What Makes the Ketogenic Diet Work? It's The Fat! (At Least Partly)

The MCT-suppliment diet is just one of many
effective high-fat, low-carb epilepsy treatments

A new study in the journal Brain reveals one mechanism by which a variant of the ketogenic diet treatment seems to work. The MCT (medium-chain triglyceride) ketogenic diet is a relatively easy to follow version of the diet that is more popular in the UK than in the US, where other lower-carb varieties predominate. It was thought that ingested MCT oil produced ketones more easily than other kinds of fats, and that the extra ketones produced were hefting the weight of seizure control. The new study, though, reveals the effectiveness of a particular fatty acid, decanoic acid, at quelling seizures in animal models. Like ketones, decanoic acid is produced by the liver when the body runs out of carbohydrates to burn and converts fat into fuel for the brain. In the animal studies at University College London, and reported in Brain, decanoic acid was shown to directly decrease the excitability of neurons and thus reduce the risk of seizures. The presence of ketones themselves didn't seem to matter much.

High-fat, low-carb, ketogenic diets have been effectively used to treat epilepsy since the 1920s.  In the late 20s and 30s it was the most popular and most effective treatment available, and was especially good for treating children, whose eating habits could be more easily controlled than those of adults. The popularity of ketogenic diets as a first-line treatment took a nose dive, though, with the discovery of the anti-seizure drug Dilantin in the late 1940s. The diet's effectiveness (better than Dilantin for hard-to-treat cases) was clear to clinicians who used it, but because it was labor intensive for patients, care givers, and doctors, and also because no one knew how it worked, it fell from fashion. Fortunately, the treatment was kept alive in a few epilepsy centers, most notably at Johns Hopkins in Baltimore, where hundreds of so-called "intractable" pediatric epilepsy patients found relief over the decades.

Ketogenic treatments became popular again in the 1990s, largely because of the publicity following an NBC Dateline documentary about the effectiveness (and lack of negative side effects) associated with the under-used treatment. Still, though, the mechanisms by which the treatment supressed seizures remained mysterious. Only in the past decade has research on how the diet works really begun to bear fruit. Different theories have spawned variations of the diet, some focusing on raising ketone levels in patients, others focusing on the beneficial effects of the fats themselves, and still others on the positive effects of minimizing carbohydrates. According to the top researchers in the field, there may well be more than one mechanism at play. That would help explain the surprisingly broad effects of the diet, which is also currently being studied as a treatment for Parkinson's, Alzheimer's, and even cancer.

This New Scientist Piece by Clare Wilson is  good, but it confuses the MCT ketogenic diet for all ketogenic treatments and assumes that the mechanism reported in the Brain paper explains all of the ketogenic diet effects. Fortunately, it's much more likely that other mechanisms will also be revealed in  months and years to come.  And each of those will open new clinical possibilities and shed light on basic metabolic processes in the brain.

Smart Implants Intercept Seizures

Image by Henrik Jonsson

A good piece by Aliyah Baruchin in the July SciAm looks at how a new generation of implantable devices may help people with epilepsy squelch seizures before they get out of control. For more than a decade doctors have been implanting Vagus Nerve Stimulators (VNS) into patients who are unresponsive to anti-seizure meds. VNS either sends a periodic stimulating pulse through the vagus nerve or allows patients, when they sense a seizure coming on, to shock themselves with a magnet passed over the implanted device. The electrical stimulation defuses the mounting synchronized brain activity that would, if allowed to mount, culminate in a seizure. VNS works pretty well for a small fraction of patients whose seizures aren't responsive to anti seizure medications.

The avant-garde in implants promises to be much more subtle and targeted. The devices will read signals from the brain and "write" back to it with appropriately limited intervention. By tracking electrical activity (or temperature) in the part of the brain causing the seizures, these devices can tell when seizure activity is imminent and then can have one of three responses to intercept the seizure before it blossoms into disabling spasms or impaired consciousness.

One of these devices, under development at the University of Kansas Medical Center, address a coming seizure by cooling the area of the brain where they are kindling. Others do so by sending an electrical pulse to the offending area as a seizure mounts. A third type delivers anti-seizure medication locally and in limited doses that do not effect the entire brain.

