New treatments for narcolepsy are currently being developed and some have already become available. The most obvious way to treat this disorder would be to replace the missing hypocretin. In rats, some results have been achieved by trickling hypocretin directly into the brain. This is not practical in humans, and intranasal preparations – sprayed into the nostril to be absorbed through the mucous membranes – have been trialled, but so far results have been underwhelming.
For the moment, there is no cure for narcolepsy. Researchers have tried to suppress the immune system in an effort to prevent its attack on the hypocretin-producing neurones of the hypothalamus, but it seems that by the time the symptoms of narcolepsy appear, the damage has already been done. The opportunity to intervene has passed.
Other strategies may hold more promise. Perhaps stem cell transplants, to regenerate the hypocretin-producing cells in the hypothalamus. Or gene replacement therapy, using viruses to insert active hypocretin precursor genes into remaining cells to encourage them to produce more hypocretin.
These technologies are in their infancy, but consider how far we have come: from a mysterious disease to a fundamental understanding of the causes and origin of narcolepsy over only a few decades. There are reasons to be optimistic, so watch this space.
7
BUZZING BEES
A long time before I actually get to meet David*, he sends me a detailed preparatory letter. ‘Dear Dr Leschziner,’ he writes, ‘I understand from my partner Debra* that you have agreed to have a telephone consultation with me with regard to a serious sleep problem that I have, which unfortunately is presenting itself with more enthusiasm as time goes on.’
He then continues to give me some background, detailing his age – seventy-two – where he lives – outside Dublin – and his successful career. It is clear that David is incredibly active, both professionally and physically, cycling huge distances on a weekly basis and sailing regularly. He says he has a great relationship with his supportive partner, and his life sounds full and happy. But there is a fly in the ointment.
‘Sleeping difficulties are not new to me, nor to my siblings, in that my brother, two sisters and I all have and always have had sleeping difficulties.’ He describes terrible insomnia starting in his twenties. He initially put it down to the fact that his life was so full and ‘I simply could not wait for the next day to come to get on with pushing my interests to new boundaries’. But his insomnia gradually worsened.
‘My period of sleep is at the most two to three hours of sleep a night on a very disruptive pattern. The shortest sleeping period is sometimes ten minutes, and at the longest would never be more than an hour, and that would be a most luxurious experience.’
It is apparent that, over the years, David has seen several physicians for his sleep. At one point he was diagnosed with sleep apnoea. He has also been prescribed countless sleeping tablets. ‘I have had short-acting pills, long-acting pills, Valium, Librium, antidepressants. With all these medications I had to stop taking them for the same reason, that while it might have helped me marginally to sleep, the next day would effectively be a write-off.’
The letter carries on over three sides of densely typed text, and my overriding impression is of someone who is battling furiously against their insomnia, trying desperately to carry on with their busy life, but failing to make progress. It ends with him telling me he has seen a Dublin psychiatrist, and he signs off despondently: ‘I had a discussion with [the psychiatrist], and at the end I asked when the next appointment would be. He said that he did not need to see me again because he felt that this pattern was so established that there was nothing he could do about it, and that was some fifteen years ago.’
A couple of days later is our scheduled telephone consultation, me in my clinic room in London, David and Debra in their house outside Dublin. He speaks with a gentle Irish accent, and sounds vigorous, garrulous and philosophical about his insomnia. He is clearly a man of words, and uses them precisely and poetically. His main concern is that his sleep is not letting him live his life to the full. We run through the contents of the letter, but there are several complaints that he mentions, alluded to in his letter, that catch my attention.
