I am struck by the parallels between her condition and forms of training for military special forces, when recruits are thrown into a pool with their hands tied behind their back. If they stop kicking furiously, they drown. She, too, cannot stop moving. And within a first few minutes of our appointment, it is apparent that Mary Rose is a victim of a phenomenon called augmentation.
The standard drug treatment for RLS is a group of medications that increase levels of a neurotransmitter called dopamine in the brain. It has long been known that these drugs, termed dopaminergic agents, are a rapid and effective treatment for RLS, and indeed this response has been used as a diagnostic criterion, a feature to support the diagnosis of RLS rather than mimics of the condition. Levodopa acts by increasing brain dopamine levels, and other drugs like ropinirole mimic dopamine. In contrast, drugs that block dopamine, like antipsychotics, can worsen RLS dramatically. This may of course give us some insight into the causes of RLS, and certainly implicates problems with dopamine regulation in people with RLS. While this beneficial effect of dopamine-boosting on RLS has been known about for decades, there is a darker side to these drugs. Especially at higher doses, they can actually drive RLS, resulting in a dramatic worsening called augmentation. High long-ferm concentrations of these drugs, perhaps also due to fluctuations in levels over a 24-hour period, can cause the symptoms of RLS, the urge to move with unpleasant sensations, to come on earlier in the day, and become more intense.
Not only that, but augmentation can also result in less relief on movement, and a spread to other parts of the body, like the arms, trunk or face. Your medical salvation has become your tormentor. And when Mary Rose and I meet, she is on a dose of ropinirole nine times more than the maximum I would ever use, in addition to very high doses of levodopa, a drug no longer used in RLS in the UK because almost everyone augments on it. In the short term, every step-wise increase in her dose has led to transient benefit, only for it to drive the underlying symptoms onward in the long term. She is one of the worst cases of augmentation I have ever seen.
These drugs also have other dramatic consequences. Dopamine, as well as being a neurotransmitter influencing movement, is also fundamental to how the brain is rewarded. The pleasure associated with shopping or gambling, for example, is mediated by dopamine. But ropinirole and other drugs in this class of dopamine mimics, termed dopamine receptor agonists, can mess up this reward system and cause it to go haywire.
In recent years, we have become aware of a side effect of these drugs called impulse control disorders. Occasionally, patients on dopamine receptor agonists show striking changes in behaviour, involving activities that generate reward – things like compulsive gambling, excessive shopping, compulsive eating or hypersexuality. And patients are often not aware that their behaviour is different. It is only when they come off the drug and their behaviour normalises that they realise that a change has occurred.
First described in patients with Parkinson’s disease, who take these drugs at much higher doses, we now understand that these changes in behaviour are not rare in patients with RLS either. My neurological colleague who specialises in Parkinson’s disease tells stories of her patients who have gambled away huge amounts of money or taken a sudden and persistent interest in online pornography. The worst case I have seen is rather less spectacular. One man I was treating would spend about £50–100 per month on his model-car collection, but after starting him on this treatment, he spent £1,000 in the first month. Fortunately, I warn everyone and their family about this potential side effect, and the drug was stopped before his collection expanded exponentially!
Towards the end of our consultation, Mary Rose and I discuss how to improve matters. Without getting her off her medication, at least for several months, it is going to be hugely difficult to help. If we leave her medication as it is, there is a good chance that this augmentation will worsen even more. However, cutting down is going to be very problematic. In the short term, without anything to replace it, she will curse me for making her condition worse. Already sleeping only a couple of hours a night, sleep is going to be totally impossible. So there is no option but to treat her symptoms with something else, while we withdraw the medication.
* * *
So, what underlies RLS? Could it really be a made-up condition, a work of fiction by the pharmaceutical industry to flog us more unnecessary medicines? There is really no diagnostic test for RLS, not like a heart trace for a heart attack, a blood test for anaemia, or an MRI scan for a brain tumour. Perhaps it is the lack of an objective test that creates doubt in people’s minds, leading them to believe that it is psychosomatic, not real. The same can be said for migraine, though, as well as some other recognised conditions.
