Early last December, an 8-year-old boy showed up in Sameer Zuberi's pediatric neurology clinic in Glasgow, Scotland. Previously healthy and active, the child had suddenly become unable to stay awake, and he described vivid, dreamlike hallucinations. His mother told the physicians at Glasgow's Royal Hospital for Sick Children that her son was no longer attending school and had dropped all outside activities, including his favorite and most successful one, tae kwon do.
For Zuberi and his colleagues, the diagnosis was easy: The boy had experienced a dramatic onset of severe narcolepsy. After standard narcolepsy drugs failed to relieve his symptoms, however, the medical team realized that his treatment would be a challenge.
Acting on a tip from other researchers, the doctors offered their patient a novel therapy. With his parents' permission, they gave the boy a large intravenous dose of molecules called immune globulins. Physicians use these components of donated blood to treat several diseases related to either inadequate or excess activity of the immune system. Zuberi was betting on a hypothesis that narcolepsy results from an immune attack that impairs the brain's control of wakefulness, dreaming, and sleep.
The bet paid off, at least for a time. By Christmas, the boy's mother reported to the researchers that her son was up and about.
"The benefit lasted for about 3 months," Zuberi says. When the boy's narcolepsy returned, another dose of the blood components again alleviated some of his symptoms temporarily. The boy has since returned to the hospital for a third round of immune-globulin treatment.
Encouraged by the therapy's modest success, Zuberi subsequently gave immune globulins to a teenage patient who'd had narcolepsy since she was a toddler. She showed no improvement, he says.
"If you act very quickly at the onset of the disease, immune therapy may be useful," infers Mehdi Tafti of Geneva University Hospitals in Switzerland. He and his colleagues were the first to use immune globulins to treat narcolepsy.
As the Glasgow physicians were considering potential treatments for the young martial-arts champ, Zuberi read a prepublication copy of Tafti's case report, which described two other cases and appeared in the December 2003 Journal of Sleep Research.
The recent cases highlight current options and challenges in dealing with narcolepsy. More than a century has passed since physicians first observed and labeled the syndrome, which consists of excessive daytime sleepiness and, typically, several other symptoms, including hallucinations and episodes of paralysis and muscle weakness.
Until just a few years ago, however, scientists knew next to nothing about what causes narcolepsy. They did devise some diagnostic tests and develop symptom-suppressing drugs, but those innovations aren't always effective.
Recent advances in understanding the disorder's biological underpinnings—in particular, the importance of a hormone called orexin—have created a new diagnostic tool and point toward more successful therapies. By illuminating how the brain regulates sleep, moreover, these new findings may eventually yield drugs that give healthy people unprecedented control over sleep and alertness.
Narcolepsy isn't merely an exaggerated urge to nod off when one should stay awake. The complex disorder features sleep-related brain activities that, at night, occur out of their normal sequence and, during the day, intrude into wakefulness. Narcolepsy is a "completely disordered sleep process," says Emmanuel Mignot of Stanford University School of Medicine.
Symptoms can include dreamlike visions and sensations of momentary paralysis, both of which strike most often as narcoleptic people are falling asleep or waking up. Also, when they doze, they often fall immediately into a stage of sleep called rapid eye movement, or REM, which in other people doesn't begin until more than an hour after they've fallen asleep. Another common sign of narcolepsy is complete loss of muscle tone, a condition that healthy people experience only during REM sleep.
During waking attacks of this condition, called cataplexy, a person remains alert but become limp and can fall. "It's a very unique symptom that's only observed in patients with narcolepsy," says Seiji Nishino, a Stanford colleague of Mignot's. Cataplexy often occurs in response to strong emotions, such as surprise, anguish, or elation.
In a similar but much milder way, those strong feelings might make healthy people drop their jaw or feel weak at the knees, Nishino says.
