Sleep medicine, like most of neurology, relies on the taking of meticulous and accurate histories to reach diagnoses. Investigations serve as an extension of the clinical method and not as tests to be interpreted in isolation. Judgment and experience are required in deciding which patients require sleep studies, which study is most appropriate for a specific patient, and how to interpret the results of testing. The holistic management of patients is emphasized, with the numeric results of a sleep study providing only a subset of the information required to empower patients to make wise health decisions.
The basic sleep history incorporates an understanding of not only patients’ nights, but also their days. More than in most areas of neurology, collateral history from bed partners, caregivers, or observers is essential to the understanding of the symptoms and their significance. Table 2-1 lists the components of the sleep history. An overview of a night’s sleep includes exploration of sleep initiation, continuity, and termination on weekdays and weekends. Specific nocturnal symptoms include breathing abnormalities at night and excessive movements during sleep. Daytime symptoms focus on sleepiness, work and leisure activities, and the presence or absence of cataplexy. Psychosocial history is especially important in sleep medicine, including the use of alcohol, nicotine, and caffeine; exercise; and symptoms of depression and anxiety. Patient-completed sleep questionnaires and validated scales, such as the Epworth Sleepiness Scale, may provide useful additional information.
Specific investigations available for assessing patients with sleep problems include laboratory-based polysomnography, home sleep apnea tests, overnight oximetry, wrist actigraphy, and multiple sleep latency tests (MSLTs). For certain disorders, EEG, MRI scans of the head, urine drug screens, neuropsychometric testing, relevant blood tests, pulmonary function tests, and others may add ancillary information.
This article takes a pragmatic approach based on the clinical problems likely to be encountered by a practicing neurologist. In each section, the salient features found on history, relevant physical examinations, and the appropriate investigations will be discussed.
THE SLEEPY PATIENT
Excessive daytime sleepiness is one of the most common indications for a sleep medicine consultation. Table 2-2 provides a practical classification of the causes of hypersomnolence and the assessment tools appropriate for each disorder. Voluntary sleep deprivation (insufficient sleep syndrome) is probably the most prevalent cause of excessive daytime sleepiness in North America, with multiple contributing factors, including both adult members of a family working outside the home, multiple jobs in a difficult economy, and the nightly use of electronic devices linked to the Internet. Hypersomnia due to medications or substances includes sleepiness associated with the epidemic of polypharmacy involving multiple psychotropic agents, pain medications including opioids, as well as the use of alcohol and illicit substances. Obstructive sleep apnea (OSA) is the most common intrinsic cause of sleepiness, but rarer disorders such as narcolepsy and idiopathic hypersomnia must also be considered. Periodic limb movement disorder is uncommon, as periodic limb movements, while frequently seen on polysomnograms, rarely cause sleepiness alone. Delayed sleep-wake phase disorder, the most important of the intrinsic circadian rhythm sleep-wake disorders, occurs predominantly in adolescents and young adults. Kleine-Levin syndrome is an extremely rare disorder of periods of hypersomnia lasting days to weeks and is associated with cognitive dysfunction, altered perception, eating disorders, and disinhibited behavior. It is important to be aware that some patients have more than one disorder: patients with years of chronic sleep deprivation may only present for help when they develop sleep apnea.
Clinical Approach and Investigations
The differentiation of sleepiness and fatigue is often a useful starting point in understanding tired patients. Sleepiness is an inability to remain awake in sedentary environments; the patients’ eyelids droop, neck extensor tone is lost, and microsleeps occur. In contrast, fatigue is a lack of physical energy with muscle exhaustion. Fatigued patients may have to lie down and sometimes sleep, but this is different from the sudden, brief inappropriate dozing experienced by a sleepy patient. Fatigue alone is usually not due to a primary sleep disorder (although fatigued patients may have associated insomnia or nonrestorative sleep), but exceptions can occur, such as in some women with sleep apnea.1
The assessment of sleepiness can be approached in the following three steps (Figure 2-1 and Case 2-1). Because multiple factors may interact to cause hypersomnolence, the diagnoses suggested in both steps one and two should be considered during the initial clinical assessment.
Step one. The clinician should consider insufficient sleep syndrome, circadian rhythm sleep-wake disorders (including shift work disorder), or the effects of drugs. All of these causes are best assessed through a history of a night’s sleep. Is waking in the morning spontaneous or due to an alarm? Does the hypersomnolent patient extend sleep by sleeping in on weekends, and does the sleepiness then improve or resolve? Similarly, does sleeping as late as desired improve alertness in a patient with a late bedtime suspected of having delayed sleep-wake phase disorder? How many jobs does the patient hold, and what are the exact work schedules and their relationship to sleep times? Does the patient have a history of recreational drug use or excessive alcohol consumption?
A sleep diary kept by the patient for 1 to 2 weeks can be very helpful in assessing sleep schedules. The sleep schedule can be confirmed with the use of wrist actigraphy, a technique involving the use of an accelerometer attached to the wrist that measures movement. Quiescent periods correlate well with episodes of sleep as defined by polysomnography. A urine drug screen may sometimes be required if undeclared drug use is suspected.