He reiterates the very long-term difficulties in getting to sleep and staying asleep, getting out of bed approximately twenty times a night, but goes on to describe some rather unusual symptoms. One thing that he has noticed is a strange feeling of vibration in his chest that often starts when he gets into bed. As soon as he moves, this vibration ceases, but comes back soon after he lies back down. In addition, of late he has also noticed some irritability in the right leg when lying still in bed. He experiences an urge to move his leg, and if he moves it he also gets instant relief. He deals with both the chest and the leg by getting out of bed. Furthermore, for the past five years or so, Debra comments that he has been active and agitated at night. She describes him thrashing his arms and legs about and punching the headboard of the bed. It usually starts within fifteen to twenty minutes of him getting into bed and can go on for several hours. He himself is not aware of this arm-waving, even though he will sometimes hit himself.
At the end of our telephone consultation, I tell him that I am not entirely sure what the arm- and leg-waving is, although it might represent him acting out his dreams.
Undoubtedly, however, what he is describing is a condition called restless legs syndrome, and probably restless chest syndrome.
* * *
The history of medicine is littered with diagnoses that have not been formally accepted or widely recognised. Some disorders like fibromyalgia or chronic fatigue syndrome spark furious debate and controversy among doctors and sufferers alike. Others are believed to have been made up by pharma companies eager to flog their wares. Restless legs syndrome (RLS) is one of these conditions. In 2013, a regular columnist in the British Medical Journal, a general practitioner, reiterated this opinion. The columnist described restless legs syndrome as a ‘pharma classic’, that it had an ‘implausible biological basis’ and was based upon subjective scales, measures of patient-reported symptoms that were ‘pseudo-scientifically converted to an illegitimate numerical rating’. He had never seen a patient with a primary complaint of restless legs syndrome ‘in twenty years of practice’.
In fact, the year before, I had also written a review article for the very same journal on restless legs syndrome, only to be told by a retired physician from Eagle Rock, Missouri, that:
Restless legs are a redundancy. Our legs have large muscle groups, which are designed for movement. In my experience, restless legs respond well to aerobic exercise, such as walking, running, biking, dancing, and swimming. Please let’s not medicalise life with endless diagnoses that just create a pretext for more pharmaceuticals.
I metaphorically slapped my forehead in frustration at this point.
In an effort to have restless legs syndrome taken more seriously, US physicians attempted to give it a name with more gravity, feeling that the name of the condition was detrimental to its acceptance. They attempted to re-christen it Willis–Ekbom disease, after Thomas Willis, an English physician who described RLS in 1685, and Karl Ekbom, who provided one of the most authoritative descriptions of the condition in the modern medical era, in the 1940s. Unsurprisingly, this far-from-catchy handle has never really taken off. To those doubters, however, I would invite them to my clinic to meet patients like David, and Mary Rose . . .
* * *
Mary Rose is a sprightly, twinkly-eyed 85-year-old who works as an art historian, is still writing and lecturing, still travelling the world. She has more energy than I have, yet is twice my age. Her outward appearance gives no clue as to the torture she endures in her nights, and also her days. When I first met her, she was seventy-seven, but had already suffered from restless legs syndrome for many years.
‘This started a very long time ago,’ Mary Rose recalls, ‘but of course I didn’t know that it was a condition called restless legs and people
just said, “Oh, you’ve got cramp; you must take quinine or sleep with corks in your bed.’ ” (I later discover that corks are a traditional remedy for night cramps, although I suspect this is not supported by a rich evidence base.)
I ask Mary Rose to describe her symptoms. ‘Well, it’s very difficult to describe, but I think the best way is like having bees buzzing inside the skin of your legs. You can’t get at them and it makes you want to scratch your legs. Also to get up if you are in bed and walk about, because it is just impossible to lie down and sleep because one’s legs are twitching in this uncontrollable way.’
She describes very typical symptoms of RLS: a terrible urge to move, usually the legs, that is only relieved by moving. This urge to move is often accompanied by unpleasant sensations – tingling, buzzing, pain, an electric feeling or cramping. From a sleep perspective, the awful thing is that the symptoms of RLS get worse in the evening and night-time, making it impossible to get off to sleep. Mary Rose says: ‘I began to dread sleep. I was finding more and more things to put off actually going to bed because as soon as I lay down and my head hit the pillow, then this twitching started up. I felt quite hopeless about how I was going to get through the night.’ Her sensations and her leg movements were letting her sleep no more than three or four hours a night, and, even then, in short, broken bursts. These leg movements that she describes are rather characteristic.
