Science News, June 19, 2004
Narcolepsy science reawakens: insights create a new order for disordered
sleep.
Science News, June 19, 2004 v165 i25 p394(3)
by Ben Harder
COPYRIGHT 2004 Science Service, Inc.
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.
DISORDERED SLEEP
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 bore 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 HLADQB1. 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 surfer 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.
OREXIN REVOLUTION
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 mite. Other researchers called the novel hormone
hypocretin, and the terms remain interchangeable.
After the discovery of orexin, Yanagisawa's team created mite 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 round
(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 mite 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 intraveuously 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 do fit 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.
TURN BACK THE ATTACK
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."
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