Progress in Neurobiology Vol. 41, pp. 533 to 541, 1993 0301-0082/93/$24.00 Printed in Great Britain. All rights reserved © 1993 Pergamon Press Ltd THE NEUROBIOLOGY OF NARCOLEPSY-CATAPLEXY MICHAEL S. ALDRICH Department of Neurology, Sleep Disorders Center, University of Michigan Medical Center, Ann Arbor, MI, U.S.A. (Received 17 July 1992) CONTENTS 1. Introduction 533 2. Clinical aspects 533 2.1. Sleepiness and sleep attacks 533 2.2. Cataplexy and related symptoms 534 2.3. Clinical variants 534 2.3.1. Narcolepsy without cataplexy 534 2.3.2. Idiopathic hypersomnia 534 2.3.3. Symptomatic narcolepsy 534 2.4. Treatment 534 3. Pathophysiology 535 4. Neurobiological studies 535 4.1. The canine model of narcolepsy 535 4.2. Pharmacology of human cataplexy 537 4.3. Postmortem studies 537 5. Genetic and family studies 537 6. Summary and conclusions 539 References 539 1. INTRODUCTION 2. CLINICAL ASPECTS Narcolepsy is a specific neurological disorder Narcolepsy has a prevalence that varies worldwide characterized by excessive sleepiness that cannot be from as little as 0.0002% in Israel to 0.16% in Japan; fully relieved with any amount of sleep and by in North America and Europe the prevalence is about abnormalities of rapid eye movement (REM) 0.03-0.06% (Dement et al., 1972; Honda, 1979; Lavie sleep. About two-thirds of patients also have brief and Peled, 1987). The onset of narcoleptic symptoms, episodes of muscle weakness usually brought on by usually in the second or third decade of life, may emotion, referred to as cataplexy. The disorder gener- occur over a few days or weeks or it may be so ally begins in adolescence and continues throughout gradual that the loss of full alertness is unrecognized life. by family or friends. The onset may be attributed to Over the past three decades, there has been remark- a variety of antecedent events including psychological able progress in understanding the fundamental or physical stress, minor or major head trauma, mechanisms responsible for narcoleptic symptoms. infections, drug abuse, or pregnancy, but whether Narcolepsy is associated with the premature onset of these precipitants contribute to development of the REM sleep and studies of the neuroanatomical and syndrome or are just coincidental i~ uncertain. neurochemical substrate of REM sleep, combined with pharmacological, physiological, genetic and 2.1. SLEEPINESS AND SLEEP ATTACKS molecular studies of narcolepsy have led to striking advances. This article provides an overview of the Excessive sleepiness and cataplexy are not the only clinical syndrome followed by a presentation symptoms of narcolepsy but they are usually the most of current views of its pathophysiology and neuro- troublesome. Sleepiness is more characteristic than an biology. increase in actual sleep time; the amount of sleep obtained over 24 hr is increased only slightly because the daytime sleep episodes are offset by frequent nocturnal awakenings. Narcoleptic sleepiness is similar to the sleepiness Address correspondence to M. S. Aldrich, Sleep Dis- that occurs with sleep deprivation in normal people: orders Center, Department of Neurology Taubman Center it is most apparent in boring, sedentary situations and 1920/0316, University of Michigan Medical Center, 1500 is partially relieved by stimulation or movement. East Medical Center Drive, Ann Arbor, MI 48109-0316, Narcoleptic sleepiness fluctuates from minute to U.S.A. minute and varies between patients: it may be mild 533 534 M.S. ALDR1CH and easily overcome by stimulation or it may be 2.3. CLINICAL VARIANTS severe and overwhelming as soon as the patient sits down. The inability to obtain full alertness after any 2.3.1. Narcolepsy without cataple.xy amount of night-time or daytime sleep is the feature In the one-third of patients with narcolepsy who do that distinguishes narcoleptic sleepiness from sleepi- not have cataplexy, age of onset, premature occur- ness associated with sleep deprivation. rence of REM sleep and severity of sleepiness are Although spontaneous daytime sleep episodes may similar to patients with narcolepsy-cataplexy, but appear paroxysmal, similar to epileptic seizures, they sleep paralysis, hypnagogic hallucinations and severe are preceded by electrophysiological evidence of in- nocturnal sleep disruption are less common (Rosen- creasing drowsiness; thus sleep "attacks" are simply thal et al., 1990). As cataplexy may develop decades episodes of falling asleep. Because narcoleptics lack after the onset of sleepiness, the eventual occurrence personal experience of full alertness and become of cataplexy can never be excluded in a given patient. habituated to chronic drowsiness, they may not per- Genetic and family studies (see below) suggest that ceive sleepiness in the usual way; this