A conversation exploring the newest discovery in narcolepsy research, with sleep researcher Jerome Siegel, Ph.D.

Narcolepsy is a rare neurological disorder that affects approximately 1 in 2,000 people in the United States, with an estimated 50% of patients undiagnosed.

The condition is categorized into two subcategories: Narcolepsy Type 1 and Narcolepsy Type 2. Narcolepsy Type 1 is characterized by episodes of sudden muscle weakness, known as cataplexy, which can greatly impact patients’ quality of life.

Recent narcolepsy research suggests that there is damage to neurons in two regions of the brain, not just one, as researchers previously believed.

Researchers from UCLA recently discovered that narcoleptic patients suffer from neuron loss in both the hypothalamus and the locus coeruleus.

The study, ‘Human narcolepsy is linked to degeneration of both locus coeruleus and hypocretin neurons,’ was recently published in Nature Communications.

Senior author Jerome Siegel, Ph.D., recently sat down with Managed Healthcare Executive to explain the findings and what they could mean for patients suffering from this condition.

This interview has been edited for length and clarity.

MHE: What are the locus coeruleus and the hypothalamus?

Siegel: Hypocretin neurons are in the hypothalamus, in the forebrain, and the locus coeruleus neurons are in the brainstem.

MHE: What did you discover about the loss of neurons in the hypothalamus and locus coeruleus?

Siegel: In our previous study, we found that in the hypothalamus, there was a loss of cells that contain hypocretin, which is connected to mood. Narcoleptics have the classic symptoms of sleepiness and loss of muscle tone, but they can also have depression, likely linked to the loss of hypocretin cells. We found there was indeed a loss of these hypocretin neurons or orexin neurons - about 90% were gone in in people with narcolepsy compared to controls. However, the cells don't seem to be related to muscle tone.

What we found in the latest study is that the humans also lose locus coeruleus cells.

What we saw is that this tissue, which is present in mice, rats, cats and dogs, is diminished in narcolepsy, and no one had seen that before. We know it from animals that this control of muscle tone across the sleep cycle is unrelated to the forebrain.

The loss of locus coeruleus cells explains the symptoms of narcolepsy, because these cells are normally maintaining arousal, and they have projections into the spinal cord that's known to maintain muscle tone.

It suggests that the main symptoms of narcolepsy might best be treated by enhancing the activity of the remaining locus coeruleus cells, which release norepinephrine.

MHE: What is the biggest unanswered question after this study?

Siegel: We still don't know what causes the neuron damage. We do know that it's immune-related, and that was 30 years ago when a Japanese researcher found that virtually all people with narcolepsy have a particular HLA type, which are properties of the antibody system in the brain. Ninety-five percent of people with narcolepsy are HLA-DR2 positive but only 25% of the general population is. So, something seems to happen in people with narcolepsy that causes degeneration throughout the brain.

MHE: Why is this discovery important for patients living with narcolepsy today?

Siegel: Now we have a mechanism that explains why norepinephrine is effective at treating narcolepsy.

What you really want to do is stimulate the thing that's most effective, that requires the least amount of treatment, and that, if there's a deficit and you're just bringing something back to normal, you're much better off than if you're just bombing the brain with transmitters and seeing what works.