Sleep in Neurological Disorders
Raman K. Malhotra
Alon Y. Avidan
It is not surprising that sleep disorders are frequently seen in patients with a variety of neurological disorders. Often, the very same areas of the brain that have suffered injuries from, for example, a stroke, a demyelinating disease, or degenerative process, are also vital in controlling and regulating sleep processes. Respiratory muscle weakness from neuromuscular disorders or degenerative processes of the brainstem that control respiration or alertness can lead to disrupted sleep and sleep complaints. Many of the sleep disorders found in neurological conditions are treated in the same way as they are in other patient populations; however, this chapter will outline some specific differences. Furthermore, more studies show that sleep disorders can worsen chronic neurological disorders such as epilepsy and stroke.
SLEEP AND HEADACHES
There is a clear bidirectional relationship between headaches and sleep. Some patients will report improvement of headache symptoms with sleep, and others will identify disrupted sleep as a trigger for their headaches. Like many other painful disorders, headaches of any type can cause sleep disruption. Seventeen percent of headache patients report having one during sleep or the early morning. Many times, the headache is a presenting symptom of an underlying sleep disorder. In one study, 55% of headache patients were found to have a sleep disorder when studied with an overnight polysomnogram (1). Insomnia is the most common sleep complaint in both adult and pediatric headache patients (2). Interestingly, children with headaches not only have more sleep fragmentation, but also more somnambulism, enuresis, and snoring (3).
Migraine Headaches
Migraine headaches are very common in the population, with an incidence of 6% in males and 18% in females. They present as unilateral, throbbing head pain usually lasting several hours, associated with nausea, vomiting, vision changes, phonophobia, or photophobia (Table 17.1). More than 50% of migraine patients report difficulties with insomnia (4), with worsened sleep quality in patients with frequent migraines (5). Migraine patients have a three times higher chance of reporting excessive daytime sleepiness, a five times higher chance of reporting severe sleep disturbance (6), and are more likely to complain of restless legs symptoms (7). Many patients with primary sleep disorders, such as narcolepsy and restless legs syndrome, suffer from higher rates (as high as 40%) of migraines than the general population (8,9).
Most migraines arise during wakefulness, but they may occur at night or awakening from sleep, mostly during REM sleep or in close proximity to REM sleep (10). Shortened sleep duration (less than 6 hours) and insomnia have both been found to exacerbate migraines (2). Children with severe or chronic migraines were found to have a prolonged sleep latency, shorter sleep times, and decreased REM and slow-wave sleep (SWS) on polysomnograms (11). Lower cyclic alternating pattern rate (decreased A1 phases) have been noted on electroencephalographies (EEGs) in migraine patients (12).
In addition to nonsteroidal anti-inflammatory drugs and “triptan” medications that are typically used in acute management of migraines, proper sleep hygiene and behavioral sleep interventions can further decrease frequency of migraine headaches (13). Many migraine sufferers get a therapeutic eff ect from sleeping (14). When considering medications for daily preventative treatments in patients with insomnia and migraines, sedating medications (i.e., tricyclic antidepressants, antiepileptics) given nightly may help with both conditions.
TABLE 17.1 Headaches and Sleep | |||||||||||||||||||||||||
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Cluster Headaches
Cluster headaches consist of severe, unilateral, periorbital pain with associated lacrimation, nasal engorgement, rhinorrhea, sweating, and flushing lasting 15 to 180 minutes. They commonly occur during sleep (both REM and non-REM sleep) and can have periodicity, occurring at the same time of night. Management includes acute treatment with oxygen (10 to 12 L/min for 15 minutes), ergotamines, or triptan medications. Preventative treatments include nightly ergotamines, amitriptyline, valproate, or daily verapamil, lithium, or prednisone. Cluster headache sufferers should be screened for sleep apnea, as there is a very high prevalence of obstructive sleep apnea (OSA) in cluster headache patients (15). Continuous positive airway pressure (CPAP) in patients with OSA can decrease frequency and severity of cluster headaches (16).
Hypnic Headaches
Hypnic headaches (alarm clock headache) are a diffuse, bilateral pain lasting 15 to 30 minutes up to several hours, that occur out of sleep mainly in late middle-aged to elderly populations (mean age of onset 63) (17). They exclusively occur out of sleep (both non-REM and REM sleep) (18) and typically cause regular awakenings from sleep at a constant time of night, usually between 1 AM to 3 AM or 4 AM to 6 AM (19). Hypnic headaches may respond to lithium (300 to 600 mg/day) or indomethacin (20).
Sleep Apnea Headache
Up to 30% of patients with sleep apnea have reported having headaches upon awakening, and even higher percentages in women with a primary headache history (21). A sleep apnea headache is usually a diffuse mild to moderate headache upon awakening, often in the frontal region, that disappears shortly after getting out of bed (22). Sleep apnea has also been reported to trigger any type of headache (cluster, migraine, hypnic). The hypoxemia, hypercapnia, increased intracranial pressure, and/or vasodilatation that are normally seen in OSA are thought to be the primary mechanism for exacerbating headaches. Sleep apnea headaches, as well as other headache types that are exacerbated by it, often improve with CPAP or surgical treatment of sleep apnea (23).