There are certain groups of people in whom RLS is much more common. We know that RLS is more likely to occur in people with iron deficiency. Even ancient Chinese texts, attributed to the Yellow Emperor in discussion with his physician Qui Bo, describe a condition very much like RLS being treated by the administration of ‘iron dust to the patient following meals’. This association was also noted by Karl-Axel Ekbom, a Swedish neurologist who provided the first ‘modern’ description of RLS. Donating blood can trigger the condition, and giving people iron supplements can treat it.
One of Ekbom’s contemporaries, Nils Nordlander, first reported treating RLS with intravenous infusions of iron in 1953. Recent imaging studies have fairly consistently shown lower levels of iron in multiple areas of the brain, particularly the substantia nigra in sufferers of RLS. The substantia nigra, meaning ‘black substance’, is an area deep in the brain, dark in colour due to the cells being packed with neuromelanin, a form of the pigment that colours our skin. This neuromelanin is a precursor to dopamine, identifying these cells as dopamine-producing neurones. This lack of iron has been confirmed on postmortem analysis of the substantia nigra, and may well explain RLS even in people with normal blood iron levels. In some RLS sufferers, it appears that there may be a problem with transport of iron into the brain.
So, we think low brain iron levels are linked to RLS, but what about dopamine? We know that drugs that boost brain dopamine levels treat RLS, and that drugs lowering dopamine levels or blocking dopamine receptors can trigger or exacerbate this condition. Studies have shown that in the brains of RLS patients, turnover of dopamine is increased, and levels of dopamine are higher, but the number of dopamine receptors is reduced. At first glance, this does not appear to make sense at all. Why should a condition defined by higher than normal dopamine levels be treated with more dopamine?
Well, the current hypothesis is that in response to having too much dopamine floating around, the brain reduces the number of receptors sensitive to it. This is fine during the day, but dopamine levels are under circadian influence; higher in the daytime before dropping in the evening. It is when these dopamine levels drop in the context of reduced receptor numbers that symptoms of RLS start. And this hypothesis may also explain augmentation. Giving people large doses of dopamine-boosting drugs may cause the brain to reduce receptor numbers further, driving this imbalance as normal dopamine levels drop, meaning that symptoms worsen and start earlier in the day. The rationale for withdrawing these drugs from Mary Rose is the hope that a drop in circulating dopamine may reverse the reduction in receptors that has occurred after years of excessive stimulation by horse doses of ropinirole and levodopa.
And the link between dopamine and iron? How do we explain this? It turns out that iron is an important factor in the synthesis of dopamine. In the brain, iron and dopamine are intimately linked. But surely low iron levels should cause lower dopamine levels, if that is the case? This remains a very grey area, but studies on rats have shown that iron deficiency does indeed result in higher levels of dopamine outside the cells, and results in lower densities of dopamine receptors, perhaps influencing other molecules in these brain regions. This highly complex system remains poorly understood, and the ‘dopaminergic theory’ of RLS remains just that – a t
heory, albeit the most plausible one.
RLS is also more common in women, especially in pregnancy. This in part may relate to iron lost due to menstruation or to the developing child, but there is more to it than this. Women suffering in pregnancy often get an extraordinary improvement in their RLS after a week or so following the birth, which simply cannot be explained by a sudden rise in iron. There must be a hormonal effect as well. Unfortunately, women getting RLS in pregnancy are at higher risk of developing it later on in life. Kidney problems can also give rise to this condition, as can various neurological disorders.
Perhaps the most important risk factor is having a family history of RLS. Roughly half of people with RLS have other members of the family with it too, and identical twins are more likely to have RLS compared to non-identical twins, strongly implying that there are genetic rather than environmental factors at play. David’s extremely strong family history of similar sleep problems may well represent a strong genetic predisposition to RLS. Huge international efforts to identify genes that contribute to RLS have been undertaken. At the latest count, these have involved 45,000 patients with RLS across multiple countries, and have identified nineteen genes that appear to raise the risk of developing this disorder. These genes are all implicated in the development of the nervous system, influencing the growth of neurones, neural circuit formation and how synapses – the communication points between nerve cells – are made.
