Rapid Eye Movement Sleep Behavior Disorder
REM sleep behavior disorder (RBD) was first reported by Schenck et al. in 1986 and is a parasomnia, which is typically characterized by vivid and usually frightening dreams or nightmares associated with a paradoxical simple or complex movement during REM sleep when muscles are usually atonic (13,23). RBD is thought to have a population prevalence of 0.5%. During REM sleep, patients enact their dreams, which can be vivid or unpleasant, and partners report vocalizations (talking, shouting, vocal threats) and abnormal movements (arm/leg jerks, falling out of bed, violent assaults) (35-40). Typical clinical features of RBD are summarized in Table 3.
Although clinical history may suggest a diagnosis, in some situations such as when there is a high risk of physical injury or loud snoring suggestive of obstructive sleep apnea, confirmation of diagnosis should be obtained by a single night of polysomnography (PSG) with video telemetry. PSG would show an increased electromyographic (EMG) activity during REM sleep. Symptoms of RBD may predate the diagnosis of PD. Schenck et al. (37) reported that in 1l of 29 men (38%), 50 years or older in whom idiopathic RBD was diagnosed, a parkinsonian disorder was identified after a mean interval of 3.7 years following the diagnosis of RBD and 12.7 years after the onset of RBD. One study (41) suggested an increased risk of developing PD in individuals who have RBD and olfactory disturbance. This concept is consistent with the recent hypothesis of Braak et al. (21) who suggest that the preclinical stages 1 and 2 of PD start at the olfactory and medullary area of the brainstem. Although the pathological basis of RBD is unknown, speculation is that RBD is related to the
TABLE 2 Symptoms and Signs of Nocturnal Akinesia and Nighttime Wearing Off
Difficulty in turning Muscle spasm/cramps Pain
Early morning dystonia
Restless legs syndrome
Periodic limb movements
TABLE 3 Clinical Features Characterizing Rapid Eye Movement Behavior Disorder Predilection for male gender
Mean age of onset 50-65 yr (wide age range reported varying from 20-80 yr) REM associated vocalizations, shouting, swearing, screaming, groaning (catathrenia) Simple and complex motor movements Muscle twitching Arm/leg jerking Kicking
Fighting (boxing or trying to hit/strangulate partner) Falling out of bed Self and partner injury Dreams associated with attacks by animals or humans or insects Behaviors are indicative of content of dream Occurs during the later half of sleep period (early morning)
Abbreviation-. REM, rapid eye movement. Source: From Ref. 13.
degeneration of lower brainstem nuclei like the PPN and periceruleal nucleus. Specifically, on the basis of the studies in cats, several brainstem areas such as lat-erodorsal tegmental nucleus (LDTN), perilocus ceruleus region (peri-LC), nucleus reticularis magnocellularis, and the ventrolateral reticulospinal tracts, in addition to the PPN, have been implicated (13). Lesions in the peri-LC regions lead to REM sleep without atonia and, in one of the first cases of RBD to come to autopsy, there was a marked reduction in the number of neurons in LC, whereas an increased number of neurons in the PPN and LDTN were observed (42). The authors suggested that RBD could have been caused by decreased cholinergic activity of the LC and reduced disinhibition of the PPN and LTDN. However, this is controversial, as others have noted depletion of neuro-melanin neurons in LC and depleted choline-acetyl transferase neurons in the LDTN and PPN in multiple system atrophy cases (43). Furthermore, why clonazepam remains the most effective drug for treatment of RBD cannot be explained by these possible pathophysiological mechanisms.
