The Nocturnal Brain

by Guy Leschziner

  As evidenced by Jamie’s story, sleepiness is not the only symptom of KLS. Kleine and Levin noted that, when awake, the patient with KLS exhibits some very bizarre behaviour. First, there is the ‘morbid hunger’, the uncontrollable urge to eat. I have seen patients eat food that they would not touch in normal life – vegetarian patients demolishing large amounts of meat, for example – and others who have entirely cleared out the family kitchen of all things edible. Often there is a tendency to junk food – sweets, chocolate, crisps. There is a case in the medical literature of a patient eating so quickly and voraciously that they died of pneumonia, having inhaled rather than swallowed some food. Jamie’s consumption of a whole packet of biscuits is tame by comparison.

  Then there is that most striking of symptoms, the hypersexuality. It is not just males who describe it; female KLS sufferers too, and it is a source of huge embarrassment for all concerned. Occasionally, it can also be dangerous. One of the first patients with KLS I saw was a young man from the north of England who, during bouts, would become so hypersexual that he would sit outside his house and proposition every passing female. When I told him I presumed his success rate was pretty poor, he replied: ‘You don’t know the kind of neighbourhood I live in!’ But, despite his apparent levity, one of the reasons for his seeking out medical attention was that he feared that his behaviour was so extreme, his sexual drive so intense, that he might undertake criminal acts.

  Although this triad of symptoms – sleepiness, excessive eating and hypersexuality – constitutes the core symptoms of KLS, we are increasingly recognising that it is actually the minority of patients who exhibit all of these features. Rather than profound sleepiness, during bouts people often feel confused or in a dreamlike state. They often describe a feeling of being in a bubble, as if the world around them is not real. Jamie recalls a sensation of his brain not being connected to the outside world. Apathy is commonly described, as is mood disturbance or anxiety. Many of my patients feel incredibly disturbed by anything unfamiliar, similar to Jamie’s response when his grandparents came to visit him in hospital. But it was not just unfamiliar people that Jamie did not like, it was also unfamiliar things.

  Jamie’s mother remembers him singing the same song over and over, or listening to the same track again and again on his iPod. Many of my patients will watch childish, predictable television over and over, typically cartoons or Disney films, sometimes several times a day, back to back, and like Jamie will sing the same song incessantly. (One particular young woman drove her family to despair with repeated renditions of ‘Let It Go’ from Disney’s Frozen.) Anything new or unexpected causes them distress. And the childlike behaviour extends to speech. Patients’ families will often report that not only do patients become less verbal during bouts, but the content of the speech will become childlike, with childish or infantile speech patterns. Jamie’s parents comment that his intonation will change. ‘Just simple words. “Dad-dee! Biscuits!’ ” Jok reports.

  Having now seen several patients in the midst of their bouts, it is easy to see why these events may be viewed as psychiatric, psychological, or someone simply swinging the lead. It is really one of the most peculiar clinical pictures I have ever encountered. Imagine a teenager lying in bed, not really awake or asleep, alternating between being completely mute and unresponsive, and suddenly getting up to eat five chocolate bars in a row, then getting back into bed. I have been high-fived, had laughable or highly inappropriate conversations, have been sworn at. I sometimes feel as if I am talking to a baby inside a seventeen-year-old’s body, with conversations about SpongeBob SquarePants playing on the television mounted on the wall in the sleep laboratory room, or about a favourite cuddly toy. I have had more sensible conversations with my daughters when they were five years old.

  At its most extreme, these bouts of Kleine–Levin syndrome can even be associated with delusions or hallucinations. It is not unusual for patients with KLS to receive an erroneous diagnosis of a psychotic disorder, such as bipolar disorder or schizophrenia, as was the case with Jamie.

  So how do we know that KLS is actually a disorder of brain function rather than a psychological or psychiatric disorder? Could this condition just be a case of a lazy teenager seeking ways to escape the stresses and strains of life as an adolescent, as many of my patients have previously been diagnosed?