But knowing which genes are involved, and which neurotransmitters are at play, does not give us the ultimate explanation for what causes RLS, only a few tantalising clues and further avenues of research down which to proceed. However, knowing that there are genetic contributions, understanding some of the chemical changes in the brain and being able to demonstrate periodic limb movements in sleep on an overnight study should at least persuade my more cynical colleagues that this is a condition that does exist, that is not a figment of the imagination or a mere marketing ploy.
* * *
I first meet David and Debra face to face in clinic a short while after the sleep study. Neither of them is at all what I expected. David is immaculately dressed, looks in robust health, and shows no outward evidence of a lifetime of poor sleep. Having chatted to Debra on the phone as well and having heard her accent, I was expecting a sixty- or seventy-something-year-old Irish woman, but she is youthful and exotic-looking.
Grateful to finally meet them in person, my heart sinks as David tells me he has only managed to take two doses of the ropinirole before stopping it. Despite an extremely low dose, he tells me that on both occasions he felt rather down on waking up after taking it, and so has not persevered. It seems that our relationship is doomed. After chatting to him further, however, I am more and more convinced that what he is describing is indeed restless legs syndrome, restless chest syndrome and restless arms syndrome. We decide to give it another shot, but this time with a similar drug that is administered by skin patch. The dopamine receptor agonist trickles in at a constant dose, absorbed through the skin, for twenty-four hours a day. Perhaps by eliminating fluctuations in the drug level, we can prevent further problems. I cross my fingers and hope.
Within a few days, my heart sinks as I see an email from Debra in my inbox. On opening it, though, I find a rather joyous message from her. ‘David started on the 1mg patch,’ she writes,
and that evening he slept solidly bar one or two visits to the bathroom for almost fourteen hours . . . Miracle! Second night and again a solid night’s sleep but a slight grogginess the following morning. Third night, he decided not to replace the patch at the usual time, and after initially falling asleep, he woke slightly agitated within his upper body (about thirty hours using the same patch), so he replaced it and had another successful night’s sleep. I know it’s early days, but having tried so many things, we are both pinching ourselves with anticipation that we’ve finally found a solution.
I breathe a sigh of relief in the knowledge that we have made a breakthrough. The clear improvement of the vibrating chest sensation with the medication, and the return when the patch runs out, really cements the diagnosis of restless chest syndrome in my own mind. I email back, saying that it is indeed early days, and the grogginess after only a few days of treatment may simply be David paying back a sleep debt accrued over decades, but we need to see if this resolves.
A few weeks later, another email from Debra:
‘Just writing to say that [the treatment] has transformed David’s life. Such quality sleeping – it is a miracle. Long may it last!! It must be six weeks now of undisturbed sleep and his quality of life has so much improved. David has spent almost his entire life trying to manage without sleep. He is like a new man.’
David’s treatment has not been without hurdles. The skin patches have caused some skin irritation, but he is reluctant to try anything else. The smallest possible dose has had life-transforming effects. Having lived a life overshadowed by terrible insomnia, he feels better now than he has felt since his twenties, and so prefers to use mild steroid cream to treat the irritation. The patch has stopped his chest and leg sensations, and Debra reports no further arm-waving in the night. I briefly try an alternative non-dopamine medication, but David soon reverts to the patch.
At our most recent meeting, some three years after we were first in contact, David’s life remains spectacularly different to what it was. He is still sleeping well, and is doing everything he wants to do without the prospect of a night of awful sleep ahead. He remains on a low dose of the skin patch, and I am keen to keep it so. Given the severity of his symptoms, he would not thank me if he were to augment in a few years’ time, and so I have added in a small amount of an alternative medication which does not have the same issues.
