Neurology_Adams

Neurology_Adams. known as “spindle coma,” in which persistent coma and the electrographic features of sleep coexist. This particular combination of events has been described after head trauma, and rarely, in association with profound metabolic encephalopathies. Despite what appears to be a genuine comatose state (not simply hypersomnolence) from a lesion of the reticular-activating system, the EEG displays frequent spindle activity and vertex waves, attesting to the integrity of thalamocortical pathways for sleep activity (see Nogueira de Melo et al). Also, in cases of traumatic bifrontal contusions, there may be a pathologic insomnia with mania that lasts days or weeks after the injury.


Neurology_Adams

Neurology_Adams. A variety of sleep disturbances may accompany brain tumors or follow surgical resection of an intracranial tumor. These include excessive daytime sleepiness, sleep apnea, and, rarely, nocturnal epilepsy. The location of the lesion, rather than the tumor type, is predictive of such a disturbance; thus, tumors affecting the hypothalamus, and pituitary are associated with excessive daytime drowsiness, whereas medullary lesions cause respiratory disturbances that may affect sleep (Rosen et al). A symptomatic form of narcolepsy is associated with tumors located adjacent to the third ventricle, and midbrain (see below). Schwartz and associates reported transient cataplexy (see further on) following surgery for a craniopharyngioma, but a delirious state has been more common in a few cases for which we have been consulted.


Neurology_Adams

Neurology_Adams. The peculiarities of sleep in Parkinson disease have been extensively studied. Many patients in the early stages of the disease complain of fragmented and unrestful sleep, particularly in the early morning hours; some advanced cases have pathologic insomnia, and this is influenced also by medications used to treat the disease and by deep brain stimulation (see Chap. 39 for a discussion of the nonmotor effects of Parkinson disease). The loss of natural body movements and the alerting effects of l-dopa contribute to the insomnia. The directly acting dopaminergic agonist drugs used for the treatment of Parkinson disease may have the side effect of a pronounced and often rapid daytime sleepiness; however, a similar problem arises in some patients with advancing disease alone. The disturbed sleep patterns in patients with Alzheimer disease, Huntington chorea, olivopontocerebellar degeneration, and progressive supranuclear palsy have attracted attention by neurologists (Parkes). Dreaming is


Neurology_Adams

Neurology_Adams. patterns in patients with Alzheimer disease, Huntington chorea, olivopontocerebellar degeneration, and progressive supranuclear palsy have attracted attention by neurologists (Parkes). Dreaming is also said to be absent in some of these conditions.


Neurology_Adams

Neurology_Adams. In striatonigral degeneration (multiple system atrophy), Lewy-body disease, and other parkinsonian syndromes, there is often a characteristic REM sleep disorder, in which the patient moves and speaks violently and aggressively during dreaming. This “REM sleep behavior disorder” (RSBD, RBD) is discussed further on but here it is commented that the movements may be so extreme as to injure the bed partner and it is often that individual who reports the nighttime behavior. The sleep disorder is often a premonitory feature of the neurologic disease by months or years (see later in this chapter and Chap. 38). Migraine, cluster headaches, and paroxysmal hemicrania all have been linked to certain sleep stages and are discussed in Chap. 9 in relation to other forms of “hypnic headaches.” Disorders of Sleep Associated With Changes in Circadian Rhythm


Neurology_Adams

Neurology_Adams. Sleep is also disturbed and diminished when the normal circadian rhythm of the sleep–wake cycle is exogenously altered. This is observed most often in shift workers, who periodically change their work schedule from day to night, and as a result of transmeridian air travel—that is, jet lag (Baker and Zee). Eastbound travelers fall asleep late and face an early sunrise. The consequent fatigue is a product of both sleep deprivation and a phase change required by changing time zones. A review of the subject can be found by Sack. One antidote is to reset one’s watch on the plane and conform to the routine of the destination—that is, to stay awake all day until the usual evening hour for sleep—and to take a short-acting sedative at bedtime. Melatonin is also used for this purpose, and a meta-analysis by Herxheimer and Petrie of four trials suggests it is slightly effective. These measures facilitate the resetting of the circadian rhythm. Westbound travelers face a late sunset and a long


Neurology_Adams

Neurology_Adams. by Herxheimer and Petrie of four trials suggests it is slightly effective. These measures facilitate the resetting of the circadian rhythm. Westbound travelers face a late sunset and a long night’s sleep and adjust more readily to resetting of the circadian rhythm than do those traveling east. Exposure to light during the extended day is helpful in entraining the sleep cycle; this adjustment is also accomplished more easily when traveling west than east. Shifting of the circadian rhythm in animals suggests that brief exposure to light at crucial times effectively resets the sleep–wake cycle; apparently, the period just before 4 a.m. is a nodal time for susceptibility to this phase change. The sleep problems caused by shift work are more complicated (see Monk).


Neurology_Adams

Neurology_Adams. The delayed-sleep-phase syndrome is a chronic inability to fall asleep and to arise at conventional clock times. Sleep onset is delayed until 3 to 6 a.m.; the subject then sleeps normally until 11 a.m. to 2 p.m. An imposed sleep period from 11 p.m. to 7 a.m. leads to a prolonged sleep latency and daytime sleepiness. By contrast, the advanced-sleep-phase syndrome is characterized by an early evening sleep onset (8 to 9 p.m.) and early morning awakening (3 to 5 a.m.). Simply delaying the onset of sleep usually fails to prevent early morning awakening. This pattern is not uncommon among healthy elderly persons (and also among college students), in whom it should probably not be defined as an insomnia syndrome. Still other persons show a completely irregular sleep–wake pattern; sleep consists of persistent but variable short or long naps throughout the night and day, with a nearly normal 24-h accumulation of sleep.


Neurology_Adams

Neurology_Adams. Several interesting and distressing sleep disturbances are known in completely blind persons, the most troubling being the lack of entrainment to the day-night cycle. As a result of the absence of retinal-hypothalamic entrainment of the circadian rhythm, there is an innate cycle that is just longer than 24 hours, resulting in bouts of insomnia as hypothalamic function moves in and out of phase with the day. In clinical trials, the melatonin receptor agonist tasimelteon has helped entrain the sleep cycle in blind individuals (Lockley et al). Although new classifications have rearranged the nosology of these phenomena, included under this title are several diverse disorders: somnolescent starts, sensory paroxysms, sleep paralysis, night terrors and nightmares, somnambulism, and REM sleep behavior disorder. Somnolescent (Sleep, Hypnic, Myoclonic) Starts


Neurology_Adams

Neurology_Adams. Somnolescent (Sleep, Hypnic, Myoclonic) Starts As sleep comes on, certain motor centers may be excited to a burst of insubordinate activity. The result is a sudden “start” or myoclonic bodily jerk of large amplitude, which rouses the incipient sleeper. It may involve one or both legs or the trunk, less often, the arms. If the start occurs repeatedly during the process of falling asleep and is a nightly event, it may become a matter of great concern to the patient. The starts are more apt to occur in individuals in whom the sleep process develops slowly; they are especially frequent under conditions of tension and anxiety. Polysomnographic recordings have shown that these bodily jerks occur at the moment of falling asleep or during the early stages of sleep. Sometimes they appear as part of an arousal response to a faint external stimulus and are then associated with a frontal K complex in the EEG. These bodily jerks are not variants of epilepsy.


Neurology_Adams

Neurology_Adams. A small proportion of otherwise healthy infants exhibit rhythmic jerking of the hands, arms, and legs or abdomen, both at the onset and in the later stages of sleep (benign neonatal myoclonus). The movements begin in the first days of life and disappear within months. There may be a familial tendency toward these movements. Coulter and Allen differentiate this state from myoclonic epilepsy and neonatal seizures by the absence of EEG changes, and its occurrence only during sleep.


Neurology_Adams

Neurology_Adams. Sensory centers may be disturbed in a similar way to the earlier-described sleep starts, either as an isolated phenomenon or in association with motor phenomena. The patient, dropping off to sleep, may be roused by a sensation that darts through the body, a sudden flash of light, or a sudden crashing sound or thunderclap of head pain—cephalgia fugax, or “the exploding head syndrome” (Pearce). Sometimes there is a sensation of being turned or lifted, and dashed to the ground; conceivably, these are sensory paroxysms involving the labyrinthine-vestibular mechanism. Though obvious causes for concern by patients, these sensory paroxysms are benign.


Neurology_Adams

Neurology_Adams. Curious paralytic phenomena, referred to as preand postdormital paralyses, may occur in the transition from the sleeping to the waking state. Sometimes in the morning and less frequently when falling asleep, otherwise healthy persons—though awake, conscious, and fully oriented—are seemingly unable to activate their muscles. Respiratory and diaphragmatic function and eye movements are usually unaffected, although a few patients have reported a sensation of being unable to breathe. They lie as though still asleep, with eyes closed, and may become quite frightened while engaged in a struggle for movement. They have the impression that if they could move one muscle, the paralysis would be dispelled instantly, and they would regain full power. It has been stated that the slightest stimulus, such as the touch of a hand or calling the patient’s name, will abolish the paralysis. Sleep deprivation is a common precipitant to the syndrome.


Neurology_Adams

Neurology_Adams. Such attacks are also observed in patients with narcolepsy (discussed later in this chapter) and with the hypersomnia of the pickwickian syndrome and other forms of sleep apnea. Some cases are familial. The weakness or paralysis is thought to be a dissociated form of the atonia of REM sleep. Usually, the attacks are brief (minutes or less); if they occur in isolation and only on rare occasions, they are of no special significance. If frequent, as in narcolepsy, they can be prevented by the use of tricyclic antidepressants, particularly clomipramine, which has serotonergic activity.


Neurology_Adams

Neurology_Adams. The night terror (pavor nocturnus) is mainly a problem of childhood. It usually occurs soon after falling asleep, during stage 3 or 4 sleep and therefore is not aligned with nightmares. The child awakens abruptly in a state of intense fright, screaming or moaning, with marked tachycardia (150 to 170 beats/min) and deep, rapid respirations. Children with night terrors are often sleepwalkers as well, and both kinds of attack may occur simultaneously. The entire episode lasts several minutes and in the morning the child recalls nothing of it or only a vague unpleasant dream. It has been suggested that night terrors and somnambulism represent impaired or partial arousal from deep sleep, as EEGs taken during such episodes show a waking type of mixed frequency and alpha pattern. Children with night terrors and somnambulism do not show an increased incidence of psychologic abnormalities and tend to outgrow these disorders. The persistence of such problems into adult life, however, has, in a


Neurology_Adams

Neurology_Adams. terrors and somnambulism do not show an increased incidence of psychologic abnormalities and tend to outgrow these disorders. The persistence of such problems into adult life, however, has, in a small number of cases, been associated with psychopathology (Kales et al). It has been found that diazepam, which reduces the duration of the deep stages of sleep, will prevent night terrors. Selective serotonin reuptake inhibitors have also been used successfully, especially when night terrors are associated with sleepwalking. Frequent night terrors have reportedly been eliminated by having parents awaken the child for several successive nights, just prior to the usual time of the attack or at the first sign of restlessness and autonomic arousal (Lask).