The big advantage of all three delivery systems is that they tailor treatment to actual brain activity rather than constantly treating a brain that may only occasionally be seizure prone.

This will be a big deal for people with epilepsy. But the practice doctors get with implanted read/write devices will change the course of neuroscience and, sooner or later, it will effect everyone. The real-time data that will be collected by these implanted devices will give scientists a huge new window into all kinds of brain activity. And once installing electrodes in brains becomes routine, applications will go well beyond treating brain disorders or enabling prosthetic devices. The Brain Machine Interface is coming; fasten your seat belts.

Thinking Makes it Go

Illustration by Leandro Castelao

Brains and machines have been flirting for decades, but at several centers around the country they are now getting married. Brain surgeon and neuroscientist Edward Chang is the focus of my story about the union, just out in San Francisco magazine. Chang and his colleagues at the UC Berkeley-UCSF Center for Neural Engineering and Prosthetics (CNEP) are developing brain-computer interfaces, including one that will read words from paralyzed patients' brains and give them voice through a prosthetic device.  Jan Rabaey is developing mirco-arrays that will read electrical signals from the cortex's surface and transmit signals through the skull to devices outside. Michel Maharbiz is even talking about "brain dust," networked wireless nanosensors, each the size of a dust mote, that could be distributed throughout the entire brain like artificial neurons and wirelessly communicate with computers in the outside world. “It’s still a vision for the future, but we think it could work,” he says.

Pinpointing the Laughter Zone

Abnormal growths near the part of the
hypothalamus called the mammillary
bodies cause laughing seizures.

There's nothing funny about gelastic epilepsy. It hits young children, worsens with time, and can lead to several devastating seizure types as well as developmental and behavioral problems. But still, the kids who have this very rare epilepsy are laughing. They can't help it.

The part of the brain responsible for laughter appears to be located on the underside of the hypothalamus, a place disturbed by all of the growths, called hypothalmic hamartomas, known to cause laughing epilepsy. This discovery was one byproduct of research examining 100 cases of gelastic epilepsy to determine how the locations and sizes of hamartomas resulted in different symptoms and outcomes. The research, recently published in the journal BRAIN, and discussed by a panel of neuroscientists at the AES meeting in Baltimore on Sunday, showed that while variously sized tumors found in proximity to different parts of the hypothalamus had different expressions, all of those causing laughter were adjacent to the part of the hypothalamus known as the mammillary bodies.

"We've known for decades that hamartomas in the hypothalamus cause laughing seizures," said Stanford neurologists Josef Parvizi, lead author of the study. "But that's like saying the problem is coming from a city. We wanted to see exactly which district in that city were involved to help us understand the networks that underlie laughter. Just knowing it was in the hypothalamus was not enough."

Parvizi collaborated with John Kerrigan at the Barrow Neurological Institute in Phoenix, which Parvizi calls "the Mecca for hypothalmic hamartoma research." Their paper, which also examined the different outcomes of children with different sized tumors, and tumors adjacent to different parts of the hypothalamus, concluded that however large they are, and wherever they are located, quick diagnosis and removal of hamartomas is key to a good outcome. "If you let this condition linger," says Parvizi, "you are going to run into trouble." 

Because in many cases the first expression of the disease is laughing seizures, gelastic epilepsy often goes long undiagnosed. Especially, for some reason, in girls. The girls in the study had surgery, on average, about 60 months later than the boys. Why? Parvizi could only speculate: "Maybe because if a boy is laughing it is considered more abnormal than if a girl is. But I don't know." 

Inside the Heads of Epilepsy Patients

On the exhibits floor of  the 75th Anniversary American Epilepsy conference in Baltimore this weekend there are many new ways to get inside the heads of epilepsy patients. NeuroPace, for example, is a brain implant that detects the coming of a seizure and responds with electrical stimulation the part of the brain causing the trouble.  It's a remarkable device...and it was predicted with amazingly high fidelity by Michael Chrichton as far back as 1971 in his novel (later turned into a movie) Terminal Man.  The clinical trial in Chrichton's story don't turn out so well, but its just a novel. Still, let's hope we really know what we're doing as we start installing computers inside of people's heads. There are high hopes, I should say, for NeuroPace. I share them.