Many of the alternatives have their own problems, however – drugs used in the treatment of RLS include certain anti-epileptic drugs, and opiates, painkillers related to codeine, all of which raise concerns of dependency. Thankfully, the evidence of dependency in patients with RLS is minimal, and my US colleagues will even use methadone, a drug routinely used for heroin withdrawal, for their most afflicted patients.
There may also be other benefits to David apart from simply getting a better night’s sleep. There is a growing body of evidence that RLS, like sleep apnoea, is associated with an increased risk of cardiovascular disease, high blood pressure and stroke. When we record the limb movements of sleep associated with RLS, we find an increase in blood pressure and heart rate that is independent of whether these leg movements disrupt sleep. So, it may be that these frequent leg movements prime the cardiovascular system to age more rapidly. This area, however, remains poorly understood, and at present we do not know if the treatment of RLS or these limb movements reduces cardiovascular risk.
And what about Mary Rose? What has happened to her RLS? Withdrawal of the levodopa and ropinirole to reverse some of the augmentation has not proved easy, but has been managed with alternative agents. After a period of a year without any dopamine-boosting drugs, she has been restarted back on a small dose of ropinirole, in combination with several other drugs. Eight years down the line, her symptoms are reasonably controlled. Now in her mid-eighties, she is still managing to keep busy, still flying around the world, and still active academically. Gardening remains her own way of dealing with her symptoms.
‘It’s a fantastic difference in the fact that I have peace of mind,’ she tells me.
Because I know that as long as I take the pills – and there are times when I forget and I know quite soon after I should have taken them, I know because the bees start buzzing in my legs – but as long as I do what we have worked out together, I’m free of restless legs. Sometimes I get an attack which is just so awful that I find I’m walking about all night, but it’s my fault because I’ve forgotten to take the pills, and then it comes back in full force and there’s nothing I can do about it except make up the pills that I’ve lost and walk about until it goes.
I am not totally convinced that sh
e is free of her symptoms. As she sits in front of me, her chair constantly creaks as she shifts and moves her legs, rotating her ankles and stretching her calves. When I point this out to her, she laughs. ‘You’re the only person who notices that! I didn’t know that I was always moving. I was completely unaware of it!’
Her sleep remains an issue. Even in the absence of the RLS symptoms, her sleep is not perfect. Decades of disruption have had their toll. ‘I’m sorry to say that I think the patterns set when I was middle-aged, now that I’m much older, have remained. They were perhaps set when I had babies and one had to get up in the night at three o’clock in the morning,’ she muses. ‘Three o’clock in the morning seems to be a time when I wake anyway.’
Once awake, it is her mind rather than the bees in her legs that buzzes with thoughts, and it takes her a while to drift off back to sleep. She has worked hard to avoid actively trying to sleep, which often makes the problem worse. ‘I make it into a passive process by listening to my audio books or music, by which time my brain is beginning to stop running and so I do actually then feel ready for sleep.’ But she is thankful at least not to be tortured by her restless legs.
* * *
David and Mary Rose are two of my most striking patients with RLS. It’s worth stressing that for the majority of people with RLS, medication is not necessary. Given how common RLS is, this is a huge relief. The decision to start drug treatment is not straightforward, a choice between the devil that is the RLS and the deep blue sea of potential side effects of treatment.
Instead, minor lifestyle changes can often suffice. A reduction in caffeine and the avoidance of tobacco or alcohol can often have a major effect. Sleep deprivation also worsens RLS, and so a regular sleep pattern can help. A common situation I come across, however, is people who have been given sedatives or antihistamines for their ‘insomnia’, which is actually being caused by RLS. Sedating antidepressants, antihistamines and a host of other medications may worsen or trigger RLS, and so a simple switching of medication can have dramatic results. Looking for and treating underlying conditions like iron deficiency can also resolve symptoms. The single most important facet to managing RLS, though, is recognising its presence in the first place – and convincing some doctors of its existence.
The Nocturnal Brain Page 15