Current Treatment Options in Neurology (2012) 14:474–492 DOI 10.1007/s11940-012-0194-5
SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR)
Neurodegenerative Disease and REM Behavior Disorder Raman Malhotra, MD1 Alon Y. Avidan, MD, MPH2,* Address 1 SLUCare Sleep Disorders Center, Department of Neurology and Psychiatry, Saint Louis University School of Medicine, 1438 South Grand Boulevard, St. Louis, MO 63104, USA Email:
[email protected] *,2Department of Neurology, UCLA Sleep Disorders Center, UCLA Neurology Clinic, 710 Westwood Blvd., Room 1-169/ RNRC, Los Angeles, CA 900951769, USA Email:
[email protected] Published online: 10 August 2012 * Springer Science+Business Media, LLC 2012
Keywords Dementia I Parkinson’s disease I Alzheimer’s disease I Sundowning I REM sleep behavior disorder (RBD) I Sleep apnea I Insomnia I Circadian rhythm disorder I ALS I Motor neuron disease I Hypersomnia I Narcolepsy I Cognitive-behavioral therapy for insomnia I Continuous positive airway pressure (CPAP) I Neurodegenerative disease
Opinion statement Patients with cerebral degenerative conditions commonly suffer from a variety of sleep disorders, including sleep-disordered breathing, insomnia, parasomnias (REM sleep behavior disorder), circadian rhythm disturbances, and restless legs syndrome. When these sleep disorders go unrecognized and untreated, they can lead to decreased quality of life and worsening neurological symptoms related to the underlying condition. Appropriate management initially requires taking a careful history from the patient and bed partner regarding their sleep. In addition, polysomnography may be required to aid in the diagnosis of sleep-disordered breathing or parasomnias. Occasionally, adjusting the dosages of sedating or sleep disrupting medications and improving sleep hygiene may improve sleep complaints. However, in most cases restoring quality nighttime sleep requires specific therapeutic intervention. In patients that suffer from sleep apnea, this usually means treatment with continuous positive airway pressure (CPAP), positional therapy, dental appliances, upper airway surgery, or weight loss. Pharmacological treatment of insomnia in patients with cerebral degenerative conditions can be difficult due to side effects (worsening balance, cognition) and lack of data in this patient population. Behavioral strategies such as cognitive-behavioral therapy have been effective and are considered safer than hypnotic therapy, but can be limited due to access to trained providers (distance and number of providers) and limited cognitive functioning of the patient. Parasomnias, namely REM sleep behavior disorder, are managed by looking for any underlying cause of arousals (sleep apnea, periodic leg movements of sleep), implementing safety precautions, and pharmacologically with either benzodiazepines or melatonin. Restless legs syndrome may improve with iron replacement or dopamine agonist therapy, as it does in other patient populations. Light ther-
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apy may be beneficial in patients suffering from circadian rhythm disorders such as advanced sleep phase syndrome.
Introduction Sleep, aging and dementia According to the United States census, in the year 2000, 34 million Americans were older than 65 years. The census bureau projects that by the year 2025, this number is expected to double to 62 million. The aging population is expanding, and this will undoubtedly increase the number of patients with neurodegenerative diseases. Patients diagnosed with neurodegenerative conditions commonly suffer from underlying sleep disorders, such as insomnia, sleep-disordered breathing, circadian rhythm disorders, and restless legs syndrome [1]. REM sleep behavior disorder is a common sleep disorder seen in neurodegenerative diseases that may either precede or follow the development of the other key features of the condition. Abnormalities, particularly in the brainstem and hypothalamus, caused by cell death, protein deposition, or other degenerative processes can play a major role in disruption of normal sleep. The primary symptoms of the neurodegenerative condition, such as muscle rigidity in Parkinson’s disease (PD) or cognitive and mood changes, may lead to disrupted sleep and insomnia. Other times, medications utilized to address the symptomatic management of the neurological symptoms may induce side effects of sleepiness or disrupted sleep. Improving sleep in these patients can lead to improvement in the underlying motor and cognitive symptoms of the degenerative condition and may improve overall quality of life. Sleep in Parkinson’s disease Parkinson’s disease results from accumulation of the protein alpha-synuclein in the basal ganglia of the central nervous system, leading to cardinal symptoms of bradykinesia, rigidity, and tremor. The process also commonly affects sleep controlling regions of the brain (hypothalamus, reticular activating system) resulting in sleep complaints in up to 90 % of PD patients [1]. In addition to damage to the central nervous system, other factors lead to higher rates of sleep disorders in this population including medication-related side effects, mood disorders, immobility, and pain. Polysomnograms in patients with PD show
decreases in slow wave sleep, total sleep time, sleep efficiency, and REM sleep. This patient cohort also experiences disrupted sleep due to difficulties turning in bed, getting comfortable, or prolonged awakenings due to the longer time it takes to get up and use the restroom. This is further compounded by the fact that patients with PD may have more nocturia and urinary frequency due to dysautonomia [2]. Underlying sleep-disordered breathing in the form of sleep apnea or sleep-related hypoventilation/hypoxemia, may have higher prevalence in Parkinson’s patients as compared to controls, though data is mixed [3]. This is also the case in respect to restless legs syndrome. Hypersomnia has also been described in Parkinson’s patients, including narcolepsy phenotype due to neurological disease, with low hypocretin levels measured in the cerebrospinal fluid [4].
