Abstracts & Commentary
Commentary by Charles P. Pollak
Synopsis: IgG from all narcolepsy patients significantly enhanced bladder contractile responses to the muscarinic agonist carbachol and to neuronally released acetylcholine compared with control IgG (P < 0.0001), whereas contraction of the sympathetically innervated vas deferens was unaltered.
Sources: Smith AJF, et al. A Functional Autoantibody in Narcolepsy. Lancet. 2004:364:2122-2124. Wise MS. A Functional Autoantibody in Human Narcolepsy? Lancet. 2004;364:2076-2077.
Immunologists in Australia have just taken an important step in unraveling the pathogenesis of narcolepsy, as well as making the diagnosis. Smith and colleagues had previously developed bioassays to detect functional autoantibodies against muscarinic receptors and calcium channels that were undetectable by conventional immunoassay. The contraction of mouse detrusor muscle strips stimulated with either carbachol or electrical fields was greatly enhanced by exposing them to IgG from 9 patients with narcolepsy (it has long been known that narcolepsy involves cholinergic hypersensitivity) but not from controls. Smith et al explain the enhanced cholinergic activity as an effect of autoantibodies transferred from the narcoleptic patients. The narcoleptic patients (men and women 22-76 years of age) had firmly based diagnoses: on Multiple Sleep Latency Tests (MSLTs), all showed mean latency to sleep of < 5 minutes and all, even 2 with no clinical history of cataplexy had 2 or more sleep-onset REM periods. All were positive for the autoantibodies.
Commentary
Great progress has been made in recent years in understanding narcolepsy, a neurological sleep disorder that was first described over 100 years ago. Confronted with a chronically sleepy patient, the neurologist should first consider as potential explanations chronic sleep deprivation (especially in early risers who sleep late on weekends) and sleep apnea. Narcolepsy may then be considered, especially in a young student who dozes in classes or someone who once fit that description. Even when narcoleptic sleepiness is intense and not to be denied, a short bout of sleep may be strongly and uniquely refreshing, though alertness can rarely be maintained for more than a few hours. Even more specific for the disorder is a history of cataplexy—muscle weakness, hypotonia and arreflexia triggered by emotions such as laughter or anger. If cataplexy can be induced or observed in the office by the neurologist, the diagnosis of narcolepsy may be confidently made on purely clinical grounds.
Confirmation of the diagnosis by objective testing, however, may be more difficult. An important advance in diagnosis was the discovery in the early 1960s of the "sleep-onset REM period"—a transition from wakefulness directly to REM sleep—which may occur at the onset of nocturnal or diurnal sleep in narcolepsy. Thus, repeated efforts to nap in the sleep laboratory (Multiple Sleep Latency Test or MSLT) may confirm the diagnosis if, in addition to characteristic clinical features, it shows consistently rapid sleep onset (< 5 minutes), and especially if at least several naps begin with REM sleep. Even in typical cases of narcolepsy, however, the MSLT may fail to confirm the diagnosis and is frequently negative if the history of cataplexy is uncertain; such cases of idiopathic hypersomnolence are rather common.
It, therefore, came as another forward leap that narcolepsy was associated with HLA (DR2 or DQ1) as strongly as any other disease. The association has since been narrowed to a gene locus on the MHC complex, HLA DQB1*0602. The gene marker is of classificatory & diagnostic use—for example, absence of DR2 could be used to rule out narcolepsy/cataplexy in doubtful cases. It furthermore suggested that narcolepsy might be an autoimmune disorder, as other HLA-linked disorders apparently are. Specific evidence of immune processes in the development of narcolepsy has been found in a canine model of narcolepsy (CSF pleocytosis around the time of disease onset, delay of symptom onset with anti-inflammatory and immunosuppressive agents). However, efforts to directly demonstrate autoimmunity have failed until now. The new discovery of putative muscarinic autoantibodies in narcolepsy, if confirmed, promises that a specific, sensitive bioassay will soon become available. It also bolsters the long-held suspicion of autoimmunity in the pathogenesis of narcolepsy. As Smith et al point out, however, the targets of the autoantibodies remain unidentified. An intriguing possibility is that the targets include cells in the lateral hypothalamus containing the neuropeptide, orexin. This might account for daytime sleepiness, as well as very low CSF orexin in narcolepsy patients. As pointed out in an accompanying editorial, Wise did not report whether the control subjects were positive for HLA DQB1*0602 (as non-narcoleptics often are) and, therefore, whether the genotype itself might have affected the bioassay.
Narcolepsy is rapidly yielding its secrets. It is possible that this disabling, neurological, sleep disorder will be become one of the first autoimmune disorders to be unraveled.
IgG from all narcolepsy patients significantly enhanced bladder contractile responses to the muscarinic agonist carbachol and to neuronally released acetylcholine compared with control IgG (P < 0.0001), whereas contraction of the sympathetically innervated vas deferens was unaltered.
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