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Many kinds of sleep disorders have been documented, ranging in severity from mild insomnia to an extremely disruptive disorder called narcolepsy. The symptoms of this disorder were first described in 1880 by the French physician Jean-Baptiste-Édouard Gélineau. His patient, a wine cask maker, was excessively sleepy during the daytime and also suffered from periodic episodes during which he suddenly lost all muscle control and fell to the ground. Gélineau named this unusual disorder narcolepsie (later anglicized to narcolepsy) from the Greek words narke, meaning “numbness” or “stupor,” and lepsis, meaning “attack” or “seizure” (as in epilepsy). The loss of muscle control in patients with narcolepsy is called cataplexy and is usually triggered by a strong emotion such as laughing or becoming angry or frustrated. A cataplexy episode may be minor, consisting of a few seconds of muscle weakness resulting in symptoms such as head dropping, knee buckling, or slurred speech. Alternatively, the patient may experience complete paralysis of the antigravity muscles that can last for several minutes. The patient remains conscious throughout the attack and is aware of his condition. We now know that there are two types of narcolepsy: type 1, which is the more common, includes symptoms of cataplexy, whereas type 2 patients exhibit the other classical symptoms but not cataplexy. The reason for this difference is not yet understood. Some narcolepsy patients additionally report unusual symptoms that may occur during the transition from wakefulness to sleep. These symptoms are hypnagogic hallucinations (vivid dreamlike sensations) and sleep paralysis (loss of muscle tone leading to a feeling of paralysis). Narcolepsy is present in about 0.03% to 0.05% of the population, with symptom onset usually occurring during adolescence (Leschziner, 2014; Scammell, 2015).
Orexin neurons in the lateral hypothalamus play a key role in a circuit that controls arousal and sleep (Figure 1). The main takeaway from this figure is that release of orexin from these cells has a powerful effect of promoting arousal and wakefulness. Reduction or loss of orexin signaling has the opposite effect of inducing drowsiness or sleep, along with other consequences not discussed here. Development of narcolepsy has been linked to two different abnormalities of the orexin system. One such abnormality shown by postmortem examination of the brains of narcolepsy patients is a nearly complete loss of orexin neurons throughout the hypothalamic areas where these cells are normally present (Thannickal et al., 2000; Figure 2). This cell death, which may be the result of an autoimmune reaction, appears to be the most common cause of narcolepsy. However, Peyron and coworkers (2000) reported the case of a single nucleotide mutation in the gene coding for orexin that virtually abolished synthesis of this neuropeptide.
Figure 1 Orexin pathways involved in arousal and wakefulness Excitatory orexin projections to the depicted brain areas play an important role in arousal and the maintenance of wakefulness. ACh, acetylcholine; DA, dopamine; GABA, γ-aminobutyric acid; HA, histamine; 5-HT, serotonin; NE, norepinephrine. (From Alexandre et al., 2013.)
Figure 2 Loss of orexin neurons in the brains of patients with narcolepsy and cataplexy The graph illustrates the mean number of orexin neurons within the hypothalamus and surrounding area in postmortem brain tissues obtained from patients with narcolepsy with cataplexy compared to controls without narcolepsy. (After Thannickal et al., 2000.)
Current treatments for narcolepsy help reduce the symptoms but do not cure the disorder (Thorpy and Bogan, 2020). Excessive daytime sleepiness is usually treated with stimulants such as methylphenidate, amphetamine, or modafinil. Unfortunately, most stimulants have adverse side effects, including significant abuse potential (see Chapter 12), and they do not always prevent attacks of cataplexy. Antidepressants may help reduce the frequency of cataplexy, which explains why the patient studied by Peyron and colleagues was being given an antidepressant along with methylphenidate.
The limitations associated with traditional narcolepsy medications have led to the development of several newer compounds. One of these is solriamfetol (trade name Sunosi), which is a combined dopamine and norepinephrine reuptake inhibitor that primarily targets the excessive daytime sleepiness in narcoleptic patients. Two other medications help reduce both excessive sleepiness and attacks of cataplexy. Of these, the most recently approved is pitolisant (trade name Wakix), which increases release of histamine in the neural circuit depicted in Figure 1 to offset the loss of orexin activation of the histaminergic neurons. This is a good example of how understanding the neural circuit associated with a disorder (and not just a single neurotransmitter) helps in the development of novel medications.
A different neurochemical mechanism is associated with the drug sodium oxybate (trade name Xyrem), the sodium salt of γ-hydroxybutyrate (GHB). GHB exerts agonist effects on the GABA system, and in healthy individuals the drug has sedating effects (see Chapter 16). Although the GABAergic effects of GHB are believed to be responsible for its therapeutic efficacy in narcolepsy, the exact mechanism is still unclear.
Lastly, research is under way to develop small molecule agonists at the orexin receptors responsible for its activity within the arousal system. This approach should work, since those receptors are still present and presumably functional in the brains of narcoleptic patients despite the loss of the peptide. Drugs of this type might have fewer adverse side effects than present medications for narcolepsy.
References
Alexandre, C., Andermann, M. L., and Scammell, T. E. (2013). Control of arousal by the orexin neurons. Curr. Opin. Neurobiol., 23, 752–759.
Leschziner, G. (2014). Narcolepsy: A clinical review. Pract. Neurol., 14, 323–331.
Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., et al. (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med., 6, 991–997.
Scammell, T. E. (2015). Narcolepsy. N. Engl. J. Med., 373, 2654–2662.
Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469–474.
Thorpy, M. J., and Bogan, R. K. (2020). Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications. Sleep Med., 68, 97–109.