‘I have always wanted to live my life as normally as possible, aside from KLS,’ Jamie says,
and so the treatment and the thought of having to go to a hospital regularly almost on a weekly basis for a check-up is not something that appeals to me. The treatment is not fully proven, is not conclusive. I just don’t want to disrupt my daily life because I enjoy it while I can. I will have three, five, six days out in an episode, but once I’m back, I just want to live my life. I get back to school as quickly as I can, catch up on my work, I try to play rugby, I try to meet all the friends and my girlfriend. So I just try to live my life.
The other treatment is to bring people out of very long episodes, and involves giving patients high doses of intravenous steroids, and has been reported as being helpful in some people. But, given the duration of Jamie’s episodes, it is not appropriate for him, and is equally not without side effects. So, for the moment, Jamie is not on treatment. Simply understanding his condition, liaising with his school, educating his teachers and friends about the syndrome, is about the limit of what modern medicine can currently do.
* * *
So, we are left with a syndrome rather than a disease, without any clear diagnostic tests and without any clear therapeutic options. The final issue I have been skirting around, however, is what we think the cause is. Are there any clues out there as to what might be going on?
The truth is there are very few. As I have already mentioned, KLS seems more common in Ashkenazi Jews than in other populations, raising the possibility of genetic factors at play. In fact, there have been a few reported cases where more than one member of a family has the condition, certainly implying but not confirming a genetic predisposition.
And what about which area of the brain is involved in KLS? Even this is uncertain. As with many sleep disorders like narcolepsy, the hypothalamus has been implicated, but there is little evidence of hypothalamic abnormalities in most patients with KLS. There are rare reports of patients with crack cocaine-induced strokes affecting the thalamus, causing sleepiness, hypersexuality and aggression, and this would obviously fit with research scans showing abnormal activity in this region of the brain during episodes of KLS. Postmortem studies of the brains of people with KLS are rare, as KLS is not a fatal condition, but there have been four patients who have died of a KLS-like condition whose brains have been closely studied. In three, there was evidence of inflammation in the thalamus and hypothalamus. It should be stressed, however, that these patients are probably not representative of ‘typical’ KLS, but they certainly raise the possibility that an immune or inflammatory process might underlie this condition.
Like other neurological conditions thought to be caused by the immune system attacking itself, e.g. narcolepsy, many patients or families report a viral infection prior to the onset of KLS. However, one always has to take reports in hindsight with a pinch of salt. Ask anyone if they remember having a cough or cold over the past few weeks and they will probably say yes, particularly if they live in London in the winter months and use public transport! But the young age of onset and the intermittent nature of KLS (a bit like multiple sclerosis, another autoimmune neurological disorder) for some researchers also implies that the cause is our immune system gone awry. It certainly looks as though viral infections can trigger people to go into bouts. Recent studies have shown bouts to be more common in winter and spring, correlating with the incidence of upper respiratory tract infections.
For me, one potential cause is what we neurologists term a ‘channelopathy’. Neurones, the nerve cells that constitute the major functional part of the nervous system, utilise a complex system of pumps and channels across their outer envelope, the cell membrane. Imagine the cistern of your toilet, into which water is slowly pumped under pressure. When you turn the flush handle, a valve opens and a torrent of water floods into the pan. Similarly, cells generate a difference in ions, electrically charged salts, between the inside and outside of the neurone. Like the water pump filling the cistern, molecular pumps use energy to shift ions from one side of the cell membrane to the other. But when electrical impulses are conducted along neurones, the flush handle is turned. Gates in the cell membrane open, allowing ions to flood through the cell membrane, like water into the toilet pan. And because these ions carry an electrical charge, there is a sudden change in electrical charge across the cell membrane. This torrent of ions is the basis for the impulses that underlie not only our nervous systems, but also our hearts and skeletal muscle. And so these molecular gates, also known as ion channels, are fundamental to our biology, to our ability to think, move, indeed live. But these ion channels are far from simple.
Structurally complex, they are made of multiple subunits, encoded by multiple genes. Some are triggered to open by electrical discharges nearby, others by the binding of chemicals like neurotransmitters. And, to add to the complexity, the composition of these channels changes throughout our lives. Different subunits are generated by our genes at different ages, so that some ion channels may alter their properties as we move from infancy to childhood to adolescence and so on. This probably explains why certain neurological disorders known to be related to ion channel problems start at particular times in our life and then disappear as we age.
Over the past few decades, with advances in genetics and molecular techniques, our understanding of many common and rare neurological disorders has changed beyond recognition. We now know that many of the conditions we see routinely in our outpatient clinics or in the emergency department are essentially disorders of these ion channels – conditions like migraine or epilepsy (the genetics of one group of ion channels in epilepsy was a focus of my doctoral thesis). Sometimes these disorders – channelopathies – result from mutations in the genes that code these channel subunits, like familial forms of epilepsy, migraine, or more unusual conditions like episodic ataxia, where sufferers experience attacks of imbalance and incoordination lasting minutes to days. Occasionally, channelopathies arise from antibodies directed against these channels, although these do not tend to be quite so episodic or intermittent.