Patients with RLS often have two types of leg movements: some are semi-voluntary, an effort to obtain relief from the torture of their sensations, and can be suppressed; but one of the hallmarks of RLS, and perhaps one of the first pieces of evidence that this is a real condition, rather than a ‘made-up’ one, are involuntary leg movements, kicking of the legs or twitches of the ankle, that occur deep in sleep.
The leg jerks, termed periodic limb movements of sleep, affect 80–90 per cent of RLS sufferers, and recur every five to ninety seconds for brief bouts or persistently throughout the night. Monitoring brainwave activity during the night confirms that patients are asleep during these kicks, but these periodic limb movements add insult to injury. Not only do sufferers experience the RLS symptoms that stop them drifting off to sleep, but once they do manage to doze off, the leg movements disrupt the quality of their sleep, and sometimes wake them up. The torment then continues, as once awake they are conscious of their RLS symptoms. It is not hard to see how this condition, when severe, can be impossible to live with.
‘I have had complete nights without any sleep at all, but on average I would say I would get periods of sleep,’ Mary Rose explains.
If I was very tired I’d go to sleep, then I’d wake for an hour or two and then go to sleep again and sometimes get up. If it became hopeless, I used to get up and go down to the kitchen and make myself a drink and go back to bed, which sometimes soothed my brain even if it didn’t soothe my legs. I can’t tell what woke me. I mean it wasn’t till I was awake that I then realised that my legs were stopping me sleeping.
Despite the severity of her condition, for many years Mary Rose had continued without a diagnosis and without formal treatment. Having given up on quinine and corks in the bed, she found some ways of at least lessening her symptoms. ‘I got up and I rubbed my legs quite vigorously with both hands or sometimes with an unguent of some kind, to massage them. To some extent this eased it [the discomfort]. I used to do that and then get back into bed again.’
Mary Rose is now widowed, but at the time her husband must have had the patience of a saint. Imagine trying to sleep next to someone bouncing in and out of bed all night, kicking and jerking away. I’m amazed when she tells me: ‘My husband was very sympathetic and always was hoping that I would find some kind of a cure, and so he never complained about my restless legs.’ She later confides that very early on they decided to sleep in separate bedrooms.
After persevering for a number of years, Mary Rose found a knowledgeable GP who gave her a diagnosis of RLS, and started her on treatment, with dramatic relief. She was given a drug called levodopa, a medication more usually given to people with Parkinson’s disease, which appeared to be a miracle treatment.
* * *
Like David and Mary Rose, many patients with RLS take years to get a diagnosis, which is very peculiar, especially given how common it is. Recent studies have suggested it affects roughly one in ten adults to some degree, and probably significant numbers of children. In fact, it seems that ‘growing pains’ in children often result in RLS in later life, and it is likely that the growing pains are simply how RLS manifests in children. In view of these statistics, it beggars belief that the GP columnist I mentioned earlier had not come across someone with this in twenty years of medical practice.
So why is it so difficult to get a diagnosis? Part of the problem is that RLS presents itself in a number of different ways. If you are lying in bed at night having trouble getting off to sleep, and you feel fidgety, it would be normal to assume that you are restless because you are having some insomnia, rather than the other way round. Frequently sufferers don’t recognise the symptoms of RLS as causing their sleep issues. Equally, the sensations that people describe are incredibly varied – a sensation of pulling, jittering, worms or insects moving, tingling, itching, aching, bubbling, fidgeting, electric current sensations, tightness, and throbbing. In some people, pain may be the predominant symptom. This range results in RLS being frequently misdiagnosed as cramps, varicose veins, or nerve problems.