Step two. The clinician should consider sleep apnea. A history of snoring and observed apneas should be obtained from a bed partner or observer. Can the snoring be heard outside the bedroom? In which position does the patient snore? Is the patient aware of snort arousals? Does the patient have a dry mouth or headache on morning wakening? How has the patient’s weight changed with time? Does the patient have a history of upper airway or nasal surgery? How sleepy is the patient?
The Epworth Sleepiness Scale2 (Supplemental Digital Content Appendix,links.lww.com/CONT/A222) is a useful screen for hypersomnolence, but is not specific for sleep apnea. The maximum score is 24; values above 10 are considered to represent hypersomnolence.
The patient’s body mass index should be calculated. The upper airway should be examined, noting the relationship of the tongue to the uvula and soft palate using the Friedman classification (Figure 2-2) as well as the size of the tonsils and the diameter of the oropharynx. Any nasal obstruction should be assessed. The configuration of the jaw and teeth should be noted and assessed for overbite or overjet. Any physical signs suggestive of an endocrinopathy such as hypothyroidism, acromegaly, or polycystic ovary syndrome should be noted.
Various validated algorithms have been developed as screening tools to predict the presence of OSA. These use different factors such as age, sex, history of snoring, observed apneas or snorts, daytime sleepiness, presence of hypertension, body mass index, and size of the neck to provide weighted total scores. They include the STOP-BANG Questionnaire,3 Berlin Questionnaire,4 and the Flemons Sleep Apnea Clinical Score.5 Overnight pulse oximetry is sometimes used as a screening test to identify patients who warrant a sleep study. However, both false positives and false negatives may occur, and the test is best used in limited circumstances to prioritize patients for urgent sleep studies when the oxyhemoglobin desaturation index is very high or when severe hypoxemia is detected.
For a definitive diagnosis of sleep apnea, either laboratory polysomnography or home sleep apnea testing may be performed. In laboratory polysomnography, the EEG is monitored with a minimum of three derivations, recording activity over the frontal, central, and occipital head regions, together with recording of eye movements (electrooculogram) and submental and anterior tibial EMG. Respiratory monitoring includes surrogate measures of nasal airflow by nasal pressure transducers and oronasal thermocouples, chest and abdominal plethysmography, pulse oximetry, and recording of upper airway sound. Body position and ECG are also recorded, and audiovisual monitoring is available. Home sleep apnea testing involves only the cardiorespiratory monitoring modalities. The advantages of laboratory polysomnography are the availability of the technologist to maintain the integrity of the system and to introduce treatment such as continuous positive airway pressure during the study, the ability to determine the time actually asleep and the different stages of sleep, and the ability to record abnormal movements. Home sleep apnea testing, in contrast, allows more natural sleep in the patient’s home and is considerably cheaper. Home sleep apnea testing is indicated for patients with a high pretest probability of moderate or severe OSA in the absence of comorbidities such as cardiac failure, severe chronic obstructive pulmonary disease, dementia, or neuromuscular diseases affecting breathing.6 Studies have demonstrated that the adherence to treatment is no different in patients undergoing home sleep apnea testing compared to laboratory polysomnography, as long as they are followed by experienced sleep specialists in academic sleep centers.7,8
Step three. Once sleep-disordered breathing has been ruled out clinically or by appropriate tests, the next step is to determine whether the sleepy patient has a central disorder of hypersomnolence such as narcolepsy or idiopathic hypersomnia. Narcolepsy type 1 is suspected if the patient gives a history suggesting cataplexy, which is characterized by brief episodes of transient muscle weakness precipitated by emotions, usually positive, and, almost always on some occasions, by laughter. Weakness may be generalized or partial and involve only the facial or lower extremity muscles. Consciousness is retained. Sleep paralysis and hypnagogic hallucinations are common in narcolepsy but are nonspecific, as they may also occur in subjects without narcolepsy and in patients with other sleep disorders. Sleep in patients with idiopathic hypersomnia is often long and deep, with severe sleep inertia on being woken in the morning and lengthy, unrefreshing daytime naps. However, the diagnosis of these disorders cannot be made on history alone, and further testing is essential.
The standard test for central disorders of hypersomnolence is the MSLT, in which the patient is given four or five opportunities to sleep at 2-hour intervals during the day.9 The time from lights out until the first epoch of any stage of sleep is measured, and the mean sleep latency is generated. Each nap opportunity is stopped after 20 minutes without sleep and given an arbitrary latency of 20 minutes for the purpose of the calculation of mean latency. A mean latency of greater than 10 minutes is considered normal alertness, and a mean latency of fewer than 5 minutes is considered pathologic hypersomnolence. Latencies between 5 and 10 minutes fall in an overlap zone, with the shorter the latency, the greater the probability of a disorder of hypersomnolence. Although a mean sleep latency of 8 minutes or fewer is one of the formal criteria for the diagnosis of narcolepsy, this should not be regarded as a cutoff value between normal and abnormal. Patients who fall asleep within 20 minutes of lights out are allowed to sleep for 15 minutes before being awakened. Entering REM sleep during this time in at least two naps (or one nap if the patient had a REM latency of 15 minutes or fewer on the preceding night polysomnogram) is suggestive of narcolepsy in the correct clinical setting.