KLS, therefore, has multiple features of a genetic channelopathy. It often comes on in adolescence, like many forms of epilepsy, migraine or other types of these disorders, and is intermittent, often triggered by tiredness, stress, alcohol or illness. Many of the drugs that have been reported as being helpful in KLS, such as lithium and anti-epileptic drugs, act on these ion channels. At present, there are multiple groups, including my colleagues and me, who are searching for genetic mutations that may underlie KLS. Many of my patients have volunteered to have their whole genome sequenced, to ascertain their entire genetic code. But we are searching for a needle in a haystack, potentially a single abnormality in a 3-billion-letter sequence. And the change may be different in each person with KLS, or indeed it may require multiple changes in multiple areas of the genome.
Tantalisingly, one of the leading research teams, headed by Emmanuel Mignot of Stanford University, the man responsible for identifying the cause of narcolepsy, has found a signal in an area of the genetic code near to a gene that has been implicated in bipolar disorder, another disorder associated with abnormal ion channel function, and with some shared features with KLS. There are also some features on studies of the constituents in the cerebrospinal fluid, removed by lumbar puncture, to suggest that there may be subtle evidence of inflammation in the brain after all. This links well to recent theories of depression and other psychiatric disorders being caused by brain inflammation, but, given the complexities of KLS, and its rarity, the challenges are huge.
Then, when you thought it couldn’t get any more difficult, it may be that KLS is more than one disorder. The range in the severity and duration of episodes is very wide, and my own view is that we sometimes misdiagnose KLS. I and my colleagues have seen a number of patients in whom their bouts are short, two days or a little more. This is in stark contrast to some people with KLS who will report bouts lasting several months. A
ccording to the diagnostic criteria, these patients with very short bouts meet the definition of KLS, but careful assessment, obsessional taking of the history, reveals features in some that hint at an alternative explanation.
A very prominent headache before the attack, severe nausea or imbalance, some tingling starting in the face, then spreading to the arm – these are all features of migraine.
For most people, migraine simply means severe headache. Many people will have experienced a migraine, and it is not a particularly pleasant experience. My migraines seem to have a particular predilection for when I am sat in my clinic room, usually with a waiting room full of patients. I suddenly begin to notice a flickering in the periphery of my visual field, a little flashing or shimmering. Over the course of a few minutes, this effect, like the heat haze above an asphalt road on a sunny day, spreads and moves more centrally. As I peer at my computer screen, flashing with patients waiting more than thirty minutes, I find it difficult to focus on the print. If I am lucky, my colleague will be running a migraine clinic next door. I know she is more organised than I am, and will often have a supply of medication for her own migraines. I will pinch a couple of ibuprofen tablets and, within a short while, my vision will return to normal. I will be left with only a slight heaviness in the head.
Like me, many people with migraine will experience these visual phenomena – sometimes shimmering, sometimes zig-zag lines, sometimes flickering – slowly marching across their eyes. And so migraine is not just a headache. For many, migraine also involves some dysfunction of the nervous system. In the case of a visual aura, as these phenomena are called, we know that there is a wave of abnormal electrical activity passing slowly over the cerebral cortex in the occipital region, the back of the brain, where vision is processed. But auras are not only visual. They can also involve other neurological functions.
Patients with migraine will often experience word-finding difficulties, or tingling in their face or limbs, as the dysfunction of the aura spreads over their verbal or sensory areas. Many of us neurologists will have had to run down to the emergency department for an urgent stroke patient to find that the pattern of weakness is in keeping with hemiplegic migraine, where the dysfunction has affected the movement part of the brain. A few neurologists might even admit to having given clot-busting medication to patients who in hindsight were simply having a migraine attack! And for some people with migraine, the aura consists of symptoms associated with the brainstem – dizziness, imbalance, incoordination. But, as we know, the brainstem is also fundamental to the regulation of sleep and the maintenance of consciousness. In extreme cases, people have been reported going into a coma during migraine attacks.
So, migraine is not purely a headache as some people believe it to be, and, in some of the patients I see, there are strong pointers that they have an unusual form of migraine rather than classical KLS. In a few, simple treatment with an anti-migraine drug has led to startling improvements. And thus my practice is always to find an alternative explanation to KLS, on the basis that we know that treatment of KLS is problematic to say the least, whereas treatment of some of the alternatives is much more straightforward.
* * *
Since Jamie’s diagnosis, the entire family has become very involved with the principal charity in the UK to support KLS patients and their families. Jok has rolled up his sleeves and has become a trustee for the charity, as well as actively helping to organise various projects to publicise Kleine–Levin syndrome. Obviously, those with KLS are incredibly keen to help with research into the understanding of their syndrome, and the treatment of it, but it is a small charity, without significant financial support, and the focus remains on getting people diagnosed as quickly as possible. Most, if not almost all, of my own patients and others in this support group have taken a long time to get a diagnosis of KLS, and their parents have often struggled physically and psychologically while trying to support their kids at a delicate and formative stage in their lives. The parents invariably say that, at the time of onset of symptoms in their child, the single most invaluable thing would have been knowing what it was that was happening to their child, and perhaps talking to other families who had gone or were going through the same torment.
