Insomnia in Neurodegenerative Disorders

Donald L. Bliwise, PhD



Introduction

Clinicians treating patients with neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), invariably encounter patients whose sleep is profoundly dis-turbed. Although sleep disturbances may partially reflect adverse effects of medications used in the treatment of these diseases, evidence suggests that deterioration of the neural substrates regulating sleep in both PD and AD may also contribute to these phenomena albeit somewhat differently for the 2 conditions.



Parkinsonism (Synucleinopathies)

Idiopathic PD and parkinsonian-like conditions (eg, diffuse Lewy body dementia and multisystem atrophy) are typically characterized neuropathologically by accumulation of alpha-synuclein throughout the substantia nigra and other midbrain regions, and occasionally the cortex. These conditions often have diverse presentations of disturbed sleep and can be classified by their predominance during nighttime, daytime, or both times of day.

Nocturnal Effects

PD and PD-like conditions are often characterized by dream-enactment behaviors, which represent the ab-sence of normal REM atonia, or REM sleep behavior disorder (REMBD). Patients experience frightening, of-ten combative dreams and engage in complex motor activities, such as arm flailing, aggressive vocalizations, and occasionally even leaving the bed and walking. In instances such as these, patients literally act out their dreams; a history of self-injury or injury to the bed partner also is not uncommon. Unlike the behaviors typi-cally ascribed to somnambulism, these movements are typically purposeful and coordinated, arise out of REM sleep, and are associated with dream recall. Furthermore, they do not represent nocturnal seizures, and a male predominance has been described. Case series have suggested that these symptoms may predate any signs of parkinsonism, such as rigidity or bradykinesia, by more than a decade,[1] although many (but not all) parkinsonian patients may show such behaviors intermittently throughout their disease course.

Polysomnographic verification of REMBD is characterized by continued tonic muscle tone in REM sleep and a high frequency of phasic muscle activity in facial and limb muscles in REM, and to some extent, in non-REM sleep. The relative persistence of such phasic muscle activity in REM sleep has been proposed as a distin-guishing feature of sleep in the synucleinopathies (cf, amyloidopathy and tauopathy).[2] Although such phasic muscle activity may be somewhat characteristic of synucleinopathies, this finding does not approach 100% sensitivity, as selected pharmacologic agents, such as selective serotonin reuptake inhibitors and tricyclic an-tidepressants, and chronic alcohol use can also be associated with such elevated motor activity in REM.

Daytime Effects

A number of reports over the last 5 years document that the use of dopamine agonists are associated with a greater likelihood of daytime sleepiness in parkinsonian patients.[3-5] Dopaminergic stimulation, at least at rela-tively low dosages, has been documented in animal models to decrease arousal.[6] Less well appreciated is that the nigrostriatal deterioration per se of the parkinsonian condition may induce sleepiness so profound as to resemble partially the phenotype of narcolepsy. A historical basis for the inability to maintain wakefulness in the condition harkens back to Oliver Sachs' classic book, Awakenings, which mentions these issues phe-nomenologically. Patients and clinicians should be warned that the sleepiness they experience can be dis-abling and may affect their ability to operate a motor vehicle. Quality of life may suffer with an impact on social and occupational domains. On daytime polysomnography (Multiple Sleep Latency Test [MSLT]), many parkin-sonian patients demonstrate short mean sleep latencies and multiple sleep onset REM periods. Although cataplexy is rare, this is consistent with the phenotype for narcolepsy.[7] The mechanisms underlying the sleepiness may involve unrecognized axon collaterals arising from midbrain structures and terminating in the thalamus, thus serving to modulate thalamocortical activation.[8]

Treatments

Historically, REMBD-like behaviors have been well controlled with clonazepam, .5-1.0 mg taken at bedtime. Because of the long half-life (10-12 hours) of this medication and the risk for falls and daytime carryover, ben-zodiazepines with shorter elimination half-lives, such as temazepam, have occasionally been substituted with varying levels of success. More recently, success has been reported with the dopamine agonist pramipexole administered at bedtime (typical dosages of .5-1.0 mg) for idiopathic REMBD in the absence of frank parkin-sonian signs.[9] For the parkinsonian patient who may already be receiving substantial dosages of dopamine agonists, bedtime dosing of sustained-release levodopa with or without a catechol-O-methyltransferase inhibi-tor, such as entacapone or tolcapone, may be considered. Some recent reports have suggested that mela-tonin may be useful for controlling REMBD in cases of Lewy body dementia.[10] However, melatonin should not be assumed to be innocuous (see section on AD treatments below), and its efficacy has been called into question. Morning administration of modafinil at dosages of 100-200 mg, or bupropion at 100 mg, may be considered for initial treatment of excessive daytime sleepiness. To minimize pill burden, initial reduction of agonist dosage or change in the time of administration of such agonists or levodopa should be considered be-fore adding stimulant-like medications.