It is important to understand that the findings on an MSLT are nonspecific and can only be accurately interpreted if the circumstances surrounding the test are meticulously controlled. In population-based studies with subjects not selected for sleep problems,10–12 two or more sleep-onset REM periods occurred in 3.9% to 13.1% of subjects, more commonly in men. In different studies, sleep-onset REM periods were associated with shift work, shorter sleep on the night before the MSLT, and lower nocturnal oxyhemoglobin saturation. It is thus essential to ensure that patients have adequate length of sleep and normal circadian rhythmicity for at least 1 week before the test. A minimum time of 7 hours in bed each night is necessary, with laboratory polysomnography performed the night before the MSLT. Sleep time should be monitored by wrist actigraphy for at least 1 week prior, complimented by the patient keeping a sleep log. In addition, all psychotropic, sedating, and REM suppressant medications should be stopped the greater of 2 weeks or 5 half-lives before the MSLT. If this cannot be safely done, then it is better not to perform the MSLT and to rely on other approaches for diagnosis.
An alternative approach to the diagnosis of narcolepsy in selected cases may be the measurement of CSF hypocretin-1 (orexin-A) concentration. CSF hypocretin-1 levels are low in 90% to 95% of patients with narcolepsy with cataplexy and in 24% to 32% of those having narcolepsy without cataplexy.13,14 For patients with a clinical diagnosis of cataplexy, the test may be helpful if an MSLT cannot be accurately interpreted, such as in the setting of untreated sleep apnea or confounding medications that cannot be safely discontinued. The test is currently only available in a few research laboratories. Essentially, all patients with narcolepsy who have low CSF hypocretin-1 concentrations also carry the human leukocyte antigen (HLA) DQB1*0602; therefore, assessment of HLA status should precede a spinal tap.13–15 Patients who are negative for this tissue type should not have lumbar punctures performed, as hypocretin-1 levels will inevitably be normal. In patients suspected of having narcolepsy, little other indication for HLA testing exists, as approximately 20% of the population are DQB1*0602 positive, resulting in the test having very low specificity for the diagnosis.
A 33-year-old man who worked as a banker presented with excessive daytime sleepiness that he had experienced since college, when he would often doze off during lectures and at his desk studying. He admitted to insufficient sleep while a student, but the hypersomnolence persisted after he started working. He found himself dozing while in his office, sitting in conferences, watching television, and reading in a chair. After driving for 20 minutes, the car frequently drifted toward the shoulder because of his sleepiness. His Epworth Sleepiness Scale score was 15. On weekdays, he went to bed at 11:15 PM and fell asleep in 15 minutes, did not wake during the night, and awoke with an alarm at 6:00 AM feeling unrefreshed. On weekends, he went to bed at about the same time, but woke up spontaneously at 8:00 AM, feeling no less tired. His wife described snoring in all positions, but had not observed apneas. He experienced a few spells of sleep paralysis on waking in the morning while at college but no hallucinations or cataplexy. He did not have symptoms of restless legs syndrome or a history of parasomnias. He had a past medical history of depression since college, and his only medication was sertraline 50 mg in the morning. He did not use tobacco or alcohol and drank only one caffeinated beverage a day.
Examination revealed a body mass index of 30.5 kg/m2, an oropharynx graded as Friedman classification grade IV with normal nose and jaw examination. Neurologic examination was normal.
He was asked to discontinue sertraline for 2 weeks under the supervision of his primary physician and to extend his time in bed to 8 hours a night for 1 week. He wore a wrist actigraph during this time, which revealed an estimated mean sleep time of 7 hours and 18 minutes. He reported no improvement in sleepiness. Therefore, polysomnography was performed, revealing a total sleep time of 430 minutes, rapid eye movement (REM) sleep latency of 87 minutes, and a respiratory disturbance index of 3 per hour. No periodic limb movements were recorded. A multiple sleep latency test the following day revealed a mean sleep latency of 3.1 minutes with REM sleep recorded within 15 minutes of sleep onset on three of the four naps. A diagnosis of narcolepsy type 2 was made.
Comment. In this case, multiple diagnoses were considered. His sleep time on weekdays was short, raising the question of insufficient sleep syndrome. However, extending sleep duration on weekends did not improve sleepiness. He had features to suggest possible obstructive sleep apnea, including snoring and the anatomic configuration of his oropharynx. Extending sleep time, confirmed by wrist actigraphy, did not improve alertness. Polysomnography did not confirm sleep apnea. A multiple sleep latency test performed after discontinuation of sertraline for 2 weeks established a diagnosis of narcolepsy. This diagnosis was classified as narcolepsy type 2, because the patient had no history of cataplexy. The case illustrates how a careful history and examination with stepwise use of appropriate testing can result in a definitive diagnosis.