Neurology_Adams

Neurology_Adams. Frightening dreams or nightmares are far more frequent than night terrors and affect children and adults alike. They occur during periods of normal REM sleep and are particularly prominent during periods of increased REM sleep (REM rebound) following the withdrawal of alcohol or other sedative-hypnotic drugs that had suppressed REM sleep chronically. Autonomic changes are slight or absent, and the content of the dreams can usually be recalled in considerable detail. Some of these dreams (e.g., the ones occurring in the alcohol-withdrawal period) are so vivid that the patient may later have difficulty in separating them from reality; indeed, they may merge with the hallucinations of delirium tremens. Nightmares are of little significance as isolated events. Fevers dispose to them, as do conditions such as indigestion and the reading of bloodcurdling stories or exposure to terrifying movies or television programs before bedtime. Some patients report nightmares and extremely vivid dreams


Neurology_Adams

Neurology_Adams. such as indigestion and the reading of bloodcurdling stories or exposure to terrifying movies or television programs before bedtime. Some patients report nightmares and extremely vivid dreams when first taking certain medications such as beta blockers and, particularly in our experience, l-dopa. We have also consulted on a few patients who complained of almost nightly nightmares and concurrent severe headaches, but without apparent depression or other psychiatric illness. Persistent nightmares may be a pressing medical complaint and are often accompanied by other behavioral disturbances or anxieties.


Neurology_Adams

Neurology_Adams. This condition occurs far more commonly in children (average age, 4 to 6 years) than in adults, and is often associated with nocturnal enuresis and night terrors, as indicated previously. It is estimated that 15 percent of children have at least one episode of sleepwalking, and that 1 in 5 sleepwalkers has a family history of this disorder. Motor performance and responsiveness during the sleepwalking incident vary considerably. The most common behavioral abnormality is for a patient to sit up in bed or on the edge of the bed without actually walking. When walking about the house, he may turn on a light or perform some other familiar act. There may be no outward show of emotion, or the patient may be frightened (night terror), but the frenzied, aggressive behavior of some adult sleepwalkers, described below, is rare in the child. Usually the eyes are open, and such sleepwalkers are guided by vision, thus avoiding familiar objects; the sight of an unfamiliar object may awaken them.


Neurology_Adams

Neurology_Adams. described below, is rare in the child. Usually the eyes are open, and such sleepwalkers are guided by vision, thus avoiding familiar objects; the sight of an unfamiliar object may awaken them. Sometimes they make no attempt to avoid obstacles and may injure themselves. If spoken to, they make no response; if told to return to bed, they may do so, but more often they must be led back. Sometimes they repeatedly mutter strange phrases or perform certain repetitive acts, such as pushing against a wall or turning a doorknob back and forth. The episode lasts for only a few minutes, and the following morning, they usually have no memory of it, or only a fragmentary recollection.


Neurology_Adams

Neurology_Adams. A popular belief is that the sleepwalker is acting out a dream. The observations of sleep laboratories are entirely at variance with this view, as somnambulism has been found to occur almost exclusively during deeper stages of NREM sleep (stage N3) and during the first third of the night when dreaming is least likely to occur. In fact, the entire nocturnal sleep pattern of such individuals does not differ from normal. Also, there is no evidence that somnambulism is a form of epilepsy. It is probably allied to talking in one’s sleep, although the two conditions seldom occur together. Sleepwalking must be distinguished from fugue states and ambulatory automatisms of complex partial seizures discussed below and in Chap. 15.


Neurology_Adams

Neurology_Adams. The major consideration in the treatment of childhood somnambulism is to guard patients against injury by locking doors and windows, removing dangerous objects from the patients’ usual routes of march, having them sleep on the ground floor, etc. Children usually outgrow this disorder; parents should be reassured on this score and disabused of the notion that somnambulism is a sign of psychiatric or any other disease.


Neurology_Adams

Neurology_Adams. In contrast to somnambulism in children the onset of sleepwalking or night terrors for the first time in adult life is most unusual, and occasionally suggests the presence of psychiatric disease or drug intoxication. Almost always, the adult sleepwalker has a history of sleepwalking as a child, although there may have been a period of freedom between the childhood episodes and their reemergence in the third and fourth decades. Adult somnambulism also occurs during N3 of NREM sleep, but unlike the childhood type, is not confined to the earlier part of the night. If one extends the category of somnambulism to all forms of nocturnal wandering, it seems to be remarkably common, with a lifetime prevalence of 29% of U.S. adults according to the survey by Ohayon and colleagues (2012).


Neurology_Adams

Neurology_Adams. Somnambulism in the adult, as in the child, can be a purely passive event unaccompanied by fear or other signs of emotion. More frequently, however, the attack is characterized by frenzied or violent behavior associated with fear and tachycardia, like that of a night terror and sometimes with self-injury. Very rarely, crimes have reportedly been committed during sleepwalking, but the authors are skeptical that organized and planned sequential activity is possible. The finding of normal sleep patterns on polysomnography distinguishes these attacks from complex partial seizures. They can be eliminated or greatly reduced by the administration of clonazepam (0.5 to 1.0 mg) at bedtime. Some patients respond better to a combination of clonazepam and phenytoin or to flurazepam (Kavey et al).


Neurology_Adams

Neurology_Adams. An associated but unclassifiable disorder is “night eating” in which the individual seeks out mainly carbohydrates and is only aware of their actions on the following morning when they see the mess they have left. Also, in the provocatively named “sexomnia,” the individual, male or female, engages in sexual activity, sometimes forcefully, and has no recollection of the events. The status of these syndromes as authentic parasomnias is unclear. REM Sleep Behavior Disorder (RBD, RSBD)


Neurology_Adams

Neurology_Adams. REM Sleep Behavior Disorder (RBD, RSBD) This is a recognized parasomnic disorder, occurring in adult life, most commonly in older men without a history of childhood sleepwalking. It is characterized by attacks of vigorous, agitated, and often dangerous motor activity accompanied by vivid dreams (Mahowald and Schenck). The characteristic features are angry speech with shouting, violent activity with injury to self and bed mate, a very high arousal threshold, and the variable but sometimes detailed recall of a nightmare of being attacked and fighting back or attempting to flee. The episodes vary in frequency in affected individuals, occurring once every week or two or several times nightly. The episodes, which occur exclusively during REM sleep, usually in the second half of the night, are out of keeping with the patient’s waking personality. Polysomnographic recordings during these episodes have disclosed augmented muscle tone but no seizure activity.


Neurology_Adams

Neurology_Adams. The rare appearance of this disorder with pontine infarctions has been mentioned earlier in the chapter. However, in a series of 93 cases of REM sleep behavior disorder reported by Olson and colleagues, more than half were associated with some other neurologic disorder, in particular Parkinson disease, multiple system atrophy, and Lewy-body dementia, but in other series, with a larger variety of degenerative and other neurologic conditions. A more systemic polysomnographic examination of 457 patients with Parkinson disease by Sixel-Döring and colleagues found REM sleep behavior disorder in 46 percent. Viewed from another perspective, Postuma and coworkers have reported that one-quarter of individuals with idiopathic REM sleep disorder later developed a neurodegenerative disorder, similar to or slightly lower than other series. These observations have led to the suggestion that this disorder is an early manifestation of a degenerative brain disease characterized by the deposition of


Neurology_Adams

Neurology_Adams. to or slightly lower than other series. These observations have led to the suggestion that this disorder is an early manifestation of a degenerative brain disease characterized by the deposition of alpha-synuclein in certain neuronal systems, as summarized by Boeve and associates.


Neurology_Adams

Neurology_Adams. The episodes can be suppressed by the administration of clonazepam in doses of 0.5 to 1.0 mg at bedtime and by melatonin, 3 to 12 mg. The advantage of the latter is that sleep apnea is not affected as it is with benzodiazepines. Discontinuation of medication, even after years of effective control, has resulted in relapse. Antidepressants are said to exacerbate the disorder with the possible exception of bupropion. Nocturnal Epilepsy (See Also Chap. 15)


Neurology_Adams

Neurology_Adams. Nocturnal Epilepsy (See Also Chap. 15) It has long been known that seizures, both convulsive and nonconvulsive, often occur during sleep, especially in children. This is such a frequent occurrence that the practice of inducing sleep has been adopted as an activating EEG procedure to obtain confirmation of epilepsy. Seizures may occur soon after the onset of sleep or at any time during the night, but mainly in stages 1 and 2 of NREM sleep or, rarely, in REM sleep. They are also common during the first hour after awakening. On the other hand, deprivation of sleep may also be conducive to a seizure.


Neurology_Adams

Neurology_Adams. Sleeping epileptic patients may attract attention to their seizures by a cry, violent motor activity, unusual but stereotyped actions, such as sitting up and crossing the arms over the chest, the adoption of a “fencing” posture, or labored breathing. After the tonic-clonic phase, patients become quiet and fall into a state resembling deep sleep, but they cannot be aroused from it for some minutes or longer. If the nocturnal seizure is unobserved, the only indication of it may be disheveled bedclothes, a few drops of blood on the pillow from a bitten tongue, wet bed linen from urinary incontinence, or sore muscles. Or the occurrence of a seizure may be disclosed only by confusion, muscle soreness, or headache, the common aftermaths of a major generalized seizure. Rarely, a patient may die in an epileptic seizure during sleep, sometimes from smothering in the bed clothes or aspirating vomitus or for some obscure reason (possibly respiratory or cardiac dysrhythmia). The question


Neurology_Adams

Neurology_Adams. may die in an epileptic seizure during sleep, sometimes from smothering in the bed clothes or aspirating vomitus or for some obscure reason (possibly respiratory or cardiac dysrhythmia). The question sometimes arises whether night terrors or sleep walking represent epileptic automatisms. Usually no such relationship is established. Measurement of serum creatine kinase concentration in the hours following an event may distinguish seizure from night terrors, and the other described sleep-related motor behaviors.


