Pathophysiology of Idiopathic Hypersomnia

Sree Roy:

Hello and welcome. I’m Sree Roy with Sleep Review, and I’m thrilled to be here with neurologist-sleep specialist Isabel Arnulf, MD, PhD, a professor of neurology at the Sorbonne University in Paris, France, and head of the Sleep Disorders Clinic at Pitié-Salpêtrière Hospital.

This episode is sponsored by Jazz Pharmaceuticals.

Today, we are chatting about the pathophysiology of idiopathic hypersomnia.

Science doesn’t fully understand the pathophysiology of idiopathic hypersomnia. Research has revealed potential clues, however. For example, idiopathic hypersomnia is associated with changes in sleep staging and architecture. What does emerging science suggest are differences in nighttime sleep?

Dr. Isabelle Arnulf:

Well, as you know, it depends on the type of idiopathic hypersomnia you are speaking about.

In the past, IH was separated into IH with and without long sleep time, depending on sleeping less or more than 10 hours per night. This separation has been removed in the 2013 ICSD criteria because of lack of enough data. But still, it corresponds to different patients.

So if you consider IH without long sleep time, the content of the night is quite close to that of narcolepsy patients, meaning that sleep is normal or short and interrupted by many arousals and awakenings. It’s not well-consolidated. Despite this, patient, of course, do not suffer from sleep apnea on or over a disturbing event during the night, so this might correspond to the mainstream monitored in many US hospital because you need to have some normal sleep, normal or short sleep, and short MSLT latency to diagnose IH without long sleep time.

In contrast, IH with long sleep time is very different and may correspond to the other part of the spectrum compared to narcolepsy. Because this patient sleeps extremely long, their long sleep time is not restricted to 10 hours. If you would monitor them over 24 hours, what is called the bedrest condition, when you let them in bed in the morning and in the afternoon and in the night, they all sleep more than 11 hours, and it’s often 13, 14 hours in a row, including a lot of consecutive sleep cycles containing either some normal amount, respective amount, of N2, N3, and REM sleep or containing some increased percentage of N3, or less frequently, REM sleep. In that case, the arousal index is, on the contrary, much lower than even in controls. It seems that this patient have high difficulty to wake up even with this very common arousal we all have during the night, to turn in the bed, for example.

So it’s in the same direction. This patient have very huge difficulty to wake up in the morning, and we used to call that major sleep inertia, or sleep drunkenness, because they’re like drunk people not able to wake up. They just return back to sleep every minute despite their alarm clock is ringing and ringing and ringing again, and they’re confused, and they’re clumsy, and really, they need people to help them to wake up. And this happened after the night but also after the naps. So you can see these are very different types of IH patients.

Sree Roy:

How might the arousal index differ in idiopathic hypersomnia versus in people without it, and why might that matter?

Dr. Isabelle Arnulf:

The arousal index is lower in IH with long sleep time than in normal people. In this case, one may wonder whether patient with IH have, in general, difficulty to wake up, including arousal and awakening and morning awakening in which it’s really hard for them to wake up. So we are facing people who have difficulty to arouse in general. In the case of IH without long sleep time, the arousal index might be increased in some cases and at least they might have a lower sleep efficiency than normal people, but this is something very different.

Sree Roy:

In addition to nighttime sleep dysfunction, other physiological changes have been observed in some patients with idiopathic hypersomnia and theorized as possible contributors to its pathophysiology. What is the GABAergic system and its possible role?

Dr. Isabelle Arnulf:

If you sleep too much, you might have a deficit in arousal system, like in narcolepsy where the hypocretin is deficient, or you might have an abnormal secretion of a sedative peptide or sedative neuromediator. You might have increased need for sleep because you are secreting too much or you are activating too much your system of sleep.

In this direction, the group of Atlanta directed by David Rye found that patient either with IH or with narcolepsy but with long sleep time and major resistance to common stimulants might be secreting endogenous GABAergic peptide, which is supposed to act like a hypnotic would do on our wakefulness. You could compare it to taking your hypnotics in the morning instead of the night and being foggy during all day because you’re fighting against the effect of hypnotics. They found that, not directly but because they had their difficulty of, this group found that the GABA receptor seems to be stimulated by something endogenous that they’re to displace with radioactivity.

Sree Roy:

What are some emerging findings surrounding idiopathic hypersomnia and autonomic system dysfunction?

Dr. Isabelle Arnulf:

It has longly been known that patient with IH have more frequent autonomic symptoms, including more frequent orthostatic hypotension or more difficulty to manage with their temperature being, feeling too hot or, on the contrary, too cold, compared to other people. It’s known in narcolepsy they are also higher. This patient, they have also autonomic problem, but they’re also more keen to develop pain, including migraines and other pains, which is known in hypersomnolent people. They are less resistant to pain in general.