Sleep in Alzheimer’s disease In Alzheimer’s dementia patients, overnight polysomnograms demonstrate low sleep efficiency, high percentage of stage N1 sleep relative to other stages, decrease in stage N3, and increased frequency of arousals and awakenings [5]. Circadian rhythm disturbances are noted at higher rates and worsen as the underlying condition progresses. There have been low melatonin levels and damage to the suprachiasmatic nucleus reported in patients with dementia, which may be one explanation for the increased frequency [6]. Other possibilities include an absence of social cues, decreased light exposure, or polypharmacy. One of the most common sleep problems in demented patients is “sundowning,” or a confused state occurring at night characterized by agitation and wandering. Sleep in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, involving degeneration of the spinal cord, brain stem, motor cortex, and corticospinal tracts, causing both upper (spasticity, hyperreflexia) and lower motor neuron signs (atrophy, fasiculations). Patients with ALS have a higher rate of sleep com-
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plaints likely stemming from pain and spasms disrupting their sleep along with difficulties with sleep-disordered breathing in the form of sleep apnea and sleep-related hypoventilation [7]. Sleep-related hypoventilation occurs secondary to diaphragmatic weakness initially appearing during REM sleep (hypoxemia, hypercapnia) when accessory respiratory muscles that are normally active during NREM sleep lose tone during REM sleep, causing decreased ventilation and leading to arousal and sleep fragmentation. If bulbar or oropharyngeal muscles are weak, this may lead to upper airway collapse resulting in obstructive sleep apnea. Brainstem centers of respiration can be involved causing central sleep apnea.
Sleep in other neurodegenerative conditions There is very little published literature regarding sleep disorders in other neurodegerative conditions, though they likely share the same pathophysiology and management as other related degenerative conditions. Patients with progressive supranuclear palsy commonly suffer from insomnia and fragmented sleep, likely due to the immobility, stiffness, and dysphagia that accompany the disease. Though less is known about the link between REM sleep behavior disorder and progressive supranuclear palsy, these patients can have dream enactment behavior as well [8]. Case reports demonstrating insomnia, sleep complaints, and REM sleep behavior disorder in patients with corticobasal degeneration have also been published [9].
Treatment Treatment of sleep disorders in patients with degenerative disorders of the nervous system can lead to improvement in quality of life and control of symptoms. Continuous positive airway pressure (CPAP) or other forms of positive airway pressure are the mainstays of treatment for sleep-disordered breathing, though other interventions such as positional therapy and weight loss may be helpful. Insomnia can be treated with a variety of pharmacological agents, though most come with concerns related to adverse effects on cognition and balance. Many of these patients will benefit from cognitivebehavioral therapy for insomnia. Circadian rhythm disorders are managed with light therapy, sleep hygiene, and melatonin. Hypersomnia can be managed with short naps and stimulant therapy.
Management of insomnia Insomnia, or difficulties getting to sleep, staying asleep, or having unrestful sleep, is typically multifactorial in individuals suffering from neurodegenerative diseases. Etiologies include poor sleep hygiene and medication-related side effects. Comorbidities include stiffness and discomfort during sleep, mood disorder, and damage to sleep regulating centers in the brain. Circadian rhythm disorders commonly cause insomnia in older patients with Alzheimer’s dementia [10]. As noted above, this can present as sundowning, or agitation and confusion at night. Other times, patients present with early morning awakening due to an advanced sleep phase syndrome [6].
Behavioral management of insomnia Sleep hygiene is helpful in reducing severity of insomnia. Patients should be instructed to set a regular bedtime and wake time, avoid stimulants (caffeine, nicotine) in the evening time, and find a quiet, cool place to sleep. They
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should be instructed to go to bed only when sleepy, and to use the bed for only sleep (or sex). Exercise (in the form of walking) and light therapy, especially in combination, did show a small improvement in sleep in one study of Alzheimer’s patients [11], though only in the participants who were able to adhere to the treatment recommendations. One study demonstrated that light therapy, exercise, and sleep hygiene education improved total time awake and night time awakenings in patients with Alzheimer’s disease ([12], Class III).
