Advances Answer Some Questions in Excessive Sleepiness, But Raise New Ones

The field of neurology is gaining a more robust understanding of some of the mechanisms at play in excessive daytime sleepiness, but the progress has not spread evenly across different sleep disorders.

In many ways, sleep medicine is in its heyday. Sleep clinics have become ubiquitous, and both patients and physicians have a better understanding of the prevalence and seriousness of sleep-related disorders.

“There’s been a huge increase in awareness of sleep disorders,” James A. Rowley, MD, a professor of medicine and chief of the Division of Pulmonary/ Critical Care and Sleep Medicine at Harper University Hospital in Detroit, Michigan, told NeurologyLive. Rowley explained that sleep specialists have worked hard to alert and educate primary care physicians and neurologists about the need to consider sleep disorders when evaluating patients who report excessive fatigue.

“People with daytime sleepiness really should have a full evalua­tion to make sure there isn’t something beyond sleep deprivation,” Rowley said. “And if a patient comes in saying they get a full 8 hours of sleep each night, it ought to be a bright red flag that something is going wrong with their sleep.”

Unfortunately, Rowley pointed out, many individuals do not get a full 8 hours of sleep each night. Some patients do not get even close to that amount, resulting in numerous effects, excessive daytime sleepiness among them. According to Christian Guilleminault, MD, a professor of psychiatry and behavioral sciences at the Stanford Center for Sleep Sciences and Medicine in California, the most common causes of excessive daytime sleepiness are simply the rigors of modern life and sleep restriction.

“Most people need 7 to 7 hours and 30 minutes of nocturnal sleep with sleep onset and offset at the same time [each night],” Guilleminault said.

When patients do not get enough sleep, or when their sleep schedule is irregular because of personal or work-related issues, they end up feeling sleepy during the day, Guilleminault added. For these patients, lifestyle changes often solve the problem. For others, however, the problem of sleepiness is related to a much more complicated underlying issue.

Among the most common causes of daytime sleepiness are narcolepsy, insomnia, restless legs syndrome, and obstructive sleep apnea. Although a significant amount of recent research has helped explain many of the neurological issues at play in narcolepsy, the neurological factors associated with other conditions are less well described. And though it may seem logical that a sleep-disturbing disorder would cause sleepiness simply by lowering the quality of a patient’s sleep, experts and investigators see a more complicated picture, and a growing body of literature is helping to explain how neurological factors directly or indirectly cause excessive daytime sleepiness, or hypersomnolence.

Research Gains

Brian James Murray, MD, an associate professor of neurology and sleep medicine at the University of Toronto School of Medicine and an affiliate scientist at the Sunnybrook Research Institute in Canada, told NeurologyLive that the recent advances have given physicians more tools to make accurate diagnoses of sleep disorders. “Over the last 20 years, we have seen significant progress in the diagnosis of sleep disorders,” he said.

Like Rowley, Murray credited increased awareness of frontline physicians with helping to improve sleep disorder diagnoses. “Secondly, we have seen improvements in ambulatory devices to screen populations for sleep disorders such as obstructive sleep apnea,” he remarked.

Some of the biggest gains in neurological science have come in physicians’ understanding of narcolepsy. These, Murray said, include improvements in the diagnostic classification system and the recognition of spinal fluid orexin/hypocretin levels as an identifier of the condition “in the right clinical context.”

The discovery of the orexin/hypocretin system, Murray explained, has “revolutionized our understanding of sleep-wake control. We have a much better understanding of daytime sleepiness and have developed new medications to address this common problem.”

The insight that low orexin can lead to excessive sleepiness has implications for other sleep disorders, as well, such as insomnia. The association of narcolepsy with a deficiency of orexin prompted investigators to consider whether inhibiting orexin might be valuable in producing sleepiness in people who have trouble falling asleep.

In 2014, the FDA approved suvorexant (Belsomra; Merck), a first-of-its-kind orexin receptor antagonist, for the treatment of adults with insomnia. The drug works by restraining orexin and thereby inducing the same kind of sleepiness that is problematic in patients with narcolepsy. Its approval broke up a paradigm dominated by benzodiazepines, such as lorazepam and temazepam and nonbenzodiazepines, such as zolpidem and eszopiclone.

In a 2014 study of suvorexant, Michael W. Neville, PharmD, and colleagues pointed out that benzodiazepines and nonbenzodiazepines have significant drawbacks.¹

“Both classes exert effects on GABA [γ-aminobutyric acid] and have more global inhibitory effects in the brain,” they wrote. “This effect results in amnesia, next-day limited sedation, and rebound insomnia. In addition, both drug classes can be habit forming and have the potential to promote dependence.”