THE PATIENT WITH NEUROMUSCULAR DISORDERS
Diaphragmatic dysfunction in neuromuscular disorders often manifests initially as sleep-disordered breathing at night, especially during REM sleep. The diaphragm is the major muscle responsible for inspiration, especially during REM sleep, when the intercostal and upper airway muscles become atonic. Secondary alterations can occur in central respiratory drive, sometimes with the development of chest wall restriction from scoliosis. The most common neuromuscular disorders seen in a sleep center are amyotrophic lateral sclerosis, muscular dystrophies (especially Duchenne muscular dystrophy and myotonic dystrophy), and bilateral phrenic neuropathies, but occasionally patients with inflammatory muscle diseases, myasthenia gravis, and polyneuropathies may also develop respiratory failure.16 Neurologists should be familiar with the assessment of the respiratory system in patients with these disorders to determine when intervention may be needed. As many of these disorders are progressive, respiratory assessments should be a routine part of such patients’ follow-up care.
The most important history to obtain is whether the patient becomes dyspneic lying flat during wakefulness or sleep. Dyspnea may also develop with effort, especially when climbing stairs.
Breathing should be assessed while sitting up and supine, and the patient should be asked to remove clothing from the chest to clearly visualize abdominal and chest movement. Diaphragm dysfunction results in paradoxical movement of the abdomen and chest when the patient lies flat. Instead of the abdomen expanding with inspiration in synchrony with the chest, it pulls inward. The respiratory rate may increase with supine breathing, and accessory respiratory muscles may be activated. If available, a pulse oximeter may show a reduction in oxyhemoglobin saturation in the supine position. Chest expansion and the use of accessory muscles should be assessed. It may also be helpful to ask the patient to cough as loudly as possible, as a reduced volume cough may give an approximate indication of reduced respiratory muscle strength. Counting aloud on a single deep breath can also be a useful bedside test, as most patients with normal tidal volume and breath support can count to the high twenties or thirties on a single breath, while patients with neuromuscular weakness of the diaphragm often cannot exceed counting to 20.
Diagnostic tests may include electrophysiologic studies of the diaphragm such as phrenic nerve conduction studies and needle EMG, often combined with ultrasound assessment.17 Overnight pulse oximetry is a very helpful screening tool for early respiratory decompensation during sleep. Initially, this may show cyclical drops in saturation for four to six periods per night, presumably corresponding to periods of REM sleep with superimposed oscillations of signal representing REM-related apneas or hypopneas, often central in origin (Figure 2-3). Later, more persistent hypoxemia may develop. Pulmonary function tests, including vital capacity, and maximal inspiratory and expiratory pressures should be obtained, and arterial blood gas measurements for daytime retention of carbon dioxide may be helpful. Laboratory polysomnography may be needed to assess optimal management with bilevel positive airway pressure.
THE PATIENT WITH RESTLESS LEGS SYNDROME
Restless legs syndrome (RLS), causing at least moderate distress and occurring at least twice a week, has a prevalence of 2% to 3%. RLS is more common in women than men, and the prevalence increases with age. Neurologists are frequently requested to diagnose and treat this common disorder.
The diagnosis of RLS is based on an accurate history. Patients must describe an urge to move the legs usually, but not always, accompanied by a discomfort in the affected limbs. While typically this takes the form of a creepy-crawly sensation, it can sometimes be described as burning, tingling, aching, or an indescribable deep discomfort. The urge to move should arise while the patient is at rest, should be relieved by movement such as walking as long as the activity continues, and is generally worse or present only in the evening or during the night.18 Care should be taken to exclude common conditions that can mimic RLS.19 Leg cramps are painful with palpable contractions in the affected muscles and are relieved by stretching or massaging the muscle rather than walking. Positional discomfort in a limb at night is relieved by changing position and does not require walking. Habitual foot tapping is a subconscious habit easily stopped when the patient is made aware of it.
The subsequent history should be focused on possible etiologies. Any family history of RLS should be noted. As iron deficiency is an important cause of RLS, patients should be asked about fresh rectal bleeding, melena, dyspepsia, menorrhagia, frequent blood donations, and vegan diets. Any symptoms of peripheral neuropathy should be elicited. As RLS may be associated with antidepressant use, determining any relationship between their initial prescription and the onset of RLS may be helpful. If the patient has been treated with dopaminergic medications in the past, it is important to compare the time of symptom onset before and after introduction of the drugs, as dopamine agonists can cause RLS augmentation, primarily characterized by an earlier onset of symptoms.20 Neurologic examination rarely provides useful information, but evidence for a peripheral neuropathy should be sought.
Polysomnography is not indicated for patients with suspected RLS, unless sleep apnea is also being considered, as the presence of periodic limb movements of sleep is neither specific nor sensitive for the diagnosis. Conversely, periodic limb movements are nonspecific findings, and their incidental presence on a polysomnogram does not imply that the patient has RLS. Serum ferritin should be measured in all patients with at least moderately severe RLS. If the patient has an acute or chronic inflammatory disorder, transferrin saturation should also be assessed, as serum ferritin is an acute phase reactant resulting in the possibility of falsely elevated levels despite iron deficiency.21 Unless other clinical indications of specific vitamin deficiencies are evident, serum folate or vitamin B12 concentrations do not need to be assessed. Renal failure rarely presents with RLS, so routine measurement of kidney function in all patients with RLS is not required. Nerve conduction studies and EMG are not indicated unless clinical suspicion of a peripheral neuropathy is present.