Pharmacological management of insomnia Although this group of patients is commonly prescribed hypnotic medications, limited studies of pharmacological treatment of insomnia in patients with degenerative disorders are currently available [13]. Pharmacological treatment of insomnia is mainly based on data from the general population and favors use of non-benzodiazepine hypnotics instead of benzodiazepines. This is largely due to the fact that the benzodiazepines appear to cause more side effects such as rebound insomnia and morning sedation [14]. One main difference between each individual non-benzodiazepine hypnotics is the half-lives. Eszopiclone has the longest half-life, followed by zolpidem, and then zaleplon. Ramelteon, a melatonin receptor (MT1 and MT2) agonist, has been shown to improve sleep onset, is not scheduled, and hence has less of a chance of abuse (Class I). Low dose doxepin has been studied and has shown improvement in sleep maintenance (Class I). Other classes of medications are sometimes used, such as sedating antipsychotics, trazadone, and antiepileptic drugs (AED), with very little data to substantiate use.
Non-benzodiazepine receptor agonists Zolpidem Standard dosage Contraindications Main drug interactions
Zolpidem tartrate immediate-release 5–10 mg at bedtime, or zolpidem tartrate extended release 6.25 or 12.5 mg at bedtime Hypersensitivity to active ingredient Central nervous system (CNS) depressants and ethanol
Main side effects
Headache, sleepiness, dizziness, severe anaphylactic/anaphylactoid reactions (angioedema and anaphylaxis have been reported).
Special points
May induce sleep-related complex nocturnal behaviors such as sleep driving or sleep eating, immediate release for sleep onset insomnia, controlled-release for sleep onset and maintenance insomnia
Eszopiclone A recent randomized, placebo-controlled trial evaluated the efficacy of eszopiclone versus placebo for insomnia in 30 PD patients ([15], Class II) showing an improvement in secondary outcomes of sleep quality and number of awakenings, but no difference in the primary outcome of total sleep time. Standard dosage 1, 2 or 3 mg at bedtime Contraindications Main drug interactions
Hypersensitivity to active ingredient CNS depressants and ethanol
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Headache, sleepiness, dizziness, gustatory side effect (unpleasant taste) Onset of action may be delayed with food, can be used for sleep onset or maintenance insomnia
Zaleplon Standard dosage Contraindications Main drug interactions Main side effects Special points
5–10 mg at bedtime Hypersensitivity to active ingredient CNS depressants and ethanol Headache Helpful for sleep onset insomnia, ultra short half-life
Melatonin (*Melatonin is considered a dietary supplement by the United States Food and Drug Administration) Standard dosage 3–5 mg at bedtime Contraindications Main drug interactions Main side effects Special points
None CNS depressants Morning sedation Not studied extensively or FDA approved for insomnia, use with caution with history of bleeding or if taking anticoagulants or antiplatelet agents. May affect other hormone levels (gonadotropins)
Ramelteon Standard dosage Contraindications Main drug interactions Main side effects Special points
8 mg at bedtime Hypersensitivity, concurrent use of fluvoxamine CNS depressants, fluvoxamine Dizziness, sleepiness, nausea Effective for sleep onset insomnia, not a scheduled medication, little evidence for abuse or tolerance.
Doxepin Standard dosage Contraindications Main drug interactions Main side effects Special points
3–6 mg at bedtime Hypersensitivity, narrow-angle glaucoma; urinary retention; use of mono amineoxidase (MAO) inhibitors within 14 days Linezolid, MAO inhibitors, QT-prolonging agents Sedation, hypertension, nausea Effective for sleep maintenance insomnia. There have been two randomized, placebo-controlled trials using melatonin (3–5 mg) in Parkinson’s patients showing an improvement in subjective and objective sleep measures ([16], Class I). One open-label trial of quetiapine
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for insomnia in PD demonstrated decreased insomnia severity ([17], Class IV) Low dose quetiapine can also improve insomnia by reducing disturbing hallucinations that can occur with PD.
Physical therapy/exercise Aerobic exercise has been shown to help improve sleep quality and insomnia in adults without neurodegenerative conditions. In patients with dementia, along with light therapy, walking improved sleep quality in patients who were able to stay adherent to the treatment protocol [12]. Physical therapy may improve sleep if it helps alleviate some of the discomfort and spasms that can occur with neurodegenerative conditions.
Other therapies Cognitive behavioral therapy for insomnia (CBTi) &
CBT uses behavioral techniques such as sleep restriction, sleep hygiene education, and stimulus control, and is considered the most effective and long lasting therapy for most forms of insomnia (Class I). This has also been the case when this intervention has been used in patients with dementia in small studies (Class IV).