Meanwhile, two floors above, in the ballroom of the Baltimore Conference Center neurologist Steven Schachter gave the Judith Hoyer Lecture on Epilepsy. Schachter does some work on high-tech translational medicine at Harvard, where he is a professor of neurology. But he also started the journal Epilepsy and Behavior, was the president of the American Epilepsy Society, and achieved about a half a dozen other things that would put an ordinary epileptologist on the map. Schachter is also the most humane neurologist I've met. He is dedicated to stopping his patients' seizures, yes, but also to helping them wrestle with the other demons that often accompany epilepsy: stigma, employment limitations, loneliness, alienation, depression. He also collects artwork made by people with epilepsy, which he uses both to gain insight into their experience and even to help guide diagnoses and treatment. In a conference that's understandably focused on epileptic brains, Schachter's talk was typically focused on people with epilepsy.

Also part of the Judith Hoyer Lecture was a magnificent performance of a composition by Cynthia Folio.  Titled When the Spirit Catches You, the piece is a musical portrait of a Folio's daughter's seizures. Permormed by the seven-member Relache Ensemble, the piece was moody, caucophenous, dreamy, and melancholy. It ends with a child's music box winding down sadly, but sweetly. It is a moving and engaging piece and I hope it is performed again and again. (A four-minute excerpt of the half-hour-long piece is here.)

Shachter's good talk and Folio's performance were recorded and reportedly will be posted on YouTube, so keep a sharp eye out for them.

For more on the AES's annual meeting in Baltimore, follow Lisa Boyland's good blog on the Epilepsy Foundation site.

Where does "Epilepsy" Come From?

Shakespeare said Caesar had
"the falling sickness" but that
Othello had "epilepsy."

It's still  premature to say where epilepsy itself comes from, but there's a feature on Science Friday's website's "Science Diction" page about the origins of the word. Apparently, "epilepsy" took over describing seizure disorders when the expressions "the falling sickness" and "the sacred disease" fell out of fashion in the early 1600s. Medical historian Howard Markel notes that Shakespeare, in 1599, calls Julius Caesar's seizures symptoms "the falling sickness." Four years later, the Bard's Othello is described as having "fallen into an epilepsy." Those occurrences, Markel argues (on scant evidence, I think), mark the English shift from the old usage to the modern one.

The word "epilepsy" comes from the Greek "epilambanem," which means to "grab," "seize" or "take possession of." Since in those days many people thought epilepsy was caused by spirit possession, the word probably had a double meaning: first, to shake as if grabbed, and second, to be taken over by a spirit.

Animal Rights Amygdala

Your right amygdala can't
 resist the pygmy marmoset.

When you see a human face, neurons in your amygdala wake up and take note. But when you see an animal, whether cute or menacing, the amygdala in your right hemisphere jumps to its feet and starts to dance. Caltech and UCLA neuroscientists found that while pictures of humans evoked strong neuronal responses in the amygdalas of 41 human research subjects, the responses were far stronger, and faster, to images of animals. The amygdala, a two-lobed part of the limbic system buried deep in the medial temporal lobes of each brain hemisphere, is a key player in emotional reaction and processing emotional memory.

The researchers, led by Caltech postdoc Florian Mormann, suggests that we are hard-wired to respond emotionally--and thus pay close attention to--animals of all kinds. This may reflect the important role animals have played throughout human history as predators, prey, and potential allies.

The response to images of animals was especially marked in the right amygdala, perhaps reflecting the  right hemisphere's commitment to processing "unexpected and biologically relevant stimuli, or with changes in the environment," according to Mormann in the Caltech press release.

The research is open to all kinds of interpretation, but it makes one thing clear: animals are important to us. We knew that already, but still, it's interesting to see it reflected in the deepest, most primal reflexes of the old brain.

The study, like so many at the coolest edges of neuroscience today, was conducted in the brains of epilepsy patients. These generous men and women were already wired up with single-neuron-reading intra-cortical electrodes in preparation for surgery and volunteered their brains for study while they were at it.  Itzak Fried, the surgeon who installed the electrodes for this study, uses them to find the foci of his patients' seizures and to conduct other research in the meantime. He has been the key to  several other important studies, including the identification of the first human mirror neurons.

