EDS is usually the first symptom of narcolepsy. The EDS of narcolepsy can occur as discrete “sleep attacks” or as constant sleepiness with intermittent worsening. Unrelenting EDS is usually the first and most prominent symptom of narcolepsy. Sleepiness may occur throughout the day, regardless of the amount or quality of prior nighttime sleep. Sleep episodes may occur at work and social events, while eating, talking, and driving, and in other similarly inappropriate situations. Only temporary relief is gained with napping. It has been said that falling asleep while standing or eating is especially suggestive of narcolepsy. Although patients may sleep at every hour of the day, the total sleep time (TST) over a 24-hour period is normal or only slightly increased (23,25,26). As mentioned previously.

Cataplexy is characterized by the sudden, temporary loss of bilateral muscle tone with preserved consciousness triggered by strong emotions, such as laughter, anger, or surprise (17,21,22,27). When loss of muscle strength is severe, almost all the voluntary muscles in the body are affected, leading to complete collapse. The muscles of the eyes are not affected during cataplexy; individuals can move their eyes during a cataplectic episode. Diaphragmatic activity is also not impaired. In mild cases of cataplexy, the loss in muscle strength can be quite subtle, partially involving only a few muscle groups.
For example, partial neck muscle weakness may cause the patient to have difficulty in keeping the head erect (head nodding), ptosis, or difficulty in speaking. In some patients, partial attacks are more frequent than complete attacks. Loss of muscle function may not be evident, and the patient may experience only a vague feeling of weakness. In one study, the legs and knees were most frequently affected (27). Patients may fall to the ground, and injuries do occur. However, most people are able to find support at the onset of an attack. The attacks start abruptly and usually take several seconds to reach their maximum intensity. Episodes of cataplexy usually last from seconds to minutes; rarely does an attack last any longer than 2 minutes. Clinical signs during an attack are the loss of muscle tone and abolished tendon reflexes. The phenomenon of virtually continuous attacks of cataplexy (status cataplecticus) can occur after sudden withdrawal of medications that suppress cataplexy.

Cataplexy occurs during times of intense emotional states. Unfortunately, up to 30% of patients with all causes of daytime sleepiness may report some sensation of weakness during emotion (27). A systematic survey of symptoms of muscle weakness associated with emotion in a large group of patients with daytime sleepiness found that weakness during joking (telling or hearing a joke), laughter, and anger were the most specific for cataplexy associated with narcolepsy (27). Involvement of the legs also seemed to be more specific for narcolepsy.

During the attack, the patient is completely awake and later will have total recall of the entire event. If episodes last longer than a few minutes, the patient may transition into REM sleep and experience HH. During an attack of cataplexy, there are cardiovascular changes consisting of increased blood pressure and decreased heart rate. The decreased heart rate is secondary to the increased blood pressure (28).

Isolated cataplexy can rarely occur with syndromes other than idiopathic narcolepsy. It has been reported in Coffin—Lowry syndrome (29,30), the Prader-Willi syndrome (31), Nieman-Pick Disease type C (32,33 and 34), Moebius syndrome (35), and Norrie disease (36,37). These patients have mental retardation and/or obvious neurologic deficits in contrast to the patient with “idiopathic” narcolepsy. The Coffin-Lowry syndrome is a rare X-linked disorder in which affected males demonstrate severe mental retardation with prominent dysmorphic features usually affecting the face and hands. Typical facial features include a prominent forehead, hypertelorism, a flat nasal bridge, downward sloping palpebral fissures, and a wide mouth with full lips. Cataplexy may be seen in up to 10% of children with Niemann-Pick type C disease
(32,33 and 34). This is a rare autosomal recessive disorder characterized by lysosomal accumulation of unesterified cholesterol in many tissues as well as lysosomal storage of sphingolipids in the brain and liver. The clinical manifestations and severity are variable. Classic findings include hepatosplenomegaly, vertical supranuclear gaze palsy, ataxia, dystonia, and dementia. In one recently reported case, the CSF hypocretin was reduced, but not into the narcolepsy range (34). Cataplexy has been reported in children with Moebius syndrome (35). The Moebius syndrome consists of congenital paresis of the seventh cranial nerve, orofacial and limb malformations, and mental retardation. Norrie disease is a rare genetic condition that has also been associated with cataplexy. It is an X-linked recessive disorder causing ocular atrophy, mental retardation, deafness, and dysmorphic features (36). Monoamine oxidase (MAO) defects occur in some patients (37). On the basis of a questionnaire study, one group of investigators has found cataplectic attacks among patients with Wilson’s disease (38). However, further studies will be needed before this becomes generally accepted.