But, in contrast to other diagnoses, there are some clues to point to the diagnosis being RLS. The first is this association with the evening or night-time. People rarely experience this in the morning, and often there is a particular time in the evening or night that symptoms will tend to start. Patients will often tell me that they only notice their RLS when they sit down to eat dinner, or watch TV in the evening. The second pointer is the association with movement. Keeping still makes the symptoms build, and movement provides transient relief. Mary Rose finds that walking around her house at night provides some abatement of her discomfort. Similarly, David’s way of dealing with his symptoms is by getting out of bed, which is clearly not conducive to a decent night’s sleep.
* * *
There are of course other reasons the diagnosis may be so problematic. David’s symptoms began in his chest a long time before affecting his leg. This is very unusual, but over the years I have seen several patients in whom the symptoms have not primarily affected the legs, including cases of restless arms, restless abdomens, and even a couple of cases of restless genitals. In fact, RLS, despite its name, may affect any part of the body. There have even been cases described of ‘phantom RLS’, symptoms occurring in an amputated limb.
When I speak to David again, shortly after his sleep study, we go through the results of his overnight admission. It is an unmitigated disaster. Over the course of the night he manages a total of only twenty minutes of sleep. There is no REM sleep, so I cannot tell him if he is acting out his dreams. For the brief period of sleep captured, it does not look like he has significant breathing issues, but twenty minutes is far from enough to refute the diagnosis of sleep apnoea he has previously been given in Dublin. Closer inspection of the overnight video, taken with an infrared camera, reveals something curious, however. The grainy black-and-white images do not provide sufficient detail for me to know what David actually looks like, but although Debra describes his arm-waving as occurring in his sleep, and David reports no memory of this activity, I see that as soon as he becomes drowsy, definitely before he is asleep, his right arm starts waving up above his head. As he does this, he wakes himself up, and the pattern repeats itself over and over again. I have seen something similar to this before. It strikes me that David’s movements might represent a way of relieving RLS symptoms in his arms, and that these movements lie somewhere between voluntary and involuntary actions. I wonder if this is simply a manifestation of restless arms, in addition to his restless chest and restless right leg.
We have a slightly diff
icult conversation, and I try to manage expectations. I tell him that I think we need to treat what we know is there – the various manifestations of RLS – but warn him that frequently even once these symptoms are treated, the insomnia that has resulted from years of sleep disruption persists and also needs subsequent treatment. I suggest we start him on a dose of ropinirole, a treatment for Parkinson’s disease, also licensed for RLS, and review his condition once he is established on treatment.
* * *
When we first meet, Mary Rose is in real trouble. The medication given to her by her GP initially worked wonderfully, almost completely abolishing her symptoms. But over the decade or so she has been on the levodopa, the RLS symptoms have become increasingly intense, and have been coming on earlier in the day. By the time she finds herself in my clinic, she is on an enormous dose of levodopa, and now also a massive dose of ropinirole, the same drug that I have started David on.
As she sits in front of me, she can barely keep still, and her legs wriggle, jerk and twitch as she tells me her story. She is totally matter-of-fact, not quite stiff upper lip, but it is clear she simply wants to describe her condition without appearing to complain. Despite her reticence, however, it is obvious that the symptoms are now unbearable, starting as soon as she wakes up in the morning, with limited relief by movement. She is stripped of the pleasure of being able to sit in an armchair and read a book. The ‘buzzing bees’ sensation has escalated. ‘It’s much worse than an itch. I can only describe it as being bitten. Not just nibbled at, but something biting you. It’s really very painful.’
She is barely sleeping. She finds the tight space of a plane seat impossible, and just has to wriggle, or pace about or stretch her legs in the aisle. ‘In a confined seat in the theatre, when you have to keep completely quiet, I can’t concentrate on the play. I’m in agony trying to keep still.’ Her garden is her main therapy; viciously attacking the weeds keeps her mobile enough to provide relief.
The Nocturnal Brain Page 14