History of narcolepsy at Stanford University

Abstract

Although narcolepsy was first described in the late nineteenth century in Germany and France, much of the research on this disorder has been conducted at Stanford University, starting with Drs. William C. Dement and Christian Guilleminault in the 1970s. The prevalence of narcolepsy was established, and a canine model discovered. Following the finding in Japan that almost all patients with narcolepsy carry a specific HLA subtype, HLA-DR2, Hugh Mac Devitt, F. Carl Grumet, and Larry Steinman initiated immunological studies, but results were generally negative. Using the narcoleptic canines, Dr. Nishino and I established that stimulants increased wakefulness by stimulating dopaminergic transmission while antidepressants suppress cataplexy via adrenergic reuptake inhibition. A linkage study was initiated with Dr. Grumet in 1988, and after 10 years of work, the canine narcolepsy gene was cloned by in 1999 and identified as the hypocretin (orexin) receptor 2. In 1992, studying African Americans, we also found that DQ0602 rather than DR2 was a better marker for narcolepsy across all ethnic groups. In 2000, Dr. Nishino and I, in collaboration with Dr. Lammers in the Netherlands, found that hypocretin 1 levels in the cerebrospinal fluid (CSF) were undetectable in most cases, establishing hypocretin deficiency as the cause of narcolepsy. Pursuing this research, our and Dr. Siegel’s group, examining postmortem brains, found that the decreased CSF hypocretin 1 was secondary to the loss the 70,000 neurons producing hypocretin in the hypothalamus. This finding revived the autoimmune hypothesis but attempts at demonstrating immune targeting of hypocretin cells failed until 2013. At this date, Dr. Elisabeth Mellins and I discovered that narcolepsy is characterized by the presence of autoreactive CD4+ T cells to hypocretin fragments when presented by DQ0602. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, our groups also established that a small epitope of pH1N1 resembles hypocretin and is likely involved in molecular mimicry. Although much remains to be done, these achievements, establishing hypocretin deficiency as the cause of narcolepsy, demonstrating its autoimmune basis, and showing molecular mimicry between hypocretin and sequences derived from a pandemic strain of influenza, are likely to remain classics in human immunology.

Challenges in the development of therapeutics for narcolepsy

“…The hypothesis that narcolepsy is an autoimmune disease that targets Hcrt neurons seems plausible but the mechanism has remained elusive for decades (Carlander et al, 1993; Mignot, 2014). Autoantibodies against HCRT peptides, HCRT receptors, or antigens co-localized on Hcrt neurons have evaded detection in numerous studies (Black et al, 2005; Overeem et al, 2006; Tanaka et al, 2006).…”

The Development of Sleep Medicine: A Historical Sketch

“…54 Finally, molecular genetic studies in animal models of the disease led to the detection of orexin/hypocretin, a transmitter of hypothalamic origin with essential functions for vigilance regulation, which is unusually low or absent in the majority of patients with narcolepsy-cataplexy. 38 …”

“…A most recent treatment approach is based on the principle to modulate the neurotransmitter orexin or hypocretin that is essentially involved in the regulation of wakefulness. 38 Although pharmacological substances have been shown to be effective for the treatment of insomnia, problems such as non-responding to treatment, loss of efficacy, unwanted effects such as, e.g., hangover and rebound after discontinuation remain. Thus it is not surprising that the debate how to best treat sleeplessness is ongoing, also in this journal.…”

Diagnosis and management of narcolepsy in the Indian scenario

“…The landmark discovery of sleep onset REM periods (SOREMPs) was made by Yoss, Daly, and Vogel. [2] The detection of HLA-DQB1*602 observed in nearly two-thirds of the patients, and reduced levels of hypocretin-1 in the cerebrospinal fluid (CSF) of patients with narcolepsy-cataplexy phenotype have broadened the perspective of this primary sleep disorder of central origin. [345] Autoreactive CD4 + T-cells triggered by environmental stimuli like viruses or vaccination, which are able to recognize fragments of hypocretin when presented by HLA-DQB1*602, are now believed to be the causative mechanism for destruction of the hypothalamic neurons resulting in narcolepsy.…”

“…[345] Autoreactive CD4 + T-cells triggered by environmental stimuli like viruses or vaccination, which are able to recognize fragments of hypocretin when presented by HLA-DQB1*602, are now believed to be the causative mechanism for destruction of the hypothalamic neurons resulting in narcolepsy. [2]…”