Drugs such as modafinil (Provigil) reduce daytime sleepiness in some people with narcolepsy. Certain antidepressants and a newly available drug called sodium oxybate (Xyrem) can mitigate cataplexy. But no standard therapy repairs the broken structure of sleep that defines narcolepsy, the researchers say.
People acquire narcolepsy at various ages. Genetics appears to play a role in some instances of the disorder, but most cases show no trail of inherited risk. Tafti reported in the April 10 Lancet a case in which one of a pair of identical twins had orexin deficiency and narcolepsy; the other had normal orexin concentrations and was healthy.
Researchers suspect that something in people's surroundings must ultimately determine who develops the disorder. "We've scratched our heads quite a bit about what that environmental factor could be," says John Harsh of the University of Southern Mississippi in Hattiesburg. He and other researchers propose that exposure to some chemical or microbe during fetal development or early in life may predispose a genetically susceptible person's immune system to attack sleep-controlling areas of the brain.
One clue is that a person's risk for narcolepsy appears to depend on the month of his or her birth. People born in March are 45 percent more likely than the general population to develop narcolepsy, while September babies have 37 percent less risk for narcolepsy than the overall population. Other months of birth have no apparent influence. An international team of researchers reported those findings in the Sept. 15, 2003 Sleep.
The study included nearly 900 patients from any one of three narcolepsy clinics in Canada, France, and the United States. Since all three populations exhibited the same seasonal pattern, it's unlikely that the finding is a fluke, contends Tafti, who worked on the study.
Using data on the birthdays of 530 U.S. residents with narcolepsy, Harsh recently replicated the finding of seasonal variation in risk. "In all four [groups], there is a March surplus and a September falloff" in risk, Harsh says. "It's uncanny how specific the peak is to March."
Colds caught by women during the second trimester of pregnancy could be a factor in narcolepsy, Harsh speculates. Maternal infections can upset the fetal immune system, which is particularly sensitive during that developmental period. An infant born in March enters its second trimester the previous September, and that's when cold infections are most common, he says.
Tafti notes that birth in March has previously been linked to elevated risk for multiple sclerosis, an autoimmune disease of the nervous system that is associated with viral infections.
The seasonality of narcolepsy risk offers circumstantial evidence for a longstanding hypothesis that the disorder is tied to autoimmunity. Two decades ago, researchers observed a link between the sleep disorder and a particular variant for a gene called HLA-DQB1. This is one of several genes that provide important instructions to the immune system, and defects in them can contribute to autoimmune diseases.
Yet numerous researchers have looked—without success—for evidence that people with narcolepsy suffer from an autoimmune attack. "Although that's still our leading hypothesis, we don't really have anything positive to hang it on," says Michael Thorpy of Montefiore Medical Center in New York City.
While the trigger for narcolepsy remains uncertain, a string of recent discoveries has improved scientists' grasp of the biological flaw.
The progress began in 1998, when scientists described previously unrecognized molecules that transmit certain signals between neurons in the brain. Masashi Yanagisawa and his colleagues at the University of Texas Southwestern Medical Center in Dallas were among the hormone's discoverers. They dubbed it orexin, after the Greek word for hunger, because they found that injections of it stimulate appetite in mice. Other researchers called the novel hormone hypocretin, and the terms remain interchangeable.
After the discovery of orexin, Yanagisawa's team created mice with a gene alteration that left the animals without the hormone. The researchers had hoped to use orexin to manipulate hunger. To their surprise, the mutant mice developed narcolepsy.
At nearly the same time, Mignot and several of his colleagues at Stanford discovered that a rare genetic mutation in dogs blocks the brain's response to orexin. That mutation produces a canine form of narcolepsy (SN: 8/14/99, p. 100).
Mignot's team and an independent group of researchers led by Jerome Siegel of the University of California, Los Angeles (UCLA) subsequently autopsied narcoleptic patients and examined the small area that normally contains orexin-making neurons in the brain region known as the hippocampus. Most people with narcolepsy had somehow lost these cells, the researchers found (SN: 9/2/00, p. 148). Consequently, orexin was nearly or entirely missing from the fluid bathing the brain and spinal cord.
