A ReLACSing Blog #23: 15 Reasons Narcolepsy Type 1 is Over-diagnosed: Part II
(This is Part II of the 15 reasons why narcolepsy type 1 (NT1, formerly narcolepsy with cataplexy) is over-diagnosed. You probably should read Part I first or to save time, watch the Part I video.
To recap the first 7 reasons:
An army of untrained sleep specialists
Poor understanding of cataplexy
Assumption that only those with NT1 can have sleep paralysis and other sleep-related symptoms
It is a logical flaw to screen for exceedingly rare conditions
The abysmally non-specific, inaccurate, imprecise, and poorly interpreted “objective” study known as the multiple sleep latency test (MSLT)
MSLT is prone to human error
Has Anyone Heard of the HLA DQB1*06:02 allele?
Let’s begin with #8:
#8 Hypocretin levels have not been commercially available until the last few years: In part I, I mentioned that it was great to work with Dr. Emmanuel Mignot, because we could do a lumbar puncture (spinal tap) on a patient and send the fluid to his lab to test for the presence of hypocretin (also called orexin) in the cerebrospinal fluid (CSF). Prior to this test’s commercial availability, other sleep physicians would informally petition Dr. Mignot, as well as a small number of other labs throughout the world, to run the test for challenging cases. Otherwise, there had been no formal process of getting the samples studied until the Mayo Clinic began offering this a few years ago thankfully. It may be of some cost. You need someone to do the lumbar puncture. It’s uncomfortable. All the women who have had epidurals for delivery of a baby are nodding, and this needle goes a little farther in. However, this is as definitive as you can get. Let’s say a person is evaluated for NT1 but the HLA for narcolepsy (HLA DQB1*06:02) is present. Remember the HLA can only rule out narcolepsy. Is the person just in the normal 1/3 of the population with the HLA or is their HLA actually contributing to narcolepsy? The CSF hypocretin level will be absent or zero in nearly everyone with NT1. In some, it will be low, meaning some of the brain cells are still alive and producing hypocretin but there has been damage from the immune system already completed. If the level of hypocretin is normal, then this is as close as one can get to ruling out this diagnosis, aside from someone mixing up the samples or screwing up the test. The book is closed and locked with a key. As a sleep physician, I would not force anyone to get this done if everything else lined up perfectly with NT1, but if I were a patient, I would demand this test if I were HLA positive.
#9 Insurance reimbursement biases clinicians to order too many MSLTs: In the American, insurance-based “sick care” system, the revenue comes to medical centers through procedures and not quality of care or time spent with patients. For sleep medicine, you have overnight sleep studies and MSLTs, the latter of which may net the sleep clinic a few thousand dollars extra with only a small amount of additional cost. Why not do it? Well, as discussed throughout, there is a worry of misdiagnosis and leading a patient and provider down the wrong management path. Though not a physically dangerous test, it can be dangerous from the standpoint of delay or downstream harms of misdiagnosis. Unfortunately, and I believe most of this is subconscious of course, doctors will err on the side of running the profitable MSLT than spending another hour or a few more clinic visits figuring out what is actually causing the daytime sleepiness. Nobody is going to make money on the HLA test either. It brings the question as to why we have a system that perversely rewards doctors for ordering crappy expensive tests that can mislead, but it does not reward the extra time, skill, and attention to detail to understand the cause and treatment of symptoms.
Photo by Artur Łuczka on Unsplash
#10 Actigraphy is largely not covered by insurance: In most cases, actigraphy is one of the simplest, yet most useful tests in the field of sleep medicine. In fact, many of you reading this as well as I, have an actigraph on your wrist right now. Actigraphy is the measurement of movement in several directions using increasingly advanced algorithms, and it can be applied to a person sleeping to approximate how much time an individual has slept and when they are sleeping. The actigraphs used in clinical sleep medicine far exceed the accuracy of commercially available ones but that gap is narrowing. A medical-grade actigraph may run in the direction of a grand in terms of cost, and then for each week of sleep measured, one has to factor in costs like shipping, handling the devices and data, and then having a qualified provider interpret the results. In the grand scheme of medical tests, this is not very expensive. However, the insurance industry largely does not cover the test at all. Sometimes sleep centers, as suggested by the American Academy of Sleep Medicine (AASM), run actigraphy prior to the PSG (polysomnogram)-MSLT combo and may get revenue as part of the total package, but few cover this test on its own. As a result, from my experience, the vast majority of sleep clinics, including most of the academic ones, either do not have actigraphy at all or rarely administer it.
