Optimism, anyone?

[rkatt]

Correct me if I’m wrong, but I remember that around 2017 there was a flutter of medical optimism following some research and discoveries. Adenosine was said to be a player in RLS and one of the most respected RLS doctors said we could look forward to a time when DAs were no longer fist-line drugs. It was even mooted a non-augmenting DA might be on the horizon. Also a specific area of the brain was discovered to be agitated during attacks and this was said to be a possible target for new treatments. What’s happened since ? Does anyone know if the medicos are working on these areas? Or did I hallucinate the whole thing?

[Hidden]

Hi, I might not be the best person to answer that, but it appears to me that there is some ongoing research into the pathophysiology of RLS (= posh name for wots gon wrong!)

There doesn't seem to be much of it going on however.

I believe the jury's still out on the adenosine hypothesis, certainly there's no treatment come out of it that's got to the clinical trial stage.

There's some interesting stuff about dysfunctional brain cell mitochondria and brain iron deficiency and some research connecting RLS and hyperthyroidism.

You do occasionally get studies published with title including the word "breakthrough", but the last one of these I read, I found barely credible because of its methodological flaws

Most of the best studies seem to be a bit dated e.g. 2014 or earlier, later articles appear to be literature reviews drawing together findings from earlier studies, rather than being new studies.

Part of the problem may be that there appears to be some vagueness about differentiating "idiopathic" RLS, sometimes called "primary". as distinct from "secondary " RLS.

Perhaps the use of the label Willis Eckbom Disease (WED) would help. RLS does not refer to a disease, it refers to a syndrome, which can result from WED, but it can also result from other diseases. However there seems to be some problem tracking down exactly what WED is.

Maybe even what's calked WED is actually the result of several underlying diseases (like RLS) and not a thing in itself.

It's very complicated.

Sorry for going off on a tangent, but it's like nuclear physics.

When I was at school the smallest things ever were protons and neutrons, now we find they're made from even smaller things, i.e. quarks and the Higgs boson.

Where will it end?

[rkatt in reply to Hidden]

Thanks! That’s so comprehensive. It’s tragic more work isn’t taking place.

[Parminter]

The dipyridamole research, by Doctor Garcia Borreguera, was on a very small group of patients. It worked well on many, but now needs big trials and a more precisely targeted drug. (Dipyridamole is an old antithrombotic drug which happened to fit the bill for research purposes).

sciencedirect.com/science/a...

The research into ecopipam, (which is a drug for Tourette's Syndrome), to allay augmentation - in other words, to make dopamine agonists more user-friendly - was also very hopeful, but also on a small group and of limited duration. The researcher involved is Doctor William Ondo. Research continues.

So yes, optimism is most certainly in order. The doctors involved are highly respected.

(This research needs money, so join the RLS Foundation and help to pay for it.)

[rkatt in reply to Parminter]

Superb. Thanks! All that is good to know.

[Joolsg in reply to Parminter]

Hear hear! The US RLS foundation seems to be the only organisation funding research into causes of and drug treatments for RLS.

[Parminter in reply to Joolsg]

The thing about these two drugs is that they are known and understood. Their safety profile is known, so it will not take much more research on larger numbers to secure answers, one way or the other.

Old drugs do not need to go through a lengthy and hugely expensive process from scratch, and doctors can use them off-label as soon as they have some confidence in outcomes.

It is more than likely that new solutions will come from re-purposed drugs. After all, this is true of all the drugs we use now. Dopamine agonists were not made for us, nor were anti-convulsants or opioids. They were picked off the shelf.

I doubt that any drug company will ever make a brand-new drug, from scratch, just for us. Not enough money in it.

This Wiki article on Ecopipam is of interest to any of us have suffered the horrors of compulsive behaviours as a result of DAs. Ecopipam is a D1 receptor antagonist - and that's The Little Bugger that causes all the trouble.

So please step up and pay your subscription, and add some extra for William Ondo!

en.wikipedia.org/wiki/Ecopipam

[ironbrain]

Possibly what needs to be understood much more fully is how autoimmune diseases come about. Having had two autoimmune conditions, psoriasis and wet eczema and currently having two, RLS and AMD, I found almost by accident recently that something called interleukin 17 (IL-17) was involved in all four. MS is also linked to it, but I don't think the leg and toe cramps I get are MS, they're generally managed by dietary considerations. I let the ophthalmologists I see for my AMD know that I had come across this information, but have not received any information from them other than I will be told of any relevant clinical trials. Of course, genes are also likely to be involved in our susceptibility.

When I read your post, I immediately started searching with combinations of RLS, adenosine, autoimmune, IL-17, etc. Articles/papers I've so far turned up are:

Anti-Inflammatory or Proinflammatory Effect of an Adenosine Receptor Agonist on the Th17 Autoimmune Response Is Inflammatory Environment–Dependent (2014)

jimmunol.org/content/193/11...

Pathological overproduction: the bad side of adenosine (2016)

bpspubs.onlinelibrary.wiley...

Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson (2018)

hindawi.com/journals/jir/20...

As for location of the problem in the brain, I believe it was thought a small region, the hypothalamic A11 dopaminergic system, at the top of the spine might be where the RLS problem lies.

Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat (2017)

nature.com/articles/s41598-...

I think now that's been put very much on the back burner and attention is now nearly all directed at the major dopamine pathway (from the /basal ganglia/thalamus/ region to the prefrontal lobe?).