The paper was published in the August 28, 2011 issue of Nature Neuroscience.

29th IEC: Treatment Chasm

Whose names were writ in water.

The last day of a good conference is  a little sad. The orphaned sessions are under attended and the presenters make self-deprecating quips about their tiny audiences. Posters are coming down and the booths set up by pharmaceutical companies and medical publishers and manufacturers of vegus nerve implants, intracranial monitoring electrodes, deep-brain stimulators and new super-sensitive EEG machines are all being disassembled and carted out. Most delegates have snuck out early to explore the Vatican or the Coliseum, or to hit the tony boutiques on Via Corsa, or to eat some of the best food on Earth.

It's a special breed that stays to the bitter end. And of those who stayed to the end of the 29th International Epilepsy Congress, many had also shut down  IEP meetings past. Tanya Spensley, for example, has been to at least half a dozen, she told me, including those in Singapore, Paris, Budapest, and Lisbon. And she is already looking forward to the 30^th IEC in Montreal in 2013.

 

Spensley is a good example of the many remarkable activists I met at the IEC who dedicate themselves to making life better for people with epilepsy. She is a Londoner, and active in her local epilepsy group there, but for several years she has also been going to Gambia, in Africa, organizing to bring medication and epilepsy education to a country of 1.7 million people that has not a single EEG machine, where people with epilepsy are thought to be contagious and are shunned, unmarriageable, and often get no medical treatment at all. 

“I often wish I could show my friends in the UK--who whinge about having to wait for service or the inconvenience of the healthcare system--what it’s like in Gambia, where some lucky families have to travel for days just to get medication they can just barely afford.”

The difference between the treatment of epilepsy in the developed and undeveloped worlds is not really a “gap.” It’s a chasm!

And Spensley is dedicated to bridging that chasm the best a single smart and dedicated person can. Quixotic? Perhaps. Heroic? Absolutely! If you’re trying to reduce the suffering of people with epilepsy, you can get a huge bang for your buck in places like Gambia. Delivering the most basic AEDs to those who are responsive to them can, for a few dollars a month, turn a difficult and convulsive life into a much easier one free of seizures. It is low-hanging and excellent fruit; not exactly easy to pick, but ripe and ready for those who want to contribute time and/or money. To contact Spensley, look at her website www.epilepsyfootprint.com 

When the Congress finally wound down and the organizers and IEC officers were shaking hands and hugging goodbye, my friend took me to an old and beautiful graveyard in the Ostiense district of Rome. The great English  poet Keats, who died in Rome of tuberculosis at 25, is buried there. It is a poignant place: beautiful but full of loss. Keats’s death was so much more that a personal tragedy. It was a loss for the world.

How many other talented and beautiful young people with unique and penetrating insights, too, die before their time? Thousands each year are taken by their epilepsy in the developed world alone. In developing countries, any guess at a number would be a wild one--these young men and women are not even counted--but it must be in the tens or hundreds of thousands.

For whatever reasons, Yeats, broken and bitter at the end of his short life, wanted an anonymous place to rest and, believing he would soon be forgotten, he asked that his grave bear this inscription: “Here lies one whose name was writ in water.” Ironic, perhaps, that since his death nearly two centuries ago, his name has been writ in water again and again by the tears of sentimental admirers who pilgrim there.

How many unrecognized poets, and artists, and engineers, and gentle or ferocious souls of all kinds, whose lives might have been spared with a little medication or understanding from their communities or families, or attention from a doctor, lie instead in unmarked, and unmourned, graves around the world? Yes, the end of a good conference is always a little sad.

29th IEC: Battling Stigma, Slow But Real Progress

Stigma is the question,
courage the anther.

It’s a common--and fair--complaint that epilepsy isn’t getting its share; it doesn’t get the research dollars it deserves, nor the social attention. Funding lags behind less disabling disorders with lower prevalence, and public understanding lags just as far. That’s the case after many decades of hard and excellent work by organizations like the Epilepsy Foundation and The Epilepsy Society on the US front and The International Bureau for Epilepsy and the International League Against Epilepsy on the international one. It is easy to get discouraged.

