New developments in the management of narcolepsy

Abstract

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.

Quickly diagnosed and treated prepubertal Type 1 narcolepsy case

“…For this reason, it is important to follow the weight of the narcoleptic children in the follow-up to evaluate the effectiveness of the treatment, not only during the diagnosis. Hyperactive/aggressive behaviour in children, problems in communication with their peers, and rarely psychotic symptoms can be observed [22]. In our patient, improvement was observed in aggressive and nervous behaviours especially towards the family after treatment.…”

“…Surprisingly, with the sleep specialists, primary care physicians, and the general public who participated in the AWAKEN study [23], it was found that knowledge and awareness of narcolepsy was very low. It is important to identify the signs of narcolepsy early, to confirm the diagnosis and to make the treatment effective [22]. It is important to remember the diagnosis of narcolepsy in childhood patients who present with symptoms of daytime sleeping and excessive sleepiness, without forgetting that narcolepsy symptoms begin most often in childhood and adolescence.…”

Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

“…High concentrations of GABA in the CNS suggest that GABA plays a major role in various brain and spinal cord functions, and modulation of GABA transmission can significantly affect CNS function. Drugs that target GABA A receptors have been used to treat anxiety, insomnia, and epilepsy; orthosteric GABA B agonists are used to treat muscle rigidity and narcolepsy . Activation of GABA B receptors by systemic administration of the GABA B agonist baclofen induces analgesia, a mechanism that is primarily mediated by GABA B receptors expressed on afferent terminals in the dorsal horn of the spinal cord and that also involves cholinergic and endocannabinoid mediators .…”

Narcolepsy: Diagnosis and management

“…Patients on these medications should be followed closely to ensure that blood pressure, pulse, and weight are not negatively affected. 18,50 Addiction and tolerance can develop with these drugs, and follow-up should include assessment for dependence. Some states may require prescription drug monitoring to ensure the drugs are not being abused or diverted.…”