  There are no tests that can be done – no MRI scans, no blood tests, no lumbar puncture – to prove the diagnosis of KLS. The diagnosis is one of exclusion, i.e. all other possibilities need to be considered first. It would be fair to say that the diagnosis of KLS is made when an ‘expert’ says it is KLS. So, is KLS another example of the emperor’s new clothes? Much like Hans christian Andersen’s Emperor parading through the streets naked, believing himself to be dressed in a magic suit that could not be seen by stupid people, applauded by his subjects, also not wanting to declare themselves stupid? A case of ‘an expert calls it KLS, so everyone believes it to be KLS’?

  In my own practice, I try hard to exclude all other possibilities. All my patients will undergo a psychiatric evaluation to rule out an alternative diagnosis. There are some similarities between bipolar disorder and KLS, with patients cycling between mania with associated insomnia and depression with prolonged sleep, but I would hope between myself and my psychiatric colleagues we should be able to distinguish the two.

  Other conditions that can mimic KLS include very unusual forms of epilepsy, genetic disorders that influence metabolism, and the equally rare Kluver–Bucy syndrome – where damage to the temporal lobe on both sides of the brain also results in excessive eating and hypersexuality, but also amnesia, difficulty recognising visual objects and placidity. Sometimes the explanation is more prosaic, in the form of the ingestion of illicit substances. All my patients have a battery of blood tests and a brain scan.

  Even so, it does ultimately come down to a diagnosis of exclusion, and the recognition of a pattern of symptoms. Much of medicine is about pattern recognition – realising that the patient in front of you sweating profusely with a racing heart, clutching his chest, is having a heart attack, much like the ten patients you have previously seen who looked exactly the same. With KLS, this is much harder. Recognising a pattern requires you to have seen several similar patients before – extremely hard in a condition that affects perhaps one in a million people. And so even ‘experts’ will have seen relatively few patients with this condition. As a junior doctor, I used to look at my senior colleagues, experts in a particular condition like lupus or sarcoid – old favourites of the scriptwriters for the medical TV series House, due to their myriad presentations and problematic diagnoses – who appeared to have developed a personal relationship with their chosen disease. They knew the personality of a disease, its foibles or idiosyncrasies. It was almost as if the science of the diagnostic process for them had been replaced by intuition, a feeling that, despite all the tests being negative, this is lupus after all. Having seen roughly forty patients with KLS now, I would not claim to have that degree of closeness, that intuitive relationship with this condition, but there are little trigger words, common phrases, familiar descriptions of symptoms by the patient or their family that approach this level of intimacy with KLS for me. I hope that I recognise it when I see it, but it is not always easy. There are several patients in whom, even after a couple of years of knowing them, I am reluctant to give a firm diagnosis of KLS, preferring to keep the door open to an alternative diagnosis that may be easier to treat.

  Even so, what I am diagnosing is a syndrome, not a disease. It is purely an association of multiple features, a recognisable pattern of symptoms. Just because there is commonality between more than one patient does not confirm a biological cause of brain dysfunction for this syndrome. I have seen countless patients with numbness, tingling or paralysis in a very recognisable way that have an underlying psychological basis. But, actually, there is some evidence of changes in brain state in people with KLS.

  The EEG –
analysis of electrical activity – shows abnormalities in the majority of patients during bouts that disappear in between bouts. While MRI and CT scans are normal in people with KLS, scans measuring brain blood flow or brain metabolism of glucose, either using radioactive substances or MR scans that monitor blood perfusion, show alterations in activity most consistently in the thalamus, but also in other brain areas.

  These changes are evident even between these bouts of sleepiness and behavioural change, and, indeed, recent evidence suggests that these brain changes are accompanied by subtle difficulties with memory even between bouts. In addition, assessments of cerebrospinal fluid during and in between bouts have shown lower levels of hypocretin, the neurotransmitter implicated in narcolepsy, during periods of sleepiness. These abnormalities could clearly not be explained by someone with psychological issues. These are as close to diagnostic tests as we have, but are insufficiently specific to use in routine clinical practice.