I had a fascinating discussion today with neurologist Mark Cook,  Chair of Medicine at St. Vincent’s hospital at the University of Melbourne. He was speculating about possible neuro-psychological explanations for epilepsy's troubles.  People may react to seizures the way children react to the sight of a snake, he says: deep-seated, reflexive fear. If a person faints in public, people draw in close, catch them, care for them. Too often, when a person seizes in public, the crowd draws back in fear and, yes, revulsion. The idea that the stigma of epilepsy is more than simply social, that there is an instinctive aversion, makes the job of the epilepsy advocate a lot harder. Yes, it is very easy to get discouraged. 

But the International Epilepsy Congress (IEC) I've been attending in Rome  is an antidote. You can’t spend three days surrounded by the dedicated doctors, researchers, and epilepsy advocates here and not feel hope for progress. And that progress will benefit everyone, not just epilepsy patients. Since 240 BC, when Hippocrates wrote On the Sacred Disease, the first medical textbook, epilepsy studies have advanced the cutting edge of neuroscience. Many, if not most, of the major landmarks in the understanding of the human brain have come from epilepsy patients and the doctors and scientists who attended to them. It’s still true.

Deep brain stimulation, brain machine interfaces, the use of viral vectors, stem cells, and anti-inflammatory agent are all frontiers being pushed back by modern epilepsy research. So, too, are optogenetics, deep brain stimulation, and the use of high-density EEG-fMRI imaging, not just for looking at seizures, but also for studying the brains of people with epilepsy between seizures.

On the social side, Mike Glynn, president of the International Bureau for Epilepsy (IBE), reports encouraging signs of progress among the those trying to correct pervasive misconceptions about epilepsy and the prejudice that stems from them. The increased focus on SUDEP, for instance, and the pressure placed on neurologists around the world to talk to the patients about it is a “huge step forward,” he said in an interview today.

“It’s a difficult discussion for everyone. But especially doctors,” he said. “And it was a brave move on the part of Solomon Moshe [President of the International League Against Epilepsy] to make it the focus of the Congress' Presidential Symposium, which was attended by an overflow crowd of 1,500 delegates.

Glynn’s organization is also working hard to seed projects that will help people with epilepsy in the developing world. “The IBE has given 50 small grants in the developing world over the past five years to initiate programs that aid people with epilepsy. An example of one that is working well, Glynn says, is in Zambia, where local activist Anthony Zimba has created an employment program for epilepsy patients. Five volunteers from the epilepsy community, organized and inspired by Zimba, are running the program, which sustains dozens of people who would otherwise have no way to make a living. They have cleared an area of scrubland for use in raising chickens for sale and growing fruit for jam production, also for sale. That the program is volunteer-run is extraordinary, says Glynn, because the stigma of epilepsy in Zambia is tremendous. "No one wants to be identified with the disease," he says.

“It takes great courage for a person to identify oneself as epileptic in Zambia,” says Glynn. “And because of that courage, the project is working and growing.”

Working in the face of deeply held (perhaps even instinctual) prejudice and fear, progress in epilepsy advocacy always requires the courage and determination of individuals, whether researchers such as Solomon Moshe, or volunteers with epilepsy, such as Anthony Zimba, developing programs to help their countrymen.

There is plenty of courage and determination at this IEC and because of it, progress toward greater understanding--of the brain, the disorder, and for each other--marches forward. 

29th IEC: Day Two: Can Epilepsy be Cured by Meditation? Can it be Cured at all?

What is epilepsy? The simplest working definition boils down to "the propensity to have seizures." Does that mean that if drugs help a patient stop seizing,  the patient’s epilepsy is cured? Most neurologists act that way; once seizure-free for two years, a patient is typically sent on their way unless they seize again.

But there’s a growing consensus that epilepsy goes far beyond seizures. In the words of Harvard epileptologist Frances Jenzen,  “seizures are often just the tip of the iceberg.” The underwater part can include all kinds of “co-morbidities” including persistent memory and cognitive problems, depression, headaches, and socialization problems. There is a hearty debate about whether these conditions are a part of the epilepsy or are caused by it. Some argue that the brain problems that caused the seizures to begin with also cause some or all of these problems. Others suggest that maybe the comorbid conditions are byproducts of having seizures. But either way, a fascinating discussion at one of today’s IEC sessions  shows that for many patients, the end of seizures does not mean the end of their epilepsy-related problems.