This series of discoveries suggests that the neurons that make orexin are probably a target of an autoimmune attack that leads to narcolepsy, Mignot says.
The findings represent "stunning progress" and a "big step forward to understanding" the disorder, says Harsh.
Since implicating orexin deficiency in narcolepsy, researchers have tried replacing the missing hormone in animals to see whether it might work as a drug in people. The approach is conceptually similar to giving injections of insulin to people who have diabetes.
Yanagisawa and his colleagues in Texas recently genetically engineered mice so that, although they have no orexin-producing neurons in the hypothalamus, they produce orexin elsewhere in brain regions that don't normally make the hormone. Unlike orexin-deficient mice, which are narcoleptic and cataplectic, the new mice sleep and act normally.
In other experiments, the researchers injected orexin into the brains of orexin-deficient mice and found that the treatment briefly increased wakefulness and suppressed cataplexy. The findings appear in the March 30 Proceedings of the National Academy of Sciences.
"Replacement therapy is very promising," Nishino says, but it faces practical obstacles. For one thing, orexin molecules break down rapidly in the body, so long-term treatment is likely to depend on frequent doses. That makes it impractical to inject the hormone directly into the brain. Yet orexin molecules don't normally enter the brain from the bloodstream, where it would be easier to introduce the chemicals, Nishino says.
Several years ago, Siegel and his UCLA colleagues reported improvements in the symptoms of Doberman pinschers with narcolepsy and cataplexy when they injected a form of orexin into the dogs' bloodstreams. Other researchers, however, say they don't understand how the compound could work in the dogs, which have a genetic mutation that impedes neurons from recognizing or responding to orexin.
In an attempt to reproduce the UCLA findings, Nishino, Mignot, and their Stanford colleagues injected the same form of orexin intravenously into Dobermans with narcolepsy but saw no effect. Administering the hormone directly into the brain briefly increased wakefulness in nonnarcoleptic dogs, but the animals showed no other change in symptoms, the researchers reported in the Dec. 15, 2003 Sleep.
"Most likely, using [orexin] itself is not going to work," says Mignot. What's needed, he says, is an agonist—a molecule that mimics the hormone's activity—that can make its way into the brain after being taken orally. "Sooner or later, a drug company will be lucky and will hit on this," he predicts.
Yanagisawa agrees that such an agonist will provide the "fundamental cure" for narcolepsy. Such a drug might serve other purposes too, he says.
"An orexin agonist may well make you leaner," Yanagisawa says. He and his colleagues have conducted preliminary studies of healthy, nonnarcoleptic mice that indicate that both alertness and metabolism pick up when animals receive the hormone.
Pharmaceutical companies don't typically regard narcolepsy drugs as potential blockbusters. But orexin agonists could see enormous demand if they can also treat other sleep problems or, as Yanagisawa suggests, facilitate weight loss by accelerating metabolism.
Understanding orexin's role in narcolepsy can also aid physicians in diagnosing the disease. In standard tests, patients are asked to try either to fall asleep or stay awake while physicians monitor certain brain activities. The results rule narcolepsy in or out in most cases.
Orexin concentrations in cerebrospinal fluid offer the first biological test for narcolepsy, says Mignot. A test of the fluid, obtained by spinal tap, can provide a quick, clear diagnosis. "It's the best test, the most definitive you can get," he says, adding that many cases of narcolepsy have gone unrecognized for years.
Mignot's group performs the orexin test for some physicians because, as yet, there's no commercial version. Zuberi, for instance, sometimes sends samples from Scotland to California to confirm a diagnosis.
In contrast, Thorpy says that he rarely recommends testing the orexin concentration in a patient's cerebrospinal fluid. He says that a normal reading, in that test don't completely rule out narcolepsy, and any spinal tap carries some risk.