Neurology_Adams

Neurology_Adams. One type of nocturnal frontal lobe seizure disorder is characterized by paroxysmal bursts of generalized choreoathetotic, ballistic, and dystonic movements occurring during NREM sleep (Lugaresi et al, 1986). Sometimes the patient appears awake and has a fearful or astonished expression, or there are repetitive utterances and an appearance of distress, similar to what is seen in night terrors, the main differential diagnosis discussed further on. The attacks may begin at any age, affect both sexes, and are usually nonfamilial. A fencing posture, in which one arm is thrust forward and the other is flexed occurs in some instances. The main form of this disorder is characterized by attacks lasting 60 s or less; they may be diurnal as well as nocturnal; some patients in addition have epileptic seizures of the more usual type; and all respond to treatment with carbamazepine. The studies of Tinuper and coworkers, using prolonged video-EEG monitoring, indicate that these brief attacks of


Neurology_Adams

Neurology_Adams. seizures of the more usual type; and all respond to treatment with carbamazepine. The studies of Tinuper and coworkers, using prolonged video-EEG monitoring, indicate that these brief attacks of nocturnal paroxysmal dystonia may actually be epileptic seizures of frontal lobe origin. In a rarer disorder that simulates these seizures, the attacks are longer (2 to 40 min), ictal and interictal EEGs are normal, and the events are not suppressed by antiepileptic drugs. Except for the lack of familial incidence and occurrence only during sleep, the disorder is very much the same as the “familial paroxysmal dystonic choreoathetosis” (see “Paroxysmal Choreoathetosis and Dystonia” in Chap. 4).


Neurology_Adams

Neurology_Adams. Encephalitis lethargica, or von Economo “epidemic encephalitis,” the remarkable illness that appeared on the medical horizon as a pandemic following World War I, provided some of the most dramatic instances of pathologic somnolence. Protracted sleep lasting for days to weeks was such a prominent symptom of this disease that it was called sleeping sickness (a term also applied to African trypanosomiasis, as noted below). The patient appeared to be in a state of continuous sleep, or somnosis, and could be kept awake only by constant stimulation. Although the infective agent of von Economo disease was never isolated, the pathologic anatomy was disclosed by many excellent studies at the time, which demonstrated destruction of neurons in the midbrain, subthalamus, and hypothalamus. Patients who survived the acute phase of the illness often had difficulty in reestablishing their normal sleep–wake rhythm. As the somnolence disappeared, some patients exhibited a reversal of the normal


Neurology_Adams

Neurology_Adams. who survived the acute phase of the illness often had difficulty in reestablishing their normal sleep–wake rhythm. As the somnolence disappeared, some patients exhibited a reversal of the normal pattern, tending to sleep by day, and stay awake at night; many of them also developed a parkinsonian syndrome months or years later. The hypersomnia was theorized to be related to destruction of dopamine-rich neurons in the substantia nigra, resulting in overactivity of the raphe (serotonergic) neurons but how this fits with current models of sleep is unclear.


Neurology_Adams

Neurology_Adams. Hypersomnia is also a manifestation of trypanosomiasis, the common cause of sleeping sickness in Africa, and of other diseases localized to the mesencephalon, and the floor and walls of the third ventricle. Small tumors in this area have been associated with arterial hypotension, diabetes insipidus, hypoor hyperthermia, and protracted somnolence lasting many weeks. Such patients can be aroused; but if left alone, they immediately fall asleep. Traumatic and vascular lesions and other diseases affecting the mesencephalon may have a similar effect.


Neurology_Adams

Neurology_Adams. Confusional awakening, or sleep drunkenness is the name given to a form of hypersomnia, characterized by a failure to attain full alertness for a protracted period after awakening from deep sleep. Unsteadiness, drowsiness, disorientation, and automatic behavior are the main features. This disorder is usually associated with idiopathic hypersomnia, and sometimes with sleep apnea or other forms of sleep deprivation, but often no such connection can be discerned. In a cross sectional study by Ohayon and colleagues using self-reported of symptoms, approximately 15% of individuals were taking medications, particularly antidepressants, or had a psychiatric disorder that may have played a role in the events. It is surprising to us that anxiolytics and soporific agents did not play a larger role.


Neurology_Adams

Neurology_Adams. An interesting type of transient unresponsiveness in elderly patients, as described by Haimovic and Beresford, has been in our experience akin to a deep sleep, but the EEG has not shown sleep patterns.


Neurology_Adams

Neurology_Adams. Kleine in 1925 and Levin in 1936 described an episodic disorder characterized by somnolence and overeating. For days or weeks, the patients, mostly adolescent boys, sleep 18 h or more a day, awakening only long enough to eat and attend to toilet needs. They appeared dull, often confused, and restless, and were sometimes troubled by hallucinations. In the series of 11 cases collected by Critchley, the age range of onset was from late teenage years to mid-1920s, with few exceptions. There may be a brief prodromal period of inertia and drowsiness. The duration of nocturnal sleep may be greatly prolonged, or, as in our patients referred to below, they may sleep for days on end. Food intake during and around the period of hypersomnia may exceed three times the normal (bulimia) and occurs almost compulsively during brief periods of semiwakefulness; to a variable extent, there are other behavioral changes such as social withdrawal, negativism, slowness of thinking, incoherence,


Neurology_Adams

Neurology_Adams. occurs almost compulsively during brief periods of semiwakefulness; to a variable extent, there are other behavioral changes such as social withdrawal, negativism, slowness of thinking, incoherence, inattentiveness, and disturbances of memory. The somnolence has been well studied by modern laboratory methods; except for the total duration of sleep, the individual components of the NREM and REM cycles are normal. Between episodes these patients are behaviorally and cognitively normal.


Neurology_Adams

Neurology_Adams. The basis of this condition has never been clarified. A psychogenic mechanism has been proposed, without foundation in our opinion. The syndrome usually disappears during adulthood, and there is limited pathologic material (see further discussion in the context of hypothalamic syndromes in Chap. 26). A series of 108 cases reviewed by Arnulf and colleagues frame the clinical features; a predominance of males, higher C-reactive protein than controls, and a history of early childhood developmental problems. There was no human leukocyte antigen (HLA) clustering, but children of Jewish heritage were overrepresented. Another large sample reported by Lavault and colleagues, is more recent but makes largely the same points. We have cared for a sibling pair who had the illness into young adulthood (Katz and Ropper). In some patients with this disorder, schizophrenic and sociopathic symptoms have been recorded between attacks, raising doubt as to whether all the reported cases are of the same


Neurology_Adams

Neurology_Adams. (Katz and Ropper). In some patients with this disorder, schizophrenic and sociopathic symptoms have been recorded between attacks, raising doubt as to whether all the reported cases are of the same type. We have seen variants of this syndrome manifesting as drowsiness and extreme inactivity lasting for a few weeks, then with a complete return to normalcy.


Neurology_Adams

Neurology_Adams. No consistent change in the level of hypocretin (orexin) has been found in the spinal fluid, as occurs in narcolepsy (see further on), and the two disorders are distinct. Imaging studies have shown various areas of reduced metabolism during episodes, including but not isolated to the hypothalamus, and between attacks; the interpretation of these findings is unclear (Portilla et al and Haba-Rubio et al). Many treatments have been tried and there is only tentative evidence from an open label, prospective e trial reported by Leu-Semenescu and colleagues that lithium may reduce the rate of relapse and duration of episodes. Other medications have not been consistently effective (e.g., antidepressant drugs), but some of the stimulants that are used for the treatment of narcolepsy may be useful (see further on).


Neurology_Adams

Neurology_Adams. Finally, it should be mentioned that sleep laboratories now recognize a form of idiopathic hypersomnia in which there are repeated episodes of drowsiness throughout the day. This condition is discussed further on, in relation to the diagnosis of narcolepsy, with which it is most often confused. A related disorder has been described of “menstrual related hypersomnia” that has a cyclic catamenial nature.


Neurology_Adams

Neurology_Adams. Excessive daytime sleepiness is a common complaint in general medical practice (Table 18-2). Certainly, the most frequent causes are inadequate sleep and the use of any one of a large variety of medications. Abuse of alcohol and illicit drugs should also be included in this category. Most conditions associated with severe fatigue produce daytime sleepiness and a desire to nap. A survey of conditions giving rise to daytime sleepiness has been accumulated by Guilleminault and Dement (1977). A notable medical cause is infectious mononucleosis but many other viral infections have the same effect. Certain chronic neurologic conditions can produce fatigue and sleepiness, multiple sclerosis and Parkinson disease being the outstanding examples. Among general medical conditions, hypothyroidism and hypercapnia must always be considered when daytime sleepiness is a prominent feature. One must not overlook the possibility that excessive daytime drowsiness is the result of repeated episodes of


Neurology_Adams

Neurology_Adams. and hypercapnia must always be considered when daytime sleepiness is a prominent feature. One must not overlook the possibility that excessive daytime drowsiness is the result of repeated episodes of sleep apnea, discussed below, or the disruption of nocturnal sleep by disorders such as the restless legs syndrome.


Neurology_Adams

Neurology_Adams. Once these causes of disrupted sleep have been addressed or excluded, sleep apnea remains the most important prevalent condition causing excessive daytime sleepiness. REM sleep is associated with irregular breathing, and this may include several brief periods of apnea up to 10 s in duration but these are not considered pathologic. The main features of sleep apnea are cyclic breathing during sleep with periods of apnea and hypoxemia. The condition is typically considered to have two varieties, sometimes coincident: obstruction of the upper airway (obstructive type) and loss of neurogenic drive for respiration (central type). Apneas occurring at the onset of sleep are not in themselves considered to be pathologic.


Neurology_Adams

Neurology_Adams. Apnea of the obstructive type in which the posterior pharyngeal muscles collapse and narrow the upper airway is far more common than the central variety. Obstructive apnea is associated with obesity and also accompanies acromegaly, hypothyroidism or myxedema, micrognathia. In children, more than in adults, adenotonsillar hypertrophy may be a factor. Instances occur as a result of neuromuscular diseases that weaken the posterior pharyngeal musculature; motor neuron disease is the most common example of this group. Obstructive sleep apnea is characterized by noisy snoring of a cyclic type. After a period of regular albeit noisy breathing, there occurs a waning of breathing efforts; then, despite repeated inspiratory efforts, airflow ceases. Following a prolonged period of apnea (10 to 30 s or even longer), the patient makes a series of progressively greater breathing efforts until breathing resumes, accompanied by very loud snorting sounds and a brief arousal.


Neurology_Adams

Neurology_Adams. Obstructive sleep apnea occurs during both REM and NREM sleep and the amount of apnea during REM exceeds that seen normally observed, as alluded to above. Just before the diaphragm contracts, the upper respiratory muscles (genioglossus, geniohyoid, tensor veli palatini, and medial pterygoid) normally contract to resist the collapse of the oropharynx. If the airway is obstructed or the muscles are weakened and then go slack, the negative intrathoracic pressure causes narrowing of this passage. Sedative medications, alcohol intoxication, excessive tiredness, a recent stroke, head trauma or other acute neurologic disease, and primary pulmonary disease may all exaggerate obstructive sleep apnea, particularly in the obese patient with a tendency to snore.


Neurology_Adams

Neurology_Adams. Hypoxia or perhaps other stimuli induce an arousal response, either a lightening of sleep or a very brief awakening, which is followed by an immediate resumption of breathing. The patient quickly falls asleep again and the sequence is repeated, several hundred times a night in severe cases, greatly disrupting the sleep pattern and reducing the total sleep time. Paradoxically, these patients are very difficult to rouse at all times during the night.


