What is the role of hypocretin system in the pathophysiology of narcolepsy?

Updated: Sep 04, 2019
  • Author: Sagarika Nallu, MD; Chief Editor: Selim R Benbadis, MD  more...
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The hypocretin system plays an important role in the pathophysiology of human narcolepsy. Patients with narcolepsy have been found to have little or no hypocretin in their CSF. [22] Postmortem pathologic examination of the brains of people with narcolepsy with cataplexy have demonstrated dramatically reduced numbers of hypocretin neurons. Hypocretin deficiency is theorized to produce instability of sleep and wake states, thereby preventing the person from sustaining more continuous sleep or wakefulness.

A large majority of patients with narcolepsy without cataplexy have normal CSF hypocretin levels. However, a small pathologic study of the brains of patients who had narcolepsy without cataplexy showed partial loss of hypocretin neurons in the hypothalamus. [23, 24, 25]

Investigators have identified low levels of histamine (a neurotransmitter that may help maintain wakefulness) in the CSF of patients with hypocretin-deficient narcolepsy. [26] Low CSF histamine levels are not limited to hypocretin-deficient narcolepsy, however; they are also seen in narcolepsy patients with normal CSF hypocretin levels and in patients with idiopathic hypersomnia. [26, 27]

It is noteworthy that low CSF histamine levels have not been found in patients with hypersomnia secondary to obstructive sleep apnea syndrome. [27] The CSF histamine level may serve as a biomarker reflecting the degree of hypersomnia of central origin. [26, 27]

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