While waiting for research on orexin-based pharmacology to bear fruit, physicians are applying their expanded understanding of narcolepsy. Some are acting on the collective hunch that narcolepsy results from an autoimmune attack.
"It may be that [the attack] is ongoing for a period, and then the process burns out," Nishino says. "It is likely that the majority of the [orexin-producing] neurons are already gone" by the time symptoms become noticeable, he says.
But prompt suppression of the immune attack might prevent the full manifestation of the disorder. That logic motivated Tafti's and Zuberi's groups to give immune globulins to the young patients last year.
"We're probably going to be trying this treatment in a few other children in the next few months," Zuberi recently told Science News. He adds, "There's no reason it shouldn't work in adults as well."
Tafti's team has now given immune globulins to several other patients with recent onset of narcolepsy. While immune-globulin therapy reduced cataplexy, "it doesn't seem to have much effect on sleepiness," Tafti notes. Although his patients report that they feel less sleepiness, they show little improvement on objective tests of their propensity to fall asleep against their will. Perhaps immune globulins deflect a prong of the autoimmune attack that's responsible for cataplexy but don't avert the process that impairs wakefulness, he suggests.
Immune-globulin treatment hasn't prevented or reversed orexin deficiency, which could be a clue to the limited effectiveness of the therapy, Tafti notes.
Zuberi says, "Its principal role may well be in individuals who are diagnosed soon after onset [of narcolepsy], which means it's going to be more important that we diagnose it early. Perhaps by treating them quickly, we can alter their long-term outlook."
Dauvilliers, Y. … M. Tafti … E. Mignot, et al. 2003. Month of birth as a risk factor for narcolepsy. Sleep 26(Sept. 15):663–665. Abstract.
Fujiki, N. … E. Mignot, and S. Nishino. 2003. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 26(Dec. 15):953–959. Abstract.
John, J., M.-F. Wu, and J.M. Siegel. 2000. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Research Online 3(1):23–28. Abstract.
Khatami, R. … M. Tafti, et al. 2004. Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 363(April 10). Full Text.
Lecendreux, M. … and M. Tafti. 2003. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a ten-year-old boy. Journal of Sleep Research 12(December):347–348. Abstract.
Mieda, M. … and M. Yanagisawa. 2004. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proceedings of the National Academy of Science 101(March 30):4649–4654. Abstract.
Travis, J. 2000. Brain-cell loss found in narcolepsy. Science News 158(Sept. 2):148. Available at Science News.
______. 1999. Animal genes illuminate human sleep. Science News 156(Aug. 14): 100. Available at Science News.
Service de Neurologie B
Unite des Troubles du Sommeil
80 avenue Augustin Fliche
34295 Montpellier cedex 5
Department of Psychology
University of Southern Mississippi
Hattiesburg, MS 39406
Howard Hughes Medical Institute
Stanford University Center for Narcolepsy
701 Welch Road B, Room 145
Palo Alto, CA 94304-5742
Stanford University Center for Narcolepsy
701B Welch Road, 1st floor
Palo Alto, CA 94304
Jerome M. Siegel
Department of Psychiatry
University of California, Los Angeles
Neurobiology Research 151A3
16111 Plummer Street
North Hills, CA 91343
Biochemistry and Genetics Unit
Department of Psychiatry
Geneva University Hospitals
2 Chemin du Petit-Bel-Air
Sleep-Wake Disorders Center
Montefiore Medical Center
111 E. 210th Street
Bronx, NY 10467
Howard Hughes Medical Institute
Department of Molecular Genetics
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd., Room Y5.210
Dallas, TX 75390-9050
Sameer M. Zuberi
Fraser of Allander Neurosciences Unit
Royal Hospital for Sick Children
Yorkhill, Glasgow G3 8SJ
From Science News, Volume 165, No. 25, June 19, 2004, p. 394.