THE YOUNG PATIENT WITH ABNORMAL MOVEMENTS DURING SLEEP
Abnormal motor activity in a child or young adult may have many causes. Simple repetitive movements may be due to periodic limb movement disorder or rhythmic movement disorder. Most episodes of recurrent complex behaviors prove to be either due to arousal disorders from non-REM sleep or nocturnal seizures, although, occasionally, sleep-related dissociative disorder and REM sleep behavior disorder (RBD) may occur. Disorders of arousal from non-REM sleep comprise a spectrum of behaviors known as sleepwalking, sleep terrors, and confusional arousals. Focal seizures during sleep can have varied manifestations and degrees of disturbance of consciousness, depending on the site of origin of the epileptic discharges.
A careful description should be obtained from both the patient and observers, understanding that they may perceive the events very differently. If the events are strongly stereotyped, seizures are more likely than parasomnias. This is especially true if similar events also occur during wakefulness. Arousal disorders arise from non-REM sleep and so are most common in the first one-third of the night, whereas seizures can occur at any time. Seizures generally last less than a minute, whereas episodes of sleepwalking can last longer. Descriptive features suggestive of seizures include clonic movements, facial and limb automatisms, dystonic limb posturing, or hypermotor behaviors such as pelvic thrusting and bicycling movements.22 In contrast, sleep terrors are characterized by intense vocalizations associated with sitting up in bed and sleepwalking by quiet standing or walking. However, some forms of focal seizures can also involve nocturnal wanderings. Enuresis is unusual during arousal parasomnias but is common during generalized seizures. Consciousness is usually reduced in arousal disorders and seizures of temporal lobe origin, whereas it is often preserved without postictal confusion in nocturnal seizures arising from the frontal lobes. Rhythmic movement disorder is characterized by regular repetitive movements such as body rocking, head shaking, or thumping of both legs. Periodic limb movements consist of regular flexion of one or both legs at intervals of 5 to 90 seconds. As they are often associated with RLS, any urge to move the legs should be explored. In young children, age-appropriate descriptors may be needed, such as “spiders,” “owies,” or “tickles.” Any family history of seizures or arousal parasomnias should be elucidated, as well as any risk factors for epilepsy, such as birth events, head injuries, febrile seizures, or meningoencephalitis. Possible precipitants for sleepwalking should be identified, such as sleep deprivation, febrile illnesses, or environmental noise. A full neurologic examination should be performed to identify any signs of focal brain disease.
In children, a diagnosis of sleepwalking or sleep terrors can often be made on history alone. However, when doubt exists regarding the diagnosis or the events have resulted in injury, further investigations are needed. A wake and sleep EEG and MRI scan of the head should be obtained. It is often necessary to record actual events to reach a definitive diagnosis. If the neurologist considers the probability of seizures to be higher than parasomnias, then admission to an epilepsy monitoring unit is appropriate. However, if parasomnias are more likely and occur at an appropriate frequency, then polysomnography with an additional 16 EEG derivations, arm surface EMG, and time-synchronized video and audio recording is indicated. It is important to ask the patient to inform the technologist if an event has occurred, as some may be minor and otherwise hard to subsequently locate on the recording. Both the video and the EEG at the time of events should be carefully reviewed. Seizures occur predominantly during non-REM sleep stages N1 and N2, whereas arousal disorders arise from sleep stage N3.23 Nocturnal frontal lobe seizures often have no surface EEG changes, so attention to the clinical phenomenology may be most important in reaching a diagnosis. The video associated with all arousals from sleep stage N3 should be reviewed, as some minor confusional arousals that might establish a diagnosis of an arousal disorder may otherwise be missed. Arousal disorders from non-REM sleep do not have specific polysomnographic appearances, and the diagnosis relies predominantly on review of the recorded behaviors. Sleep deprivation the night before the study may increase the probability of inducing both seizures and arousal disorders. Making a deliberate loud noise near the patient during sleep stage N3 has been reported to precipitate abnormal arousals.
THE OLDER PATIENT WITH ABNORMAL MOVEMENTS DURING SLEEP
RBD predominantly affects middle-aged and older patients, of whom approximately 80% are men. An important and close relationship exists between RBD and synucleinopathies, with 15% to 65% of patients with Parkinson disease, 68% to 80% of those with dementia with Lewy bodies, and 60% to 90% of those with multiple system atrophy (MSA) exhibiting RBD.24 The risk of phenoconversion from idiopathic RBD to parkinsonism or dementia may be as high as 75% 10 years after RBD diagnosis.25,26 Especially in younger patients, antidepressant use may be associated with RBD.27 RBD is also commonly seen in patients with narcolepsy.