REM Sleep Behavior Disorder: Differential Diagnosis
A list of differential diagnoses of RBD is provided in Table 4. Somnambulism usually complicates early non-REM sleep and exhibits purposeful movements such as walking away from the bed not necessarily associated with violent dreams or abrupt
TABLE 4 Possible Differential Diagnosis of Rapid Eye Movement Behavior Disorder
Parasomnias of non-REM sleep Somnambulism Confusional arousal Night terrors Nocturnal panic attacks Nightmares Nocturnal seizures
Severe periodic limb movements of sleep Obstructive sleep apnea
Abbreviation: REM, rapid eye movement.
movements such as kicking, fighting, or jumping. Night terrors and confusional episodes occur early in sleep unlike RBD and may involve screaming or incoherent speech but there is no recall of the dream. Nocturnal panic attacks in PD may complicate nocturnal akinesia with dysautonomia such as palpitations, hyperhydrosis, and immediate full awareness without dream enactment, whereas seizures may be associated with tonic-clonic posturing, tongue biting, incontinence, and postictal confusion.
Excessive Daytime Sleepiness and Sudden Onset of Sleep
EDS is a common complaint of PD patients. One study (4) reported a prevalence of 15.5% in PD patients compared with only 1% in healthy age-matched controls. Gjer-stad et al. (44) examined the occurrence of EDS in 142 patients, 7% had EDS, and after follow-up of four years this had risen to 29%. The authors concluded that EDS occurs at a rate of 6% in new PD patients per year. The causation is complex and may represent a destabilization of the flip-flop switch of wakefulness due to dopaminergic denervation (22,28). In addition, the effect of poor nocturnal sleep and antiparkin-sonian or other drugs may be causative (Table 5). EDS may manifest as some patients feel sleepy and drift off slowly to sleep, whereas others may experience fatigue. A controversial notion is the concept of sudden onset of sleep without any preceding drowsiness, resembling narcolepsy in some patients (17,45,46). Some had originally suggested the term "sleep attacks" linked to use of nonergot dopamine agonists (47). However, recent reviews suggest that "sleep attacks" are not drug-specific but rather a class effect of all dopamine agonists used to treat PD as well as dopaminergic agents such as levodopa and, furthermore, use of the term "sleep attack" is discouraged (47-49).
Like RBD, EDS can occur early in PD and may predate the diagnosis in some cases (50,51). However, based on a study in 15 untreated PD patients, Kaynak et al. (52) reported that there is no evidence of EDS in untreated PD, and EDS occurs after treatment with dopaminergic agents. Arnulf et al. (53) performed a PSG and multiple sleep latency test (MSLT) in PD patients with and without hallucinations. EDS was present in 50% of each group, whereas sleep onset REM periods and sleep latency below 10 minutes characteristic of narcolepsy were present mainly in the hallucinating group (53). This would suggest that a subset of PD patients may have an intrinsic susceptibility to sudden onset of sleep, which may be unmasked by the use
TABLE 5 Possible Causes of Excessive Daytime Sleepiness in Parkinson's Disease
Nonmedication-related Advancing disease Nocturnal sleep disruption Parasomnias Depression
Dopaminergic treatment Antihistamines Hypnotics Anxiolytics
Selective serotonin reuptake inhibitors
Source: From Ref. 6.
of some dopaminergic drugs. Tan et al. (54) reported that irresistible sleepiness not preceded by obvious somnolence or warning was present in 14% of a Chinese PD population compared to less than 2% in controls (54). Such subjects may, therefore, be susceptible to falling asleep while driving or operating machinery. EDS needs to be differentiated from fatigue. Also, postprandial hypotension in PD may unmask sleepiness and akinesia (55). Fatigue may be present in up to 43% of PD patients and is usually associated with sleepiness, although tiredness is a key feature (56).
Driving, Excessive Daytime Sleepiness, and Sudden Onset of Sleep
The combination of motor dysfunction of PD, the propensity to EDS, and fatigue may pose a particular problem in relation to driving. After a survey of 6620 patients and 361 phone interviews, Meindorfner et al. (57) found that 60% of this PD population was still driving and 11% had caused at least one traffic accident in the preceding five years (57). The risk factors identified for accidents included a high Epworth Sleepiness Scale (ESS) score, moderately severe motor disability of PD, and a previous history of sudden onset of sleep while driving.
