THE ANA Q&A: UNDERSTANDING NARCOLEPSY

Narcolepsy affects an estimated 135,000 to 200,000 people in the United States, possibly more. It is a chronic sleep disorder characterized by abnormally fast transition into rapid eye movement (REM) sleep patterns — sometimes during the day or in the middle of activities — and can be debilitating. The primary symptom of narcolepsy is excessive daytime sleepiness (hypersomnolence); many patients also experience cataplexy (sudden muscle weakness, limpness, or inability to move), sleep paralysis, and hypnagogic hallucinations (vivid hallucinations experienced as a person is falling asleep). There are two known disease subtypes: narcolepsy and narcolepsy with cataplexy.

We spoke with Pradeep Sahota, MD, FAAN, FANA, FAASM, FAES, FACP, Professor and Chairman of the Department of Neurology, Director of the Sleep Disorders Center, and Director of the Sleep Medicine Fellowship Program at the University of Missouri School of Medicine, to learn about new developments in narcolepsy treatment and pathophysiology.

Q: What progress have we seen recently in understanding and treating narcolepsy?

From the discovery of neurotransmitter orexin and orexin receptors and clinical application in the form of CSF orexin levels (it is now known that narcolepsy with cataplexy is caused by the loss of hypothalamic neurons that produce orexins/hypocretins, neurotransmitters that sustain wakefulness and prevent disordered REM sleep; CSF orexin levels then become a useful diagnostic tool), to the development of a new class of wake-promoting agents (modafinil being the first one), to development of medications that affect both hypersomnolence and cataplexy (starting with GHB and now pitolisant), we have made significant progress in understanding the pathophysiology and management of narcolepsy and narcolepsy with cataplexy.

Q: What challenges remain?

The glass is half full, if you will. While we have made progress on all fronts, we are far from addressing the full spectrum of challenges that narcolepsy presents. For example:

1. Challenges with clinical presentation:
   It still takes five years or longer from time of presentation, in many instances, for the patient to finally be diagnosed with narcolepsy. Children present differently than adults. That may not be recognized.
    
2. Challenges with pathophysiology:
   Orexin deficiency is a hallmark of narcolepsy with cataplexy. However, the pathophysiology of narcolepsy without cataplexy is less well understood. It is also yet unclear as to what, within the orexin neuronal network, causes distinct symptoms of narcolepsy with cataplexy.

   The role in narcolepsy of other neurotransmitters, including histamine, is starting to be better defined, along with their implications for therapy. One possible cause of narcolepsy with cataplexy might be an immune-mediated attack on orexin cells leading to their loss, yet the nature of such a mechanism is not well understood. Nor do we fully understand the relative role of genetic vs. environmental factors.
    

3. Challenges in specific populations:
   I referred to diagnostic challenges in the pediatric population. There is also a paucity of clinical trials for treatment of narcolepsy in children. Similarly, we do not have enough data on best management in pregnant women.
    
4. Challenges in diagnosis & diagnostic tests:
   • The Multiple Sleep Latency Test (MSLT), while helpful as a diagnostic test, can show similar findings in other conditions. While patients with narcolepsy have uncontrollable sleepiness, the test measures a patient’s ability to fall asleep when asked to do so with early onset REM sleep. It also requires a prior night of polysomnographic sleep study — hence cost becomes a factor.
   • Orexin levels in CSF, while consistently abnormal (low) in patients with cataplexy, are not affected in patients without cataplexy — which seems to have another pathophysiological mechanism not well understood at this time. Additionally, lumbar puncture to test CSF orexin can be difficult or impractical.
   • We know that the HLA-DQB1*0602 gene is associated with narcolepsy with cataplexy, yet the immune mechanisms, including immunological markers, are not identified.

     It is important that we develop some biomarkers or immunological markers for accurate diagnosis of narcolepsy.
      

5. Challenges with treatment: 
   For treatment of sleepiness, we have gone from stimulants to wake-promoting agents to newer medications affecting the histaminergic system. While these options are helpful in the management of patients, they are not a panacea. As narcolepsy with cataplexy manifests from loss of orexin cells, orexin replacement should be a possible treatment. Effective delivery, including the ability to cross the blood-brain barrier, remains a challenge; researchers are currently considering the intranasal route. For cataplexy, we have gone from use of non-sedating antidepressants to GHB, and pitolisant may also be of benefit. We are not close to treating these conditions with the most robust efficacy; however, significant progress has been made in the last 25 years or more with understanding and management.

Q: What work is your lab undertaking to advance understanding and treatment of narcolepsy?

We have been involved with clinical trials in narcolepsy. We were involved in the first two seminal multi-center trials — of modafinil and GHB and more recently of solriamfetol. We had the opportunity to present that data at an ANA Meeting in the past. In addition, we are working in our lab on understanding the mechanisms of sleep in a rodent model. Our current research includes studying the role of sleep and sleep disturbances in alcohol use disorder and post-traumatic stress disorder using animal models. This is led by my colleague Dr. Thakkar.

Q: What should the public know about narcolepsy that it often does not?

A significant delay is present in the diagnosis of narcolepsy, even with the emergence of sleep medicine as a discipline and expanding knowledge of narcolepsy. New onset of excessive sleepiness in adults and, paradoxically, hyperactivity in children needs to be evaluated.

Cataplexy presents differently in children than in adults, consisting of facial hypotonia (slackening of the facial muscles) with head drop, eyelid droop, and tongue protrusion or other involuntary (chorea-like) movements of the tongue, lip licking, lip biting, lip chewing, grimaces, and features referred to as “cataplectic face” with repetitive mouth opening and weakness of facial muscles.

The public should be aware of and seek out diagnostic testing to prevent delays in diagnosis and treatment, and know that there are multiple therapeutic options available for narcolepsy.

Q: What should ANA members know about narcolepsy?

Sleep is a brain state — believe it or not! Hence, neurologists and neuroscientists need to be actively engaged in understanding the mechanisms of sleep — including narcolepsy, where there is often a significant diagnostic delay with implications for functioning and quality of life for our patients. A knowledge of symptomatic presentation of patients with narcolepsy, early diagnosis, and early treatment can make a difference in the lives of our patients. We as neurologists should take the opportunity to be knowledgeable about narcolepsy and also be pro-active in educating our primary care colleagues so that it can be better identified, diagnosed earlier with prompt treatment.