Quelling the frenzy of restless legs syndrome

Restless legs syndrome (RLS) does what it says on the can. Victims need to only sit or lie down for a few seconds before creepy-crawly sensations literally drive them up the wall. The discomfort is as insatiable as the urge to move is uncontrollable. It is, literally again, a nightmare; a frantic evening quickly followed by a frenetic night.

The Colour Economy: Frantic on Vimeo. Jer Thorp on Flikr. https://www.flickr.com/photos/blprnt/2542831577/
The Colour Economy: Frantic on Vimeo. Jer Thorp on Flikr. https://www.flickr.com/photos/blprnt/2542831577/

Neurologists rarely struggle to make the diagnosis of RLS. And with the efforts of support groups such as the RLS foundation, patients are now well-informed about the diagnosis. To the chagrin of the neurologists, patients often come with a list of medications they have tried, and failed.

Frantic future. Jim Choate on Flikr. https://www.flickr.com/photos/137864562@N06/27938018674
Frantic future. Jim Choate on Flikr. https://www.flickr.com/photos/137864562@N06/27938018674

The list of RLS risk factors is quite long. Some of these are modifiable, and the ‘must-exclude’ condition here, iron deficiency, requires checking the level of ferritin in blood. Other modifiable risk factors are quite diverse such as obesity, migraine, and even, surprisingly, myasthenia gravis (MG). Most RLS risk factors, such as peripheral neuropathy and Parkinson’s disease (PD), are unfortunately irreversible; in these cases some form of treatment is required.

Frantic Face Sculpture. Eric Kilby on Flikr. https://www.flickr.com/photos/ekilby/14875258474
Frantic Face Sculpture. Eric Kilby on Flikr. https://www.flickr.com/photos/ekilby/14875258474

But what really works in RLS? And what is the evidence? To the rescue come the latest Practice guideline summary: Treatment of restless legs syndrome in adults, published in the journal Neurology. Below, in summary, are the interventions that work in RLS.

Strong evidence (Level A)

  • Pramipexole
  • Rotigotine
  • Cabergoline (but beware of cardiac risks)
  • Gabapentin enacarbil

Moderate evidence (level B)

  • Ropinirole
  • Pregabalin
  • Ferric carboxymaltose 
  • Pneumatic compression

Weak evidence (level C)

  • Levodopa
  • Oxycodone/naloxone (prolonged release)
  • Near-infrared spectroscopy
  • Transcranial magnetic stimulation (TMS)
  • Vibrating pads (to improve subjective sleep)

Add-on treatments in haemodialysed patients

  • Vitamin C 
  • Vitamin E 

Enough to guarantee a well-deserved nighttime sleep!

https://pixabay.com/en/bed-cornfield-sleep-good-night-921061/
https://pixabay.com/en/bed-cornfield-sleep-good-night-921061/

You may wish to look at another set of RLS guidelines also recently published in the journal Sleep titled Guidelines for the first-line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation

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Will a pill really hold the cure for CMT?

Charcot Marie Tooth disease (CMT) is the most important inherited peripheral neuropathy. As with most genetic diseases, there is no cure for CMT. The best neurologists can offer at the moment is supportive treatment for complications of CMT such as foot drop and foot deformities.

By Benefros at English Wikipedia - Own work, originally from en.wikipedia; description page is/was here., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2111831
By Benefros at English Wikipedia – Own work, originally from en.wikipedia; description page is/was here., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2111831

 

Neurologists are however very keen to go beyond platitudes and ankle supports for their patients with CMT. The holy grail of course is gene therapy, but this is still a far-off dream. As neurologists labour towards this utopia, they are also looking down to earth at drug treatments.

Prompted by reports that Vitamin C, yes Vitamin C,  effectively prevented neuropathy in mice, neurologists carried out a major trial in people with CMT. This was reported in Lancet Neurology titled Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Alas, Vitamin C was way off the mark in CMT.

Macrophages and red blood cells. The Journal of Cell Biology on Flikr. https://www.flickr.com/photos/thejcb/4115424607
Macrophages and red blood cells. The Journal of Cell Biology on Flikr. https://www.flickr.com/photos/thejcb/4115424607

Not deterred, the indefatigable neurologists have turned their sights on another agent. Perhaps because Vitamin C is too common, they went for something more exotic this time- inhibition of colony stimulating factor 1 (CSF1). The reason for picking on CSF1 is the observation that CMT is characterised by a low level inflammatory process, and CSF1 promotes inflammation by stimulating the production of the inflammatory cells called macrophages. The plan therefore is to wipe out macrophages by cutting their supply line, CSF 1. And the military-style strategy went according to plan.

Five baby mice eating icecream. Radagast on Flikr. https://www.flickr.com/photos/radagast/1417560
Five baby mice eating icecream. Radagast on Flikr. https://www.flickr.com/photos/radagast/1417560

The study, reported in the journal Brain, is titled Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice. The researchers fed an inhibitor of CSF 1 to mice models of CMT. Following the successful outcome, they proudly announced that “an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies“. Two for the price of one! Next stop, human trials-the waterloo of many a researcher!

DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154
DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154

 

Do you want to explore the genetic neuropathies a bit more? You couldn’t do better than this excellent review in Practical Neurology by Alexander Rossor, Matthew Evans, and Mary Reilly titled A practical approach to the genetic neuropathies. Click away!