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Light therapy has been shown to help with sleep in the elderly and patients with dementia. This is especially true if they suffer from a circadian rhythm disturbance. Many patients with neurodegenerative conditions will suffer from advanced sleep phase syndrome (falling asleep early in the evening and awakening early in the morning) as this type of circadian rhythm disturbance is more common in the elderly. In advanced sleep phase syndrome, light should be timed in the evening in order to cause a delayed bedtime and minimize early morning awakenings that typically occur with this condition. Even in elderly patients without circadian rhythm disturbances, morning or all-day light improved sleep at night [18]. The combination of melatonin at night and light has shown improvements in sleep parameters as well ([19, 20], Class II)
Light therapy
Management of sleep apnea Sleep-disordered breathing is common in patients with neurodegenerative conditions. Studies are limited regarding treatment in this group, though continuous positive airway pressure (CPAP) has been shown to be effective in certain groups such as dementia patients in treating the disease and improving symptoms. Of note, many patients with neurodegenerative conditions may have central sleep apnea and may respond differently to the treatments that are effective in obstructive sleep apnea.
Continuous positive airway pressure (CPAP) CPAP is considered first-line therapy in adults with obstructive sleep apnea. CPAP functions as a pneumatic splint, preventing upper airway collapse
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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) during sleep. CPAP is administered through a nasal or oral mask over the mouth and/or nose. In the general population, CPAP has been shown to improve subjective and objective measures of sleepiness, mood, and quality of life ([21], Class 1) Only case reports have been published regarding use of CPAP in PD patients, though clinically this is a commonly used therapy. There have been published reports (small studies) demonstrating use of CPAP in reducing subjective daytime sleepiness in Alzheimer’s disease with sleep apnea [22]. One randomized placebo controlled trial demonstrated decreased arousals and more stage N3 sleep with use of CPAP as compared to placebo CPAP [23]. Recent trials with CPAP have shown benefits of slowing cognitive decline and improving cognition in patients with Alzheimer’s disease ([24] [25], Class III). In ALS patients, treatment of underlying sleep-disordered breathing has resulted in improved quality of life and survival ([26], Class III). Compliance with CPAP may be more difficult in this specific group of patients due to the underlying neurological condition. The neurodegenerative condition may make physically putting on the mask difficult or can make it psychologically difficult to understand the importance of using the mask during sleep. Even in the general population, compliance with CPAP can range as low as 23 % [27]. Common side effects include nasal congestion, claustrophobia, eye or skin irritation, and dry mouth.
Diet and lifestyle Body mass index (BMI) Weight loss has been shown to improve severity of obstructive sleep apnea as measured by the apnea-hypopnea index (AHI) in obese patients. In one study, a 10 % weight loss resulted in improvement in the degree of obstructive sleep apnea, as reflected by a 10 % reduction in the AHI [28]. There are no specific studies regarding weight loss in obese patients with neurodegenerative conditions and sleep apnea, though it makes sense that reversing one known risk factor of sleep apnea will improve the condition.
Avoidance of potential exacerbating factors Avoiding alcohol and other medications that can relax the upper airway such as benzodiazepines will also improve obstructive sleep apnea. Alcohol worsens obstructive sleep apnea by increasing nasal resistance and reducing genioglossus muscle activity. Reducing use of narcotics and opioids will improve central sleep apnea.
Positional therapy When obstructive sleep apnea is worse in the supine position, having the patient avoid sleeping in the supine position can be an effective supplemental therapy, or a conservative measure in patients who cannot implement other therapies or have mild disease [29]. There are devices, such as belts with bumpers attached,
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that do not allow the person to roll on their back during sleep, and pillows that try and keep the patient sleeping in the lateral position. These techniques are limited by long-term compliance and effectiveness, along with discomfort with sleeping in one position the entire night [30].
Pharmacological treatment In two double-blinded placebo controlled studies, donepezil demonstrated improvement in severity of obstructive sleep apnea in dementia and nondementia patients, but did not bring breathing events to within normal limits [31, 32] (Class 2).
Upper airway surgery Upper airway surgery, typically in the form of uvulopalatopharyngoplasty, can be used as treatment in patients with obstructive sleep apnea if they are not able to tolerate CPAP. This surgery has not been studied in patients with neurodegenerative conditions. Furthermore, the advanced age and higher surgical risk in this patient population would likely make this a less desirable treatment option.
Assistive devices Oral appliances are indicated for treatment of mild to moderate obstructive sleep apnea. They can also be used in cases of moderate to severe obstructive sleep apnea in CPAP and surgical options have failed. They have been shown to improve both subjective and objectives measures of sleepiness, and improve the degree of sleep-disordered breathing as measured by sleep study. There have been no reports of use of oral appliances in patients with neurodegenerative disease, and it would be important to ensure that the patients did not have a central apnea component of sleep-disordered breathing which is commonly seen in patients with neurodegenerative disease.