If and when the mechanisms are understood, it remains to be seen whether the damage causing RLS is repairable. I'm not aware it's within sight to be able to regrow the dead neurons in Parkinson's disease, for example, and retina and RPE regrowth for CNV/AMD is still at an early clinical trial stage. It may be that we will have reached the stage when we can recreate the whole human body before RLS can be cured, but I don't really want to sound like a pessimist

[rkatt in reply to ironbrain]

Thanks. That’s so brilliantly researched. I’ve long suspected my RLS is connected to an autoimmune problem. Actually, as long as research continues at any level I tend towards the optimistic end of the spectrum. My fantasy is that real help might come from tech. Something like a headset that affects brain waves from without. I know this sounds like sci-fi, but ...

[Hidden in reply to rkatt]

Who knows. there are lots of current advances in medical technology some involving the implantation of electronic nerve interfaces enabling the highly selective and controlled electrical stimulation of nerves using external circuitry.

There don't appear to be any proven to be effective versions of these, publically available as yet. I imagine it won't be long before they can be offered by health providers.

These interfaces seem to use arrays of "nanocapacitors" and can be inserted under the skin to control pain or even under the skull to help the blind see, the deaf hear, control epilepsy and relieve Tourettes.

If you see anything claiming to use this technology openly on sale, it's probably a scam!

[rkatt in reply to Hidden]

Thanks, yep at this stage such a device on open sale would be dubious.

[Hidden in reply to ironbrain]

Wow and thanks, you have been busy.

As regards the location for RLS in the brain, I'm afraid I've read something recently that also found associations between RLS and the spinal chord and even peripheral nerves.

Although not a medical researcher it seems to me that a more reliable definition is needed of what exactly "primary WED is, since it appears that there are many diverse factors that are being cited as contributing to the Restless Legs Syndrome. Not everything that causes the syndrome is a primary cause.

A recent study, I've read, even seems to be suggesting that the cause of a secondary form of RLS is also the primary cause. I think this just confuses things rather than clarifying.

OR, perhaps there's really no such thing as primary WED, just secondary forms of RLS with some overlap.

" Breakthrough" studies which appear to isolate the cause of one form of RLS, do not explain all forms.

This might be similar to the syndrome of "jaundice". There is NO primary form of this syndrome. There are three main types of jaundice, pre-hepatics, hepatic and post hepatic. For each class there are several causes, which may actually be unrelated to each other.

[Accipiter in reply to Hidden]

You can test this, put one electrode of a TENS unit at the back and top of one leg, and the other on the other leg. This passes the current though the sciatic nerves and into the spine. Hit the legs with some serious pulses and you will experience some of the worst RLS symptoms. If it was a neurological condition this wouldn't be possible.

It could indicate the spine, parasympathetic nervous system maybe, adds to the sensitivity of trigger points in the lower leg. Based on my experiences and what I have read, my opinion is that the brain just responds with symptoms to conditions in the affected limbs.

I disagree, without proof, that there are different types of RLS, as this type of expression accounts for all the variations.

More data is needed.

[Hidden in reply to Accipiter]

I'm sorry, I don't quite follow what you're saying. It appears that you're saying if you pass an electrical current (using TENS) through a nerve or muscle group, you get RLS symptoms.

It's true if you pass an electrical current through a nerve or even through a muscle then you will get a reaction.. Since the TENS machine produces pulses, I imagine it will produce twitching. Depending on what you mean by "the worst RLS symptoms" the reaction produced may mimic RLS symptoms, but it isn't actually RLS.

I'm also confused by you saying this would not be possible if it were a neurological condition. Apologies if I've misunderstood this, but you appear to be saying RLS is not neurological.

If that's the case then what you're saying contradicts what the majority of the literature says. It also contradicts the fact that theb main medications which are effective act on the nervous system.

As regards different types of RLS, it is generally recognised in the literature that there are at least two main types, i.e. "primary" (idiopathic) RLS and "secondary" RLS.

However, I didn't use the word "type" I wrote "form".

There may be different forms of secondary RLS in respect of the fact that there are various conditions which can cause the syndrome.

Perhaps "form" isn't the right word.

It's possible that there are different causes of primary, idiopathic RLS or what"s called WED.

The point I was perhaps clumsily trying to make was that some of the confusion between various explanations of RLS might arise because the explanations don't fit all cases. This might be because what's considered to be "RLS" is different.

e.g. hyperthyroidism is one explanation for RLS, but I don't have hyperthyroidism. Yet I've recently read a study in which the authors seemed to be claiming that all cases of RLS can be explained by hyperthyroidism.

I was thinking that if RLS is just that i.e. a syndrome, in the same way that jaundice is a syndrome then there are different "types" of jaundice which differ in that they have different causes. The explanation for one type therefore does not explain all types. This would be like saying.everybody who has jaundice has a drink problem.

Everybody who has RLS has a potassium deficiency?

Everybody who has RLS has too much thyrotrophic hormone?

Everybody who has RLS has low iron stores?

[Accipiter in reply to Hidden]

TENS of this method makes the RLS symptoms worse that night, and for a week or so. Nothing is experienced at the time.

Although I have triggered symptoms with electrodes on the right muscle, but this is difficult to replicate. It was interesting to experience symptoms while awake and explore how they are made.

Not engaging on the debate on the neurological stuff, as it is very cult like in certain circles. The point was certain exercises, and TENS in this case, makes symptoms worse quickly. If it was neurological from dopamine, iron, glutamate or whatever, the symptoms should be more consistent and even, as these levels aren't subject to extreme changes.

My opinion is that too much is read into the drugs that work as indicating the cause of RLS; as nicotine can work, a stretch can work or even burying a crystal in the back yard can help.

[Hidden]

Thanks for the clarification, I had apparently misunderstood .