Parkinsonism (Synucleinopathies)

Idiopathic PD and parkinsonian-like conditions (eg, diffuse Lewy body dementia and multisys-tem atrophy) are typically characterized neuropathologically by accumulation of alpha-synuclein throughout the substantia nigra and other midbrain regions, and occasionally the cortex. These conditions often have diverse presentations of disturbed sleep and can be classified by their predominance during nighttime, daytime, or both times of day.

Nocturnal Effects

PD and PD-like conditions are often characterized by dream-enactment behaviors, which repre-sent the absence of normal REM atonia, or REM sleep behavior disorder (REMBD). Patients experience frightening, often combative dreams and engage in complex motor activities, such as arm flailing, aggressive vocalizations, and occasionally even leaving the bed and walking. In instances such as these, patients literally act out their dreams; a history of self-injury or injury to the bed partner also is not uncommon. Unlike the behaviors typically ascribed to somnambu-lism, these movements are typically purposeful and coordinated, arise out of REM sleep, and are associated with dream recall. Furthermore, they do not represent nocturnal seizures, and a male predominance has been described. Case series have suggested that these symptoms may predate any signs of parkinsonism, such as rigidity or bradykinesia, by more than a dec-ade,[1] although many (but not all) parkinsonian patients may show such behaviors intermittently throughout their disease course.

Polysomnographic verification of REMBD is characterized by continued tonic muscle tone in REM sleep and a high frequency of phasic muscle activity in facial and limb muscles in REM, and to some extent, in non-REM sleep. The relative persistence of such phasic muscle activity in REM sleep has been proposed as a distinguishing feature of sleep in the synucleinopathies (cf, amyloidopathy and tauopathy).[2] Although such phasic muscle activity may be somewhat characteristic of synucleinopathies, this finding does not approach 100% sensitivity, as selected pharmacologic agents, such as selective serotonin reuptake inhibitors and tricyclic antidepres-sants, and chronic alcohol use can also be associated with such elevated motor activity in REM.

Daytime Effects

A number of reports over the last 5 years document that the use of dopamine agonists are as-sociated with a greater likelihood of daytime sleepiness in parkinsonian patients.[3-5] Dopaminer-gic stimulation, at least at relatively low dosages, has been documented in animal models to de-crease arousal.[6] Less well appreciated is that the nigrostriatal deterioration per se of the parkin-sonian condition may induce sleepiness so profound as to resemble partially the phenotype of narcolepsy. A historical basis for the inability to maintain wakefulness in the condition harkens back to Oliver Sachs' classic book, Awakenings, which mentions these issues phenomenologi-cally. Patients and clinicians should be warned that the sleepiness they experience can be dis-abling and may affect their ability to operate a motor vehicle. Quality of life may suffer with an impact on social and occupational domains. On daytime polysomnography (Multiple Sleep La-tency Test [MSLT]), many parkinsonian patients demonstrate short mean sleep latencies and multiple sleep onset REM periods. Although cataplexy is rare, this is consistent with the pheno-type for narcolepsy.[7] The mechanisms underlying the sleepiness may involve unrecognized axon collaterals arising from midbrain structures and terminating in the thalamus, thus serving to modulate thalamocortical activation.[8]

Treatments

Historically, REMBD-like behaviors have been well controlled with clonazepam, .5-1.0 mg taken at bedtime. Because of the long half-life (10-12 hours) of this medication and the risk for falls and daytime carryover, benzodiazepines with shorter elimination half-lives, such as temazepam, have occasionally been substituted with varying levels of success. More recently, success has been reported with the dopamine agonist pramipexole administered at bedtime (typical dosages of .5-1.0 mg) for idiopathic REMBD in the absence of frank parkinsonian signs.[9] For the parkin-sonian patient who may already be receiving substantial dosages of dopamine agonists, bed-time dosing of sustained-release levodopa with or without a catechol-O-methyltransferase inhibi-tor, such as entacapone or tolcapone, may be considered. Some recent reports have suggested that melatonin may be useful for controlling REMBD in cases of Lewy body dementia.[10] How-ever, melatonin should not be assumed to be innocuous (see section on AD treatments below), and its efficacy has been called into question. Morning administration of modafinil at dosages of 100-200 mg, or bupropion at 100 mg, may be considered for initial treatment of excessive day-time sleepiness. To minimize pill burden, initial reduction of agonist dosage or change in the time of administration of such agonists or levodopa should be considered before adding stimu-lant-like medications. AD and Related Dementias (Amyloidopathies and Tauopathies)

Reported sleep disturbances in PD and AD suggest a relatively greater likelihood of sleep prob-lems in PD patients, yet it belies the dramatic upheavals reported in some patients with AD. Of-ten subsumed by phrases, such as "day/night reversal" or "sundowning," such disturbances of the sleep-wake cycle may occur in as many as 25% of all AD patients at some point during their illness. In general, a greater likelihood for disrupted nocturnal sleep and increased levels of day-time sleepiness appear to be correlated with the stage of the disease. This has been demon-strated polysomnographically, actigraphically, and even with simple behavioral observa-tions.

