Narcolepsy-A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

Abstract

Narcolepsy is a chronic, long-term neurological disorder characterized by a decreased ability to regulate sleep-wake cycles. Some clinical symptoms enter into differential diagnosis with other neurological diseases. Excessive daytime sleepiness and brief involuntary sleep episodes are the main clinical symptoms. The majority of people with narcolepsy experience cataplexy, which is a loss of muscle tone. Many people experience neurological complications such as sleep cycle disruption, hallucinations or sleep paralysis. Because of the associated neurological conditions, the exact pathophysiology of narcolepsy is unknown. The differential diagnosis is essential because relatively clinical symptoms of narcolepsy are easy to diagnose when all symptoms are present, but it becomes much more complicated when sleep attacks are isolated and cataplexy is episodic or absent. Treatment is tailored to the patient's symptoms and clinical diagnosis. To facilitate the diagnosis and treatment of sleep disorders and to better understand the neuropathological mechanisms of this sleep disorder, this review summarizes current knowledge on narcolepsy, in particular, genetic and non-genetic associations of narcolepsy, the pathophysiology up to the inflammatory response, the neuromorphological hallmarks of narcolepsy, and possible links with other diseases, such as diabetes, ischemic stroke and Alzheimer's disease. This review also reports all of the most recent updated research and therapeutic advances in narcolepsy. There have been significant advances in highlighting the pathogenesis of narcolepsy, with substantial evidence for an autoimmune response against hypocretin neurons; however, there are some gaps that need to be filled. To treat narcolepsy, more research should be focused on identifying molecular targets and novel autoantigens. In addition to therapeutic advances, standardized criteria for narcolepsy and diagnostic measures are widely accepted, but they may be reviewed and updated in the future with comprehension. Tailored treatment to the patient's symptoms and clinical diagnosis and future treatment modalities with hypocretin agonists, GABA agonists, histamine receptor antagonists and immunomodulatory drugs should be aimed at addressing the underlying cause of narcolepsy.

Keywords: cataplexy; hypocretin; narcolepsy; sleep cycle disorder; sleep disorder.

Figure 1

Schematic figure represents the possible mechanism for the autoimmune hypothesis for narcolepsy with cataplexy. Several environmental triggers are capable enough for molecular mimicry and elicit an immune response against microbiological/environmental factors. The microbiological-specific immune cells can cross-react with autoantigens and can activate autoimmune responses against hypocretin-secreting neurons in the hypothalamus, where the melanin-concentrating hormone is relatively spared.

Figure 2

A representation of the normal narcolepsy state. Compared to normal individuals, narcolepsy patients with cataplexy have low levels of hypocretin (HCRT) due to a loss of hypocretin neurons. The flip-flop model of the sleep–wake state in normal conditions is balanced by stabilizing modulator hypocretin, while hypocretin deficiency unbalances the sleep–wake transition in narcoleptics. In normal individuals, hypocretin is thought to stabilize wakefulness during the day by both activating the ribocortex and stimulating the ascending arousal system to increase wake-promoting neuron activity. Sleep-promoting neurons inhibit both wake-promoting neurons and hypocretins. The wake-promoting and sleep-promoting neurons include excitatory neurotransmitters and inhibitory neurotransmitters. The main five symptoms of narcolepsy are manifested by narcolepsy patients.

Figure 3

Diagrammatic representation of the pathological linking between narcolepsy, diabetes and stroke. Hypocretin A and hypocretin B are two types of hypocretins that mediate narcolepsy’s functional role via G protein coupled receptor-hypocretin receptors type 1 and type 2. The downstream cascade activates various transcription factors and implicates in the regulation of several processes. The main common pathogenesis for narcolepsy, diabetes and stroke is hypocretin deficiency. There are numerous underlying pathophysiological mechanisms that are associated that link these diseases.