Mary Lou Smith, a psychology professor at the University of Toronto, discussed longitudinal studies of whether cognitive, academic, social, emotional, and behavioral effects linger even when a patient’s seizures are controlled with surgery or drugs. Unfortunately, she says “the impact is substantial, even for those in remission and off of their anti-epileptic drugs.” Marriage rates are lower, IQ is lower, and self reported quality-of-life still lags behind the general population.

Even patients who’ve had successful surgery, are off all medication, and have had no seizures for five years continue to suffer. Though this group scores the same as a control group for seven other quality of life measurements, they remain less well adjusted when it comes to social function.

But for most others, who remain on medication, things look less rosy. “Stigma plays an important role in the lingering effects, but it doesn’t explain everything,” Smith says. “There may well still be underlying neurologic issues and other kinds of social and psychological issues, too.”

Smith is not minimizing the hardships caused by seizures themselves. “A life without them is definitely easier than a life with then,” she says. “But it is not necessarily better.” And it almost certainly is not all better.

Would continued treatment by doctors help? Or perhaps other kinds of interventions? Teaching compnsating techniques for memory loss, say, or treatment for anxiety or depression?

“It makes sense that they would help,” says Smith. “But the studies haven’t been done. We’ve gone through the research phase of documenting the problem, and now its time to start exploring solutions.”

Meditation and Other Alternatives

Another promising session looked at “Alternative, Spiritual, and Traditional Therapies for Epilepsy.” Speakers discussed ancient and traditional Chinese medicine, traditional Latin American and African treatments for and beliefs about epilepsy, and the effect of meditation on epilepsy. No reliable evidence  was cited that traditional therapies were effective at treating epilepsy. In fact, the combination of impotent and sometimes brutal treatments (one African treatment entails putting the heads of epileptic patients into latrines) and the litany of depressing traditional explanations for epilepsy (e.g. spirit occupation, bad winds, contact with a woman who has had an abortion) was very discouraging. The most hopeful talk was the last one, about meditation, delivered by UCLA neurologist Jerome Engel who clearly thinks there is some value there. Engel described reasons to believe that meditation might help control seizures (it increases hippocampus growth, increases fiber connectivity throughout the brain, it generates lots of activity in the mesial temporal lobe, where a lot of epilepsy is focused.) But at the end of that positive litany, he acknowledged that the studies on meditation and seizure control were equivocal at best: some even suggested that meditation could bring seizures on!

“There’s still no really good control study of the effect of meditation on epilepsy,” he finally concluded. Anticlimactic? You bet. But honest. Dr. Engel said he’s had one NIH grant application to do such a study turned down but he’s waiting on another. Let’s hope he gets it and so his next talk will have some harder data. 

Autism and Epilepsy

Synapse: #2 = synaptic vesicle

Thirty percent of children diagnosed with autism also suffer from epilepsy, a conundrum that has led neuroscientists to search for shared underlying mechanisms or causal connections. One intriguing but controversial theory, posed by clinical neuroscientist Aditi Shankardas is that many children diagnosed with autism are actually suffering from persistent sub-clinical epileptic seizures that can be unveiled with electroencephalography (eeg) and treated with anti-convulsants. Watch Shankardas's TED lecture and expect to see more on her here soon, when I have tracked down her bonafides.

Better-documented progress deciphering the epilepsy-autism connection was published online in Human Molecular Genetics this week. A team led by Patrick Cossette, a neurologist at the Université de Montréal, has pinpointed a mutation of the synapsin gene--SYN1--that can lead to both epilepsy and autism by deregulating the function of synapses. The synapsin gene plays a key role in forming the membrane that surrounds neurotransmitters before they make their way to a neuron's synapse, where they influence neighboring neurons. These membranes, also known as synaptic vesicles, regulate how and when neurotransmitters are released. The team discovered the gene while studying one large French-Canadian family all of whom have epilepsy and many of whom also suffer from autism.

For more on epilepsy's comorbidities, including autism, see my article "Epilepsy as a Spectrum Disorder" in EpilepsyUSA.