RLS and periodic leg movements (PLM) commonly occur together and both can be effectively treated by dopaminergic drugs, raising speculation that there may be an underlying dopaminergic dysfunction and a link with PD. An observational study by Ondo et al. (58) reported RLS to occur in PD at a rate twice that of the general population. A comparative study by Lussi et al. (59) suggested a prevalence rate of RLS of 24% in PD. RLS may occur across all stages of PD and even in untreated PD (60). Wetter (60) examined sleep and PLM patterns in de novo PD and multiple system atrophy using two nights of PSG (60). They reported frequent problems with sleep disruption and an increased PLM index in de novo PD. These observations are in agreement with recent clinical findings in a study of untreated PD versus controls and advanced PD using a bedside sleep scale (61). However, a confusing issue is that, in some cases (more than 65% of PD patients in the study reported by Ondo et al.), RLS may emerge after the diagnosis of PD, when patients are already on dopamin-ergic therapy, which is thought to be first-line treatment for RLS. Furthermore, in PD, RLS may be confused with akathisia, which may be related to dopaminergic dyskinesia.
EDS may overlap with daytime somnolence due to sleep-disordered breathing. Obstructive sleep apnea causing sleep-disordered breathing may be suggested by a history of loud crescendo snoring and irregular snoring with snorting, gasping, and gaps, particularly in an overweight subject. Partner corroborated history of apnea, daytime fatigue, and somnolence also suggest sleep apnea. Formal PSG will identify sleep apnea, which may occur in up to 50% of patients with PD with resultant daytime sleepiness (18,62). Sleep apnea may coexist with RLS, PLM, or RBD, and it is important to diagnose the apnea as treatment for RBD with clonazepam, for instance, may aggravate sleep apnea.
Nocturia has been consistently shown to be one of the most common problems causing sleep disruption in PD. A survey by Stocchi et al. (63) reported nocturia in 43% of 200 PD patients. An overall prevalence of nocturia in PD of 30% to 80% has been reported (6,64). A validation study of the Parkinson's Disease Sleep Scale (PDSS) and an independent Spanish validation of the PDSS both reported nocturia as the most prevalent nocturnal symptom of PD (65,66). The causation is unclear. Nocturia may reflect a symptom of nocturnal wearing off while an underlying striatal dopamine Dl-receptor-related dysfunction has also been implicated (67,68). Nocturia associated with nocturnal off periods may lead to incontinence and bed soiling. Nocturia also appears to be a problem of advancing PD rather than early or untreated PD, as indicated in a study using the PDSS in untreated and advanced PD patients compared to controls (6l).
Depression is common in PD and affects sleep quality, causing insomnia (6,7). Dementia will also lead to sleep dysfunction with evidence of RBD, insomnia, and nocturnal hallucinations. Hallucinations may complicate nocturnal sleep and some have suggested an overlap with RBD (39,53). An eight-year follow-up study of cases with RBD and PD suggested a high rate of development of visual hallucinations in those with RBD (69). Sinforiani et al. (70) have reported that RBD could be a risk factor for future development of hallucinations and cognitive failure, based on neuropsychiatric evaluations in 110 patients.
Insomnia and nighttime agitation may be caused by late dosing of selegiline, probably as a result of its amphetamine metabolites, whereas other drugs, such as amanta-dine and anticholinergics, may also produce an alerting effect. The effect of rasagiline on sleep is unclear and needs to be ascertained. Selective serotonin reuptake inhibitors (SSRIs) may need to be avoided at bedtime, as they may impair sleep onset (7). Dopamine agonists and levodopa have a variable and dose-dependent effect on sleep, either promoting or disrupting sleep, although studies suggest that overnight sustained dopaminergic stimulation improves sleep in PD, by reducing nocturnal akinesia, RLS, and PLM (6,7).
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