Emerging treatments In the general population, a few trials have shown some effectiveness in treating obstructive sleep apnea with nasal expiratory positive airway pressure delivered using a small valve attached externally into each nostril [33]. The device helps pressurize and stabilize the upper airway during the critical end-expiratory period. The results are variable and do not consistently bring the apnea-hypopnea index down to normal levels. There have been no studies looking at this device in patients with neurodegenerative disease. Some small trials have also looked at the effectiveness of implanted hypoglossal nerve stimulators for treatment of obstructive sleep apnea by increasing upper airway tone during sleep [34].
Management of hypersomnia Excessive daytime sleepiness is a commonly described problem in neurodegenerative conditions, and can result in significant adverse effects on daily life, social interactions, and work performance. Many times, the sleepiness stems from medication side effects (particularly of dopamine agonists and Ldopa), though some of the hypersomnia may be due to damage to brainstem
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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) centers regulating alertness. There have been reports of narcolepsy-like conditions in PD patients found to have decreased levels of hypocretin in their cerebrospinal fluid [4]. This same syndrome has been reported in patients with Lewy Body dementia (DLB) and Alzheimer’s dementia. Regardless of the exact etiology, the symptoms of excessive daytime sleepiness must be taken seriously if adverse effects such as motor vehicle accidents are to be avoided. There are several pharmacological agents that can help reduce daytime sleepiness. In addition, ensuring good sleep hygiene, napping, and avoiding sleep deprivation are important conservative measures.
Diet and lifestyle Short naps can be effective in combating excessive daytime sleepiness in patients with narcolepsy. This has not been specifically studied in patients who develop hypersomnia due to their neurodegenerative condition.
Pharmacological treatment Modafinil has been studied to improve excessive daytime sleepiness in Parkinson’s patients. It is already FDA approved and shown to be effective in reducing sleepiness in patients with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. The results in PD patients are mixed with some randomized, placebo-controlled trials showing effectiveness, and one large recent study not showing effectiveness. (Class 1,[35–37]) There have also been open-label studies in patients with ALS and sleepiness. Methylphenidate has been shown in one study to improve fatigue in patients with PD, and is used clinically to help with sleepiness and fatigue ([38], Class III). Sodium oxybate was used in one open-label study of 27 PD patients with sleep dysfunction. Use of sodium oxybate improved nighttime sleep quality, daytime sleepiness, and fatigue ([39], Class III). Side effects were seen in 27 % of patients; the most common were dizziness and nocturia/enuresis.
Modafinil Standard dosage Contraindications Main drug interactions Main side effects Special points
200–400 mg daily (sometimes in divided doses BID) None Powerful hepatic (P45) inducer and will lower efficacy of steroidal drugs (i.e oral contraceptives, in younger patients) Headache, nausea, rash, anxiety Use with caution in patients with heart disease, hypertension, mania, anxiety, and depression
Armodafinil (S- isomer of racemic modafinil) Standard dosage 150–250 mg daily Contraindications Main drug interactions
None Same as modafinil
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Headache, nausea, rash, anxiety Use with caution in patients with heart disease, hypertension, mania, anxiety, and depression
Methylphenidate Standard dosage Contraindications
Main drug interactions Main side effects
5–80 mg daily Marked anxiety or agitation, and glaucoma. Do not use during or within 14 days of treatment with an MAO inhibitor. Use with caution in patients with a history of heart disease, hypertension, psychiatric disorders, seizures, or drug abuse MAO inhibitors, inhalational anesthetics, primidone, tricyclic antidepressants, warfarin. Insomnia, irritability, headache, decreased appetite, nausea
Management of motor disturbances of sleep Restless legs syndrome (RLS) & &
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Epidemiology: Symptoms of RLS have been identified in 5–15 % of normal subjects, in up to 15–20 % of uremic patients, and up to 30 % of patients with rheumatoid arthritis. RLS clinical manifestations: The most recent diagnostic criteria developed at an NIH workshop with members of the International Restless Legs Syndrome Study Group (IRLSSG) requires four essential criteria for the diagnosis of RLS [40]. (A) An irresistible urge to move the limbs with or without disagreeable leg sensations; (B) The symptoms begin or worsen during inactivity while lying or sitting; (C) Partial or complete relief of the discomfort with leg movement and the return of the symptoms upon cessation of leg movements; (D) These symptoms are worse in the evening or night than during the day or only occur in the evening or night. RLS has two forms with separate etiologies and age of onset: Early onset RLS: Age of onsetG45. Tends to cluster in families, has a slower progression and has approximately a 2:1 female-to-male ratio. Late onset RLS: Age of onset945 has an equal male-to-female ratio, has a more rapid progression, is more severe with more frequent daily symptoms, little or no family history and is more commonly associated with underlying medical conditions such as neuropathy, radiculopathy or myleopathy [41]. RLS is prevalent in neurological conditions such as Parkinson’s disease [42, 43], spinocerebellar ataxia (SCA-3) [44, 45] and in low back pain, myelopathy, and arthropathy [46]. Differential diagnosis includes chronic myelopathy, peripheral neuropathy, akathisia, painful legs and moving toes syndrome. Diagnostic evaluation: All patients need to meet the diagnostic criteria for RLS and have a screening neurological evaluation for comorbidities such as underlying neuropathy. Sleep studies may be helpful to ex-
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clude other underlying primary sleep disorders such as OSA or when the RLS does not respond to conventional therapy.