Suvorexant does not share the same drawbacks, largely because rather than inducing sleep, the therapy works by deactivating the mechanisms that cause wakefulness.

Role of Histamines

Around the same time that investigators began working on orexin-based therapies, another study exploring the role histamines play in narcolepsy was published.2 In addition to the loss of orexin/hypocretin neurons, narcolepsy is associated with an increase in histamine-producing neurons.

“This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy, such as preserved consciousness during cataplexy and fragmented nighttime sleep,” wrote principal investigator Thomas Scammell, MD, a professor in the Department of Neurology at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development.”

Scammell detailed that the results of his research suggested that drugs that reduce histamine signaling might help promote better sleep in patients with narcolepsy, and conversely, drugs that can boost histamine might help promote wakefulness and reduce daytime sleepiness.

Indeed, last May, the FDA gave fast track and breakthrough therapy designations to pitolisant, a drug currently being developed by Harmony Biosciences for the treatment of cataplexy in patients with narcolepsy and for excessive daytime sleepiness in patients with narcolepsy.

Pitolisant is a selective histamine 3 receptor antagonist/inverse agonist that enhances histaminergic neurons in the brain to boost wakefulness and reduce the risk of cataplexy. Data presented in 2018 showed that the drug led to long-term improvements in excessive daytime sleepiness. Under the Epworth Sleepiness Scale (ESS), patients in the study had scores of 16.8 at baseline, 13.4 after 1 year, and 10.6 by year 5. ESS scores of up to 10 are considered normal, according to the authors of that study.³

Although pitolisant is not yet approved in the United States, it is currently offered through an expanded access program called Pitolisant Expanded Access Clinical Evaluation, or PEACE, to patients with excessive daytime sleepiness associated with narcolepsy as well as cataplexy associated with narcolepsy. Pitolisant is already on the market in Europe, under the brand name Wakix.

More recently, a study conducted by Guilleminault and colleagues looked at functional brain images in hopes of better understanding differences between the 2 types of narcolepsy.⁴ They noted that type 1 narcolepsy is characterized by cataplexy and the “destruction of hypocretin neurons in the lateral hypothalamus, with the elimination of 5 well-delineated axonal bundles.” They found that patients with type 1 narcolepsy and those with type 2 narcolepsy suffer from excessive daytime sleepiness, though cognitive impairment and other comorbidities are much more severe in patients with type 1 narcolepsy.

“These findings reflect the destruction of the 5 axonal bundles coming out of the destroyed hypocretin neurons,” Guilleminault and colleagues wrote. “Clearly, type 2 narcoleptics do not present with such severe handicap and are clinically closer from the so-called hypersomniacs than from the type 1 narcoleptics.”

Sleepiness With Restless Legs Syndrome

Another common cause of excessive daytime sleepiness is restless legs syndrome (RLS), a condition famously characterized by individuals’ incessant urge to move their legs. Rowley said many patients who present with daytime sleepiness eventually receive a diagnosis of RLS. He added that the likely cause of that sleepiness is RLS-related sleep disturbance.

“A lot of those patients kick their legs during nighttime,” Rowley said. “They don’t get a good night’s sleep.”

It’s not known exactly how many patients with RLS have problems with daytime fatigue. Results from one study showed that about one-third (37%) of patients with RLS reported excessive daytime sleepiness. That 2009 study, however, included only 27 patients.⁵ Although genetic factors are believed to play a role in RLS, investi­gators have recently focused on levels of dopamine and iron in the brain. Investigators at Johns Hopkins University have also found that glutamate levels are implicated, with too much glutamate leading to arousal.⁶

Results from research published in 2018 suggest that hyper­arousal in a part of the brain’s motor cortex is the underlying mech­anism at play in RLS, with the brain essentially sending a signal to the legs in preparation of movement, even though the individual has no plans to actually move the legs.⁷

Rowley said a number of questions about RLS remain, the answers to which might have implications for the excessive daytime sleep­iness seen in some patients with RLS. In the meantime, existing treatments for RLS range from behavioral changes to therapies that increase dopamine. Other patients are prescribed opioids, which have been shown to relieve symptoms in some individuals.

Sleep Apnea and the Brain

Perhaps the biggest area of focus in the sleep medicine commu­nity of late has been obstructive sleep apnea (OSA). A 2017 review found that the prevalence of OSA in the United States general population ranged from 9% to 38%, with men at the highest risk for the condition.⁸

As the name suggests, the most obvious characteristic of OSA is the physical obstruction of the airway. Guilleminault recently published a study looking at the orofacial underpinnings of OSA, which “show that orofacial growth development may be impaired during the fastest growth time (birth to 6 years), and [this] leads to a narrow upper airway.”⁹ That narrowing can be exacerbated by the tonsils and adenoids and fat deposits in the tongue, both of which can also obstruct the airway.