Neurology_Adams

Neurology_Adams. Obstructive sleep apnea is predominantly a disorder of overweight, middle-aged men and usually presents as excessive daytime sleepiness, a complaint that is sometimes mistaken for narcolepsy (see below). Other patients, usually those with the much-less-common central form of apnea, complain mainly of a disturbance of sleep at night, or insomnia, which may be incorrectly attributed to anxiety or depression. The occurrence of an obstructive sleep apnea is accompanied after a period of weeks or months by progressive hemoglobin oxygen desaturation, hypercapnia and hypoxia, a transient increase in systemic and pulmonary arterial pressures, and sinus bradycardia or other arrhythmias. Morning headache, inattentiveness, grogginess, and decline in school or work performance are other symptoms attributable to sleep apnea. Ultimately, systemic and pulmonary arterial hypertension, cor pulmonale, polycythemia, and heart failure may develop. When combined with obesity, these symptoms have been


Neurology_Adams

Neurology_Adams. attributable to sleep apnea. Ultimately, systemic and pulmonary arterial hypertension, cor pulmonale, polycythemia, and heart failure may develop. When combined with obesity, these symptoms have been referred to as the “pickwickian syndrome,” so named by Burwell and coworkers, who identified this clinical syndrome with that of the extraordinarily sleepy, red-faced, fat boy described by Dickens in The Pickwick Papers.


Neurology_Adams

Neurology_Adams. The full-blown syndrome of obstructive sleep apnea is readily recognized by the features of daytime sleepiness, loud snoring, and the typical habitus of affected individuals. However, in patients who complain only of excessive daytime sleepiness and do not have the typical body ahbitus, the diagnosis may be elusive and require all-night polysomnographic sleep monitoring. This disorder has been observed in patients with a variety of severe and life-threatening lower brainstem lesions—bulbar poliomyelitis, lateral medullary infarction, spinal (high cervical) surgery, syringobulbia, brainstem encephalitis, as well as with striatonigral degeneration, Creutzfeldt-Jakob disease, anoxic encephalopathy, and olivopontocerebellar degeneration. When a unilateral lesion (e.g., infarction) of the medulla is the cause, there is almost always involvement of crossing fibers between respiratory nuclei (see discussion in Chap. 25).


Neurology_Adams

Neurology_Adams. In addition to these symptomatic forms of sleep apnea, there is a disorder referred to as primary, or idiopathic, hypoventilation syndrome (“Ondine’s curse,” as described in Chap. 25). This last term is now applied to many forms of total loss of automatic breathing, especially during sleep. Awakenings during the night are frequent, usually after an apneic period, and insomnia is a common complaint. Snoring is mild and intermittent. In the few autopsied cases of congenital central hypoventilation of childhood, Liu and colleagues found the external arcuate nuclei of the medulla to be absent, and the neuron population in the medullary respiratory areas to be depleted. Complex sleep apnea, or “treatment emergent central sleep apnea,” occurs most often in patients with cardiovascular conditions, particularly congestive heart failure, wherein, after sleep apnea is treated with positive airway pressure, central apnea emerges.


Neurology_Adams

Neurology_Adams. Treatment The approach is governed by the severity of symptoms and the predominant type of apnea, central or obstructive. In the treatment of obstructive apnea, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) is the most useful measure. These therapies are delivered by a tight-fitting nasal mask that is worn at night and connected to a pressure-cycled ventilator that is triggered by the patient’s breath. The increased airway pressure maintains patency of the nasoand oropharynx, thereby reducing the obstruction. A nasal device that passively resists nasal collapse by providing expiratory resistance is used by some specialists for mild sleep apnea. All of these approaches have a level of discomfort that is not tolerable to some patients.


Neurology_Adams

Neurology_Adams. Patients benefit from losing weight, lateral positioning during sleep, and avoidance of alcohol and other sedative drugs. Surgical correction of an upper airway defect may be helpful, but it is difficult to predict which patients will benefit. There are no clear guidelines for procedures such as uvulopalatopharyngoplasty and related surgeries or uvulectomy and tonsillectomy, except in children. These may obliterate snoring more than it ameliorates the sleep apnea. Oral alignment devices that are produced by dentists, aimed at advancing the mandible, have been helpful to some patients, especially for those who cannot tolerate positive pressure.


Neurology_Adams

Neurology_Adams. Those few patients with the most severe hypersomnia and cardiopulmonary failure who cannot tolerate nocturnal positive pressure ventilation require tracheostomy and nocturnal respirator care. (See Parkes for a fuller account of therapeutic measures.) Some patients with nonobstructive apnea may also benefit from nighttime treatment with CPAP, but the results are far less consistent than with the obstructive type. Curiously, treating obstructive sleep apnea has not reduced cardiovascular events in recent clinical studies (McEveoy et al).


Neurology_Adams

Neurology_Adams. In central apnea, any underlying abnormality, such as congestive heart failure or nasal obstruction, should, of course, be treated insofar as possible. Where no underlying cause can be found, one of several medications—acetazolamide, medroxyprogesterone, protriptyline, and particularly clomipramine—may be helpful in the short run (Brownell et al). However, drug treatment has proven generally unsatisfactory. Low-flow oxygen may also be useful in reducing central sleep apnea.


Neurology_Adams

Neurology_Adams. This clinical entity has long been known to the medical profession. Gélineau gave it the name narcolepsy in 1880, although several authors had described the recurring attacks of irresistible sleep even before that time. Gélineau had also mentioned that the sleep attacks were sometimes accompanied by falls (“astasias”), but it was Loewenfeld, in 1902, who first recognized the common association between the sleep attacks and the temporary paralysis of the somatic musculature during bouts of laughter, anger, and other emotional states; this was referred to as cataplectic inhibition by Henneberg (1916), and later as cataplexy by Adie (1926). The term sleep paralysis—used to designate the brief, episodic loss of voluntary movement that occurs during the period of falling asleep (hypnagogic, or predormital) or less often when awakening (hypnopompic, or postdormital)—was introduced by S.A. Kinnier Wilson in 1928. Actually, Weir Mitchell had described this latter disorder in 1876, under the


Neurology_Adams

Neurology_Adams. predormital) or less often when awakening (hypnopompic, or postdormital)—was introduced by S.A. Kinnier Wilson in 1928. Actually, Weir Mitchell had described this latter disorder in 1876, under the title of night palsy.


Neurology_Adams

Neurology_Adams. Sometimes sleep paralysis is accompanied or just preceded by vivid and terrifying hallucinations (hypnagogic hallucinations), which may be visual, auditory, vestibular (a sense of motion), or somatic (a feeling that a limb or finger or other part of the body is enlarged or otherwise transformed). These four conditions—narcolepsy, cataplexy, hypnagogic paralysis, and hallucinations—constitute a clinical tetrad. Wilson has reviewed the historical aspects and early accounts of this subject. The most important observations regarding the pathophysiology of this process have been special relationship to a disordered pattern of REM sleep, and the more recent finding of abnormalities in hypothalamic substances that induce sleep, as discussed below.


Neurology_Adams

Neurology_Adams. Narcolepsy is encountered regularly by neurologists; Daly and Yoss recorded about 100 new cases a year at the Mayo Clinic. Dement and colleagues have estimated the prevalence at 50 to 70 per 100,000 in the San Francisco and Los Angeles areas. Men and women are affected equally.


Neurology_Adams

Neurology_Adams. As a rule, narcolepsy has a gradual onset between the ages of 15 and 35 years; in fully 90 percent of narcoleptics, the condition is established by age 25. Narcolepsy is usually the first symptom, less often cataplexy, and rarely sleep paralysis. The essential disorder is one of frequent attacks of irresistible sleepiness. Several times a day, usually after meals or while sitting in class or in other boring or sedentary situations, the affected person is assailed by an uncontrollable desire to sleep. The eyes close, the muscles relax, breathing deepens slightly, and by all appearances, the individual is dozing. A noise, a touch, or even the cessation of the lecturer’s voice is enough to awaken the patient. The periods of sleep rarely last longer than 15 min unless the patient is reclining, when he may continue to sleep for an hour or longer. At the conclusion of a nap, the patient feels somewhat refreshed. It should be emphasized that there are many narcoleptics who tend to be


Neurology_Adams

Neurology_Adams. when he may continue to sleep for an hour or longer. At the conclusion of a nap, the patient feels somewhat refreshed. It should be emphasized that there are many narcoleptics who tend to be pervasively drowsy throughout the day. What distinguishes the typical narcoleptic sleep attacks from commonplace postprandial drowsiness and napping is the frequent occurrence of the former (two to six times every day as a rule), their irresistibility, and their occurrence in unusual situations, as while standing, eating, or carrying on a conversation. Blurring of vision, diplopia, and ptosis may attend the drowsiness and may bring the patient first to an ophthalmologist.


Neurology_Adams

Neurology_Adams. In addition to episodes of outright sleep, narcoleptics, like other very drowsy persons, may experience episodes of automatic behavior and amnesia. Initially the patient feels drowsy and may recall attempts to fight off the drowsiness, but gradually he loses track of events. The patient may continue to perform routine tasks automatically but does not respond appropriately to a new demand or answer complex questions. Often there is a sudden burst of words, without meaning or relevance to what was just said. Such an outburst may terminate the attack, for which there is complete or nearly complete amnesia. In many respects, the attacks resemble episodes of nocturnal sleepwalking. Such attacks of automatic behavior and amnesia are common, occurring in more than half of a large series of patients with narcolepsy-cataplexy (Guilleminault and Dement, 1978). Affected patients are frequently involved in driving accidents, even more frequently than epileptics.


Neurology_Adams

Neurology_Adams. Nocturnal sleep is often disrupted and reduced in amount. The number of hours in a 24-h day spent in sleep by the narcoleptic is not greater than that of a normal individual. Narcoleptics have an increased incidence of sleep apnea and periodic leg and body movements, but not of somnambulism.


Neurology_Adams

Neurology_Adams. Approximately 70 percent of narcoleptics first seeking help will report having some form of cataplexy, and about half of the remainder will develop cataplexy later in life. Cataplexy refers to a sudden loss of muscle tone brought on by strong emotion—that is, circumstances in which hearty laughter or, more rarely, excitement, surprise, anger, or intense athletic activity cause the patient’s head to fall forward, the jaw to drop, the knees to buckle, even with sinking to the ground—all with perfect preservation of consciousness. Cataplectic attacks occur without provocation in perhaps 5 percent of cases. The attacks last only a few seconds or a minute or two and are of variable frequency and intensity. In most of our patients, they have appeared at intervals of a few days or weeks. Exceptionally, there are many attacks daily and even status cataplecticus, in which the atonia lasts for hours. This is more likely to happen at the beginning of the illness or upon discontinuing tricyclic


Neurology_Adams

Neurology_Adams. there are many attacks daily and even status cataplecticus, in which the atonia lasts for hours. This is more likely to happen at the beginning of the illness or upon discontinuing tricyclic medication.