lack of aware- narcolepsy without cataplexy is probably a less severe ness probably accounts for descriptions of "sleep manifestation of the same disorder. attacks". Chronic sleepiness leads to memory disturbances, visual problems and episodes of amnesia lasting for 2.3.2. Idiopathic hypersomnia seconds to 30 minutes or more, associated with semi-purposeful activity, referred to as automatic Patients with this syndrome have excessive sleepi- behavior. Memory problems are probably caused by ness without cataplexy or abnormalities of REM drowsiness and brief episodes of sleep with associated sleep. Although the syndrome is unrelated to nar- impaired attention and concentration rather than by colepsy in most cases, its occurrence in some family a specific disturbance of brain regions involved in members of narcoleptics and the fact that some memory. Failure of fusion induced by drowsiness in patients with this syndrome eventually develop cata- exophoric patients is the likely cause of blurred and plexy and REM sleep abnormalities suggest that double vision. Episodes of automatic behavior occasionally it may be a variant of narcolepsy. usually occur during monotonous or repetitive activi- ties and may be associated with brief pauses in speech 2.3.3. Symptomatic narcolepsy or movement, irrelevant words or remarks and non- sensical activities. Acquired brain lesions as a cause of narcolepsy have been of interest since cases of narcolepsy were described following the epidemic of encephalitis lethargica more than 60 years ago. Although post-en- 2.2. CATAPLEXY AND RELATED SYMPTOMS cephalitic narcolepsy is now extremely rare, either Brief episodes of weakness brought on by excite- from death of affected patients or a change in disease ment or emotion, called cataplexy, occur in about patterns, narcolepsy can develop in association with two-thirds of patients and are almost unique to brain lesions adjacent to the third ventricle, an area narcolepsy. Precipitants of cataplexy include laugh- concerned with sleep-wake regulation (see Aldrich ter, anger, embarrassment, excitement and athletic and Naylor, 1989 for review). Although many such activities. With severe attacks, there is complete patients have the HLA marker associated with idio- atonic areflexic paralysis of striated muscles sparing pathic narcolepsy (see below), this is not enough to only respiratory muscles; the more common milder suggest that narcolepsy can occasionally arise from episodes can cause facial weakness, slurred speech, brain lesions alone in the absence of the usual genetic drooping eyelids, weakness of grip, head nodding, or substrate. slight buckling at the knees. Episodes last from a few seconds to several minutes; consciousness is not 2.4. TREATMENT impaired initially but longer episodes may be associ- ated with auditory, visual, or tactile hallucinations Although narcoleptic symptoms respond to medi- and the onset of REM sleep. cation, they are usually not fully controlled. Thus, Two other symptoms, sleep paralysis and hypna- maintaining alertness and avoiding cataplexy during gogic hallucinations, are common in narcolepsy. Sleep specified times of the day, such as during work, paralysis refers to episodes occurring at sleep onset or school, or driving, are the main goals of therapy. For upon awakening of inability to move, sometimes sleepiness, amphetamines and related compounds associated with a sensation of struggling to move or such as methylphenidate and pemoline are the most awaken. They last up to several minutes and end effective medications. Many clinicians also rec- spontaneously or after mild stimulation. Hypnagogic ommend one or more short naps each day; such naps hallucinations also occur during the transitions be- often provide a period of relative alertness lasting tween sleep and wakefulness. They resemble dreams 1-2 hr. Tricyclic anti-depressants are the most effec- in that the apparent reality of visual, tactile, or tive medication for the treatment of cataplexy and auditory features is usually unquestioned, but they permit almost complete control of the symptoms in differ because some awareness of the environment is about 80% of patients. However, patients with Severe preserved. Unlike cataplexy, sleep paralysis and hyp- cataplexy may develop tolerance to their effects and nagogic hallucinations can occur in otherwise normal a temporary withdrawal of medication may be re- people after sleep deprivation or a change in sleep quired to restore efficacy. Abrupt discontinuation of schedule. anti-cataplectic medication can lead to nearly con- NEUROBIOLOGY OF NARCOLEPSY~ATAPLEXY 535 tinuous incapacitating cataplexy lasting for several ements for the generation of REM sleep are located hours or days. in the ports. The rostral ponfine