What is the pathophysiology of narcolepsy?

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

Narcolepsy is thought to result from genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation. Current data implicate certain human leukocyte antigen (HLA) subtypes and abnormal hypocretin (orexin) neurotransmission, which leads to abnormalities in monoamine and acetylcholine synaptic transmissions, particularly in the pontine reticular activating system. [13, 14]

Understanding of the neurochemistry of narcolepsy began with research involving narcoleptic dogs (eg, special laboratory-bred Dobermans and Labradors). In these animal models, the disorder is transmitted in an autosomal recessive fashion with full penetrance and is characterized mainly by cataplexy. [15] Muscarinic cholinergic stimulation increases cataplexy in these animals, and cholinergic blockade eliminates the symptom. Nicotinic agents have no effect on the cataplexy.

Receptor subtypes such as the alpha1-noradrenergic receptor appear to mediate cataplexy. Prazosin, an alpha1-antagonist, worsens symptoms in human and canine subjects.

The pons is not the only neuroanatomic site that is responsible for mediating cataplexy; the mesocorticolimbic dopaminergic system also has been implicated. This connection with the limbic system in part explains the relationship of cataplexy to emotion.

The centrality of hypocretin transmission in the pathophysiology of narcolepsy was demonstrated when hypocretin knockout mice displayed cataplexy and sleepiness. [16, 17] Further evidence for impaired hypocretin functioning in humans was found with the discovery of low levels of hypocretin in the cerebrospinal fluid (CSF) of narcoleptic patients. [18]

Subsequently, abnormal immune modulation was associated with the clinical development of narcolepsy in children in Scandinavia and Finland. After vaccination against the H1N1 influenza virus with a vaccine using a potent ASO3 adjuvant, narcolepsy in Finnish children increased 8- to 12-fold. All affected children who underwent HLA typing were found to have the HLA DQB*0602 allele. [19, 20]


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