Synopsis: IgG from all narcolepsy patients significantly enhanced bladder contractile responses to the muscarinic agonist carbachol and neuronally released acetylcholine, as compared to the control IgG.

Source: Smith A, et al. A Functional Autoantibody in Narcolepsy. Lancet. 2004;364:2122-2124.

This report, for the first time, has identified a potential autoantibody which may play a role in narcolepsy. Narcolepsy-cataplexy appears to result from a deficiency of orexin (hypocretin) neutotransmission. Orexin is an excitatory neurotransmitter that promotes wakefulness and suppresses REM sleep. Evidence suggests that impaired orexin signaling causes both narcolepsy and cataplexy. Orexin-containing neurons originate in the lateral hypothalamus and have extensive projections to both cholinergic and monoaminergic brainstem nuclei. There appears to be reciprocal feedback from the brainstem nuclei into hypothalamic orexin-containing neurons. In addition, studies in neuroleptic dogs show central cholinergic hypersensitivity, which is linked to cataplexy. The ascending cholinergic pathways contribute importantly to arousal and maintenance of wakefulness.

Autoimmune mechanisms have, for a long time, been thought to be important in the development of narcolepsy. This is due to familial clustering, onset during adolescence, and a close association with HLA-DQB1*0602 allele. Initial attempts to identify neural autoantibodies in both canine and human narcolepsy, however, have been unsuccessful.

In the present study, Smith and colleagues obtained serum samples from 9 patients with narcolepsy and 9 healthy controls. All the narcolepsy patients were positive for HLA-DR2/DQB1*0602 and had marked daytime sleepiness. Seven patients had unequivocal cataplexy. Eight had abnormal REM-onset sleep, confirmed by multiple sleep latency testing. The human IgG was purified and then injected into mice. The mice received injections of 10 mg of IgG on 2 consecutive days. They were then sacrificed in 2 detrusor muscle strips per mouse, which were tested for contractile responses to electrical field stimulation and to the muscarinic agonist carbachol. Smith et al observed that IgG from all narcolepsy patients significantly enhanced bladder contractile responses to the muscarinic agonist carbachol and neuronally released acetylcholine, as compared to the control IgG. They examined sympathetically innervated vas deferens as a control, and there was no alteration in its response.

Commentary

These studies are the first to identify the possibility of an autoantibody in narcolepsy. It is possible that it functions similar to the antithyroid-stimulating hormone receptor antibody, which occurs in Grave’s disease. It appears to be difficult to detect in serum, using conventional techniques. Smith et al’s technique is very sensitive in picking up autoantibodies, however, the precise mechanism by which they increase cholinergic neurotransmission is not clear. It is also not yet known whether these autoantibodies will cross the blood brain barrier and result in increased cholinergic neurotransmission. If they were to do so, it might eventually lead to downregulation and damage to the ascending cholingeric pathways involved with arousal and wakefulness, which originate in the brainstem and, thereby, produce daytime sleepiness. These studies, however, do support the hypothesis that autoimmunity plays a role in the pathophysiology of narcolepsy. Identification of the neural target could lead to new possibilities for diagnosis and treatment of this disabling disease.

Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.