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).
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.
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 shown in Fig. 18-4: the locus coeruleus (noradrenergic), the tuberomammillary nucleus (histaminergic), the raphe nucleus (serotonergic), and the ventral tegmental area (dopaminergic).
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.
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.
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).