The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.
Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.1 The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.
Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.
General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.
Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.