Sree Roy:

We’ll be right back with Dr. Arnulf after the short break.

This episode is sponsored by Jazz Pharmaceuticals. Jazz Pharmaceuticals is a global biopharmaceutical company, with a focus in neuroscience and sleep medicine, committed to improving the lives of patients and their families. Jazz is also the proud creator of sleepcountshcp.com. The goal of sleepcountshcp.com is to increase awareness of idiopathic hypersomnia and support symptom recognition to help patients receive a quality diagnosis and appropriate disease management. sleepcountshcp.com provides evidence-based educational materials and resources to improve communication between healthcare professionals and their patients. Visit jazzpharma.com and sleepcountshcp.com for more information.

What is the evidence that supports the idea of altered functional or regional connectivity in the brain in people with idiopathic hypersomnia?

Dr. Isabelle Arnulf:

The group of Canada of Montreal of Dang-Vu has done some functional imaging in IH people during wakefulness compared to normal people, and most of their IH patient were IH patient with long sleep time. And what they found is that the frontal or prefrontal brain area is hypoactive during wakefulness compared to normal people, and this hypoactivity corresponds to what we see in people asleep in N2 sleep. The frontal lobe is the first to fall asleep in our brain, and because this hypometabolism in the hypoactivity and hypometabolism in the prefrontal and frontal lobe correlated with the degree of sleepiness, whether measured on MSLT or on Epworth Sleepiness Scale, they give the tantalizing idea that our patients with IH might be half asleep: having their prefrontal lobe asleep, whereas the posterior part of their brain would be awake, which totally correspond with what our patient used to say in IH. They’re, of course, some sleep attack, but most of the time, patient are foggy, and they say, “It is really as if I were half asleep all day.” I think this finding corresponds well to what the patient feel. Plus, they found that, as the frontal part of the brain was hypofunctional, the posterior part of the brain was trying to work more to compensate. It was hyperactive as if it was a sort of compensation for this deficient frontal lobe during wakefulness.

Sree Roy:

There were fascinating studies done on skin fibroblasts suggesting that circadian period length may be different in people with idiopathic hypersomnia versus in people without it. What role might circadian rhythm dysfunction have in idiopathic hypersomnia?

Dr. Isabelle Arnulf:

We early showed that patients with idiopathic hypersomnia are more evening person than the general population. In the past, the group of Prague led by Nevsímalová have shown that patient with idiopathic hypersomnia have a blunted melatonin secretion during the night and delayed melatonin secretion, which further supports the idea that the patient with IH have a longer inner night because all this circadian system is, all these measures are measuring our inner night.

And this was further substantiated by the analysis of the fibroblast, which because every cell has its inner clock in our body, the analysis of fibroblast have shown that in IH patients the inner night may be longer.

All in all, it cannot totally explain IH; otherwise, we would say, okay, it’s delayed sleep phase syndrome, which is something we commonly see and in which condition the patient are able to, when they are, realign on normal sleep time, they have a good functioning during that time. In contrast, IH patient, even if they’re allowed to follow their own rhythm and to go to bed later and to wake later in the morning, still are sleepy during the rest of the day, which mean that the circadian aspect of being a late person is just a contributor to the sleepiness but does not cause it.

Sree Roy:

What has science discovered about the possible role of dysfunction of energy metabolism in idiopathic hypersomnia?

Dr. Isabelle Arnulf:

We earlier showed that patient with idiopathic hypersomnia are much thinner than patient with narcolepsy. We don’t know what causes this lower body weight in these patients. First, they are mostly women, and then, they’re sleeping a lot. And maybe it’s because we sleep a lot that we have a better metabolism because we know that sleep is doing good to our metabolism, but I’m not aware of any other explanation for this thinner aspect in IH patients.

Sree Roy:

What further research would you like to see conducted on the pathophysiology of idiopathic hypersomnia?

Dr. Isabelle Arnulf:

We need a lot of—more research to understand the mechanism, the pathophysiology, of idiopathic hypersomnia. For example, we need a brain bank. This has really helped in the narcolepsy field and could surely help in the IH field. We also need more imaging, brain imaging, functional brain imaging, of course. We need to have more DNA analysis because, contrary to narcolepsy, IH seems to be more familial, to have more familial cases, than narcolepsy patients. And we need more registries, of course. Each time it’s a rare disorder, we need to put all data together between centers to go ahead.

Sree Roy:

Thanks so much for chatting with us about the pathophysiology of idiopathic hypersomnia. You can find Sleep Review at sleepreviewmag.com. Thank you so much for tuning in to this episode.