Why is actigraphy so important? The quantity and pattern of sleep are essential for promoting alertness and good wake-time functioning for the human body. Anyone with an erratic sleep pattern or getting insufficient sleep can become drowsy and will not perform at their best. A person with a reduced sleep time or physiologically inappropriate sleep pattern leading up to the PSG-MSLT is one of the main causes of false positive results on the MSLT. This can lead to misdiagnoses of NT1, narcolepsy type 2 (NT2, narcolepsy without cataplexy), and idiopathic hypersomnia (IH). If the individual returns MSLT results consistent with narcolepsy and reports any questionable hint of cataplexy (hey, the screening forms asked five questions about cataplexy, maybe I do have it?), here you could have an NT1 misdiagnosis. Actigraphy is crucial to ensure these very common and fixable problems related to timing and quantity of sleep have been excluded before looking into rare (or yet to be discovered) central disorders of hypersomnolence. Similar to food and meal recall in nutritional epidemiological studies, individuals often have a difficult time remembering when exactly they fell asleep and how long they slept two nights prior, much less for the entire week. Sleep diaries filled out the next morning after sleeping are very helpful, but there is often a discordance between what a person can remember and what actually happens. Keep in mind that it is hard to be aware of whether you are asleep if you are asleep! As a simplified rule, people have to be asleep a long time to realize they were asleep or awake a long time to realize that they woke up.
In an ideal world rid of the purse string control by the insurance industry, patients suspected of any central disorder of hypersomnolence would be required to do 2 weeks of standalone actigraphy before any overnight sleep testing or MSLT could be performed. This would identify, in my opinion, 80% of the causes of daytime sleepiness before diagnostic sleep testing would even be needed.
My favorite story to tell as an illustration is that I saw a college student with a sleep medicine fellow (fellows are physicians who have completed residency training in a specialty and are doing subspecialty training under supervision). The fellow presented the patient to me stating the student could not stay asleep in class despite getting 8 hours of sleep every night, and he does not have risk factors for other sleep disorders like sleep apnea, so we should look into a central disorder of hypersomnolence.
I interrogated the fellow by asking, “First, this dude is like 18 years old, man. How do you know he doesn’t need like 9 hours of sleep every night, man? What college kid do you know who’s banging out 8 hours of sleep and religiously waking up at 7 am every morning, even on weekends? Folks (I’m giving up the Detroit Lions coach Dan Campbell’s “man” and switching to a favorite Bidenism as I just watched the State of the Union Address), folks, what are the chances he’s getting enough sleep? C’mon! Let’s do actigraphy and if he’s on a regular schedule, getting 8+ hours of sleep per night, then we can do the PSG-MSLT.” (By the way, folks, this is exactly how I used to talk to the sleep fellows.)
Epilogue: after one week of actigraphy, the college student averaged only 5.5 hours of sleep, including two nights in which he was up until 4 am and two other nights in which he got less than four hours of sleep. His wake up times varied from 8 am to noon during the seven days (remember, our bodies function best if we wake up at the same time every day). And this was despite the fact that he was being watched! Usually there is a phenomenon called the Hawthorne effect in which subjects who are being studied alter their behavior because they are aware that someone is tracking them. So this was probably a good week of sleep for this student. Had we ordered the PSG-MSLT, he would have met criteria for either NT2 or IH and would be on Adderall® for the next 10 years. Look, actigraphy is important. Let’s get insurance to pay for this. Finish the job! (This is clearly not an evergreen blog post. By the time Part II of this is posted, no one will remember the four Bidenisms used in the last two paragraphs, much less in February of 2024 or 2025.)
#11 Drug companies have an obvious financial incentive for more people to be diagnosed: There are some fantastic wake-promoting, alertness-stimulating, and cataplexy-reducing drugs out there on the market, which can be a godsend to people with NT1. Treatment has improved immensely for this condition, just in my career alone. The role of industry in this area and many others cannot be denied. However, I imagine it is hard to make money on a drug for 0.014% of the population. What if it were actually 0.1% the population? That’s 7X more people taking these medications. But even better, the same medications can be stretched into other dubious conditions for use including NT2, IH, and “disorders” such as the so-called “excessive daytime sleepiness in obstructive sleep apnea.” If the percentage of people having NT1 is 0.02%, why not try to capture any portion of those of the 20% who may have obstructive sleep apnea? There is a huge marketing push by these companies to promote their products, but also to educate clinicians and the public to increase awareness of the conditions and available treatments.