  * * *

  The relief of a more certain diagnosis was dramatic for Jamie and his family. Oriele recalls that their first thoughts were that, now they knew what it was, and that it was not life-threatening, they as a family could get on with life and deal with it. Jok also remembers feeling optimistic. After all, Jamie had already gone for over a year between his first and second episodes. Their initial positivity soon evaporated, however, as Jamie began to have episodes every few months. Jok says:

  The first four or five [episodes] were very distinct ten-day episodes and there was very much a pattern within those ten days. The first two or three days were very deep sleep, hardly any interaction. He would be almost catatonic. We actually set up a baby monitor because he wouldn’t come out of his bedroom, he wouldn’t get up. He would only wake to eat and he would be very demanding, just saying, ‘Food!’ and ‘Now!’

  Often these demands would be interspersed with swear words. He would request chicken, pasta, sometimes cold meats, but a particular type of German biscuit, covered with a slab of delicious dark chocolate, was one of his real cravings. ‘If I took two [biscuits] up he would ask for three. Sometimes I would just give him two and that would be okay. But sometimes he would come down and he would search the cupboard looking for the packs of biscuits. We would have to be very creative in our hiding, but [if he found them] he would go through the whole packet.’

  After these initial few days of marked stupor, Jamie would lighten a little. He would start moving around a little, playing music on a speaker in his bedroom. But his behaviour would be far from normal. His father describes him getting frustrated, and sometimes throwing the speaker across the room, trying to turn it off. Oriele recalls Jamie using the chocolate biscuits to mark off the days of his episodes on his bedroom wall, like a prisoner in Alcatraz marking the passing of his sentence. The marks are still evident above Jamie’s bed. There are other examples of very bizarre behaviour that Jamie reports. I am not sure how much of it Jamie actually recalls, or is simply as a result of repeated telling by his parents, passing into family folklore.

  On one occasion his mother came in with some food and switched the light of his bedroom on. ‘So I said: “Mum, turn the effing lights off, you bitch,” and then my mum said: “Jamie, that’s not very nice!” So I said: “Please turn the effing lights off!” clearly something in my brain was connecting, that it would be more polite to say “please”, but I was quite childish.’

  On another occasion, Jamie had been thrashing around and had knocked some of the stuffing out of his pillow. His mother came in and asked why his bedroom floor was covered in stuffing. ‘I sat bolt upright and I said: “I’ve been shitting feathers!’ ” Jamie chuckles. ‘We can look back now and just laugh because it is weird, it is just funny.’

  What was far from funny were the effects on his education. In the year after his diagnosis, Jamie’s events were happening on an almost monthly basis. ‘My school attendance was down at 60 per cent. In a way I was fortunate, because a fair few of my episodes had happened during school holidays, so I didn’t miss too much school.’ I would shudder to think what Jamie’s idea of really missing too much school is. But, despite his repeated prolonged absences, he managed to perform startlingly well in his exams.

  ‘I got eight A*s, one A, and one B,’ he tells me, trying to suppress his pride. I tease him that he is obviously an underachiever. ‘I was very, very happy,’ he beams. ‘The school actually published a photo of me receiving my results. The shock on my face, the pure delight of getting my results. It reminded me that I was okay. And also how lucky I am that I was awake for my exams.’ Jamie was also awarded a prize for his exam achievements in the face of his illness, but Jok interrupts: ‘You missed collecting your prize. You were asleep at the time.’

  The impact on his love life has not been insignificant either. In fact, his KLS precipitated the first contact between his and Megan’s parents. Megan takes up the story.

  ‘We hadn’t been going out for very long, but I kind of knew he had this [condition]. We had gone to the cinema. I remember him being so rude towards me. I remember thinking, He is not very nice. I don’t think I like him any more,’ she laughs. As the film started, Megan saw Jamie fall asleep, reinforcing in her mind his impoliteness.

  When we came out, he just began walking and I didn’t know where he was walking to. I didn’t know London very well. I nearly did just walk away from him. But then I started thinking, Could this be an episode? This is not him. He took my phone away, so I couldn’t try to call anyone and say he is not right. This lady was tutting at us because I had his arm over my shoulder to kind of hold him up. He looked like he was on drugs.