Neurology_Adams

Neurology_Adams. Most attacks of cataplexy are partial (e.g., only a dropping of the jaw or “weakening of the knees”). Wilson found that the tendon reflexes were abolished during the attack. Pupillary reflexes are absent in some cases. Infrequently, cataplexy precedes the advent of sleep attacks, but usually it follows them, sometimes by many years. Sleep paralysis and hypnagogic hallucinations together are stated to occur in about half the patients. Of course, hypnagogic paralysis and hallucinations occur in otherwise normal persons, and normal children, especially when tickled, may laugh to the point of cataplexy. About 10 percent of persons with sleep attacks indistinguishable from those of narcolepsy have none of the associated phenomena (“independent narcolepsy”), and in these cases, REM periods are not found consistently at the onset of sleep (see further on).


Neurology_Adams

Neurology_Adams. Once established, narcolepsy and cataplexy usually continue for the remainder of the patient’s life. The degree of sleepiness rarely lessens, although cataplexy, sleep paralysis, and hallucinations improve or disappear with age in about one-third of patients who have those features (Billiard and Cadilhac). No other condition is consistently associated with narcolepsy-cataplexy, and none develops later.


Neurology_Adams

Neurology_Adams. A familial component has been recognized for years; the risk of narcolepsy in a first-degree relative of an affected individual is 1 to 2 percent, more than 25 times that in the general population. As reviewed by Chabas and colleagues, important insights into the pathogenesis have come from studies of recessively inherited narcolepsy in three species of dogs, in which mutations have been identified in a gene encoding a receptor for the protein hypocretin (Lin et al). These studies implicate the peptide hypocretin in the control of sleep. The hypocretins were thought in the past to regulate feeding behavior and energy metabolism; indeed, they were also designated “orexins,” from the Greek word for appetite. In mice, inactivation of two hypocretin receptors reproduces narcolepsy. In both humans and animals, hypocretin-containing neurons in the hypothalamus send projections widely through the brain and particularly to structures implicated in control of sleep as discussed earlier and


Neurology_Adams

Neurology_Adams. humans and animals, hypocretin-containing neurons in the hypothalamus send projections widely through the brain and particularly to structures implicated in control of sleep as discussed earlier and shown in Fig. 18-4: the locus coeruleus (noradrenergic), the tuberomammillary nucleus (histaminergic), the raphe nucleus (serotonergic), and the ventral tegmental area (dopaminergic).


Neurology_Adams

Neurology_Adams. A number of compelling observations implicate hypocretin and its receptors in human narcolepsy. First, a narcoleptic patient has been described with a mutation in the gene encoding human hypocretin. Second, hypocretin-secreting neurons are depleted in the brains of human narcoleptics, and CSF hypocretin levels are reduced or absent in affected patients. In some studies, the absence of CSF hypocretin distinguished narcoleptic individuals from patients with other categories of sleep disorders.


Neurology_Adams

Neurology_Adams. Several lines of evidence suggest an autoimmune causation for narcolepsy. For example, it has long been known that there is an almost universal association with specific alleles of the histocompatibility antigen HLA-DQB1 (Neely et al; Kramer et al). Therapeutic approaches to narcolepsy based on a presumed autoantibody have also been developed as noted below. Because the mode of inheritance of narcolepsy is not clearly mendelian (Kessler et al), it has been proposed that the disease reflects a genetic predisposition, possibly with a superimposed autoimmune reaction that impairs the function of hypocretin neuronal systems or damages the neurons that secrete the peptide. A relationship has been found between narcolepsy and outbreaks of H1N1 respiratory infection, or administration of the vaccine, implicating an infectious or post infectious inflammatory cause (Han et al; Dauvillers et al, 2010). This is reminiscent of the postinfectious sleep states of von Economo encephalitis.


Neurology_Adams

Neurology_Adams. As mentioned earlier, a secondary or symptomatic narcolepsy syndrome on occasion results from cerebral trauma, multiple sclerosis, craniopharyngioma, or other tumors of the third ventricle or upper brainstem, head trauma, or a sarcoid granuloma within the hypothalamus (Servan et al).


Neurology_Adams

Neurology_Adams. Our understanding of narcolepsy was greatly advanced by the demonstration by Dement and his group that this disorder is associated with a reversal in the order of the two states of sleep, with REM rather than NREM sleep occurring at the onset of the sleep attacks. Not all the sleep episodes of the narcoleptic begin with REM sleep, but almost always a number of sleep attacks with such an onset can be identified in narcoleptic-cataplectic patients in the course of a polysomnographic sleep study. The hypnagogic hallucinations, cataplexy, and sleep-onset paralysis (caused by inhibition of anterior horn cells) all coincide with the REM period. These investigators have also shown that the night sleep pattern of patients with narcolepsy-cataplexy may begin with a REM period. This may occur in normal subjects, though infrequently and usually with severe sleep deprivation. Furthermore, the nocturnal sleep pattern is altered in narcoleptics, who have frequent body movements and transient


Neurology_Adams

Neurology_Adams. in normal subjects, though infrequently and usually with severe sleep deprivation. Furthermore, the nocturnal sleep pattern is altered in narcoleptics, who have frequent body movements and transient awakenings and a decrease in sleep stage N3, as well as in total sleep duration. Another important finding in narcoleptics is that sleep latency (the interval between the point when an individual tries to sleep and the point of onset of EEG sleep patterns), measured repeatedly in diurnal nap situations, is greatly reduced. Thus, narcolepsy is not simply a matter of excessive diurnal sleepiness (essential daytime drowsiness) or even a disorder of REM sleep but a generalized disorganization of sleep–wake function.


Neurology_Adams

Neurology_Adams. The greatest difficulty in diagnosis relates to the problem of separating narcolepsy from the daytime sleepiness of sedentary, obese adults who, if unoccupied, doze readily after meals, while watching television or in the theater. Many of these patients prove to have obstructive sleep apnea. Excessive daytime somnolence, easily mistaken for narcolepsy, may also attend heart failure, hypothyroidism, excessive use of soporific, other medications including antihistamines, use of alcohol, cerebral trauma, and certain brain tumors (e.g., craniopharyngioma; see Table 18-2). A more serious form of recurrent daytime sleepiness, referred to as independent narcolepsy or essential narcolepsy, is described further on. However, both of these forms of daytime drowsiness are isolated disturbances, lacking the other disturbances of sleep and motor activity that characterize the narcolepsy syndrome. The brief attacks of automatic behavior and amnesia of the narcoleptic must be distinguished from


Neurology_Adams

Neurology_Adams. lacking the other disturbances of sleep and motor activity that characterize the narcolepsy syndrome. The brief attacks of automatic behavior and amnesia of the narcoleptic must be distinguished from hysterical fugues and complex partial seizures.


Neurology_Adams

Neurology_Adams. Cataplexy must also be distinguished from syncope, drop attacks (see Chap. 17), and atonic seizures; in atonic seizures, consciousness is temporarily abolished. The careful documentation of narcolepsy by laboratory techniques is imperative when the diagnosis is in doubt, in part because of the potential for abuse of stimulant drugs used for treatment. Overnight polysomnography followed by a standardized multiple sleep latency test, in which the patient is afforded opportunities for napping at 2-h intervals, permit the quantification of drowsiness and increase the probability of detecting short-latency REM activity (within 15 min from the onset of each sleep period). According to some investigators, a reduced level (below 110 pg/mL) of hypocretin in the spinal fluid is virtually diagnostic of narcolepsy in the proper clinical circumstances (see Mignot et al). We would comment, however, that it is not necessary to resort of these studies in clinically typical cases.


Neurology_Adams

Neurology_Adams. No single therapy will control all the symptoms. Narcolepsy responds best to (1) strategically placed 15to 20-min naps (during lunch hour, before or after dinner, etc.); (2) the use of stimulant drugs in the daytime—modafinil, dextroamphetamine sulfate, or methylphenidate hydrochloride to heighten alertness; and (3) antidepressants (sertraline, venlafaxine, protriptyline, imipramine, or clomipramine) for control of cataplexy. All these drugs are potent suppressants of REM sleep. Monoamine oxidase (MAO) inhibitors also inhibit REM sleep and can be used if they are tolerated. Modafinil (200 mg daily, up to 600 mg in divided doses) may prove to be the safest of the stimulants (Fry), but experience with this agent is still being acquired. Methylphenidate, because of its prompt action and relative lack of side effects, is also widely used. It is usually given in doses of 10 to 20 mg tid on an empty stomach. Alternatively, amphetamine 5 to 10 mg may be given 3 to 5 times a day; this is


Neurology_Adams

Neurology_Adams. relative lack of side effects, is also widely used. It is usually given in doses of 10 to 20 mg tid on an empty stomach. Alternatively, amphetamine 5 to 10 mg may be given 3 to 5 times a day; this is ordinarily well tolerated and does not cause wakefulness at night. Pemoline, a potent stimulant (50 to 75 mg daily) is no longer available in the United States because of potential hepatic toxicity. The tricyclic antidepressants had been used to reduce cataplexy, but they have been overtaken by selective serotonin reuptake inhibitors such as sertraline and by norepinephrine reuptake inhibitors such as venlafaxine. Sodium oxybate, whose active agent is gamma-hydroxybutyrate, is also beneficial for cataplexy and narcolepsy in many individuals.


Neurology_Adams

Neurology_Adams. The combined use of these stimulant and tricyclic antidepressant drugs may be indicated. A problem with the stimulant drugs is the development of tolerance over a 6to 12-month period, which requires the switching and periodic discontinuation of drugs. Excessive amounts of amphetamines may induce a schizophreniform psychosis. The stimulant drugs and the tricyclic antidepressants increase catecholamine levels; their chronic administration may produce hypertension. An entirely different approach, based on a presumed autoimmune attack on hypothalamic neurons, has introduced immune globulin infusions in early cases of narcolepsy. This must still be considered preliminary but the results are interesting (see Dauvillers et al, 2004).


Neurology_Adams

Neurology_Adams. Narcoleptics must be warned of the dangers of falling asleep and lapses of consciousness while driving or during engagement in other activities that require constant alertness. The earliest feeling of drowsiness should prompt the patient to pull off the road and take a nap. Long-distance driving should probably be avoided completely.


Neurology_Adams

Neurology_Adams. As has been indicated, recurrent daytime sleepiness may be the presenting symptom in a number of varied disorders other than narcolepsy. When chronic daytime sleepiness occurs repeatedly and persistently without known cause, it is classified as essential or idiopathic hypersomnolence. Roth distinguishes this state from narcolepsy on the basis of longer and unrefreshing daytime sleep periods, deep and undisturbed night sleep, difficulty in awakening in the morning or after a nap (“sleep drunkenness”), all of these occurring in the absence of REM-onset sleep and cataplexy. Admittedly, this condition proves difficult to distinguish from narcolepsy unless laboratory studies exclude the latter, and even then, there is overlap between the two syndromes (Bassetti and Aldrich). Treatment, however, is the same as that for narcolepsy. Idiopathic hypersomnia, as defined in this manner, proves to be a rare syndrome once narcolepsy and all other causes of daytime sleepiness have been excluded.


