The 5-min pupillary alertness test is sensitive to modafinil: A placebo controlled study in patients with sleep apnea

Rationale: The extent of pupillary miosis during 5 min in darkness is a simple, recently introduced alertness test which may become useful in the clinical assessment of normal and pathological sleepiness. Objectives: In this study, we further validated this test by testing its sensitivity to the effects of modafinil, a non-stimulant, alertness-promoting drug. Methods: Twelve unmedicated patients recently diagnosed with obstructive sleep apnea (OSA) after polysomnography, received placebo or modafinil (200 mg), according to a double-blind, cross-over design. The patients' resting pupil diameter (RPD) was sampled over 5 min in darkness before (10:00 a.m.) and after treatment (2:00 p.m.), and their light reflexes were elicited and recorded in darkness with an infrared video pupillometer. Results: We found a circadian miosis at 2:00 p.m. in the placebo treatment condition, which was reversed by modafinil. This effect correlated with modafinil-induced increase in subjective alertness, and it was greater in the most severely affected patients in terms of lowest oxygen saturation, independently of body mass index, age, or apneic episodes during sleep. Modafinil reduced the light reflex amplitude, suggesting an increase in the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus. Conclusions: These effects of modafinil are best explained via an activation of the hypoxia-sensitive nucleus locus coeruleus. The 5-min pupillary alertness test has promising predictive validity, and it holds promise as a fast and sensitive method for the objective assessment of excessive daytime sleepiness, monitoring of disease progression, and response to treatment.