Spotlight on Sleep: Updates in Diagnosis and Treatment of Narcolepsy and Idiopathic Hypersomnia

The recent availability of a number of new medications for the management of excessive daytime sleepiness highlights the importance of efficient and accurate diagnosis of central disorders of hypersomnolence, such as narcolepsy and idiopathic hypersomnia. Delayed diagnosis is a known problem for narcolepsy and idiopathic hypersomnia, often with years elapsing from symptom onset to diagnosis.¹ Underrecognition of these disorders, symptom overlap with more common disorders, and limitations in diagnostic testing can make timely diagnosis challenging. Even with a high degree of clinical suspicion, current diagnostic tests have limitations for idiopathic hypersomnia² that may lead to delays in care for people with this condition. However, efficient and accurate diagnosis of these conditions is important, as there is increasing availability of medications that improve quality of life and substantially alleviate symptoms of these disorders. These new medications allow for shared decision-making about how to best manage symptoms of severe sleepiness for people with these lifelong sleep disorders. Contemporary management of narcolepsy and idiopathic hypersomnia should account for the individual’s preferences and priorities to support optimal functioning in school, at work, and within social and family realms.

Recognizing Central Disorders of Hypersomnolence

Narcolepsy and idiopathic hypersomnia are central disorders of hypersomnolence, with diagnosis based on clinical history and supportive neurophysiologic testing. Excessive daytime sleepiness also is a core symptom of several other neurologic disorders, such as myotonic dystrophy and Parkinson disease, and this discussion is relevant to these conditions as well. Excessive daytime sleepiness is the central feature of narcolepsy; additional symptoms can include sleep paralysis, sleep-related hallucinations, and cataplexy (episodes of muscle weakness associated with strong emotion, which is present in narcolepsy type 1). Idiopathic hypersomnia is also characterized by excessive daytime sleepiness, and people with idiopathic hypersomnia may also experience difficulty waking up in the morning (sleep inertia), prolonged sleep duration (12 to 14 hours or more per night), and cognitive clouding (“brain fog”). Differentiation among narcolepsy type 1 (formerly narcolepsy with cataplexy), narcolepsy type 2 (formerly narcolepsy without cataplexy), and idiopathic hypersomnia can be challenging because of symptom overlap among these conditions and may be based on features of supportive testing (Table).

Fatigue and daytime sleepiness are common clinical complaints and are not specific to narcolepsy and idiopathic hypersomnia. Distinguishing sleepiness attributable to narcolepsy or idiopathic hypersomnia from sleepiness related to insufficient sleep, circadian disruption, a medical or psychiatric disorder, or medications requires careful clinical evaluation and an in-depth review of detailed patient sleep history. Even with a clear clinical and sleep history, identifying the underlying diagnosis for daytime sleepiness can be challenging.

Insufficient sleep is a common cause of daytime sleepiness and can result in excessive daytime sleepiness with lapses into sleep in inappropriate settings and difficulty waking up in the morning. Symptoms that are classically associated with narcolepsy, such as sleep paralysis and sleep-related hallucinations, can emerge in healthy sleepers in the setting of sleep loss. Thus, information about habitual sleep duration is critical in the evaluation of a central disorder of hypersomnolence. It is important to ask about school or workday sleep habits and unrestricted sleep patterns (weekends, vacations), and whether daytime sleepiness resolves with habitually getting more sleep.

People can have difficulty estimating their own sleep duration; keeping careful sleep logs or reviewing objective data from activity trackers can be helpful for supporting the clinical history, and also may be eye-opening for people if their routines vary from their subjective recall of sleep habits. Careful evaluation for adequate sleep duration is essential, as the most common diagnostic test for narcolepsy and idiopathic hypersomnia (the Multiple Sleep Latency Test [MSLT]) does not differentiate these conditions from insufficient sleep.

Symptoms of narcolepsy or idiopathic hypersomnia and insufficient sleep are so closely related that people with central disorders of hypersomnolence often present to the sleep clinic years after symptom onset because their parents, teachers, or doctors attributed their sleepiness to sleep loss.

Cataplexy

Cataplexy—episodic muscle weakness triggered by emotion—differentiates narcolepsy type 1 from other disorders of hypersomnolence. Positive emotions (eg, laughter, anticipation) trigger cataplexy most commonly, and episodes last for seconds to minutes before complete resolution. Cataplexy can be generalized, with falling or slumping to the floor, or partial, with drooping eyelids, jaw, or neck, or slurred speech. There is no loss of consciousness during cataplexy episodes and weakness typically is symmetric, which may help differentiate a cataplexy episode from seizure or transient ischemic attack. If provoked in a clinical setting, loss of deep tendon reflexes can be confirmed in cataplexy. Cataplexy is specific for narcolepsy type 1, but also occurs rarely in other disorders.

