No Rest for Restless Legs: Glutamate Keeps the Midnight Oil Burning


The sleepless nights caused by Restless Legs Syndrome (RLS) creates misery for millions of RLS sufferers. Current treatment for RLS involves medication – successfully treating the legs, but not the sleeplessness. 

Restless Legs Syndome, also known as Willis-Ekbom disease (WED) “jimmy legs, “”spare legs” or “the kicks” is a neurological disorder which creates an uncontrollable urge to move the legs. Other parts of the body can be affected too – the torso, the head, even “phantom” limbs.

RLS symptoms, according to the NHS website occur typically at night and include:

  • tingling, burning, itching or throbbing sensations
  • a ‘creepy-crawly’ feeling in the legs
  • feeling like fizzy water is inside the blood vessels in the legs
  • cramping in the calf’s or legs

RLS varies in severity, and can be extremely painful and distressing. Occurring predominantly when trying to sleep — the painful, tingling sensations can only relieved by getting up and moving. This constant interruption of sleep can lead to chronic tiredness and depression.

Yet, even when the Restless Legs are successfully treated, the sleepless nights remain.

The sleep puzzle of treating RLS may have been solved by Dr. Richard Allen, associate professor of neurology at John Hopkins University.

Looking into the link between sleep and RLS, Dr. Allen’s team used MRI scanning to analyse the brain images of 28 RLS patients and  20 non-RLS sufferers.

RLS participants selected for study in the RLS group had to exhibit sever symptoms to be included:

  • RLS symptoms six or seven nights a week
  • symptoms having persisted for at least six months
  • experiencing an average of 20 involuntary movements a night.

The study took two parts; one involved MRI scanning, the other a sleep study. In part 1, the research team recorded MRI images and glutamate activity in the thalamus – the part of the brain involved with the regulation of consciousness, sleep and alertness.

Glutamate is the principle excitatory neurotransmitter in the brain.

Glutamate, the culprit neurotransmitter involved in arousal, was found in abnormally high levels in the group of 28 participants who had Restless Legs Syndrome. The higher the level of glutamate, the more difficult it was for a person to sleep and to stay asleep.

The second stage involved a two-day sleep study in which RLS patients reported just 5.5 hours of sleep on average. Researchers identified a direct link in this group between glutamate levels in the thalamus and the number of hours of sleep. There was no such association in the non-RLS control group.

Dr. Richard Allen is hopeful that the team may have discovered the reason why restless legs syndrome also affects sleep. He says:

“We may have solved the mystery of why getting rid of patients’ urge to move their legs doesn’t improve their sleep.

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.”

The results of the study could lead to developments in the way RLS is treated, potentially helping to ending sleepless nights for those diagnosed with restless legs syndrome.

Dopamine-related drugs do work for many people with RLS, yet some lose benefit and require ever-higher doses. If the dose is too high, medication can aggravate symptoms to a state worse than that prior to treatment.

Dr. Richard Allen points out that despite drugs already being available that can reduce glutamate levels in the brain, such as the anticonvulsive drug gabapentin enacarbil, they have not yet been given as a first-line treatment for RLS patients.

Dr. Allen adds that as more is understood about the neurobiology, his findings could apply to some forms of insomnia as well as restless legs syndrome.

“It’s exciting to see something totally new in the field – something that really makes sense for the biology of arousal and sleep.”


John Hopkins University press release; Restless legs, insomnia and brain chemistry

Medical News Today, Restless legs syndrome; study raises hope for better drugs

Image credit: with thanks to xymonau of RGB Free Stock