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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The emerging research boosting Parkinson’s disease treatment

Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptoms which rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).

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Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.

1. Increasing evidence for the benefit of exercise

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OK, not every advance has to be groundbreaking. It is self-evident that exercise is beneficial for many chronic disorders, but proving this has been difficult…until now that is. Researchers, publishing in the journal Movement Disorders, looked at the benefits of exercise on cognitive function in PD, and their verdict is-yes, it works! The study, titled Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial, comes with strings attached- you have to keep at the exercise for 2 years! A review  in the same journal indicates that exercise also improves mood and sleep in PD.

2. Lithium for treatment of dyskinesias

By Dnn87 - Self-photographed, CC BY 3.0, Link
By Dnn87Self-photographed, CC BY 3.0, Link

Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.

3. Transcranial magnetic stimulation (TMS)

By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link
By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link

Transcranial magnetic stimulation (TMS) is playing an increasing role in neurology as I discussed in a previous post titled Are magnets transforming neurology? It is almost inevitable therefore that TMS will crop up in attempts to treat PD. And so it has, going by a meta-analysis and systematic review published in JAMA Neurology. The paper is titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease. The reviewers passed the judgement that repetitive TMS improves motor symptoms in PD. Perhaps time to invest in TMS!

4. MRI guided focused ultrasound (MRgFUS)

By Frmir - Own work, CC BY-SA 3.0, Link
By FrmirOwn work, CC BY-SA 3.0, Link

MRI guided ultrasound (MRgFUS) is not new to medicine. It is used, for example, in the treatment of solid tumours and uterine fibroids. It is however innovative in the treatment of tremor and dyskinesia in PD. This came to my attention via a press release from University of Maryland titled Metabolic Imaging Center uses new ultrasound technology to target deep structures of the brain. MRgFUS non-invasively transmits ultrasound waves to the globus pallidus, one of the deep brain structures involved in PD. How this works still remains fuzzy to me, but it is exciting enough to generate a lot of research activity with articles such as MRI guided focused ultrasound thalamotomy for moderate-to-severe tremor in Parkinson’s disease in the journal Parkinson’s Disease; and Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease, published in Neurology. Watch out, deep brain stimulation!

5. Nasal mucosal grafting

Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471
Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471

What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose. It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!

6. Fetal stem cell transplantation

Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806
Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806

It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetal stem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space

7. Pluripotent stem cell transplantation

By Judyta Dulnik - Own work, CC BY-SA 4.0, Link
By Judyta DulnikOwn work, CC BY-SA 4.0, Link

The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beatsopen sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was published in the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.

 

Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595
Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595

There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:

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