Treatment for RLS Non-pharmacological & &
Obtain a regular sleep-wake schedule, avoid sleep deprivation. Dietary: avoid alcohol, caffeine, nicotine and food items reach in vasoactive biogenic amines such as phenylethylamines and tyramine (red wine, aged cheese, fermented food products).
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A suggested first step for patients with symptoms consistent with RLS is measurement of serum ferritin level. Patients with levels less than 45 ug/L should begin iron replacement therapy [47] with iron sulfate. The United States Food and Drug Administration (FDA) approved four medications for managing moderate to severe RLS (three dopamine agonists –pramipexole [48], ropinirole [49]and rotigotine patch [45a]) and one prodrug for the anticonvulsant and analgesic drug gabapentin, gabapentin enacarbil [50]).
Pharmacological
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Pramipexole (non-ergot-derived dopamine D3- and D2-receptor agonist) Standard dosage 0.125–1.5 mg/daily. Adjust dosage carefully and slowly according to individual requirements and response. Contraindications Main drug interactions
Main side effects Special points
Hypersensitivity to pramipexole or any component of the product. Concurrent use of pramipexole & cimetidine may result in an increased risk of pramipexole adverse effects. Concurrent use of kava and pramipexole may result in decreased effectiveness of pramipexole. Concurrent use of vitex and pramipexole may result in increased dopaminergic side effects [51]. Orthostatic hypotension, constipation, sleep attack (6 %), hallucinations. Pramipexole is renally excreted. The clinician needs to exercise caution and begin a “start low and go slow” dosing titration regiment in the setting of endstage renal disease and impaired creatinine clearance. Plasma concentrations do not peak until about two hours after ingestion, hence the medication should be dosed ideally several hours prior to the onset of RLS. Impaired impulse control (e.g., urges to gamble, increased sexual urges, other intense urges) has been reported consider dose reduction or therapy withdrawal if symptoms occur [51].
Ropinirole (non-ergot-derived dopamine D3- and D2-receptor agonist) 0.25–2 mg/daily. Adjust dosage carefully and slowly according to individual requirements and response.
Standard dosage
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Contraindications
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Hypersensitivity to ropinirole or any component of the product.
Main drug interactions
The drug is metabolized through the CYP1A2 isoenzyme of the cytochrome P-450 (CYP) system. Key drug–drug interactions with both inhibitors and inducers of this system should be appreciated. For example, warfarin levels may be increased with the use of ropinirole [51].
Main side effects
Abdominal pain, constipation, nausea, vomiting and dizziness. Orthostatic hypotension, sleep attacks/somnolence and hallucinations may also occur [51].
Special points
As in pramipexole, plasma concentrations do not peak until about two hours after ingestion, hence the medication should be dosed ideally several hours prior to the onset of RLS. Impaired impulse control (e.g., urges to gamble, increased sexual urges, other intense urges) has been reported consider dose reduction or therapy withdrawal if symptoms occur [51].
Rotigotine patch At the time of writing this manuscript, rorigotine patch has been approved for RLS treatment.
