A hundred years of narcolepsy research.

The emergence of a clinical syndrome: The first convincing descriptions of narcolepsy-cataplexy were reported in Germany by Westphal (1877) (100) and Fisher (1878) (25). The unique association of episodes of muscle weakness triggered by excitement and sleepiness were described in these two reports. In both cases, hereditary factors were noted, with the mother of Westphal’s patient and one sister of Fisher’s patient presenting narcolepsy symptoms. The leading hypothesis to explain narcolepsy at the time was to refer to the well publicized case of von Zastrow. Von Zastrow was a recently arrested pathological rapist widely believed to experience pathological sleepiness as a result of repressed homosexuality and excessive masturbation. Gelineau (1880) (28, 29) is widely recognized for giving narcolepsy its name and for recognizing the disorder as a specific clinical entity. Its description of a wine cask maker with narcolepsy in la Gazette des hopitaux de Paris was classical but Gelineau did not strictly differentiate muscle weakness episodes and sleep attacks triggered by emotions. Rather, Gelineau suggested a common physiology for these two symptoms. Loewenfeld (1902), was the first to give a name to muscle weakness episodes triggered by emotions or “cataplexy” (53). The 1917-1927 epidemic of encephalitis lethargica led to a renewed interest in narcolepsy and sleep research but also added much confusion to the nosological definition of narcolepsy. Encephalitis lethargica often presented initially with somnolence and the term “narcolepsy” was often used to describe any form of daytime sleepiness. The association of somnolence and occulomotor paralysis also led to the pioneer work of Von Economo (1930) and the recognition of the posterior hypothalamus as a critical region for the promotion of wakefulness (98). In fact, Von Economo should be credited as being one of the first investigators to correctly propose that a region in the posterior hypothalamus was lesioned in human narcolepsy. In 1930, he wrote: “it is very probable, though not proved, that the narcolepsy of Gelineau, Westphal and Redlich has its primary cause in an yet unknown disease of that region” (98). As narcolepsy with cataplexy was also observed in some cases of encephalitis lethargica, clinicians long debated the existence of idiopathic narcolepsy and the importance of cataplexy for defining the clinical entity. Large case series of narcolepsy-cataplexy were reported by Addie (1926) (1), Wilson (1927) (101) and Daniels (1934) (17). The review by Daniels is considered by many as one of the most insightful clinical reviews published to this date. Further work at the Mayo Clinic, by Yoss and Daly (103) and in Prague by Bedrich Roth (91), then led to the classic description of the narcolepsy tetrad. Various methods were initially proposed in the treatment of narcolepsy, including intrathecal injection of air, cerebrospinal fluid removal and X-ray irradiation of the hypothalamic region. Ephedrine treatment was generally used as the only marginally effective treatment for daytime sleepiness until Prinzmetal and Bloomberg introduced amphetamines in 1935 (87). Yoss and Daly introduced methylphenidate in the 1960s (104). Shortly after the discovery of t r icycl ic antidepressants in 1957, Akimoto, Honda and Takahashi used imipramine in the treatment of human cataplexy (2), e s t a b l i s h i n g t h e d u a l stimulant/antidepressant pharmacological treatment most commonly used in narcoleptic patients to this date.