The melanopsin-mediated pupil response is reduced in idiopathic hypersomnia with long sleep time

Abstract

Idiopathic hypersomnia (IH), characterized by an excessive day-time sleepiness, a prolonged total sleep time on 24 h and/or a reduced sleep latency, affects 1 in 2000 individuals from the general population. However, IH remains underdiagnosed and inaccurately treated despite colossal social, professional and personal impacts. The pathogenesis of IH is poorly known, but recent works have suggested possible alterations of phototransduction. In this context, to identify biomarkers of IH, we studied the Post-Illumination Pupil Response (PIPR) using a specific pupillometry protocol reflecting the melanopsin-mediated pupil response in IH patients with prolonged total sleep time (TST > 660 min) and in healthy subjects. Twenty-eight patients with IH (women 86%, 25.4 year-old ± 4.9) and 29 controls (women 52%, 27.1 year-old ± 3.9) were included. After correction on baseline pupil diameter, the PIPR was compared between groups and correlated to sociodemographic and sleep parameters. We found that patients with IH had a lower relative PIPR compared to controls (32.6 ± 9.9% vs 38.5 ± 10.2%, p = 0.037) suggesting a reduced melanopsin response. In addition, the PIPR was not correlated to age, chronotype, TST, nor depressive symptoms. The melanopsin-specific PIPR may be an innovative trait marker of IH and the pupillometry might be a promising tool to better characterize hypersomnia.

Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1

“…More recently, we showed for the first time that patients with IH with prolonged sleep time had reduced PIPR as compared with healthy subjects (Rach et al, 2022), indicating a lower reactivity of the melanopsinergic system. We suggested that a reduced sensitivity of the melanopsin system could lead to a phenotype of both decreased overall alertness and delayed sleep-wake timing in IH with long sleep time (Rach et al, 2022). This reduced ipRGCs integration of the light signal could also be present in individuals suffering from another hypersomnia subtype, and contribute to a "light-related vulnerability to sleepiness", but this has never been explored.…”

“…Women and men aged 18 years or older with a diagnosis of IH ( n = 36), NT1 ( n = 27) or healthy controls ( n = 43) were included between 2020 and 2022 at the Sleep Disorders Center of the University of Strasbourg. There is a major overlap of IH and control participants with our previous study, as several participants (28 IH patients and 29 healthy subjects) were also included in this work (Rach et al, 2022). Given the heterogeneity of IH phenotypes and in order to identify biomarkers of hypersomnia subtypes, only IH patients with prolonged sleep time were included in the study.…”

“…Controls and patients who completed all inclusion and non‐inclusion criteria gave their written informed consent prior to their enrolment in the study. The method has been described elsewhere in a previous published work (Rach et al, 2022). Participants completed a detailed medical and sleep history interview, a physical examination and a psychiatric interview (MINI 2.0; Lecrubier et al, 1997).…”

“…Before the pupillometry, subjects were placed in a white polychromatic light (200 lux, light source = RGB‐LED, broadband light emitted by fluorescent tubes from the ceiling guaranteeing an uniform illumination of the room) room for 30 min to allow the pupils to adapt to light, as previously described (Rach et al, 2022). Participants seated in front of the pupillometer build at the Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (Abbott et al, 2021; van der Meijden et al, 2016).…”

“…This pupil response, named the post-illumination pupil response (PIPR), reflects the prolonged activity over time of the melanopsin-containing cells (Gamlin et al, 2007), and has been reported to be reduced in major depressive disorder (MDD; Laurenzo et al, 2016), seasonal affective disorder (SAD; Roecklein et al, 2013) and delayed sleep-wake phase disorder (Abbott et al, 2021). More recently, we showed for the first time that patients with IH with prolonged sleep time had reduced PIPR as compared with healthy subjects (Rach et al, 2022), indicating a lower reactivity of the melanopsinergic system. We suggested that a reduced sensitivity of the melanopsin system could lead to a phenotype of both decreased overall alertness and delayed sleep-wake timing in IH with long sleep time (Rach et al, 2022).…”