How are hypocretin neurons affected in patients with narcolepsy?

Updated: Sep 04, 2019
  • Author: Sagarika Nallu, MD; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Hypocretin neurons, thought to be autoexcitatory, project from the lateral hypothalamus into these regions and serve to maintain wakefulness. A deficiency of hypocretin neurons may decrease the threshold for transitioning between wakefulness and sleep (so-called sleep state instability). This is a proposed explanation for the sleepiness and REM intrusion into wakefulness found in narcolepsy. [14]

Destruction of hypocretin-producing neurons appears to be an autoimmune process. [28] A study in a mouse model found that the serum of narcolepsy patients was reactive with over 86% of hypocretin neurons from the mouse hypothalamus. [29] levels of a specific autoantigen against Tribbles homolog 2 (Trib2) have been found to be higher in narcolepsy patients with cataplexy than in normal controls or patients with other inflammatory neurologic disorders. High Trib2-specific antibody titers correlated with more severe cataplexy. [29]

The autoimmune model of narcolepsy inspired trials of intravenous (IV) immunoglobulin (IVIG) therapy in narcoleptic patients with low levels of hypocretin-1. In these trials, IVIG reportedly improved cataplexy and sleepiness in many cases, but the effects did not last long. IVIG did not normalize CSF hypocretin levels, except in 1 patient. [30] In 2 children given IVIG early after diagnosis of narcolepsy, the cataplexy and sleepiness improved, but some components of the disease worsened in 1 child. [31]


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