Narcolepsy Linked to Brain Cell Loss

W A SH I N G T O N, Aug. 29, 2000 -- Narcolepsy, a disorder that leaves tens of thousands of people constantly groggy and some unable to work, could be caused by the loss of specific brain cells, U.S. researchers said today.

People with narcolepsy have lost nearly all of the neurons that secrete a particular message-carrying chemical called hypocretin, a team at the University of California, Los Angeles, (UCLA) found.

Another team at Stanford University confirmed that people with narcolepsy are lacking hypocretin.

This could lead to an effective treatment for the condition, which affects about one in every 2,000 people, or some 135,000 Americans, said Cheryl Kitt, a sleep disorder specialist at the National Institute of Neurological Disorders and Stroke (NINDS).

A Clue to Treatment

“The excitement is that it finally gives us a clue to where treatment may occur,” Kitt said in a telephone interview.

“It is possible in the future that the administration of hypocretin itself might be a treatment for narcolepsy,” added Kitt, who approved NINDS funding for the two studies.

She said researchers were already starting studies in animals.

“It is very unusual in neurology to find a very specific group of nerve cells that are missing in a disorder,” Kitt said. Parkinson’s disease, in which cells that produce dopamine are mistakenly destroyed by the body, is another rare example.

Psychiatrist Jerome Siegel of UCLA and of the Veteran’s Affairs Medical Center in Sepulveda, California, studied the brains of four people with narcolepsy who had died, and compared them to normal brains.

Missing Neurons in Hypothalamus

The people with narcolepsy were missing neurons found in the hypothalamus region of the brain that secrete hypocretin, Siegel reported in the journal Neuron.

“There are none to be seen — basically zero in the patient,” Kitt said.

This tied in with findings by Dr. Emmanuel Mignot and colleagues at Stanford University, who in 1999 found that a lack of hypocretin caused narcolepsy in dogs, and who reported today they had confirmed it causes narcolepsy in people.

They also found the hypocretin-producing cells were missing in human patients.

“We think that there’s something that specifically kills the cells that make hypocretin. We don’t know how or why, but it’s most likely an autoimmune disease,” said Mignot, who reported the findings in the journal Nature Medicine.

Cells Attack Healthy Tissue

Siegel and Kitt agreed that an autoimmune disorder, in which the body’s immune cells mistakenly attack healthy tissue, may be to blame.

“Narcolepsy can have an onset in adolescence and certainly the early 20s and 30s, which is similar to other autoimmune diseases like multiple sclerosis,” Kitt said.

But Siegel also said it could be those cells are susceptible to certain toxins in the environment.

Hypocretin peptides, also known as orexins, were discovered only two years ago. They can stimulate appetite and feeding and regulate the state of arousal.

Kitt said it was not surprising that a loss of hypocretin would disrupt sleep, because of its role in the brain.

That means misery for narcoleptics, many who cannot work as a result or get drivers’ licenses. “They have sudden attacks of sleep. It also disrupts their nighttime sleeping,” she said.

“It affects concentration, irritability and the overall feeling of well-being. They are not happy people.”

Besides amphetamines, only one drug is approved for the treatment of narcolepsy — Cephalon Inc.’s (CEPH.O) Provigil, known generically as modafinil. Its mechanism of action is not understood.

Orphan Medical Inc. (ORPH.O) plans to ask for U.S. Food and Drug Administration approval of its drug Xyrem for narcolepsy. The drug is GHB, or gamma hydroxybutyrate, which was banned in 1991 after being widely abused as a “date rape” drug because it could make people fall into a deep sleep.