Neurology_Adams

Neurology_Adams. This state, as remarked earlier, has been induced in animals by lesions in the tegmentum (median raphe nuclei) of the pons. Comparable states are known to occur in humans but are rare. Asomnia in hospital practice is a result of delirium of any type, including delirium tremens and drug-withdrawal states. Drug-induced psychoses and mania may induce a similar state. We have seen a number of patients with a delirious hyperalertness lasting a week or more after temporofrontal cerebral contusions or in association with a hypothalamic lymphoma. None of the various treatments we have tried has been successful in suppressing this state. It was transitory in the traumatic cases.


Neurology_Adams

Neurology_Adams. Several paresthetic disturbances, sometimes distressing in nature, may arise during sleep. Everyone is familiar with the phenomenon of an arm or leg “falling asleep.” Immobility of the limbs and maintenance of uncomfortable postures, without any awareness of them, permit undue pressure to be applied on peripheral nerves (especially the ulnar, radial, and peroneal). Pressure of the nerve against the underlying bone may interfere with intraneural function in the compressed segment of nerve. Sustained pressure may result in a sensory and motor paralysis—sometimes referred to as sleep or pressure palsy. Usually, this condition lasts only a few hours or days, but if compression is prolonged recovery may be delayed. Deep sleep or a stupor, as in alcohol intoxication or anesthesia, renders patients especially liable to pressure palsies merely because they are not able to heed the discomfort of a sustained unnatural posture.


Neurology_Adams

Neurology_Adams. Acroparesthesias are frequent in adult women and are not unknown in men. The patient, after being asleep for a few hours, is awakened by numbness or a tingling, prickling, “pins-and-needles” feeling in the fingers, and hands. There are also aching, burning pains or tightness, and other unpleasant sensations. With vigorous rubbing or shaking of the hands or extension of the wrists, the paresthesia subsides within a few minutes, only to return later or upon first awakening in the morning. At first, there is a suspicion of having slept on an arm, but the frequent bilaterality of the symptoms and their occurrence regardless of the position of the arms dispels this notion. Usually the paresthesia is in the distribution of the median nerves, and almost invariably proves to be caused by carpal tunnel syndrome.


Neurology_Adams

Neurology_Adams. Nocturnal grinding of the teeth, sometimes diurnal as well, occurs at all ages and may be as distressing to the bystander as it is to the patient. It may also cause serious dental problems unless the teeth are protected in some way. There are many hypothetical explanations, all without proof. Stress is most often blamed, and claimants point to EMG studies that show the masseter and temporalis muscles to be excessively contracted. When present in the daytime, it may also represent a fragment of segmental dystonia or tardive dyskinesia. Nocturnal Enuresis (See Also Chap. 25)


Neurology_Adams

Neurology_Adams. Nocturnal Enuresis (See Also Chap. 25) Nocturnal bedwetting with daytime continence is a frequent disorder during childhood, which may persist into adult life. Approximately 1 of 10 children 4 to 14 years of age is affected, boys more frequently than girls (in a ratio of 4:3); even among adults (military recruits), the incidence is 1 to 3 percent. The incidence is much higher if one or both parents were enuretic. Although the condition was formerly thought to be psychogenic, the studies of Gastaut and Broughton revealed a peculiarity of bladder physiology. The intravesicular pressure periodically rises to much higher levels in the enuretic than in normal persons, and the functional bladder capacity of the enuretic is smaller than normal. This suggests a maturational failure of certain modulating nervous influences.


Neurology_Adams

Neurology_Adams. An enuretic episode is most likely to occur 3 to 4 h after sleep onset, and usually, but not necessarily, in stages 3 and 4 sleep. It is preceded by a burst of rhythmic delta waves associated with a general body movement. If the patient is awakened at this point, he does not report any dreams. Imipramine (10 to 75 mg at bedtime) has proved to be an effective agent in reducing the frequency of enuresis. A series of training exercises designed to increase the functional bladder capacity and sphincter tone may also be helpful. Sometimes all that is required is to proscribe fluid intake for several hours prior to sleep and to awaken the patient and have him empty his bladder about 3 h after going to sleep. One interesting patient, an elderly physician with lifelong enuresis, reported that he had finally obtained relief (after all other measures had failed) by using a nasal spray of an analogue of antidiuretic hormone (desmopressin) at bedtime. This has now been adopted for the treatment


Neurology_Adams

Neurology_Adams. had finally obtained relief (after all other measures had failed) by using a nasal spray of an analogue of antidiuretic hormone (desmopressin) at bedtime. This has now been adopted for the treatment of intractable cases. Diseases of the urinary tract, diabetes mellitus or diabetes insipidus, epilepsy, sleep apnea syndrome, sickle cell anemia, and spinal cord or cauda equina disease must be excluded as causes of symptomatic enuresis.


Neurology_Adams

Neurology_Adams. Relation of Sleep to Medical Illnesses The high incidence of thrombotic stroke that is apparent upon awakening, a phenomenon well known to neurologists, has been studied epidemiologically by Palomaki and colleagues. These authors have summarized the evidence for an association between snoring, sleep apnea, and an increased risk for stroke. As already mentioned, cluster headache and migraine have an intricate relationship to sleep, the former almost always occurring during or soon after the first REM period, and the latter often curtailed by a sound sleep.


Neurology_Adams

Neurology_Adams. Patients with coronary arteriosclerosis may show electrocardiogram (ECG) changes during REM sleep, and nocturnal angina has been recorded at this time. Snoring is strongly associated with chronic hypertension. Asthmatics frequently have their attacks at night, but not concomitantly with any specific stage of sleep; they do have a decreased amount of stage N3 sleep and frequent awakenings, however. Patients with hypothyroidism have shown a decrease of stages N3 sleep, and a return to a normal pattern when they become euthyroid. Demented patients generally exhibit reduced amounts of REM and slow-wave sleep, as do children with Down syndrome, phenylketonuria, and other forms of brain damage. Alcohol, barbiturates, and other sedative-hypnotic drugs that suppress REM sleep produce extraordinary excesses of REM during withdrawal periods. This may, in part, account for the hyperactivity and confusion, and perhaps the hallucinosis, seen in withdrawal states.


Neurology_Adams

Neurology_Adams. Allen RP, Chen C, Garcia-Borreguera D, et al: Comparison of pregabalin with pramipexole for restless leg syndrome. N Engl J Med 370:621, 2014. Arnulf I, Lin L, Gadoth N, et al: Kleine-Levin syndrome: A systematic study of 108 patients. Ann Neurol 63:482, 2008. Aserinsky E, Kleitman N: A motility cycle in sleeping infants as manifested by ocular and gross bodily activity. J Appl Physiol 8:11, 1955. Baker SK, Zee PC: Circadian disorders of the sleep–wake cycle. In: Keyger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 3rd ed. Philadelphia, Saunders, 2000, pp 606–614. Bassetti C, Aldrich MS: Idiopathic hypersomnia: A series of 42 patients. Brain 120:1423, 1997. Bassetti C, Mathis J, Gugger M, et al: Hypersomnia following para-median thalamic stroke: A report of 12 patients. Ann Neurol 39:471, 1996. Billiard M, Cadilhac J: Narcolepsy. Rev Neurol (Paris) 141:515, 1985.


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Neurology_Adams. Billiard M, Cadilhac J: Narcolepsy. Rev Neurol (Paris) 141:515, 1985. Boeve BF, Silber MH, Saper CB, et al: Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130:2770, 2007. Braun AR, Balkin TJ, Wesenten NJ, et al: Dissociated pattern of activity in visual cortices and their projections during human rapid eye movement sleep. Science 279:91, 1998. Brownell LG, West PR, Sweatman P, et al: Protriptyline in obstructive sleep apnea. N Engl J Med 307:1037, 1982. Burwell CS, Robin ED, Whaley RD, Bickelmann AG: Extreme obesity associated with alveolar hypoventilation: A pickwickian syndrome. Am J Med 21:811, 1956. Chabas D, Taheri S, Renier C, Mignot E: The genetics of narcolepsy. Annu Rev Genomics Hum Genet 4:459, 2003. Coulter DL, Allen RJ: Benign neonatal sleep myoclonus. Arch Neurol 39:192, 1982. Critchley M: Periodic hypersomnia and megaphagia in adolescent males. Brain 85:627, 1962.


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Neurology_Adams. Coulter DL, Allen RJ: Benign neonatal sleep myoclonus. Arch Neurol 39:192, 1982. Critchley M: Periodic hypersomnia and megaphagia in adolescent males. Brain 85:627, 1962. Culebras A, Moore JT: Magnetic resonance findings in REM sleep behavior disorder. Neurology 39:1519, 1989. Daly D, Yoss R: Narcolepsy. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 15: The Epilepsies. Amsterdam, North-Holland, 1974, pp 836–852. Dauvillers Y, Carlander B, Rivier F, et al: Successful management of cataplexy with intravenous immunoglobulins shortly after narcolepsy onset. Ann Neurol 56:905, 2004. Dauvillers Y, Montplaisir J, Cochen V, et al: Post-H1N1 narcolepsy-cataplexy. Sleep 33:1428, 2010. Dement WC, Carskadon MA, Ley R: The prevalence of narcolepsy. Sleep Res 2:147, 1973. Dement WC, Kleitman N: Cyclic variations in EEG during sleep and their relation to eye movements, bodily motility and dreaming. Electroencephalogr Clin Neurophysiol 9:673, 1957.


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Neurology_Adams. Dement WC, Kleitman N: Cyclic variations in EEG during sleep and their relation to eye movements, bodily motility and dreaming. Electroencephalogr Clin Neurophysiol 9:673, 1957. Earley CJ: Restless legs syndrome. N Engl J Med 348:2103, 2003. Ekbom KA: Asthenia crurum paresthetica (irritable legs). Acta Medica Skand 118:197, 1944. Fry JM: Treatment modalities for narcolepsy. Neurology 50(Suppl):S43, 1998. Gastaut H, Broughton R: A clinical and polygraphic study of episodic phenomena during sleep. Recent Adv Biol Psychiatry 7:197, 1965. Gillin JC, Spinweber CL, Johnson LC: Rebound insomnia: A critical review. J Clin Psychopharmacol 9:161, 1989. Grimaldi D, Silvani A, Benarroch EE, Cortelli P: Orexin/hypocretin system and autonomic control. Neurology 82:271, 2014. Guilleminault C, Dement WC: 235 cases of excessive daytime sleepiness: Diagnosis and tentative classification. J Neurol Sci 31:13, 1977. Guilleminault C, Dement WC: Sleep Apnea Syndromes. New York, Liss, 1978.