SLEEP AND NEUROMUSCULAR DISEASE
Studies have found that up to 40% of patients who have been diagnosed with a neuromuscular disease also suffer from a sleep disorder (24). The symptoms, namely sleepiness or fatigue, can be mistakenly attributed to the underlying neuromuscular disease, when in reality, they stem from disrupted sleep at night. Drooling from increased secretions at night, frequent nocturia from incomplete bladder emptying, and difficulties getting comfortable secondary to muscle spasms and rigidity can all lead to fragmented and unrefreshing sleep in these patients. Furthermore, respiratory muscle compromise can cause sleep-disordered breathing in the form of sleep apnea or sleep-related hypoventilation/hypoxemia. This can lead to heart failure, pulmonary hypertension, and cardiac arrhythmias. In patients with diaphragmatic weakness, significant changes in breathing initially can appear during REM sleep (hypoxemia, hypercapnia). Accessory respiratory muscles that are normally active during non-REM 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 OSA. Brainstem centers of respiration can be involved in the disease process decreasing respiratory drive during sleep causing central sleep apnea (CSA).
oropharyngeal muscles are weak, this may lead to upper airway collapse resulting in OSA. Brainstem centers of respiration can be involved in the disease process decreasing respiratory drive during sleep causing central sleep apnea (CSA).
Sleep history and examination should be performed in order to identify patients who are at high risk of certain sleep disorders such as sleep-disordered breathing or insomnia. A detailed neurologic examination showing weakness, especially in muscles involved in respiration, can be useful in diagnosis. Measures of pulmonary function (such as spirometry or blood gases) can be helpful in patients suspected of having sleep-related hypoventilation/hypoxemia. An overnight polysomnogram (possibly with end-tidal CO2 monitoring) is usually needed to make the diagnosis of sleep-related breathing disorder (e.g., OSA, CSA, hypoventilation). A polysomnogram may also show increased number of awakenings, sleep fragmentation, and reduced total sleep time. Electromyography and nerve conduction studies may be necessary to categorize the type of neuromuscular disease, and may also be used to detect diaphragm muscle weakness and/or phrenic nerve involvement.
Treatment focuses on optimizing management of the underlying neuromuscular condition. To improve insomnia and sleep disruption, it is essential to make the sleeping environment more comfortable. For example, mattresses available with special accommodations (such as an air mattress) can make position changes easier and may reduce discomfort at night. Sleep-related hypoventilation/hypoxemia can be addressed with conservative measures such as weight loss if patients are obese along with avoiding medications that are respiratory suppressants. Many times, supplemental oxygen worn during sleep will be necessary to improve baseline oxygen saturations (25). In REM sleep-related hypoventilation, protriptyline has been shown to improve nocturnal oxygen desaturation, but is limited by the anticholinergic side effects (26). Mechanical ventilation in the form of CPAP, bi-level positive airway pressure (BiPAP) (with large IPAP/EPAP gap of greater than 7 cm of water), and nasal intermittent positive pressure ventilation (NIPPV) have been shown to be most practical and effective to use for supporting ventilation during sleep (27). Tracheostomy provides an effective emergency measure for dealing with acute respiratory failure, though the long-term benefits and risks of this procedure should be discussed with patients when long-term prognosis is unfavorable.
Motor Neuron Disease
Sleep disorders are commonly seen in motor neuron disease patients. 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). Several studies have shown that ALS patients have more sleep-disordered breathing and more sleep fragmentation as compared to controls (28). Sleep-related hypoventilation commonly occurs late in the disease course secondary to involvement of bulbar and respiratory muscles, namely the diaphragm. CSA may occur secondary to degeneration of central nervous system centers regulating respiration. BiPAP and noninvasive positive pressure ventilation have been shown to be eff ective in treating oxygen desaturations and daytime symptoms, as well as improving quality of life and survival (29). Compliance can be challenging in patients with bulbar weakness secondary to mask fit and leak.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness secondary to circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction. Respiratory failure can be seen, sometimes initially presenting solely during sleep. In addition, rates of OSA have been found to be high in myasthenic patients (30). Some myasthenic patients with OSA
who undergo thymectomy have resolution of their sleep apnea postoperatively (31) and do not require treatment with positive airway pressure (CPAP/BiPAP).
who undergo thymectomy have resolution of their sleep apnea postoperatively (31) and do not require treatment with positive airway pressure (CPAP/BiPAP).
Myopathies and Muscular Dystrophies
Sleep disturbances (insomnia, sleep fragmentation, and sleep-disordered breathing) have been reported in a variety of muscle diseases: Becker and Duchenne muscular dystrophy, myotonic dystrophy, glycogen storage disorders, polymyositis, and mitochondrial myopathies. Myotonic dystrophy is an autosomal-dominant disorder causing a distal myopathy and facial, masseter, levator palpebrae, sternocleidomastoid, forearm, and hand muscle weakness. Fatigue is reported in 76% of patients, and sleepiness is reported in 52%. Respiratory, pharyngeal, and laryngeal muscles can sometimes be involved. Craniofacial abnormalities predispose patients to OSA, as the prevalence of OSA is high, even without daytime sleepiness and with normal daytime pulmonary function values (32).
