Postmortem Evidence of CRH Neuron Reduction in Narcolepsy Without Cataplexy With Borderline Hypocretin-1 Levels

Narcolepsy is classified as type 1 (NT1) or type 2 (NT2) mainly according to hypocretin deficiency rather than cataplexy. While CRH neuron loss in the PVN has been described in NT1, it remains unclear whether similar changes occur in narcolepsy without cataplexy. We report a 42-year-old woman with excessive daytime sleepiness since age 15, without cataplexy. Two multiple sleep latency tests and lumbar punctures performed 8 years apart showed mean latencies of 8.3 min with three SOREMPs and 10.8 min with two SOREMPs, along with borderline low-intermediate hypocretin-1 levels of 100 pg/mL initially and 122 pg/mL at follow-up. HLA DQB1*06:02 was positive, and brain magnetic resonance imaging was normal. The patient later developed severe depression and committed suicide. CRH neuron counts were compared with a control and a NT1 hypothalamus. All hypothalami were formalin-fixed, paraffin-embedded and processed for thionin staining and immunohistochemistry for hypocretin and CRH, with neurons manually counted. Only the anterior hypothalamus was available from this case, precluding the assessment of hypocretin neurons, although CSF levels indicated a borderline low-intermediate reduction. Thionin staining confirmed that the PVN was fully included in our case and revealed an almost complete loss of CRH-positive neurons in the PVN compared with controls, consistent with findings in NT1. This report indicates that narcolepsy without cataplexy, accompanied by borderline low CSF hypocretin-1 levels, is associated with a marked reduction in CRH neurons in the PVN, which may contribute to excessive daytime sleepiness and impaired wakefulness regulation, without triggering cataplexy.