A ReLACSing Blog #16: Does Narcolepsy Type 2 Exist?

Unlikely.

In the last blog about the so-called periodic limb movement disorder (PLMD), which is also unlikely to exist, I illustrated that there is a thought error in medicine in which an unusual or unique finding is falsely assumed to be pathological and linked to a set of symptoms as a cause. Narcolepsy type 2 is much like PLMD in which the “condition” is created from an abnormal test result, rather than originating from scientific discovery of a biological process. Narcolepsy type 2, which I will discuss here, and PLMD have some differences but both lead to labeling a person with a misleading diagnostic term and delay the help derived from addressing the true underlying causes of their symptoms.  

First, what is narcolepsy type 2? We don’t know (!)–at least with a biological understanding–but somehow we have a set of diagnostic criteria. Since it is “type 2,” you may have guessed there may be a type 1. Narcolepsy type 2 (NT2) is also known as narcolepsy without cataplexy. Narcolepsy type 1 (NT1), or narcolepsy with cataplexy, is conversely derived from a very well-defined biological process in which the brain cells (neurons) in a part of the brain called the hypothalamus are destroyed through an autoimmune process, or the body’s immune system mistakenly attacking itself (think conditions like lupus, rheumatoid arthritis, etc.). This causes loss of an important brain chemical called hypocretin (also called orexin) that regulates sleep in the brain. This leads to disruption of normal processes that control sleep and sleep cycles. Due to the discoveries in NT1, we have a known biological process, objective tests that correspond to the biology, and a corresponding set of classic symptoms including excessive daytime sleepiness, sleep paralysis, hallucinations when coming in and out of sleep, and of course, cataplexy, for which the condition is named. Cataplexy is an unusual phenomenon in which there is sudden loss of muscle tone–almost a paralysis–of some of the muscles in the face, shoulders, or legs for a split-second or up to a few seconds that is triggered by emotions such as laughter and surprise, but the person is still completely awake. It is actually an intrusion into wakefulness of the muscle paralysis that normally occurs during rapid eye movement sleep (REM sleep). Cataplexy is a hallmark of the disorder illustrating significant disruption to sleep cycles such that something that should occur during a specific stage of sleep now occurs while one is awake.

Narcolepsy type 2 does not have the cataplexy or most of the other symptoms of sleep stage disruption but got its name from sharing a common symptom–excessive daytime sleepiness–combined with a similar test result to those with narcolepsy type 1. Excessive daytime sleepiness is not unique to a disease or condition and can happen to any human. Anyone who has pulled an all-nighter or been a parent of a newborn knows what it is like to be excessively sleepy during the day. The abnormal test result that can be construed as similar to NT1 is primarily where the problem comes in as these results can also be seen in just about anyone if put under the right set of circumstances.

When I was a fellow at Stanford, I had the privilege to take part in small educational sessions with the late Dr. William Dement, who is known as the “father of sleep medicine”. Dr. Dement told us a story about how he, Dr. Mary Carskadon, and colleagues sought to create a test that would be unique to NT1 to help diagnose and define the condition, called the multiple sleep latency test (MSLT). The MSLT in its current form is a set of napping opportunities during the daytime done 4-5 times, two hours apart, in which a person lies down and has 20 minutes to fall asleep. They can sleep up to 15 minutes before they are woken up. Brain waves and eye movements are measured as they are in overnight sleep studies (PSG/polysomnography) so clinicians can fairly accurately measure when the patient fell asleep and what stages of sleep they enter. Dement, however, said that he was taken aback that when the test was administered to others who did not have NT1, results on the MSLT could look similar to those with NT1, hence, one of the reasons we have NT2. Sometimes, if you apply a test to the wrong group of people, you can get a result that you do not expect and may not be able to explain well. 

Now let’s go back to the definition of narcolepsy type 2. According to the 3rd edition of the International Classification of Sleep Disorders (ICSD-3), which is the main diagnostic manual for sleep medicine, the diagnostic criteria include (to summarize): (1) a person with a strong need to sleep (excessive sleepiness), (2) no cataplexy, (3) normal hypocretin levels (if measured), and (4) the following specific test results on the MSLT: the person must fall asleep on average in less than 8 minutes on the 4-5 naps and enter into REM sleep at least two times within 15 minutes (which can also include entering REM sleep within 15 minutes on the sleep study the night before the MSLT). These are the numbers met by the vast majority of patients with NT1 and how Dement and Carskadon created this test. Most patients I have seen with true NT1 fall asleep in like 1-2 minutes any chance they get and may go into REM sleep within 15 minutes nearly every time they sleep, some starting off in REM sleep! These ICSD-3 cutoffs are somewhat arbitrary and were decided by a panel of sleep experts to balance correctly capturing most with a disorder without capturing too many people who don’t have it (sensitivity & specificity). Unfortunately, there are a lot of people who fall asleep in less than 8 minutes on average during an MSLT and may have two or more naps in which they go into REM sleep abnormally. A lot of these people do not have narcolepsy at all but in fact are diagnosed with NT2.