Gabapentin enacarbil (gabapentin prodrug) Standard dosage 300–600 mg/daily at 5 PM. A dose of 300 mg/day is suggested for patients with renal impairment. The reader is asked to consult the product dosage recommendations based on the patient’s creatinine clearnace (CrCl) [51]. Contraindications Main drug interactions Main side effects Special points
Not recommended for CrCl less than 15 mL/min and on hemodialysis [51]. Hypersensitivity to gabapentin or any component of the product. Dizziness (13–17 %), Headache (10–12 % ), Somnolence (20 %). Dosage adjustment is recommended for CrCl of 59 mL/min or less; suicidal ideation and behavior, worsening of depression, and unusual changes in mood or behavior may take place as early as one week following initiation; monitoring recommended. Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, including fatal cases, has been reported; evaluate early signs/symptoms and discontinue gabapentin enacarbil if confirmed. If symptoms persist despite these therapies, other medications including benzodiazepines such as clonazepam or temazepam [52], levodopa/carbidopa [53] (levodopa/carbidopa is generally not used as a regular therapy except on special situations such as going to a movie or to travel by plane) may be considered. The drawback of levodopa therapy is the potential for augmentation which is the development of an increased symptom severity earlier in the day [54]. For refractory cases of RLS, opiates, which are reserved as a treatment of last resort, have a proven efficacy [55] with methadone, which can be utilized for the most severe cases of RLS.
Periodic limb movement disorder of sleep (PLMDS) &
Epidemiology: Periodic leg movements (PLM) are common with advancing age. They may be found in up to 34 % of patients over the
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&
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age of 60 years. PLM are very common in a variety of sleep disorders including RLS (80–90 %) and RBD (≈70 %) [56]. PLM are electrographic findings characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep. The movements usually occur in the legs and consist of extension of the big toe in combination with partial flexion of the ankle and knee often associated with a partial arousal or awakening [57]. PLM appears to increase in prevalence with advancing age, and is common in chronic uremia and other metabolic disorders. Clinically, PLM can result in disrupted and fragmented, restless sleep and lead to symptoms of insomnia or hypersomnia when it is called PLMDS. The sleep literature is still unclear on whether periodic leg movements in the absence of comorbid conditions cause insomnia or hypersomnia. Differential diagnosis: Hypnic jerks, arousals from OSA, nocturnal epileptic seizures and myoclonic epilepsy. Management of PLMDS: The treatment of PLMDS and RLS are somewhat similar, in that many patients respond to agents such as low-dose dopamine-agonist and benzodiazepines such as clonazepam. However, none of the medications that are FDA-indicated for RLS, have an FDA indication for PLMDS. An important consideration when treating PLMDS is that many patients may have coexistent OSA [58, 59] and treatment with agents that may worsen sleep apnea (e.g., benzodiazepines) should be used with care [60].
REM sleep behavior disorder (RBD) &
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RBD is characterized by augmentation of electromyogram (EMG) tone during REM sleep, and by elaborate and complex motor activity associated with dream mentation. Spells consist of punching, kicking, yelling, and falling out of bed, and usually correlate with the reported dream imagery. Important demographic features of RBD include higher incidence in men (about 90 %) and highest incidence after the age of 50 years. About 25 % of patients with Parkinsonism have dream enactment behaviors suggestive of RBD, and studies utilizing PSG found RBD in up to 47 % of PD patients with sleep complaints [61, 62]. Approximately 60 % of cases are idiopathic; the remaining cases are associated with underlying neurologic disorders such as neurodegenerative disorders (Synucleinopathies such as Parkinson’s disease, olivopontocerebellar atrophy [OPCA; the sporadic OPCA is generally included under multiple system atrophy (MSA)] and diffuse Lewy body disease [DLBD] with a characteristic α-Synuclein inclusion in the nerve cell bodies). Diagnostic evaluation: PSG reveals augmented muscle tone during REM sleep; or excessive REM sleep-related EMG twitches exceeding normal limits. Differential diagnosis: The differential diagnosis includes any complex phenomenon during sleep including sleep-related seizures, arousal disorders (confusional arousals), posttraumatic stress disorder (PTSD) and precipitous arousals with OSA (“pseudoRBD”).
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Management of REM sleep behavior disorder (RBD) Non-pharmacological therapy [63••]: achieving optimal environmental safety, which has level A evidence of therapy, is prudent in every patient with likely RBD. This can be achieved by modifying the sleep environment as follows: & Removing hard or sharp objects next to the bed & Sleeping on a padded mattress on the floor & Covering windows with heavy curtains & Using pillow barricades & Sleeping in a sleeping bag until treated & Until managed, sleeping alone Pharmacotherapy for RBD may be in the form of: clonazepam, which is effective in 90 % of cases with little evidence of tolerance or abuse [64–66] and has level B evidence of data [63••]; or melatonin, which also has level B evidence of data [63••, 67].
Clonazepam Standard dosage
0.125–2 mg QHS (Higher doses may be used in older adults with caution). Adjust dosage carefully and slowly according to individual requirements and response.
Contraindications
Known hypersensitivity to clonazepam or other benzodiazepines. Clinical or biochemical evidence of significant hepatic impairment. Contraindicated in patients with untreated acute angle-closure glaucoma [68].
Main drug interactions
The pharmacokinetics of clonazepam may be affected by use with other antiepileptics [68].
