Sunday, May 01, 2005

Narcolepsy 3

Part 1, Part 2
This is 3rd in a series about narcolepsy.
In the last 5-6 years there has been a revolution in our understanding of narcolepsy. In 1999 hypocretin (orexin) was discovered. Most cases of human narcolepsy are due to a loss of hypocretin cells in the lateral hypothalamus, which results in very low levels of hypocretin in the cerebrospinal fluid. In contrast, narcolepsy in animal models (e.g. Doberman pinschers) is usually due to dysfunction of the hypocretin receptors.
Hypocretin neurons project to multiple areas in the brainstem and hypothalamus involved in the regulation of the alternation of sleep/wake and REM/non-REM cycles. There are 2 main theories about the function of hypocretin: 1) hypocretin promotes wakefulness and 2) hypocretin promotes stability of sleep/wake/REM/non-REM states. These 2 theories are not mutually exclusive.
Thus narcolepsy, a hypocretin deficient state, can be thought of as 1) a disorder of excessive daytime sleepiness in which a person has irresistable episodes of sleep and/or 2) a disorder of unstable sleep/wake/REM/non-REM states in which daytime wakefulness is interrupted by periods of sleep and nighttime sleep is frequently restless and fragmented (intrusion of wakefulness). Cataplexy can be explained in this model as a mixture of REM sleep and wakefulness- cataplexy is the intrusion of the muscle atonia (decreased/absent muscle tone) of REM sleep into wakefulness.
Hypocretin is also involved in appetite, feeding and metabolism. This is an area I know very little about, so I won't mention it further.
That's it for now. I know I've been promising to talk more about Xyrem- I'll try to do this in part 4.

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