Although, Guilleminault said the main problem in young people with OSA is maxillary deficiency. Though common, he explained, this deficiency is “never recognized by the pediatrician” but is sometimes recognized by well-informed orthodontists.

This condition leads “to abnormal upper airway resistance and continuous disturbance of sleep [not recognized with simple poly­somnography],” according to Gulieminault. However, despite the physical conditions present in OSA, the condition is also closely tied to the brain.

“The brain fundamentally controls expression of this disorder,” Murray noted. “Sleep apnea is not present in wakefulness but emerges when the nervous system produces sleep.”

Murray added that the relationship between sleep apnea and OSA—the most common form of the disorder—is complex. “First, a number of neurological conditions, such as neuromuscular disor­ders, can produce sleep apnea by reducing motor control of the upper airway,” he said. “Second, sleep apnea is a risk factor for the development of sleep disorders such as stroke. Furthermore, treat­ment of sleep apnea may help improve neurorehabilitation and neurological outcomes in a variety of conditions.”

A 2005 study from Guilleminault and colleagues implicated abnormal upper airway sensory input as likely at play in the devel­opment of apneas.¹⁰ Such inputs could be the reason that a subset of patients who successfully undergo continuous positive airway pressure (CPAP) treatment still report excessive sleepiness. Results from that study showed that 22% of patients who were effectively using CPAP, defined as using the device for more than 6 hours per night, still had excessive sleepiness during the day.¹¹

However, CPAP—and in some cases, surgery—remains the best available treatment for people with OSA. Guilleminault told NeurologyLive that there is no good pharmacologic treatment for the disorder yet, but patients with OSA who suffer from excessive daytime sleepiness can take medication to address the lingering sleepiness. Murray pointed to methylphenidate and modafinil (Provigil; Cephalon) as common and viable options to improve sleepiness, adding that “new medications are being developed and will be here shortly.”

Guilleminault was involved in a study on one of those new ther­apies, solriamfetol, in 2018.¹² The drug is being evaluated for the treatment of both OSA and narcolepsy. It is a novel treatment, oper­ating as a selective norepinephrine-dopamine reuptake inhibitor.

“It is well tolerated and effective in reducing sleepiness and is an alternative to modafinil and armodafinil,” Guilleminault and colleagues noted. “Unlike stimulants like methylphenidate and dextroamphetamine, it does not have cardiac effects, rebound hypersomnia, or withdrawal effects.”

A double-blind study of more than 450 patients with OSA published in December 2018 found solriamfetol was successful at boosting wakefulness and alertness in patients with OSA.¹³ In the trial, patients with OSA were randomized across 5 arms for 12 weeks of treatment: solriamfetol at doses of 37.5 mg (n = 59), 75.0 mg (n = 61), 150.0 mg (n = 118), and 300.9 mg (n = 119), and placebo (119 patients). The mean sleep latency was 13 minutes at the highest dose of solriamfetol and 4.7 at the lowest. In the placebo group, the latency was 0.2 minutes. The ESS score was —7.9 in the high­est-dose arm and –5.1 with the lowest versus –3.3 with placebo.

Treatment of Symptoms of Sleepiness

Studies like those mentioned for OSA raise the question of whether it is prudent to treat excessive sleepiness on its own as opposed to targeting the underlying condition. After all, treating a prominent symptom could allow patients to feel “cured” even as the more serious underlying problem worsens.

Murray said therapies that treat sleepiness are necessary but should not be the first step a physician and patient take. “Physicians should always address the root cause of the problem first if at all possible. When treatment options have been exhausted for the root cause, symptomatic management should be consid­ered to help improve neurological function and quality of life,” he told NeurologyLive.

Indeed, Rowley noted that although it is best to treat the under­lying condition, “there’s also more and more research coming out about the ill health effects of not being able to sleep.” He added that the new drugs currently in development focus more acutely on targeting the parts of the brain that help people stay awake. These developments could be an important step, he explained.

Murray said there are a number of other emerging developments. He sees histamine-modulating medications and new monoamin­ergic reuptake inhibitors as important players. More broadly, he also believes scientists should invest research in trying to get a better understanding of the relationship between inflammation and sleepiness. Results from a 2017 study have already suggested that excessive daytime sleepiness in OSA was associated with low-grade inflammation.¹⁴

In the meantime, Rowley said all the new science has paved the way for major steps forward in sleep medicine. The advances can be a lot for primary care physicians to keep track of, and Rowley suggested that is why consulting a sleep medicine specialist is important if physicians suspect there is more going on than poor sleep habits.

“As a sleep doctor, it’s just taking a careful history and a physical,” he said. “We can usually tell up front whether it’s a primary sleep disorder or just sleep deprivation.”

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