Collateral history from a bed partner or caregiver is essential for establishing a diagnosis of RBD. The patient is typically described as punching or flailing the arms, thrashing in bed, kicking the legs, and vocalizing (usually shouting). Bed partners are often inadvertently injured, and the patient can fall out of bed with resultant abrasions, lacerations, ecchymoses, and fractures. Ambulation is unusual, but may occur in 11% of patients.28 The movements vary between episodes and do not have the stereotyped quality of seizures. Urination does not occur. Dream enactment episodes in RBD occur usually in the second half of the night. If the patient is awakened, a description of dream content can often be obtained, with the most common theme being defense against attack.29
A history of snoring, snort arousals, or observed apneas should be elicited. OSA may mimic RBD, with abnormal behavior at the time of the arousals terminating apneas. Additionally, OSA is common in older men, the same population that develops RBD, and is especially common in patients with MSA. It is also important to ask about the occurrence of nocturnal stridor, as the combination of definite stridor and RBD is almost diagnostic of MSA and is not seen in Parkinson disease.30 Stridor is described as a harsh, high-pitched inspiratory sound different from snoring. It sometimes helps if the neurologist can mimic the two sounds, but many observers still have difficulty differentiating them, and an audio recording of the patient on a smartphone is often helpful.
If RBD is suspected, the patient and partner or caregiver should be questioned about symptoms that would suggest the presence of a neurodegenerative disorder or a possible prodrome of a synucleinopathy. Topics that should be covered include tremor, handwriting, speech, gait unsteadiness and falls, lightheadedness, sphincter and sexual function, smell, cognitive status (memory, direction finding, judgment), and hallucinations. Like RBD, anosmia and chronic constipation may be very early manifestations of Lewy body diseases. The presence of abnormal olfaction, for instance, increases the risk of phenoconversion in a patient with otherwise isolated RBD by a hazard ratio of 2.3.31 Conversely, any patients with diagnosed or suspected Parkinson disease, dementia with Lewy bodies, or MSA should be questioned about dream enactment behaviors, symptoms of sleep apnea, and stridor.
Neurologic examination in patients with RBD should concentrate on a clinical assessment of mental function, testing for orthostatic hypotension, and assessment for subtle or overt signs of parkinsonism or dementia. At the least, this should include assessing for tremor and testing eye movements; speech; muscle tone; rapid alternating movement rate of the tongue, hands, fingers, and feet; and the finger-nose and heel-knee test. Gait should be checked, including tandem walking, and the pull test should be performed to assess for postural stability. Sometimes soft signs of cogwheel rigidity at one wrist can be elicited with reinforcement, or primitive reflexes, such as a persistent glabellar reflex, snout, or palmomental reflex may be found at a younger age than normally seen.
If RBD is suspected, polysomnography should be performed to confirm the diagnosis. This is necessary because sleep apnea may be present either as a comorbidity or as an alternative explanation of the motor activity, and because the serious implications of the disorder mandate a definitive diagnosis. Polysomnography for the evaluation of RBD should include at least one upper extremity surface EMG derivation, such as extensor digitorum communis or flexor digitorum superficialis,32 in addition to the conventional recordings from the anterior tibial and the submental muscles (Figure 2-433). Additional EEG derivations should be added if suspicion exists of a possible seizure disorder. Time-synchronized video and audio recordings are essential, and any episode of increased muscle activity should be carefully reviewed. In addition to either a history of dream enactment behavior or such behavior observed during polysomnography, a diagnosis of RBD requires loss of REM sleep atonia with either increased phasic or persistent tonic activity. Whether muscle tone is abnormal in REM sleep is usually determined by experienced sleep specialists subjectively assessing the record. Normative data, however, are available.34,35
Additional neurologic tests will depend on the clinical scenario. If symptoms suggest autonomic dysfunction, autonomic testing, including a thermoregulatory sweat test, may be helpful. Neuropsychometric testing may better characterize perceived cognitive problems. Abnormalities on dopamine transporter single-photon emission computed tomography (SPECT) scans and objective tests of smell and color vision have experimentally been shown to predict phenoconversion in patients with RBD, but are not used routinely in clinical practice (Case 2-2).36
A 59-year-old man presented with strange behaviors at night that he had been experiencing for the last year. His wife described him flailing his arms, kicking, and shouting at least 3 times a week. On occasion, he had hit her, once leaving a bruise. He had fallen out of bed several times, once injuring his shoulder. When woken during an episode, he described dreams of being attacked by unknown assailants. He did not snore. He had lost much of his sense of smell about 10 years earlier, which he ascribed to a nasal infection. He had no other neurologic symptoms.
Neurologic examination was normal apart from a nonfatiguing glabellar reflex and positive palmomental reflexes. He had reduced arm swing on the left when walking.
Polysomnography with additional extensor digitorum communis surface EMG showed loss of normal muscle atonia during rapid eye movement (REM) sleep, with the patient vocalizing and punching in the air. Respiration was normal.
A diagnosis of REM sleep behavior disorder was made, and melatonin was prescribed. At a nightly dose of 9 mg, most dream enactment behavior resolved. Neurologic examination 1 year later revealed a mild rest tremor of the left hand and cogwheel rigidity at the left wrist elicited only when he was asked to simultaneously move his right arm.
