PD, is characterised by uncomfortable paresthesias referred to the legs occurring at rest. Patients are forced to move in order to get some relief. Such motor restlessness prevents sleep initiation and maintenance and causes reduction of total sleep time, with increased stage I sleep. Dopaminergic agonists markedly improve RLS. These associations suggest a primary role of dopamine in the pathogenesis of RLS: an abnormal modulation of sensory information through the dopaminergic system originating in the diencephalon or in the upper brainstem has been proposed [44]. RLS is often associated with PLMs, described as stereotypic movements affecting one or both legs

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and sometimes involving the arms, the typical movement being a flexion at the ankle, knee and hip, with an extension of the toes. PLMs usually occur during the lighter stages of NREM sleep and can cause arousals or awakenings. They are reported in up to one-third of patients with PD. Dopamine pathways are implicated in the pathogenesis of this disorder; a loss of central inhibition to a spinal or brainstem pacemaker has been suggested. The corticospinal tract or other pathways involving the basal ganglia could mediate the inhibition [45,46]. About 60% of PD patients complain of respiratory difficulties during sleep. Abnormalities of upper airway and thoracic muscular tone and poorly co-ordinated respiratory efforts may cause obstructive sleep apnoea syndrome. Patients with dysautonomia may present central apnoeas [30]. Laryngeal stridor and sleep apnoeas are also common in patients with MSA [40].

5. Conclusions The history of sleep disorders in ED is as old as the first clinical descriptions, but only the recent introduction of dopaminergic drugs and EEG technology has permitted detailed studies. However, the mechanisms responsible for sleep complaints in these patients are not yet completely understood. Different aspects that should be taken into account are: motor disability, drug effects and primary sleep dysfunction. The effects of dopamine on sleep are complex and not always unequivocal. Pharmacological as well as animal experiments show that dopaminergic drugs affect sleep depending on dose, species and receptor specificity of the specific drug. The results obtained in human studies only partially agree with this experimental data, but we must consider that much of what we know about sleep and extrapyramidal diseases stems from studies performed 20 –30 years ago with less stringent diagnostic criteria and less standardised PSG techniques. Recent attention to quality of life and improvement in treatment encourage physicians to regard sleep complaints as troublesome conditions that must be addressed during the complete follow-up of these patients.

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