Main side effects
The principal adverse effect of clonazepam is drowsiness, which occurs in about 50 % of all patients when starting therapy. Performance of activities requiring mental alertness and physical coordination may be impaired, and it may suppress breathing—hence it must be used with great caution in patients with untreated OSA or COPD.
Special points
There is little evidence of tolerance or abuse with this form of treatment. Treatment with this drug has little or no effect on the characteristic elevated limb-EMG tone during the night, but it acts to prevent the arousals and reduces phasic muscle bursts associated with REM-sleep. Caution should be exercised when using it in patients with chronic respiratory diseases (COPD) or impaired renal function, and it is contraindicated in patients with documented hypersensitivity, severe liver disease, or acute narrow-angle glaucoma. Abrupt discontinuation of clonazepam can precipitate withdrawal symptoms [65].
Melatonin The reader is reminded that in the United States, melatonin, a food supplement, is not approved by the FDA, and has poor regulation in terms of pharmacologic preparation. Its use, especially in older patients with dementia, has not been widely studied for efficacy and side effects.
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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) Standard dosage
3–12 mg QHS.
Contraindications
Not recommended for patients with autoimmune disease or hereditary galactose intolerance disorders, Lapp lactase deficiency, or glucose-galactose malabsorption. Melatonin should not be used in patients with hepatic impairment because of reports of decreased clearance in such patients [68].
Main drug interactions
Cytochrome P450 isoenzymes CYP1A1 and CYP1A2 are involved in the metabolism of melatonin and as a result, other drugs that inhibit or induce these isoenzymes may affect melatonin levels. Melatonin’s coadministration with fluvoxamine, methoxsalen, cimetidine, or estrogens will increase melatonin concentrations through inhibition of its metabolism [68].
Main side effects Special points
&
&
Headache, nasopharyngitis, back pain, and arthralgia. Melatonin is believed to exert its therapeutic effect by restoring REM-sleep atonia and may restore RBD-related circadian rhythm desynchronization. The proposed mechanism of action is through possible direct restoration of the mechanism producing REM sleep muscle atonia. One study reported that melatonin was effective in 87 % of patients taking 3–9 mg at bedtime [69], and a later study reported resolution in those taking 6–12 mg of melatonin at bedtime [70].
Other agents that may be helpful include REM-suppressing agents such as imipramine (25 mg p.o Q.H.S),as well as carbamazepine (100 mg, p.o T.I.D.), pramipexole or levodopa [71, 72], in cases where RBD is associated with Parkinson’s disease [63••, 73]. A recent report demonstrated that a customized bed alarm (customized with a sound to deliver a message during vigorous dream enactment) may be an effective method to prevent Sleep Related Injury (SRI) in RBD patients, who experience refractory episodes despite appropriate therapy [74].
Management of circadian rhythm sleep disorders in neurodegenerative disease Advanced sleep phase syndrome &
& &
Advanced sleep phase syndrome (ASPS) is defined by an abnormal advancement of the major sleep period, characterized by sleep and wake-up times that are several hours earlier relative to conventional and desired times [75, 76]. The prevalence of ASPS increases with aging. The evidence supporting the effectiveness of melatonin to phase-shift circadian rhythms in older persons with ASPS is limited. The use of timed exposure to evening bright light has resulted in delaying the circadian rhythms and improving sleep efficiency [77, 78].
Light therapy Standard procedure
Variable protocols, ranging from 30 minutes to 2 hours in duration with differing light intensities.
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Complication
Eyestrain, headache, nausea, sleep disturbance, hyperactivity, hypomania, and agitation.
Special points
May be less effective in persons with cataracts.
Cost/cost effectiveness
Light boxes may range in price but generally are between $ 200–500 [79].
Conclusions Sleep disturbances in older persons with dementia may stem from primary sleep disorders, such as obstructive sleep apnea syndrome or restless legs syndrome, or may be secondary to chronic medical or psychiatric disorders, circadian rhythm abnormalities, medication effects, and neurocognitive diseases. When sleep disorders become chronic, they may also exacerbate underlying medical and psychiatric illnesses. The effects of chronic excessive daytime sleepiness may result in disturbed cognitive function, confusion, psychomotor retardation, and increased risk of injury. These disturbances may invariably alter the individual’s quality of life, and may place social as well as economic burdens on family and caregivers. For these reasons, a complete and thorough evaluation is not only essential, but also mandatory prior to developing an appropriate treatment strategy for these sleep-related disorders.
Disclosure Dr. Malhotra has served on the speakers’ bureau for Cephalon. Dr. Avidan has served as a consultant for Merck & Co. and Best Doctors, and has received speaking honoraria from Cephalon/Teva Pharmaceuticals and Purdue Pharma.
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