Effect of Oxygen Administration on Paroxysmal Motor Events in Alternating Hemiplegia of Childhood.

Alternating hemiplegia of childhood (AHC) (OMIM No. 614820) is an early-onset neurodevelopmental encephalopathy frequently caused by mutations in the ATP1A3 gene (OMIM *182350) encoding for the α3 subunit of the Na+/K+-ATPase.1 It is typically characterized by intellectual disability, motor dysfunction, and various paroxysmal events.1 The occurrence of plegic or dystonic attacks is an important determinant of quality of life for patients and caregivers because: (i) they are unpredictable, (ii) they can last several hours and/or occur several times daily, (iii) they are associated with important motor disability, and (iv) they can be extremely painful/stressful. Current prophylactic and acute treatments have limited efficacy and poor tolerability. Severe episodes are often treated by sleep induction using sedative drugs associated with disabling side effects.2 We recently reported the efficacy of high-flow oxygen administration as an acute treatment for the dystonic attacks in a 25-year-old patient suffering from AHC.3 Here, we expand this observation and report the effect of high-flow oxygen administration (100% O2 at a flow rate of 12 L/min after the beginning of the episode and for a duration of 15 min) in two children with ATP1A3-related AHC who had dystonic, plegic, or mixed attacks. Table 1 shows the patients' baseline characteristics together with the details of oxygen efficacy. Both patients exhibited improvements in the paroxysmal attacks. Oxygen was administered in a total of 60 episodes with no side effects and resulted in the resolution of 93% of the events within 20 min after the beginning of oxygen administration. Oxygen was effective in more than 90% of the severe paroxysmal episodes. Between the episodes, the caregivers reported less fatigue and an overall improvement in alertness. No side effects were reported. Physician evaluation, n (%)d Mild or moderate events resolved/total mild or moderate events Caregiver evaluation, n (%)e Mild or moderate events resolved/total mild or moderate events The effect of oxygen therapy could be explained by its impact on spreading depolarization (SD). SD is a wave of neuronal and glial depolarization in the gray matter associated with abnormal neurotransmitter release and synaptic dysfunction, resulting in a reduction of spontaneous neuronal activity. SD may be responsible for paroxysmal neurological manifestations including various movement disorders. Na+/K+-ATPase plays an important role in restoring the ion gradients across the plasma membrane; decreased activity of this transporter results in neuronal hyperexcitability which can promote SD.4 AHC is associated with a loss of function of Na+/K+-ATPase5; paroxysmal manifestations in AHC may thus reflect increased susceptibility to SD.6 Following SD, the normalization of ion concentrations requires increased activity of the Na+/K+-ATPase, resulting in high levels of ATP and oxygen consumption. In mice, increasing oxygen concentration in the breathing air shortens SD duration.7 High-flow oxygen inhalation could thus reduce the duration of paroxysmal events in patients with ATP1A3-related AHC. Current treatments for AHC are disappointing, whereas short-duration oxygen administration is widely available, cheap, easy to administer, and safe in both the adult and pediatric populations. Controlled studies are mandatory to confirm our observation. However, considering the major impact of paroxysmal motor events on the quality of life of the patients and the burden for caregivers, this therapeutic strategy might be life changing for both patients and families. The parents of the children have given written consent for publication. We thank Chantal Sylvestre for her help in the patients' care and for fruitful discussions. (1) Project: A. Conception, B. Organization, C. Execution/Data Collection; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. M.T.P.: 1C, 2A, 2B. Q.W.: 1C, 2A, 2B. A.R.: 1C, 2B. D.G.: 1C, 2B. M.M.: 1C, 2B. E.P.: 1C, 2B. E.R.: 1A, 1B, 1C, 2A, 2B. M.T.P., Q.W., and D.G. have no disclosures to declare. A.R. received an honorarium for lecturing from PTC Therapeutics. E.P received honoraria for lecturing from Eisai and for participating in an advisory board for StrideBio. She also received research support from AFHA (Association Française de l'Hémiplégie Alternante) and from Fundacio La Marato de TV3 (Spain). M.M. received honoraria for lecturing from Jazz Pharma, Eisai, LivaNova and Neuraxpharm. E.R. received honoraria for lecturing from Orkyn, Aguettant, Elivie and for participating in an advisory board for Merz-Pharma. He received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Enjoysharing, Fondation Desmarest, Amadys, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Societé Française de Médecine Esthétique, and Dystonia Medical Research Foundation. The data that support the findings of this study are available from the corresponding author upon reasonable request.