The hallucinations of narcolepsy that occur at nocturnal sleep onset are called hypnagogic and those on awakening are termed hypnopompic. The hallucinations are typically bizarre and may be frightening. Patients sometimes have a fair degree of insight that they are hallucinatory in nature, but often consider them no less frightening. The duration is usually <10 minutes, and the frequency is quite variable. Visual imagery is the predominant feature for many patients. Colored forms that may be changing are sometimes of intense hues and dramatically described. A commonly described vision is that of an animal or stranger in the room. Auditory or vestibular hallucinations (sensation of falling) may also occur. Early series reported that about 30% of patients with narcolepsy had sleep-related hallucinations (2).

However, later series have reported proportions up to 70% in groups of NwithC (20). Aldrich studied the results of questionnaires in groups with NwithC, NwithoutC, and IH. The proportion of NwithC patients reporting sleep-related hallucinations was higher than in the NwithoutC or IH groups. The proportion reporting hallucinations in the IH group was slightly higher than in the NwithoutC group (20).

SP is partial or complete paralysis during the onset of sleep or upon awakening. Patients are awake and conscious during the attack. There is no emotional precipitant. The episodes may last longer than a typical cataplectic attack. People who experience SP sometimes experience hallucinations simultaneously. Early series reported about 25% of patients with narcolepsy having SP (2,23). Later series have found that up to 50% to 80% of patients with NwithC report SP (17,20). Aldrich found that more patients with NwithC reported SP than in groups of NwithoutC patients with and IH (20). The proportion of patients reporting SP was similar in the NwithoutC and IH groups.

Adequate ventilation is maintained during SP as diaphragmatic function is spared. However, some patients have a sensation of dyspnea. SP is often very frightening, due to the inability to move, speak, or communicate during the episode. SP may also occur in the general population, but usually is a fairly uncommon event. In normal subjects, SP often follows periods of sleep deprivation or reduced sleep.

Patients with narcolepsy often experience disturbed nighttime sleep with tossing and turning in bed, leg jerks, nightmares, and frequent awakenings. In general, NwithC patients have more disturbed sleep than NwithoutC patients (20). Automatic behaviors occur for which there may be partial amnesia. For example, patients report driving a car and not remembering the trip. They may find themselves doing activities that make no sense, like putting salt in iced tea. These episodes typically involve activities that are habitual or not demanding of skill. Inattentiveness related to drowsiness may occur. Aldrich reported that the proportions of patients reporting automatic behavior were similar in groups of NwithC, NwithoutC, and IH (20). Patients with narcolepsy may also have REM behavior disorder (39). In this disorder, skeletal muscle atonia is absent during REM sleep and dreams may be acted out. As the hypocretin system has affects on appetite, perhaps it is not surprising that some patients with NwithC have an increased body mass index (BMI) (24,40). Obstructive sleep apnea (OSA) is also not uncommon (41). If cataplexy is not present, narcolepsy may be suspected only if daytime sleepiness persists after adequate treatment of the sleep apnea.

A number of areas in the brain are thought to be important for wakefulness and project to the cortex either directly or via the thalamus (6,50,51) (Fig. 14-1; Table 14-3). Cholinergic neurons in the lateral dorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei located in the dorsal pons release acetylcholine and project to the thalamus, producing thalamocortical activation. A population of these neurons is active only during wakefulness (“wake on”), whereas another population is active during both wakefulness and REM sleep (wake on-REM on). Noradrenergic neurons releasing NE are located in the locus caeruleus (LC) situated in the caudal pons/rostral medulla. Serotonergic neurons of the dorsal raphe nuclei (DRN) in the pons release serotonin (5HT). These noradrenergic and serotonergic neurons project to the cortex and other brainstem nuclei and are most active during wakefulness, less active during NREM sleep, and minimally active during REM sleep (52,53). The ascending pathways from the LDT/PPT, LC, and DRN are sometimes referred to as the ascending reticular-activating system. Histaminergic neurons in the tuberomammillary nucleus (TMN) in the ventral posterior hypothalamus also contribute to pathways maintaining wakefulness. These neurons are active during wake and inactive during NREM and REM sleep (54). Dopaminergic transmission also appears to be important for promoting wakefulness, but the site(s) of action is (are) not known with certainty. Amphetamines are believed to promote wakefulness by increasing extracellular concentrations of dopamine (55,56). The dopaminergic area in the ventral tegmental area (VTA) of the midbrain is believed to have important projections to the LC (57,58). By altering LC activity, dopaminergic neurons or dopaminergic agonists/antagonists may have an important effect on wakefulness and sleep (59,60). The activity of dopaminergic neurons does not vary with sleep state (61). The activity of selected brain areas during wake and sleep is summarized in Table 14-4.