Comment. This case indicates how REM sleep behavior disorder and anosmia can precede phenoconversion to a clinical synucleinopathy, sometimes by years. At presentation, the patient exhibited minor neurologic signs insufficient to diagnose parkinsonism, but a year later it was possible to confirm a diagnosis of Parkinson disease.
Sleep medicine remains a clinical specialty. Diagnoses can often be made by taking meticulous histories and obtaining collateral information from observers. Investigations should be used judiciously in a stepwise fashion and interpreted in the setting of the clinical problem. A holistic approach to the patient is necessary, integrating physical and psychosocial factors and not overrelying on the quantitative results of sleep studies in isolation from the patient’s overall problem. Reaching the correct diagnoses of sleep disorders can be very satisfying experiences for the physician and patient as they often lead to long-lasting and effective management strategies.
- Diagnoses in sleep medicine are dependent on careful and meticulous histories, which are aided by observers, and investigations should be seen as an extension of the classic clinical method, rather than independent diagnostic tools.
- Obstructive sleep apnea is the most common intrinsic cause of sleepiness, but rarer disorders must also be considered. Periodic limb movements are frequently seen on polysomnograms, but are an uncommon cause of sleepiness unless associated with restless legs syndrome.
- Differentiating sleepiness and fatigue is important, as fatigue alone is not usually due to a primary sleep disorder. An exception is that women with sleep apnea may present with fatigue rather than sleepiness.
- The first step to diagnosing hypersomnolence is to consider insufficient sleep syndrome, shift work disorder, other circadian rhythm sleep-wake disorders, or drug effects. This is best accomplished through a history supplemented as appropriate by a sleep log, wrist actigraphy, and urine drug screens.
- Assessment for sleep apnea includes taking a history of snoring, snort arousals, observed apneas, and daytime sleepiness (including scales such as the Epworth Sleepiness Scale), measuring the body mass index, and a physical examination of the palate, tongue, jaw, nose, and neck.
- Indications for home sleep apnea testing are a high pretest probability of moderate or severe obstructive sleep apnea in the absence of comorbidities such as cardiac failure, severe chronic obstructive pulmonary disease, dementia, or neuromuscular diseases affecting breathing.
- A short mean sleep latency (8 minutes or fewer) and two or more sleep-onset rapid eye movement periods on a multiple sleep latency test suggest narcolepsy, but only if patients have adequate sleep length and normal circadian rhythmicity for at least 1 week and have discontinued psychotropic medications for at least 2 weeks.
- Because of low specificity for the diagnosis of narcolepsy, testing for the human leukocyte antigen DQB1*0602 should be restricted to patients in whom a spinal tap for measurement of CSF hypocretin-1 concentration is contemplated.
- Patients with neuromuscular disorders should be assessed for respiratory dysfunction at all visits. Clinical screening assessments include inquiring about orthopnea and observing for paradoxical diaphragmatic movement in the supine position. Overnight oximetry may show early rapid eye movement sleep-related oxyhemoglobin desaturations.
- Restless legs syndrome is diagnosed clinically by a history of an urge to move, often associated with leg discomfort, that comes on at rest, is relieved at least temporarily by movement, and is worse in the evening or at night.
- Serum ferritin should be checked in patients with restless legs syndrome, but other tests such as polysomnography or routine nerve conduction study and EMG are generally not indicated.
- Complex nocturnal motor behaviors in a child or young adult are usually due to seizures or a non–rapid eye movement arousal parasomnia such as sleepwalking. Events that are stereotypical are more likely to be seizures.
- Polysomnography to elucidate nocturnal spells should include 16 EEG derivations and video recordings. The video associated with each arousal should be reviewed, as confusional arousals can otherwise be missed.
- Collateral history from a bed partner or caregiver is essential for the diagnosis of rapid eye movement sleep behavior disorder. Symptoms suggesting a synucleinopathy should also be elicited, and the patient should be examined for signs of parkinsonism, cognitive impairment, or dysautonomia.
- The diagnosis of rapid eye movement sleep behavior disorder requires polysomnography with submental, arm, and anterior tibial EMG derivations, and video to record any dream enactment behaviors.
1. Chervin RD. Sleepiness, fatigue, tiredness, and lack of energy in obstructive sleep apnea. Chest 2000;118(2):372–379. doi:10.1378/chest.118.2.372.
2. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540–545.
3. Nagappa M, Liao P, Wong J, et al. Validation of the STOP-Bang Questionnaire as a screening tool for obstructive sleep apnea among different populations: a systematic review and meta-analysis. PLoS One 2015;10(12):e0143697. doi:10.1371/journal.pone.0143697.
4. Netzer NC, Stoohs RA, Netzer CM, et al. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Int Med 1999;131(7):485–491. doi:10.7326/0003-4819-131-7-199910050-00002.
5. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5 pt 1):1279–1285.
6. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3(7):737–747.