I and one of my paediatric colleagues act as medical advisers to this charity, and over the years I have attended several of their annual meetings. When I stand there discussing the latest research, or lack thereof, I am struck by the range of this condition. Some of those patients present have attacks once a year, maybe even less. Several have gone for several years without attacks, while a few have gone for a decade or more before having a further attack out of the blue. Others have attacks every month, perhaps even more frequently, and in a few of these patients, KLS defines their lives. They cannot maintain jobs, relationships, social lives, or an education. For them, KLS becomes who they are, a debilitating condition that overrides anything else. And for their parents, KLS often takes over their lives as well. The unpredictability of KLS bouts and the complete vulnerability that ensues leaves parents on tenterhooks, waiting for the next phone call from school, from friends, or from their child’s workplace, to rush home to look after their incapacitated offspring.
Within the spectrum of severity, Jamie’s KLS sits somewhere in the middle. Not the worst of any of my patients, but not the mildest either. I am, however, amazed by how little Jamie allows his KLS to define him. In part, this is due to the fantastic support network he has around him. His parents, Jok and Oriele, are constantly there for him, but are practical people who focus on facilitating Jamie to lead the life that he would lead without KLS. His girlfriend Megan is obviously a rock – I am not sure many seventeen-year-old girls would have the maturity to cope with a partner with KLS and all that it entails. Jamie says of his family: ‘My family and Megan are really accepting – “He is in an episode, he is doing things, saying things he doesn’t mean, and he wouldn’t normally do.” I can’t imagine how tricky it is for them to watch me go through these things and know that as much as they try, as much as they care, there is not a lot they can do. They just kind of have to sit back and let it pass.’ Jamie also has a close circle of friends who look out for him.
Whenever I see Jamie, though, what is most evident is his strength of character, his resilience, and his desire to get on with his life. I ask him if he, like other people I look after, has a personal relationship with his illness. He responds: ‘I feel it is part of me, but because it is a temporary thing, because it comes every now and then, I don’t feel any kind of personal relationship with it. It is just there, it lingers, but I push it to the back of my mind and forget about it. There are days when I don’t even think about it.’
Jamie lives in the hope that one day a bout of his KLS will be his last. ‘It will hopefully subside. This comfort is driving me, because hopefully, one day, I will look back and say, “See what I’ve done despite KLS.’ ”
And as I sit around a table with Jamie and his family, I have no doubt that Jamie will go on to achieve many things.
I look over to Oriele and Jok and think to myself that if Jamie were my son, I would feel rather proud.
13
INCEPTION
I love Christian. I love it when I see his name on my clinic list for the day. He will always make me laugh. Sometimes, my sleep clinics are rather emotionally draining, since many people are debilitated by their sleep problems, and have associated psychological and social problems. Christian, however, is like a breath of fresh air.
Please don’t get the wrong idea, though. Christian has severe narcolepsy and cataplexy, to the extent that he cannot maintain employment, and finds it difficult to lead a normal life. But he has something about him, a slightly off-beat, occasionally surreal view of the world, and a lovely turn of phrase that is a pleasure to listen to. As he sits back in the armchair in my clinic room, casually dressed, with a neatly trimmed beard and cropped hair, he tells me of his latest narcolepsy experiences with a degree of ins
ight, humour and analysis that I rarely encounter.
Intelligent and eloquent, he has been living with narcolepsy since his teenage years. And my impression is that he likes to talk about his narcolepsy with me because he feels that no one around him understands this aspect of his life. ‘Apart from close friends obviously, you’re one of the only people that I can actually sit down with and tell about these experiences,’ he says. ‘And you’re not looking at me like I’m just insane, you know?’ I laugh. ‘I mean you might think I’m insane, but you don’t look at me in that way!’
Christian experiences almost all the features of narcolepsy, which started when he was a teenager but, like many people with this disorder, he was only diagnosed after many years, at the age of thirty-two. He is now forty years old, and he has the profound sleepiness that plagues all with this condition. It is this that is the biggest issue for him, the one that prevents him from working. ‘I’ve fallen asleep – and had some really funny looks – at White Hart Lane, watching the Spurs v Man City game,’ he tells me. ‘It was a packed ground – we’re talking 30,000–40,000 people – shouting, singing and hollering. It wasn’t quiet.’ I am not known for my love of football, and I am not sure I would mind falling asleep at a match, but of more concern is some of the other situations in which Christian has found himself dozing off.
He previously worked for a company that made medical instruments. Part of his job would involve him driving a fork-lift truck, loading large containers onto delivery lorries. He would often park somewhere out of the way, out of view of his colleagues: ‘I would rest on the steering wheel and I’d literally go to sleep. It could be for a minute, it could be for ten minutes.’ He was not always able to pre-empt his naps, however. ‘I’ve driven into them [the lorries] before. I’ve driven along, picked up a pallet. And then I’ve woken up with a cold feeling – a jolt, sudden reality thing’ – he claps his hands loudly, miming the crash – ‘as soon as I’ve hit the container. Bang. Oh, Christ! Luckily it wasn’t a person or anything valuable.’
The Nocturnal Brain Page 24