Sadly, there is little development in the drug pipeline for a logarithmically more common condition in restless legs syndrome (RLS), but largely due to promotion of these conditions by drug manufacturers, there is far more interest and knowledge about central disorders of hypersomnolence than RLS. An increased awareness of a condition with constant bombardment of advertising with new medications leads to over-diagnosis of the condition, particularly when juxtaposed with the diagnostic flaws above and in Part I.
#12 Researchers have career and financial incentives to diagnose patients and enroll them in trials: Though this may be mostly subconscious, if you are an academic physician involved in a clinical trial, and you only see 1–2 new patients per year with a rare condition like NT1, you may have a quick trigger when trying to diagnosis new patients and enroll them in a drug-sponsored trial. Many physicians looking for promotion and advancement can build on their academic foundation by running successful clinical trials and some receive money as paid speakers or consultants for drug companies. You can see the conflict of interest here. I have not uncommonly seen patients without NT1, even those that do not even meet the arbitrary MSLT criteria, and the previous physician will document “MSLT is likely a false negative and the patient has NT1 and should start on treatment.” Of course, no HLA or CSF hypocretin were done and the patient likely had circadian rhythm problems as a cause of the excessive daytime sleepiness.
#13 Misunderstanding of the concept of diagnosis of exclusion: More in NT2, IH, and the so-called periodic limb movement disorder (PLMD), but also in NT1 to some extent, these rare conditions are in a category of diagnoses of exclusion. Going back to reason and logic, to label a patient with a condition that has no specific test for diagnosis with an unknown biological basis (idiopathic), you have to exclude all other likely and known conditions first before you can say that the diagnosis of exclusion is the cause. Examples in medicine include fibromyalgia, psychogenic non-epileptic seizures, systemic exertional intolerance disease/chronic fatigue syndrome, etc. For NT1, this had been the case until the past two decades when the HLA and hypocretin tests became available. Because few are doing these tests and relying on the less accurate clinical evaluation and MSLT, NT1 remains a diagnosis of exclusion in many ways. However, sleep clinicians are constantly trying to rule in these conditions. “The MSLT is likely a false positive.” “The patient has circadian rhythm abnormalities (that are in fact the cause of sleepiness), but they probably also have narcolepsy as well.” These arguments are made far too much and are logically flawed. One cannot argue the presence of both a known cause along with an unknown cause that is a diagnosis of exclusion. If the patient has another cause, then it has not been excluded!
#14 Medications for NT1 can be performance-enhancing for anyone: Antidepressants like SSRIs and SNRIs, e.g. fluoxetine (Prozac®) and venlafaxine (Effexor®) respectively can be used to reduce cataplexy in NT1, but these typically are easy to obtain for depression or anxiety and do not provide a huge performance bump. Three of the other main classes of treatment involve the oxybate salts, wake-promoting medications, and stimulants. These all can have powerful effects including in healthy individuals with no sleep disorder. Oxybate salts (e.g. Xyrem®/Xywav®) are among the most powerful sedative medications/”sleeping pills” (though these are liquid and not pills, sleeping liquids anyone?). In NT1, they can reduce or eliminate cataplexy and consolidate disrupted sleep stage transitions to improve sleep quality and daytime alertness. In those without narcolepsy, they could be used theoretically to sedate people heavily and seemingly cover up a lot of abnormalities such as insomnia or fragmented (“light”) sleep with frequent awakenings throughout the night. These can even get people to sleep when there is circadian rhythm disruption from shift work, jet lag, or just an erratic sleep schedule. Wake-promoting agents like modafinil (Provigil®) can make people more alert. They do not have to have NT1 to be made more alert. Someone getting inadequate sleep at night would be more alert after taking modafinil. Amphetamines and other central nervous system stimulants can stimulate any brain, and moreover can impart a euphoric feeling as well. This is why these drugs are DEA Schedule II due to higher abuse potential.
