Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy

Study Objectives: Narcolepsy with cataplexy is characterized by a loss of approximately 90% of hypocretin (Hcrt) neurons. However, more than a quarter of narcoleptics do not have cataplexy and have normal levels of hypocretin in their cerebrospinal fluid, raising the possibility that their disease is caused by unrelated abnormalities. In this study we examined hypocretin pathology in narcolepsy without cataplexy. Design: We examined postmortem brain samples, including the hy- pothalamus of 5 narcolepsy with cataplexy patients; one narcolepsy without cataplexy patient whose complete hypothalamus was available (patient 1); one narcolepsy without cataplexy patient with anterior hypo- thalamus available (patient 2); and 6 normal brains. The hypothalamic tissue was immunostained for Hcrt-1, melanin-concentrating hormone (MCH), and glial fibrillary acidic protein (GFAP).
Measurements and Results: Neither of the narcolepsy without cata- plexy patients had a loss of Hcrt axons in the anterior hypothalamus.
The narcolepsy without cataplexy patient whose entire brain was avail- able for study had an overall loss of 33% of hypocretin cells compared to normals, with maximal cell loss in the posterior hypothalamus. We found elevated levels of gliosis with GFAP staining, with levels in- creased in the posterior hypothalamic nucleus by (295%), paraventric- ular (211%), periventricular (123%), arcuate (126%), and lateral (72%) hypothalamic nuclei, but not in the anterior, dorsomedial, or dorsal hy- pothalamus. There was no reduction in the number of MCH neurons in either patient.
Conclusions: Narcolepsy without cataplexy can be caused by a partial loss of hypocretin cells.