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Neurology_Adams. Guilleminault C, Dement WC: Sleep Apnea Syndromes. New York, Liss, 1978. Haba-Rubio J, Prior JO, Guedj E, et al: Kleine-Levin syndrome: functional imaging correlates of hypersomnia and behavioral symptoms. Neurology 79:1927, 2012. Haimovic IC, Berseford HR: Transient unresponsiveness in the elderly. Report of five cases. Arch Neurol 49:35, 1992. Han F, Lin L, Warby SC, et al: Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 70:410, 2011. Hauri P, Olmstead E: Childhood onset insomnia. Sleep 3:59, 1980. Heim B, Djamshidian A, Heidbreder A, et al: Augmentation and impulsive behavior in restless leg syndrome. Coexistence or association? Neurology 87:36, 2016. Herxheimer A, Petrie KJ: Melatonin for the prevention and treatment of jet lag. Cochrane Database Sys Rev 2:2002, CB001520. Hobson JA: Dreaming as delirium: A mental status analysis of our nightly madness. Semin Neurol 17:121, 1997.


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Neurology_Adams. Hobson JA: Dreaming as delirium: A mental status analysis of our nightly madness. Semin Neurol 17:121, 1997. Hobson JA, Lydic R, Baghdoyan H: Evolving concepts of sleep cycle generation: From brain centers to neuronal populations. Behav Brain Sci 9:371, 1986. Kales A, Cadieux RJ, Soldatos CR, et al: Narcolepsy-cataplexy: 1. Clinical and electrophysiologic characteristics. Arch Neurol 39:164, 1982. Kales AL, Kales JD, Soldatos CR: Insomnia and other sleep disorders. Med Clin North Am 66:971, 1982. Katz JD, Ropper AH: Familial Kleine-Levin syndrome: Two siblings with unusually long hypersomnic spells. Arch Neurol 59:1959, 2002. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults. Neurology 40:749, 1990. Kessler S, Guilleminault C, Dement W: A family study of 50 REM narcoleptics. Acta Neurol Scand 50:503, 1974. Kramer RE, Dinner DS, Braun WE, et al: HLA-DR2 and narcolepsy. Arch Neurol 44:853, 1987.


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Neurology_Adams. Kessler S, Guilleminault C, Dement W: A family study of 50 REM narcoleptics. Acta Neurol Scand 50:503, 1974. Kramer RE, Dinner DS, Braun WE, et al: HLA-DR2 and narcolepsy. Arch Neurol 44:853, 1987. Kupfer DL, Reynolds CF: Management of insomnia. N Engl J Med 336:341, 1998. Landolt HP, Glatzel M, Blättler T, et al: Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease. Neurology 66:1418, 2006. Lask B: Novel and non-toxic treatment for night terrors. BMJ 297:592, 1988. Lavault S, Golmard J-L, Groos E, et al: Kleine-Levin syndrome in 120 patients: differential diagnosis and long episodes. Ann Neurol 77:529, 2015. Leu-Semenescu S, Le Corvec T, Groos E, et al: Lithium therapy in Kleine-Levin syndrome. Neurology 85:1655, 2015. Lin L, Faraco J, Li R, Kadotani H, et al: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365, 1999.


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Neurology_Adams. Lin L, Faraco J, Li R, Kadotani H, et al: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365, 1999. Liu HM, Loew JM, Hunt CE: Congenital central hypoventilation syndrome: A pathologic study of the neuromuscular system. Neurology 28:1013, 1978. Lockley SW, Dressman MA, Licamele L, et al: Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 31;386, 2015. Loomis AL, Harvey EN, Hobart G: Cerebral states during sleep as studied by human brain potentials. J Exp Psychol 21:127, 1937. Lu J, Sherman L, Devor M, Saper CS: A putative flip–flop switch for control of REM sleep. Nature 441:589, 2006. Lugaresi E, Cirignorra F, Montagna P: Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry 49:375, 1986.


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Neurology_Adams. Lugaresi E, Cirignorra F, Montagna P: Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry 49:375, 1986. Lugaresi E, Medori R, Montagna P, et al: Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315:997, 1986. Madsen PL, Vorstrup S: Cerebral blood flow and metabolism during sleep. Cerebrovasc Brain Metab Rev 3:281, 1991. Mahowald MW, Schenck CH: REM sleep parasomnias. In: Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Saunders, 2005, pp 897–916. Markand OHN, Dyken ML: Sleep abnormalities in patients with brainstem lesions. Neurology 26:769, 1976. Martin PR, Loewenstein RJ, Kaye WJ, et al: Sleep EEG in Korsakoff’s psychosis and Alzheimer’s disease. Neurology 36:411, 1986. Mellinger GD, Balter MB, Uhlenhoth EH: Insomnia and its treatment: Prevalence and correlates. Arch Gen Psychiatry 42:225, 1985. McEvoy RD, Antic NA, Heeley E, et al: CPAP for Prevention of


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Neurology_Adams. Mellinger GD, Balter MB, Uhlenhoth EH: Insomnia and its treatment: Prevalence and correlates. Arch Gen Psychiatry 42:225, 1985. McEvoy RD, Antic NA, Heeley E, et al: CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea New Engl J Med 375:919, 2016. Mignot E, Lammers GJ, Ripley V, et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59:1553, 2002. Monk TH: Shift work. In: Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 3rd ed. Philadelphia, Saunders, 2000, pp 600–605. Neely SE, Rosenberg RS, Spire JP, et al: HLA antigens in narcolepsy. Neurology 137:1858, 1987. Nogueira De Melo A, Kraus GL, Niedermeyer E: Spindle coma: Observations and thoughts. Clin Electroencephalogr 21(Suppl 3):151, 1990. Ohayon MM, Mahowald MW, Dauvilliers W, et al: Prevalence and comorbidity of nocturnal wandering in the US adult general population. Neurology 78:1583, 2012.


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Neurology_Adams. Ohayon MM, Mahowald MW, Dauvilliers W, et al: Prevalence and comorbidity of nocturnal wandering in the US adult general population. Neurology 78:1583, 2012. Ohayon MM, Mahowald MW, Leger D: Are confusional arousals pathological? Neurology 83:834, 2014. Olson EJ, Boeve BF, Silber MH: Rapid eye movement sleep behavior disorder: Demographic, clinical, and laboratory findings in 93 cases. Brain 123:331, 2000. Palomaki H, Partinen M, Erkinjuntti T, et al: Snoring, sleep apnea syndrome, and stroke. Neurology 42(Suppl 6):75, 1992. Parkes JD: Sleep and Its Disorders. Philadelphia, Saunders, 1985. Pearce JMS: Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry 52:907, 1989. Pérez-Díaz H, Iranzo A, Rye DB, Santamaría J: Restless abdomen. A phenotypic variant of restless leg syndrome. Neurology 77:1283, 2011. Popper KR, Eccles JC: The Self and the Brain. Berlin, Springer-Verlag, 1977.


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Neurology_Adams. Popper KR, Eccles JC: The Self and the Brain. Berlin, Springer-Verlag, 1977. Portilla P, Durand E, Chalvon A, et al: Hypoperfusion temporomésiale gauche en TEMP dans un syndrome de Kleine-Levin. Rev Neurol 158:593, 2002. Postuma RB, Gagnon JF, Vendette M, et al: Quantifying the risk of neurodegeneration disease in idiopathic REM sleep behavior disorder. Neurology 72:1296, 2009. Rechtschaffen A, Gilliland MA, Bergman BM, et al: Physiological correlates of prolonged sleep deprivation in rats. Science 221:182, 1983. Rechtschaffen A, Monroe LJ: Laboratory studies of insomnia. In: Kales A (ed): Sleep: Physiology and Pathology—A Symposium. Philadelphia, Lippincott, 1969, p 158. Rosen GM, Bendel AE, Neglia JP, et al: Sleep in children with neoplasms of the central nervous system: Case review of 14 children: Pediatrics 112:46, 2003. Roth B: Narcolepsy and Hypersomnia. Basel, Springer-Verlag, 1980. Sack RL: Jet lag. N Engl J Med 362:440, 2010.


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Neurology_Adams. Roth B: Narcolepsy and Hypersomnia. Basel, Springer-Verlag, 1980. Sack RL: Jet lag. N Engl J Med 362:440, 2010. Saper CB, Scammell TE, Lu J: Hypothalamic regulation of sleep and circadian rhythm. Nature 437:1257, 2005. Schwartz JW, Stakes WJ, Hobson JA: Transient cataplexy after removal of a craniopharyngioma. Arch Neurol 34:1372, 1984. Servan J, Marchand F, Garma L, et al: Narcolepsie revelatrice d’une neurosarcoidose. Rev Neurol (Paris) 151:281, 1995. Shiromani PJ, Armstrong DM, Berkowitz A, et al: Distribution of choline acetyltransferase immunoreactive somata in the feline brainstem: Implications for REM sleep generation. Sleep 11:1, 1988. Sixel-Döring F, Trautmann E, Mollenhauer B, Trenkwalder C: Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 72:1048, 2011. Solms M: New findings on the neurological organization of dreaming: Implications for psychoanalysis. Psychoanal Q 64:43, 1995.


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Neurology_Adams. Solms M: New findings on the neurological organization of dreaming: Implications for psychoanalysis. Psychoanal Q 64:43, 1995. Solms M: The Neuropsychology of Dreams: A Clinico-Anatomical Study. London, Lawrence Erlbaum Associates, 1996. Stefansson H, Rye DB, Hicks A, et al: A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357:639, 2007. Steriade M, McCormick DA, Senjowski TJ: Thalamocortical oscillations in the sleeping and aroused brain. Science 262:679, 1993. Tinuper P, Cerullo A, Cirignotta F, et al: Nocturnal paroxysmal dystonia with short lasting attacks: Three cases with evidence for an epileptic frontal lobe origin for seizures. Epilepsia 31:549, 1990. Tyler DB: Psychological change during experimental sleep deprivation. Dis Nerv Syst 16:239, 1955. Wilson SAK: Neurology. London, Edward Arnold, 1940, pp 1545–1560.


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Neurology_Adams. Tyler DB: Psychological change during experimental sleep deprivation. Dis Nerv Syst 16:239, 1955. Wilson SAK: Neurology. London, Edward Arnold, 1940, pp 1545–1560. Figure 18-1. Conventional EEG (30 mm/s) of a young healthy woman in stage 2 (N2) sleep showing vertex waves (large arrows) and sleep spindles (small arrows), best seen in the central regions.


