Orexin and Human Narcolepsy: The Story Continues
Abstracts & Commentary
Sources: Scammell TE, et al. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology. 2001;56:1751-1753; Arii J, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology. 2001;56:1775-1776; Dalal MA, et al. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology. 2001;56:1749-1751.
The past 2 years have been a gold rush in our understanding of the biological basis of narcolepsy. Progress in this area is summarized in recent editorials by Fred Plum (Neurology Alert. 2000;19:25-27) and Silber and Rye (Neurology. 2001; 56:1616-1618).
The peptides orexin A and orexin B (also termed hypocretin 1 and hypocretin 2) were discovered in the late 1990s (Sakurai et al. Cell. 1998;92:573-585). These peptides are largely distributed in specific nuclei of the hypothalamus and reticular activating system and were first described as possessing potent appetite-stimulating effects. The Silber and Rye editorial includes a diagram of the distribution of orexin-positive neurons.
In 1999, Lin and colleagues reported mutations in 1 of the 2 known hypocretin (Hcrt) receptors (Hcrt-2) in narcoleptic canines (Cell. 1999;98:409-412). Also, transgenic mice that bore mutant Hcrt receptors (Chemelli RM, et al. Cell. 1999;98:437-451) displayed cataplexy and altered REM sleep. Thus, as of 1999, it was clear that the orexin system played a crucial role in animal models of narcolepsy. It remained to be shown that this system had a similar role in human narcolepsy. Peyron and colleagues described mutations in Hcrt receptors in a case of early onset narcolepsy (Nat Med. 2000;6:991-997), but, unlike the dog, the majority of cases of human narcolepsy are not associated with mutations in Hcrt receptor. Both Peyron et al and Thannickal and colleagues (Neuron. 2000;27:469-474) found reduced numbers of orexin-containing neurons in human narcoleptic brains. Also, several groups have reported extremely low levels of orexin in the cerebrospinal fluid of narcoleptic patients. Thus, many cases of human narcolepsy can be explained by a selective degeneration of orexin-containing neurons.
Although most cases of human narcolepsy are idiopathic, this disorder has been rarely described in the context of brain injury. Scammell and colleagues recently reported a 23-year-old man with a history of craniopharyngioma who developed an extensive diencephalic stroke at age 18 immediately following tumor resection. Although he made a substantial neurological recovery, he subsequently developed all of the salient features of the narcoleptic tetrad (hypersomnolence, cataplexy, sleep paralysis, and hypnagogic hallucinations). Unlike most patients with idiopathic narcolepsy, this patient was negative for the HLA-DQB1*0602 allele. Scammell et al found an approximately 40% reduction in CSF orexin levels in this patient.
Arii and colleagues described another patient, a 16-year-old girl, who developed intermittent daytime somnolence approximately 4 months following resection of a hypothalamic Grade 2 pilocytic astrocytoma. Other components of the narcoleptic tetrad were not present in this patient. She was found to have an approximately 60% reduction in CSF orexin A (hypocretin-1). It is interesting that while Scammell et al and Arii et al found reductions in CSF orexin A in their patients with "secondary" narcolepsy, the reductions were not as profound as those reported in patients with primary, idiopathic narcolepsy.
If brain orexin deficiency is indeed central to most cases of human narcolepsy, it points the way to potential novel treatments. One potential treatment is orexin (a 115-amino acid peptide) itself. Kastin and Akerstrom showed that, in mice, orexin A could readily penetrate the blood brain barrier by simple diffusion (J Pharmacol Exp Ther. 1999;289:219-223). However, Dalal et al showed that, in humans, this must not be the case. They examined blood and CSF orexin A levels in 11 narcoleptic patients. CSF orexin A levels were markedly (> 90%) reduced as compared to normal control. Plasma orexin A levels were not statistically different from control. Thus, orexin A itself is unlikely to be of therapeutic value in human narcolepsy. However, it may be that bioactive fragments of orexin A may be of value.
Commentary
In our view, the recent findings regarding the pathophysiology of narcolepsy represent one of the most exciting developments in neurology in the past few years. Neurologists should pay special attention to this field, as it is likely that developments which are likely to directly bear on patient care will rapidly emerge. One can predict that drugs modulating the orexin system will soon find their way into the therapeutic armamentarium. Indeed one may already have: there is some evidence that the analeptic drug Provigil (modafinil) activates orexin-containing neurons (Chemelli RM, et al. Cell. 1999;98:437-451) in experimental animals. —Rosario R. Trifiletti
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