Johns Hopkins researchers believe they may have
discovered an explanation for the sleepless nights
associated with restless leg syndrome, a symptom
that persists even when the disruptive, overwhelming
nocturnal urge to move the legs is treated
successfully with medication.
Neurologists have long believed RLS is related to a
dysfunction in the way the brain uses the
neurotransmitter dopamine, a chemical used by brain
cells to communicate and produce smooth, purposeful
muscle activity and movement.
Disruption of these neurochemical signals,
characteristic of Parkinson's disease, frequently
results in involuntary movements.
Drugs that increase dopamine levels are mainstay
treatments for RLS, but studies have shown they
don't significantly improve sleep. An estimated 5
percent of the U.S. population has RLS.
The small new study, headed by Richard P. Allen, an
associate professor of neurology at the Johns
Hopkins University School of Medicine, used MRI to
image the brain.
Researchers found glutamate, a neurotransmitter
involved in arousal, in abnormally high levels in
people with RLS.
The more glutamate the researchers found in the
brains of those with RLS, the worse their sleep.
The findings are published in the journal Neurology.
"We may have solved the mystery of why getting rid
of patients' urge to move their legs doesn't improve
their sleep," Allen says.
"We may have been looking at the wrong thing all
along, or we may find that both dopamine and
glutamate pathways play a role in RLS."
For the study, Allen and his colleagues examined MRI
images and recorded glutamate activity in the
thalamus, the part of the brain involved with the
regulation of consciousness, sleep and alertness.
They looked at images of 28 people with RLS and 20
people without. The RLS patients included in the
study had symptoms six to seven nights a week
persisting for at least six months, with an average
of 20 involuntary movements a night or more.
The researchers then conducted two-day sleep studies
in the same individuals to measure how much rest
each person was getting.
In those with RLS, they found that the higher the
glutamate level in the thalamus, the less sleep the
subject got.
They found no such association in the control group
without RLS.
Previous studies have shown that even though RLS
patients average less than 5.5 hours of sleep per
night, they rarely report problems with excessive
daytime sleepiness.
Allen says the lack of daytime sleepiness is likely
related to the role of glutamate, too much of which
can put the brain in a state of hyperarousal — day
or night.
If confirmed, the study’s results may change the way
RLS is treated, Allen says, potentially erasing the
sleepless nights that are the worst side effect of
the condition.
Dopamine-related drugs currently used in RLS do
work, but many patients eventually lose the drug
benefit and require ever higher doses.
When the doses get too high, the medication actually
can make the symptoms much worse than before
treatment.
Scientists don’t fully understand why drugs that
increase the amount of dopamine in the brain would
work to calm the uncontrollable leg movement of RLS.
Allen says there are already drugs on the market,
such as the anticonvulsive gabapentin enacarbil,
that can reduce glutamate levels in the brain, but
they have not been given as a first-line treatment
for RLS patients.
RLS wreaks havoc on sleep because lying down and
trying to relax activates the symptoms.
Most people with RLS have difficulty falling asleep
and staying asleep.
Only getting up and moving around typically relieves
the discomfort.
The sensations range in severity from uncomfortable
to irritating to painful.
As more is understood about this neurobiology, the
findings may not only apply to RLS, he says, but
also to some forms of insomnia.
The study was funded in part by the National
Institutes of Health’s National Institute of
Neurological Disorders and Stroke (R01 NS075184 and
NS044862), the National Institute on Aging
(P10-AG21190) and the National Center for Research
Resources (M01RR02719).
Allen has received honoraria serving on advisory
boards from impax, Pfizer and UCB and honoraria for
scientific lectures, consultancy and research
support from UCB, GSK, Pfizer and Pharmacosmos.
Other Johns Hopkins researchers involved in the
study include Peter B. Barker, D.Phil.; Alena Horska,
Ph.D.; and Christopher J. Earley, M.D., Ph.D.
For more information
Thalamic glutamate/glutamine in restless legs
syndrome: Increased and related to disturbed sleep
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