  Now in full episode, Megan, a slight girl, had to try to get Jamie home. ‘He’s a big lad; it was quite a challenge.’ Jamie is indeed a big lad. Even at the age of seventeen, he must be at least twelve stone of muscle. Eventually, Megan managed to get him onto a bus and succeeded in retrieving her phone from him. But even then, he refused to let her call his parents. In desperation, she called her own parents, who then spoke to Jok and Oriele for the first time. ‘The first contact between our parents! It was over an episode,’ Jamie laughs awkwardly.

  Jok remembers coming home to find Megan and Jamie there already, Jamie fast asleep, and Megan sitting on the sofa, crying. ‘We were familiar with it by then, we kind of knew what this was. It was obviously more distressing for Megan, who had never seen this. But we had a nice chat while Jamie slept, and we hadn’t really met Megan properly till then.’ But, as Megan went to leave, she went upstairs to say goodbye to Jamie. ‘I said goodbye, and he sat up and told me to eff off!’

  I am amazed at Megan’s staying power. I suspect most teenagers would have disappeared at this point, but over a year later they are still together and going strong. If anything, dealing with the adversity of Jamie’s KLS must have meant their relationship has matured much more quickly than it otherwise would have done.

  Over time, Jamie’s symptoms have altered a little. It is now three years since that fateful school skiing trip. His episodes are now less dominated by profound sleepiness. ‘I just feel completely derealised,’ he comments, describing that dreamlike state, the detachment from the world around him that is so typical of KLS. ‘I just sit in front of the television. A big thing to keep me sane while in an episode is watching films I’ve seen before, or TV shows where I can predict what’s going to happen. So quiz shows, for example. If I can think and answer [the question] in my head and then it pops up on the screen, for me that’s reassuring. It keeps me grounded, connected to the world around me.’

  After his school exams, Jamie went for six or seven months without an episode.

  There was always something in the back of my head [saying] that it was going to come back, it was going to hit me. Then it came back in October of 2017. It has been tricky, the past few months. I had one half term where I had a week on, a week off, a week on, a week off, and that for me was really difficult because trying to play rugby, trying to get to fitness, I feel I
put a lot of weight on when I am in an episode. Also catching up with schoolwork – I kind of catch up and then I drop behind again.

  The ongoing episodes beg the question why I haven’t successfully treated Jamie. The short answer is that there is no successful treatment, or at least nothing that works consistently. Numerous drugs have been tried in KLS – stimulant drugs during a bout, and a range of pharmacological agents, mostly anti-epileptic drugs, on an ongoing basis in an attempt to reduce the frequency and severity of episodes. But what is clear is that no drug works particularly well. And because of the nature of KLS, clearly demonstrating that any treatment works is problematic. The bouts of KLS come and go, without a clear regular pattern, and so knowing if the KLS is responding to any particular treatment, unless the effects are dramatic, is difficult. KLS often gets better on its own, burning itself out after ten to fifteen years, if you are lucky, and so any improvement may simply be the normal behaviour of the condition rather than an effect of treatment.

  The only way to answer the question as to the effectiveness of any particular drug is a randomised controlled trial, where patients are randomised to one treatment or another, so that the two groups can be compared. For this, however, you need reasonably sized groups of patients. The rarity of KLS, perhaps as rare as one per million of the population, i.e. as few as seventy people in the UK, or 300 people in the US, means that ever recruiting enough patients to any trial is nigh-on impossible. So, while there are several case reports of drugs appearing to have an effect in one or two individuals, the jury is still out.

  Perhaps the strongest evidence is for two treatments. The first, as a preventative, is lithium, a drug more widely used for bipolar disorder. A systematic assessment has suggested it has some benefits. But it also has several side effects, some life-threatening, and requires very regular blood tests to ensure that the dose is not at toxic levels. Unsurprisingly, this treatment has never really attracted Jamie.