However, the fifth criteria for diagnosis, as is the case in PLMD, is that this term “NT2” is a diagnosis of exclusion. In other words, the MSLT findings cannot be better explained by a known cause like disruption to sleep schedule, obstructive sleep apnea, medication effects, and simply not getting enough sleep. No one seems to remember this fifth criteria or at least has the time to investigate the known causes of excessive daytime sleepiness and disruption to sleep. It is again a logical flaw to seek to diagnose an unknown condition that is a diagnosis of exclusion before every known condition has been excluded. Sadly, even if NT2 does exist and the criteria above accurately identify people with NT2, the test is misapplied to the vast majority of people who take the MSLT. In my career, I have not encountered one patient labeled as “NT2” who did not have a better explanation for daytime sleepiness and abnormal MSLT results, after talking to the patient about the clinical circumstances at the time of their testing and diagnosis. The diagnoses needing to be excluded were never excluded!

For example, if you take a 100% healthy nurse from the hospital and have them work three night shifts in one week and then run the daytime MSLT on them, they probably will meet the first four criteria above, except for #5. The results look like someone with narcolepsy: they fall asleep in, say, 4 minutes on average. They inappropriately go into REM sleep in three of the naps. However, the cause is not NT2, it is the shift-work and disruption to the circadian rhythm prior to the test that led to the test results. They did not have a “condition” but a set of circumstances that produced similar results. The MSLT is a test that lacks precision, but more importantly it is non-specific to any condition. A number of changes to medications, sleep deprivation, shift-work, poor sleep schedules, taking 3-4 naps per day, poor sleep quality from sleep apnea, mental health conditions like severe anxiety and even chronic insomnia can lead to the same abnormal testing outcome. Of course, there are mitigating processes in place to prevent a misdiagnosis. An overnight sleep study is performed the night before the MSLT to ensure sufficient sleep the night before the study and to exclude another sleep condition like sleep apnea that could affect the MSLT results. The American Academy of Sleep Medicine also recommends that actigraphy, which is a wrist-worn device that tracks body movements (think FitBit, Oura ring, Apple Watch, etc.) to estimate sleep schedule and quantity, should be done for the two weeks before the sleep study. If actigraphy cannot be done, and it is generally not done due to lack of insurance reimbursement, the patient should at least keep a sleep diary to ensure they are getting consistent sleep on a consistent schedule. Taking 4-5 naps during the day, waking up at different times anywhere from 5 am to 11 am on a given day, or averaging 5 hours of sleep per night is a recipe for a falsely abnormal MSLT result and NOT narcolepsy. 

I do want to mention a few of the drivers of NT2 misdiagnoses. As I have mentioned in previous blogs, the insurance-based fee-for-service reimbursement system heavily incents the ordering of sleep studies over quality of care and time spent evaluating patients. This creates a bias toward ordering more MSLTs so centers can charge an extra few thousand to run the daytime test as a side benefit, whereas the insurance would reimburse the physician pennies more for spending an hour talking to the patient to find out they are sleepy due to an erratic sleep schedule and educate them on how they can fix it. The drug companies have created drugs–very helpful and much needed–for NT1, but this is such a rare condition, even with it being extremely over-diagnosed as well, that they push to expand their customers by promoting treatment of these questionable conditions like NT2 and idiopathic hypersomnia (future blog post…) so more people can be prescribed the drug. A third cause of over-diagnosis is the lack of reimbursement for actigraphy, so much so that many centers, even major academic ones, don’t even have a device at all to test patients because it would cost them money instead of generating money. Fourth is the lack of time and attention to detail by sleep clinicians. They simply cannot do a thorough evaluation of the root causes of daytime sleepiness if given 15 minutes face-to-face with a patient. As mentioned above, there can be some logical and tactical flaws leading to the NT2 diagnoses as well. However, NT2 is fundamentally a case of misapplication of a non-specific test with misinterpretation of an abnormal result, which can lead one down the wrong path to improvement of health. 

If NT2 does not exist, we will thus fail to find the biological mechanism. Yes, it could be a mash-up of different circumstances that lead to the same results, much like PLMD. In this case, it would have multiple known biological causes as in the examples above, but not be a unique process at all that should be given its own name. Others have even speculated that it could be a lesser or incomplete form of NT1, but most diagnosed with NT2 lack any semblance of NT1 to support this theory. For now, the diagnosis of narcolepsy type 2 should be held under significant scrutiny from both patients and medical professionals. Future blog posts will be dedicated more specifically to the true causes of daytime sleepiness in these misidentified patients, and what can be done to mitigate the symptoms.

-Andy Berkowski, MD of ReLACS Health, who would have met NT2 criteria during residency as well as those first three months after each of those babies was born!