The issue here is that if these treatments were the best solution to other common causes of sleepiness, we would already be using them all the time as performance-enhancers, but the medical field has identified specific situations where the risks of the drugs are outweighed by the benefits. A stimulant can be a short cut compared to getting that 7-hour night of sleep. As a medical field, we have determined the better treatment for this type of individual is to get 7–8 hours of sleep than to get insufficient sleep and take a stimulant (let’s, ahem, leave coffee out of this!). The patient with NT1 can be very drowsy during the day after getting 8 hours of sleep so this person may benefit from the stimulant medication because of limited preferable options.
Thus, if someone were misdiagnosed with NT1, they have little incentive to get off their NT1 medication as it probably has benefits of which they do not want to let go. It is much harder to get 7–8 hours of sleep every night, wake up at the same time every day, stop drinking alcohol close to bedtime, cut out those 2-3 clock-disrupting naps on the weekends, etc. than it is to take wake-promoting pill every morning.
#15 Some patients want to have narcolepsy(!): For many, it actually feels better to have a rare condition and be treated as special than to be told there is nothing permanently wrong and that they have to put in the work to change a bunch of behaviors to get better. Like the physicians above who may err on over-diagnosing NT1, patients may do this subconsciously. There is a condition called Munchausen syndrome or factitious disorder in which an individual feigns illness to assume the role of a sick person. What I am describing is not intentional as in these conditions, but is similar in concept. If one has a rare immune-mediated disorder leading to destruction of a portion of the brain, it is of course not their fault. It garners empathy from those around them, even special accommodations, whether it is social support or reduced responsibilities or expectations. If the same person did not have this condition but it turns out was misdiagnosed due to, for example, a crappy sleep pattern or unfortunate medication withdrawal effect leading to a false positive MSLT, then that elicits a different perception of themselves and significantly less empathy from others. I feel like there was an episode of House many years ago in which Dr. House reversed the terminal diagnosis of a patient and everything fell apart for that individual. Of course no one would consciously wish to have a condition with permanent brain damage leading to an array of disruptive and unpleasant symptoms including the inability to stay awake or regulate sleep cycles. However, there are some subconscious feelings that seemingly are paradoxical but make the state of sickness more attractive.
There is also malingering, however. Some patients want the medications as above in #14. Others may seek tangible benefits from having a disorder such as disability and other accommodations. I have seen numerous patients who went to lengths to prolong their misdiagnosis due to some of the perks. For example, I had a young man who initially went to a previous sleep center with difficulty falling asleep. He likely had a circadian rhythm issue called delayed sleep-wake phase syndrome (DSWPS), in which a person has a natural tendency to sleep late and wake up late, which was incompatible with his early morning schedule. For months, he was treated for difficulty falling asleep but saw a new physician after several months, and he reported how sleepy he was during the day, particularly in the morning. The physician decided to test the patient for narcolepsy, even though DSWPS perfectly explained the insomnia and daytime sleepiness and nobody with NT1 has trouble falling asleep by definition. The center performed the MSLT without actigraphy and administered the test beginning very early in the morning, which led to a false positive result. He was told he had narcolepsy. At the next appointment, he suddenly had all the textbook symptoms of NT1 including cataplexy, sleep paralysis, hypnopompic hallucinations, etc. He then was treated with wake-promoting agents and stimulants and deemed disabled and unable to perform his responsibilities. His organization paid for a substantial education program as he could no longer fulfill his physical duties on the job. He ended up in my clinic with the entire set of records as above. We discussed the diagnosis of NT1 and how circadian rhythm disorders like DSWPS can cause symptoms of difficulty falling asleep and staying awake in the morning. This condition also could explain the results of his MSLT and the false conclusion he had narcolepsy. I arranged to have the narcolepsy HLA test done. For months thereafter, can you guess whether he got the test done?
To double-down on this point to which I casually alluded several times earlier, the majority of patients in whom I suspected a misdiagnosis of NT1 have never followed up for the HLA. I have been on the phone with insurer after insurer, doing peer-to-peer reviews and prior authorizations, for what turns out to be a fairly inexpensive test. Yet, very few actually went through with just a simple blood test.
The field of sleep medicine, itself, needs to wake up and reconsider how it is handling the diagnosis of narcolepsy.
-Andy Berkowski, MD of ReLACS Health, who feels bad for those with NT1 and those misdiagnosed with NT1, as the latter situation does not necessarily lead to a happier ending as it should
