Aude Raoux

Pitolisant, an Inverse Agonist of the Histamine H3 Receptor: An Alternative Stimulant for Narcolepsy-Cataplexy in Teenagers With Refractory Sleepiness

ObjectiveNarcolepsy is a rare disabling sleep disorder characterized by excessive daytime sleepiness and cataplexy (sudden loss of muscle tone). Drugs such as pitolisant, which block histamine H3 autoreceptors, constitute a newly identified class of stimulants because they increase brain histamine and enhance wakefulness in animal and human adult narcolepsy. MethodsWe report our experience with the off-label use of pitolisant in 4 teenagers with narcolepsy/cataplexy with severe daytime sleepiness, refractory to available treatments (modafinil, methylphenidate, mazindol, sodium oxybate, and D-amphetamine). ResultsAll teenagers developed their disease during childhood (11.3 ± 2.4 years; 50% boys) and were 17.3 ± 0.8 years old at the time of pitolisant therapy. Pitolisant treatment was increased from 10 to 30 mg (n = 1) and 40 mg (n = 3). The adapted Epworth Sleepiness Score decreased from 14.3 ± 1.1 to 9.5 ± 2.9 (P = 0.03) with pitolisant alone to 7 ± 3.4 when combined with mazindol (n = 1), methylphenidate (n = 1), or sodium oxybate plus modafinil (n = 1). Mean sleep onset latency increased from 31 ± 14 minutes to 36 ± 8 minutes (P = 0.21) on the maintenance of wakefulness test. The severity and frequency of cataplexy were slightly improved. Adverse effects were minor (insomnia, headache, hot flushes, leg pain, and hallucinations) and transitory, except for insomnia, which persisted in 2 teenagers. The benefit was maintained after a mean of 13 months. ConclusionsPitolisant could constitute an acceptable alternative for the treatment of refractory sleepiness in teenagers with narcolepsy.

Depressive feelings in children with narcolepsy.

OBJECTIVES We aimed to evaluate depressive feelings and their correlations in children and adolescents with narcolepsy collected in national reference centers for narcolepsy. METHODS We compared clinical and sleep characteristics of patients with and without depressive symptoms evaluated on the Childrens Depression Inventory (CDI). RESULTS Our study sample included 88 children (44 boys; 44 de novo patients) with a mean age of 11.9 ± 3.1 years at diagnosis (37.5% were aged ⩽ 10 years). Obesity was found in 59% of the sample and cataplexy was present in 80.7%. The DQB1*0602 allele was positive in 93.5% of our sample. There were 25% of children who had clinically depressive feelings (CDI>16), especially girls older than the age of 10 years. Bivariate associations indicated that depressive feelings were associated with fatigue (48%), hyperactivity (31%), insomnia (16%), and excessive daytime sleepiness (EDS) (14-24%). In the multivariate model adjusted for gender and age, only fatigue explained the variability of the depression score. CONCLUSION In our large cohort, high levels of depressive symptoms essentially expressed by fatigue affected 25% of children with narcolepsy. The girls older than 10 years of age were especially vulnerable. The similar prevalence of depressive feelings in treated vs never-treated patients suggests a specific need for diagnosing and managing this symptom in young patients with narcolepsy.

Quality of Life in Children with Narcolepsy

To evaluate the health‐related quality of life (HRQL) and its correlates in children and adolescents with narcolepsy.

High bicarbonate levels in narcoleptic children

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 ± 4 years, 43% boys) and 51 patients presenting de‐novo narcolepsy (N) (12.7 ± 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L−1 were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L −1 (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice.

Pitolisant, agoniste inverse des récepteurs presynaptiques H3 : un traitement alternatif contre la somnolence diurne excessive chez les adolescents narcoleptiques sévères

diazépines (alprazolam) et de somnifère (zopiclone et zolpidem). Au total, 42,2 % prenaient un traitement antidépresseur associé la plupart du temps aux traitements anxiolytiques. Dans 5 % des cas, les patients ont eu recours aux neuroleptiques (phénothiazine). Les facteurs influençant la prise de traitement semblent être le sexe, la sévérité de l’insomnie. Dans notre échantillon, un patient sur cinq a bénéficié d’une thérapie cognitivo-comportementale (TCC). Dans 6 % des cas, la TCC est réalisée seule et dans 19 % des cas, elle est associée à une pharmacothérapie. Ces résultats nous montrent que l’usage chronique des benzodiazépines est largement répandu dans la population des patients insomniaques adressés en centre du sommeil et pointent la nécessité de renforcer les prises en charge psychothérapique.