Long-term outcome and medical and psychiatric comorbidities of narcolepsy, in adult and pediatric patients.

Background and Aims: Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and disturbed nocturnal sleep, often accompanied by metabolic and psychiatric comorbidities. Despite advances in diagnosis and symptomatic treatment, its long-term prognosis and the multidimensional burden of disease remain incompletely understood. This PhD project aimed to contribute to the understanding of the prognosis of narcolepsy through four complementary aims: (1) assessing psychiatric comorbidity, (2) characterizing the Maintenance of Wakefulness Test (MWT) in drug-naïve narcolepsy type 1 (NT1) and type 2 (NT2), (3) investigating microsleep and autonomic dynamics during MWT, and (4) describing the long-term clinical evolution of childhood-onset NT1. Methods: In Aim 1, a cross-sectional study compared adults with NT1 and matched controls using validated psychological questionnaires to assess the prevalence and co-occurrence of depressive, anxiety, and suicidal symptoms. In Aim 2, drug-naïve patients (NT1 and NT2) underwent standardized diagnostic hospitalization with polysomnography, MSLT, and MWT, to describe the characteristics of MWT and its relation to subjective and objective sleepiness measures. In Aim 3, MWT recordings of treated and untreated patients with NT1 were analyzed to quantify microsleep their temporal distribution, and associated heart rate variations preceding sleep onset. In Aim 4, a longitudinal follow-up study of childhood-onset NT1 evaluated clinical trajectories up to ten years after diagnosis, assessing evolution of EDS and cataplexy, treatment response, and predictors of long-term symptom control. Results: Depressive and anxiety symptoms, suicidal thoughts, and hopelessness were significantly more frequent in NT1 than in matched controls, confirming a major psychiatric burden. In drug-naïve patients, MWT mean sleep latency showed partial concordance with subjective and MSLT measures of sleepiness, underscoring its complementary role in assessing functional sleepiness. Microsleep analysis revealed that their accumulation and heart-rate modulation predicted imminent sleep onset, identifying a sensitive physiological correlate of vigilance instability.