Neuronal loss in the medulla causes decreased ventilator response to hypoxic or hypercapnic stimuli (33). Patients can present with hypersomnia, not only because of respiratory muscle weakness and subsequent sleep-related hypoventilation, but also secondary to loss of neuronal cells in the dorsomedial nuclei of the thalamus and hypothalamus (34). Decreased levels hypocretin (orexin) in the cerebrospinal fluid from the hypothalamus has also been noted (35). Th is can lead to sleep-onset REM periods on multiple sleep latency testing (36). Modafinil and other stimulants are sometimes used clinically to treat hypersomnia, though studies have shown mixed results regarding effectiveness (37, 38 and 39).
SLEEP IN CEREBRAL DEGENERATIVE DISORDERS
Description of different sleep disorders occurring in central nervous system degenerative disorders have been recognized for decades, but further investigation into the pathophysiology and treatments has only been recently explored. Most of this work has been done in patients with Parkinson disease and Alzheimer dementia.
Parkinson Disease
Sleep disorders can be seen in 74% to 90% of patients of Parkinson disease. Up to 76% have reported feeling sleepy with 21% reporting falling asleep with driving (40). Parkinson symptoms result from accumulation of the alpha-synuclein protein in the central nervous system. Direct effects of neuronal damage in regions of the brain involved in sleep regulation (brainstem, hypothalamus, reticular activating system) can produce sleep complaints, along with sleep disruption from typical motor symptoms of the disease. REM-sleep behavior disorder (RBD) is found in 15% to 33% of Parkinson patients, with up to 58% having REM sleep without atonia on their polysomnograms (41). Clinical symptoms include sleep fragmentation and early awakening, likely secondary to the immobility, stiffness, or tremors that can accompany Parkinson disease, along with underlying mood disorders or circadian rhythm abnormalities (42). Interestingly, the tremors usually are attenuated or disappear during sleep. Hypersomnia and fatigue secondary to sleep-disordered breathing has been reported, but it is unclear if prevalence of sleep apnea is increased as compared to the general population in this age group (43). Hypersomnia, sometimes presenting as “sleep attacks,” may be secondary to medications used for Parkinson disease (dopamine agonists and L-dopa) or may be intrinsic to the disease and damage to centers in the brain responsible for alertness (44). Restless legs syndrome and periodic leg movements are very common in Parkinson disease, probably at a higher prevalence than the general population (45). RBD prevalence is increased in not only Parkinson disease, but many other synucleinopathies, such as multiple system atrophy and diffuse Lewy body dementia. This parasomnia may predate development of
other symptoms of Parkinson disease by several years. RBD patients have an estimated 5-year risk of future neurodegenerative disease of 17.7%, and as high as 52.4% at 12 years (46).
other symptoms of Parkinson disease by several years. RBD patients have an estimated 5-year risk of future neurodegenerative disease of 17.7%, and as high as 52.4% at 12 years (46).
Diagnosis of sleep disorders in this population includes a thorough sleep history and detailed physical examination. Overnight polysomnogram is usually necessary to diagnose sleep-disordered breathing or parasomnias such as RBD. REMsleep without atonia in the chin or limb electromyography leads may be noted along with complex motor activity during REM sleep. Sleep studies have also shown decreased SWS, total sleep time, and REM sleep with overall sleep fragmentation (44). Further neurological evaluation and follow-up may be warranted if concern for future development of Parkinson disease is present in a patient who presents with RBD.
Management of sleep disorders in Parkinson disease patients starts with practicing good sleep hygiene, cognitive-behavioral therapy, and treating underlying symptoms such as stiffness and tremor, which may reduce sleep disruption and insomnia. If motor symptoms of Parkinson disease are interrupting sleep, nighttime dosing of dopamine agonists or extended release levodopa may be needed (47). For patients with RBD, safety measures such as making sure bed partner is safe and there are no dangerous objects next to the bed while sleeping (sharp corners of furniture, weapons, lamps, etc.) are essential. Clonazepam (0.5 to 2 mg) at bedtime is usually considered the first-line pharmacologic therapy, followed by melatonin 3 to 12 mg for RBD. Other treatment options include pramipexole, paroxetine, and donepezil (48). Sleep-disordered breathing can be treated with what is available in other patient populations, mainly CPAP, BiPAP, dental appliances, positional therapy, weight loss, or surgery.
Alzheimer Dementia
Sleep disorders of all types are common in Alzheimer disease and other dementias. Diffuse neurofibrillary tangles and beta-peptide protein deposits in the central nervous system are the likely causes. Possible suprachiasmatic nucleus cell loss and lower melatonin levels can lead to disrupted a circadian rhythm (49)
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