Challenges in Interpretation of Diagnostic Testing for Excessive Sleepiness

When there is clinical concern for a central disorder of hypersomnolence, supportive testing most often includes overnight polysomnography (PSG) followed by the MSLT performed in a sleep center. The MSLT evaluates the propensity to fall asleep, measured by sleep latency, and abnormalities in transition to rapid eye movement (REM) sleep. The accuracy of the MSLT for detecting narcolepsy or idiopathic hypersomnia depends on a number of factors, including habitual sleep schedule, recent sleep loss, and medications. Thoughtful interpretation of these sleep studies is required, as shortened sleep latency and sleep-onset REM may be seen on MSLT because of insufficient sleep or circadian rhythm disorders, and in people taking or withdrawing from certain medications. To minimize confounding factors on the MSLT, it is ideal for patients to document adequate sleep preceding the test, to use prescribed treatments for any other existing sleep disorders (most commonly sleep apnea), and to have a conversation with their doctor about which medications to continue or taper for the sleep study.³ If possible, medications with alerting, sedating, or REM-modulating potential should be stopped before the study. In practice, people may be reluctant to stop medications. It is important to note, however, that commonly prescribed medications, such as selective serotonin reuptake inhibitors, can modulate REM sleep. It is imperative that a primary circadian rhythm disorder, unrecognized or untreated depression, or more than mild sleep apnea are excluded before the MSLT; these conditions can be recognized through clinical evaluation and an in-depth review of the patient's sleep history and the overnight PSG (for sleep apnea).

Even when following best practices, overnight polysomnography with MSLT is not a perfect test. Whereas this test has relatively good sensitivity and reliability for narcolepsy type 1, the sensitivity and reliability are limited for idiopathic hypersomnia,^4,5 with up to half of people with idiopathic hypersomnia having normal PSG test results. Alternative diagnostic testing to document prolonged sleep time—either with an extended sleep study (allowing the individual to sleep as long as possible) or using wrist actigraphy—may be a more sensitive test for idiopathic hypersomnia; however, these tests may be logistically challenging and often are not available.

Advances in the understanding of narcolepsy type 1 etiology have generated new targets for diagnostic testing (eg, low orexin [hypocretin] in cerebrospinal fluid testing is diagnostic) and offer potential for targeted therapies (eg, investigation of orexin receptor agonists for treatment of narcolepsy). However, little is known about the physiologic mechanisms that underlie symptoms in narcolepsy type 2 and idiopathic hypersomnia, which hinders identification of reliable biomarkers in this population.

Patient-Centered Care

There is no treatment for narcolepsy or idiopathic hypersomnia, which typically are considered lifelong disorders. A subset of people with idiopathic hypersomnia may have spontaneous improvement, although there are limited data to predict who may experience remission. Current therapies target minimizing symptoms of sleepiness and cataplexy. For people with narcolepsy or idiopathic hypersomnia, education about the disorder and resources for managing symptoms can improve quality of life. Most people with narcolepsy ultimately use at least one medication for symptom management; however, healthy sleep depends on an approach that balances pharmacologic treatment and lifestyle adaptations (Box).

Sleep health is a foundation: just as sleep deprivation or irregular sleep schedules affect daytime function for healthy sleepers, sleep loss and erratic sleep routines worsen symptoms in people with narcolepsy and idiopathic hypersomnia. People with narcolepsy have increased incidence of other sleep disorders (eg, restless legs syndrome, periodic limb movement disorder, sleep-disordered breathing), and addressing these disorders can improve sleepiness. For some people, a scheduled daytime nap considerably improves both sleepiness and cognitive symptoms, and if school or workplace accommodations can be made to allow time and space for sleep, this may allow for management of sleepiness with less need for medication.

The emergence of new therapies over the past few years allows for nuanced discussions about symptoms, side effects, and comorbidities when determining care plans. Until recently, discussions about treatment of excessive daytime sleepiness included stimulant medications of various formulations: modafinil (Provigil; Teva Pharmaceuticals, Tel Aviv, Israel), armodafinil (Nuvigil; Teva Pharmaceuticals, Tel Aviv, Israel), and sodium oxybate (Xyrem; Jazz Pharmaceuticals, Dublin, Ireland). Newer wake-promoting medications (solriamfetol [Sunosi; Axsome Therapeutics, New York, NY] and pitolisant [Wakix; Harmony Biosciences, Plymouth Meeting, PA]) as well as new formulations of oxybate (low-sodium oxybate [Xywav; Jazz Pharmaceuticals, Dublin, Ireland], and an extended-release formulation [Lumryz; Avadel Pharmaceuticals, Dublin, Ireland] with Food and Drug Administration approval in May 2023) offer flexibility for people with narcolepsy or idiopathic hypersomnia.

The American Academy of Sleep Medicine has strong or conditional recommendations for these medications based on the available supporting medical literature.⁶ In practice, certain considerations may prompt treatment with one therapy over another depending on the most bothersome symptoms (ie, sleepiness, cataplexy) or concern about side effects. For example, there are specific considerations for people with childbearing potential, because modafinil, armodafinil, and pitolisant decrease efficacy of hormonal contraceptives, and limited safety data exist regarding most of these medications for use during pregnancy. New options, such as orexin agonists and the norepinephrine reuptake inhibitor reboxetine (Edronax; Pfizer, New York, NY), are in clinical trials, and will offer additional options to personalize management of this group of disorders.

Summary

A careful clinical and sleep history that includes evaluation of sleep time and duration and thoughtful application of available diagnostic testing contributes to improved diagnosis of central disorders of hypersomnolence. Availability of a number of new medications over the past few years allows for nuanced conversations about preferences when embarking on a treatment plan. The goal of treatment for people with excessive daytime sleepiness is to support full participation in their academic, professional, and social lives.