7. Rosen CL, Auckley D, Benca R, et al. A multisite randomized trial of portable sleep studies and positive airway pressure autotitration versus laboratory-based polysomnography for the diagnosis and treatment of obstructive sleep apnea: the HomePAP study. Sleep 2012;35(6):757–767. doi:10.5665/sleep.1870.
8. Kuna ST, Gurubhagavatula I, Maislin G, et al. Noninferiority of functional outcome in ambulatory management of obstructive sleep apnea. Am J Resp Crit Care Med 2011;183(9):1238–1244. doi:10.1164/rccm.201011-1770OC.
9. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1):113–121.
10. Goldbart A, Peppard P, Finn L, et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. Sleep 2014;37(6):1043–1051. doi:10.5665/sleep.3758.
11. Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006;129(pt 6):1609–1623. doi:10.1093/brain/awl079.
12. Singh M, Drake CL, Roth T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 2006;29(7):890–895.
13. Andlauer O, Moore H 4th, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 2012;35(9):1247F–1255F. doi:10.5665/sleep.2080.
14. Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008;7(7):649–662. doi:10.1016/S1474-4422(08)70140-6.
15. Tafti M, Hor H, Dauvilliers Y, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 2014;37(1):19–25. doi:10.5665/sleep.3300.
16. Fermin AM, Afzal U, Culebras A. Sleep in neuromuscular diseases. Sleep Med Clin 2016;11(1):53–64. doi:10.1016/j.jsmc.2015.10.005.
17. Boon AJ, O’Gorman C. Ultrasound in the assessment of respiration. J Clin Neurophysiol 2016;33(2):112–119. doi:10.1097/WNP.0000000000000240.
18. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 2014;15(8):860–873. doi:10.1016/j.sleep.2014.03.025.
19. Hening WA, Allen RP, Washburn M, et al. The four diagnostic criteria for restless legs syndrome are unable to exclude confounding conditions (“mimics”). Sleep Med 2009;10(9):976–981. doi:10.1016/j.sleep.2008.09.015.
20. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med 2016;21:1–11. doi:10.1016/j.sleep.2016.01.017.
21. Silber MH, Becker PM, Earley C, et al. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc 2013;88(9):977–986. doi:10.1016/j.mayocp.2013.06.016.
22. Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology 2016;86(19):1834–1842. doi:10.1212/WNL.0000000000002666.
23. Derry CP, Harvey AS, Walker MC, et al. NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis. Sleep 2009;32(12):1637–1644.
24. McCarter SJ, St Louis EK, Boeve BF. REM sleep behavior disorder and REM sleep without atonia as an early manifestation of degenerative neurological disease. Curr Neurol Neurosci Rep 2012;12(2):182–192. doi:10.1007/s11910-012-0253-z.
25. Iranzo A, Fernández-Arcos A, Tolosa E, et al. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients. PLoS One 2014;9(2):e89741. doi:10.1371/journal.pone.0089741.
26. Postuma RB, Gagnon JF, Vendette M, et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009;72(15):1296–1300. doi:10.1212/01.wnl.0000340980.19702.6e.
27. Postuma RB, Gagnon JF, Tuineaig M. Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal? Sleep 2013;36(11):1579–1585. doi:10.5665/sleep.3102.b.
28. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123(pt 2):331–339. doi:10.1093/brain/123.2.331.
29. Uguccioni G, Golmard JL, de Fontréaux AN, et al. Fight or flight? Dream content during sleepwalking/sleep terrors vs. rapid eye movement sleep behavior disorder. Sleep Med 2013;14(5):391–398. doi:10.1016/j.sleep.2013.01.014.
30. Silber MH, Levine S. Stridor and death in multiple system atrophy. Mov Disord 2000;15(4):699–704. doi:10.1002/1531-8257(200007)15:4<699::AID-MDS1015>3.0.CO;2-L.
31. Postuma RB, Gagnon JF, Bertrand JA, et al. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 2015;84(11):1104–1113. doi:10.1212/WNL.0000000000001364.
32. Frauscher B, Iranzo A, Ho¨gl B, et al. Quantification of electromyographic activity during REM sleep in multiple muscles in REM sleep behavior disorder. Sleep 2008;31(5):724–731.
33. Silber MH, St. Louis EK, Boeve BF. Rapid eye movement sleep parsomnias. In: Kryger M, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 6th ed. Philadelpha, PA: Elsevier, 2016:993–1001.
34. Frauscher B, Iranzo A, Gaig C, et al. Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 2012;35(6):835–847. doi:10.5665/sleep.1886.
35. McCarter SJ, St Louis EK, Duwell EJ, et al. Diagnostic thresholds for quantitative REM sleep muscle densities, phasic burst duration, and REM atonia index in REM sleep behavior disorder with and without comorbid obstructive sleep apnea. Sleep 2014;37(10):1649–1662. doi:10.5665/sleep.4074.
36. Holtbernd F, Gagnon JF, Postuma RB, et al. Abnormal metabolic network activity in REM sleep behavior disorder. Neurology 2014;82(7):620–627. doi:10.1212/WNL.0000000000000130.