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Neurology_Adams. Figure 18-2. Representative polysomnographic recordings from adults in the awake state and various stages of sleep. Recordings are made at conventional sleep laboratory speed of 10 mm/s (i.e., at the paper speed of one-third standard clinical EEG recordings). A. Upper tracings: Awake state (with eyes closed). Alpha rhythms are prominent in EEG. Normally active chin EMG. B. Middle tracings: Stage 1 (N1) sleep. Onset of sleep is defined by the diminished amplitude of alpha waves in the occipital EEG channel (“flat” appearance). C. Lower tracings: Stage 2 (N2) sleep, characterized by appearance of high-amplitude single-complex (K) waves and bursts of 13to 16-Hz waves (sleep spindles) on a background of low frequency. D. Upper tracings: Stage 3 (N3) sleep. Appearance of high-voltage slow (delta) waves. E. Middle tracings: Deepest stage of N3 sleep, with predominant delta-wave activity occupying 50 percent of a 30-s tracing. F. Lower tracings: Rapid eye movement (REM) sleep, characterized


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Neurology_Adams. waves. E. Middle tracings: Deepest stage of N3 sleep, with predominant delta-wave activity occupying 50 percent of a 30-s tracing. F. Lower tracings: Rapid eye movement (REM) sleep, characterized by episodes of REM and occasional muscle twitches in an otherwise flat chin EMG. Technical Note: Four sites from the same montage are illustrated in each recording: C3/A2, left central to right mastoid; O2/A1, right occipital to left mastoid; ROC/A1, right outer canthus to left mastoid; LOC/A2, left outer canthus to right mastoid. A chin EMG tracing is added to each recording. (Adapted with permission from Butkov N. Atlas of Clinical Polysomnography. Vol 1. Synapse Media, Medford, OR, 1996.)


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Neurology_Adams. Figure 18-3. Sleep architecture, or sleep cycles. REM sleep (darkened areas) occurs cyclically throughout the night at intervals of approximately 90 min in all age groups. REM sleep shows little variation in the different age groups, whereas stage 4 sleep decreases with age. Stages 3 and 4 are now considered N3. (Redrawn by permission from Kales, Kales, and Soldatos.)


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Neurology_Adams. Figure 18-4. Schematic representation of the “flip-flop” mechanism of transition between sleep and waking, which is determined by the state of activity of the ventrolateral preoptic nucleus (VLPO). Arrowheads denote excitation and perpendicular line ends are inhibitory. A. During wakefulness, the monoaminergic nuclei (LC, locus ceruleus; TMN, tuberomammillary nucleus; raphe nuclei) inhibit the VLPO, thereby relieving the inhibition of the monoaminergic cells, and that of the orexin (ORX) neurons. Because the VLPO neurons do not have orexin receptors, orexin serves to reinforce the monoaminergic tone, rather than directly inhibiting the VLPO. B. During sleep, firing of VLPO neurons inhibits the monoaminergic cell groups, thereby relieving their own inhibition. This inhibits the orexin neurons, further preventing monoaminergic activation that might interrupt sleep. The mutual inhibition between the VLPO and the monoaminergic cell groups forms a flip-flop switch, which produces sharp


Neurology_Adams

Neurology_Adams. further preventing monoaminergic activation that might interrupt sleep. The mutual inhibition between the VLPO and the monoaminergic cell groups forms a flip-flop switch, which produces sharp transitions in state, but is relatively unstable. The addition of the orexin neurons stabilizes the switch. (Reproduced with permission from Saper, Scammell, and Lu.)


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Neurology_Adams. ABCChin EMGChin EMGR9Relatively low-voltage, mixed-frequency EEGNormally active chin EMGNormally active chin EMGC3/A2O2/A1ROC/A1LOC/A2AlphaAlphaEyes closedSlow-rolling eye movementsK-complexSleep spindleLOC/A2ROC/A1O2/A1C3/A2 Figure 18-2. (Continued) Derangements of Intellect, Behavior, and Language Caused by Diffuse and Focal Cerebral Disease CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory CHAPTER 21 Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum CHAPTER 22 Disorders of Speech and Language


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Neurology_Adams. CHAPTER 21 Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum CHAPTER 22 Disorders of Speech and Language Physicians sooner or later discover, through clinical experience, the need for special competence in assessing the mental faculties of their patients. They must be able to observe with objectivity the patient’s attention, intelligence, memory, judgment, mood, character, and other attributes of cognitive performance, and personality in much the same fashion as they observe the patient’s movements, gait, and reflexes. The systematic examination of these intellectual and affective functions permits the physician to reach conclusions regarding the patient’s mental status and its relationship to his illness. Without such data, there are likely to be errors in the diagnosis and treatment of the patient’s neurologic, general medical, and psychiatric disease.


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Neurology_Adams. The content of this section will be more clearly understood if a few of the introductory remarks to the later section on psychiatric diseases are anticipated here. The main thesis of the neurologist is that mental and physical functions of the nervous system are two aspects of the same neural process. Mind and behavior both have their roots in the self-regulating, goal- seeking activities of the organism, the same ones that provide impulse to all forms of mammalian life. But the prodigious complexity of the human brain permits, to an extraordinary degree, the solving of difficult problems, the capacity for remembering past experiences, and casting them in a symbolic language that can be written and read, and the planning for events that have yet to take place. The constant but sometimes meandering internal verbal experience of this ideation during waking was aptly named “stream of thought” by William James. Somehow there emerges in the course of these complex cerebral functions, a


Neurology_Adams

Neurology_Adams. meandering internal verbal experience of this ideation during waking was aptly named “stream of thought” by William James. Somehow there emerges in the course of these complex cerebral functions, a continuous awareness of one’s self and the operation of one’s psychic processes. It is this continuous inner consciousness that might be called mind. Whether this is an emergent property of various mental functions or simply their representation as an idea in the mind cannot be answered, but any wide separation of the mental from the observable behavioral aspects of cerebral function is probably illusory. Biologists and psychologists have reached this view by placing all known activities of the nervous system (growth, development, behavior, and mental function) on a continuum and noting the inherent purposiveness and creativity common to all of them. The physician is persuaded of the truth of this view through daily clinical experience, in which every possible aberration of behavior and


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Neurology_Adams. inherent purposiveness and creativity common to all of them. The physician is persuaded of the truth of this view through daily clinical experience, in which every possible aberration of behavior and intellect appears at some time or other as an expression of cerebral disease. Furthermore, in many brain diseases, particularly the forms of confusion addressed in the first chapter in this section on confusional states, one witnesses parallel disorders of the patient’s behavior and a dissolution or distortion of the introspective awareness of his own mental capacities.


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Neurology_Adams. The reader will find that Chaps. 19 and 20 are concerned with common disturbances of the sensorium and of cognition, which stand as cardinal manifestations of cerebral diseases. The most frequent of these are delirium and related acute confusional states, as well as disorders of learning, memory, and other intellectual functions. A consideration of these abnormalities leads naturally to an examination of the symptoms that result from focal cerebral lesions, which are discussed in Chap. 22, and of derangements of language, which are discussed in Chap. 22. As emphasized in those chapters, even these disturbances fall between the readily localizable functions of the cerebrum and those that can be assigned only broadly to large regions or systems of the brain.


Neurology_Adams

Neurology_Adams. Because the psychiatric causes of disordered thinking and behavior have special qualities that make them separable from most of the conditions considered in the next several chapters, they are discussed in Chaps. 47 to 49 at the end of the book, rather than here.


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Neurology_Adams. The striking state in which a patient with previously intact mentality becomes confused is observed daily on the medical, surgical, and emergency wards of a general hospital. Occurring, as it often does, during an infection with fever or in the course of a toxic or metabolic disorder (such as renal or hepatic failure) or as an effect of medication, drugs, or alcohol, it never fails to create problems for the physician, nurses, and family. The physician has to cope with the problem of diagnosis, often without the advantage of a lucid history, and any program of therapy is constantly impeded by the patient’s inattention, agitation, sleeplessness, and inability to cooperate. Nurses are burdened with the need to provide satisfactory care and a safe environment for the patient, and at the same time, maintain a tranquil atmosphere for other patients. The family must be supported as it faces the frightening prospect of a deranged mind with peculiar behaviors and all it signifies.


Neurology_Adams

Neurology_Adams. These difficulties are magnified when the patient arrives in the emergency ward, having behaved in some irrational way, and the clinical analysis must begin without knowledge of the patient’s background and underlying medical illnesses. It is our view that such patients should be admitted to a general medical or neurologic ward. Transfer of the patient to a psychiatric service is undertaken only if the behavioral disorder proves impossible to manage on a general hospital service. The definition of normal and abnormal states of mind is difficult because the terms used to describe them have been given so many different meanings in both medical and nonmedical writings. Compounding the difficulty is the fact that the pathophysiology of the confusional states and delirium is not fully understood, and the definitions depend to some extent on their clinical causes and relationships. The following nomenclature has proved useful and is employed in this and subsequent chapters.


Neurology_Adams

Neurology_Adams. Confusion is a general term denoting the patient’s incapacity to think with customary speed, clarity, and coherence. Its most conspicuous attributes are impaired attention denoting reduced power of concentration, accompanied usually by disorientation—which may be manifest or is demonstrated only by direct questioning—inability to properly register immediate events and to recall them later, a reduction in the amount and quality of all mental activity, including the normally constant inner ideation and sometimes, by the appearance of bewilderment. Thinking, speech, and the performance of goal-directed actions are less affected but are nevertheless impersistent or abruptly arrested by the intrusion of the slightest external stimulus. Reduced perceptiveness and accompanying visual and auditory illusions or hallucinations are variable features that may be appended to the picture. This is what may be termed the global confusional state.


Neurology_Adams

Neurology_Adams. These disturbances appear in many contexts. The medical and psychiatric literature has adopted the term delirium to describe all confusional states (discussed further on). We try to retain the term delirium to describe a special activated state of agitation, hallucinations, and sometimes tremulousness, which is invariably accompanied by the confusional state. Also, as pointed out in Chap. 16 on coma, a confusional state may appear at any stage in the evolution and resolution of a number of diseases that lead to drowsiness, stupor, and coma—typically in the metabolic encephalopathies but also in diseases affecting those parts of the brain that maintain normal arousal.


Neurology_Adams

Neurology_Adams. Confusion is also a characteristic feature of the chronic syndrome of dementia, where it is ultimately the product of failure of cognition, language, memory, and other intellectual functions; there it is the long-standing and progressive nature of the mental confusion that differentiates dementia from the acute confusional and delirious states that carry quite different implications. Finally, intense emotional disturbances, of either manic or depressive type, may interfere with attentiveness and coherence of thinking and thereby produce an apparent confusional state.


Neurology_Adams

Neurology_Adams. Restricted forms of what could be called a type of confusion appear as a result of certain focal cerebral lesions, particularly of the frontal, parietal, and temporal lobe association areas. Then, instead of a global inattention and incoherence, there are specific and circumscribed syndromes, such as unilateral neglect of self or of the environment, inability to identify persons or objects, and sensorimotor defects as described in Chap. 21. Yet another special form of confusion arises as a result of disordered language function, which also alters the stream of thought; this aphasia is a consequence of lesions in the language areas of the left temporal lobe. These are considered separately in Chap. 22.