Disruption of the Sleep-Wake Cycle

Sleep disturbance in the AD patient can be dramatic. Patients who may appear relatively docile and even somnolent during the daytime may become aggressive and hostile in the early eve-ning hours. A recent consensus statement has proposed that less than 6 hours of sleep be-tween the hours of 9 pm and 6 am may constitute a significant sleep disturbance in AD.[11] In the nursing home environment, this often has been assumed to reflect timing of meals or staff changes, but amassing evidence suggests that such behavioral patterns may be generated en-dogenously regardless of the environmental context.

Synchronization of behavioral and physiological circadian rhythms originates within a region of the anterior hypothalamus, the suprachiasmatic nucleus. This region undergoes gliosis and neu-ronal loss in AD, and aberrant "internal time keeping" has been speculated to underlie much of the disturbed sleep in AD. More recent neuropathologic studies have examined this region more closely and found a virtual absence of beta-amyloid,[12] instead noting an abundance of phos-phorylated tau protein, the key constituent of neurofibrillary tangles. Some data suggest that pa-tients with dementia variants, such as frontal-temporal dementia (FTD), which primarily mani-fests as other types of protein degradation (tauopathies) may show more distinctive changes in circadian rhythms compared with patients with amyloidopathies such as AD. Some researchers have suggested that FTD patients demonstrate phase advances (earlier bedtimes and tempera-ture peaks) in circadian rhythms relative to phase delays in such measures, which is more typi-cally seen in AD.[13] Patients specifically described as sundowning may also have abnormalities of rhythms.[14]

Treatments

The general consensus has been that typical sedatives/hypnotics, including benzodiazepine si-te-specific agonists, are seldom useful in sleep disturbances of the grossly demented patient, although the absence of randomized trials does not preclude the possibility that they might be. More typically, the off-label use of newer antipsychotics with sedative properties (eg, risperi-done, .5-2.0 mg; olanzapine, 5-10 mg; and quetiapine, 25-50 mg) is implemented with varying degrees of success.[15] Older antipsychotics, such as haloperidol and thioridazine, are not fa-vored in the geriatric population because of cases associated with sudden cardiac death.[16] It remains to be seen whether newer agents have a more favorable safety profile.

Many cholinesterase inhibitors, the most commonly used drug class for treatment of AD, may induce sleep disturbances in a dose-dependent fashion. Rates of incident, treatment-emergent insomnia are dose-dependent and may vary from 8% to 10% for donepezil; pharmacosurveil-lance data for donepezil indicated that users were twice as likely to be taking concomitant seda-tives/hypnotics compared with AD patients not on cholinesterase inhibitors.[17] Bad dreams may also be reported among patients receiving cholinesterase inhibitors, which may reflect increased REM sleep pressure prompted by cholinergic stimulation. Rivastigmine and galantamine may offer lower incidences of sleep disturbances, but conclusive data do not exist. Data suggesting incident insomnia with memantine, an NMDA receptor antagonist recently approved for use in the United States for moderate-to-severe AD, have not been published to date. Anecdotal clini-cal evidence suggests that it may be less likely to produce incident insomnia relative to choli-nesterase inhibitors.

Speculation on alterations in the circadian timing system has guided many treatment efforts that try to establish more normal chronobiology. Hence, efforts to synchronize sleep-wake rhythms with bright light (typically 2 hours duration in the morning or evening at intensities in excess of 2500 lux) have shown some modest improvements in sleep and a reduction in agitation in some studies. Although previous open-label studies suggested benefit, melatonin's efficacy showed only limited success in a randomized, placebo-controlled, parallel group, multisite clinical trial at dosages of 2.5 and 10 mg.[18] Animal data of melatonin receptors located throughout the heart and brain have shown melatonin to be a potent vasoconstrictor.[19] When coupled with its un-regulated production within the United States, the risk-benefit ratio of its use in a geriatric popu-lation at risk for cardiac and cerebrovascular disease may not be favorable. Moreover, system-atic reporting of adverse events with melatonin is not available in the United States.

Behavioral interventions remain a mainstay alternative to pharmacology. Restriction of daytime sleep and any type of physical activity, even if of a limited nature (eg, wheelchair propulsion), may be useful adjunctive treatments. Avoidance of nighttime awakenings by staff must be bal-anced by considerations, such as movement and the risk for bed sores vs iatrogenic nocturnal agitation caused by interruptions. Several observational studies have demonstrated agitation and poor sleep in relation to such forced awakenings, as well as excessive noise and light in the nursing home environment at night. Curiously, although the brunt of evidence suggests that day-time naps should be avoided to promote sleep at night, nursing facilities allowing daytime naps evidenced lower rates of agitation. Finally, it should always be recognized that suboptimally treated medical conditions, such as fecal impaction, undiagnosed febrile illness, and poor nutri-tional status, may also lead to nocturnal delirium in the dementia patient that warrant immediate attention and treatment.[20] Insomnia in Neurodegenerative Disorders

[Medscape Neurology & Neurosurgery 6(2), 2004. © 2004 Medscape]



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