Before You Know It, You've Decided

UCLA brain lab examines free will.

Whenever you are ready to, touch your index finger to the end of your nose. No hurry. Just do it when you want to.

Have you done it yet? No? That's fine. Take your time. But as soon as you're ready, touch your nose. Finished? Good. 

If UCLA professor Itzhak Fried and his collaborators had just now been looking into your brain--through tiny super-sensitive electrodes that pick up firing signals from individual neurons--chances are pretty good that they could have predicted when you were going to touch your schnoz before the conscious "you" did. By as much as a full second and a half! Does this call into question the freedom of your will? I don't think so; for one thing, just because a decision is not conscious doesn't mean it's not "free." Even so, showing that awareness of a decision may only arrive sometime after an action has been initiated by other parts of the brain is interesting enough regardless of what it suggests about free will. 

 
The experiment--published in the February 10, 2011, Neuron, and described by Daniela Schiller and David Carmel this week in Scientific American--went like this: Fried's team implanted electrodes into the brains of 12 epilepsy patients who were being prepared for surgery. The temporary implants were required to precisely pinpoint the areas where seizures were originating. But once in place, the researchers used the electrodes to watch individual neurons fire while asking the patients to press a button whenever they wanted to. The subjects were watching a hand sweeping around a clock face and would report to the researchers the exact time that they made the decision to push. 

Not surprisingly, the experiment engaged a lot of neurons in the supplementary motor area, a part of the frontal lobe known to be involved in movement planning. More interesting is that many of these brain cells began firing in a way that predicted button pushing a full second and a half before the person reported having made a decision. At seven-tenths of a second, there was a crescendo of neural firing, enough to let Fried's group predict the timing of the coming action with 80 percent accuracy. Not bad. 

Fried, who specializes in epilepsy surgery and neuroresearch, has long been looking at the brain for insights to questions otherwise locked in the realm of philosophy. His team identified the first human mirror neurons, sometimes described as the roots of empathy, and shed much light on the nature of memory, recognition, and other key issues. Once again patients with epilepsy, and the doctors who try to understand and help them, are pushing back the frontiers of neuroscience. 

Chopin: Art and Epilepsy

Frédéric Chopin (1810-1849)

Van Gough, Dostoevsky, da Vinci, Giorgio de Chirico, Michelangelo, and Dickens are all argued to have had epilepsy. Their diagnoses are mostly ex post facto and speculative, and some of are more controversial than others, but there definitely seems to be some kind of association between epilepsy and the making of great and revolutionary art.

A Spanish radiologist at the Xeral-Calde Hospital Complex in Lugo, Spain, has just published  a study in the latest issue of Medical Humanities arguing that Frédéric Chopin should be added to the roster of genius artists suffering from temporal lobe epilepsy (TLE).

A close reading of Chopin’s diaries and letters, and of Chopin’s lover George Sands’s first-hand accounts, reveal a young composer suffering from symptoms that look a lot like TLE, says the radiologist, Manuel Varquez Caruncho. Chopin’s complex, recurring, short, and predominantly visual hallucinations are much more symptomatic of TLE than schizophrenia or medication poisoning, the leading alternative hypotheses. Chopin’s hallucinations—he once walked out of a concert in the middle of performing a piece because he saw strange creatures spilling out of his piano—lasted a maximum of a  couple of minutes, and Chopin could remember and discuss them clearly. They were also recurring; all of which suggests TLE.

Artists with epilepsy whose seizures are focused in one part of the brain may have heightened sensibilities that relate to that region’s function. Van Gough’s use of wild and otherworldly colors, for example, may partly be a product of his intense vision-modifying seizures.  Others experience amplified smells, sounds, or even ecstatic—and sometimes, religious--emotions in association with their seizures. Sometimes these alterations are subtle; sometimes they are overwhelming. Dostoevsky said of his auras, “I would feel the most complete harmony in myself and in the whole world and this feeling was so strong and sweet that for a few seconds of such bliss I would give ten or more years of my life, even my whole life perhaps.”

When these extraordinary modes of experience are combined with extraordinary expressive talent (as they will inevitably be, given how common epilepsy is) the product may be a paradigm-shifting artist. Chopin, if Caruncho is right, certainly fits the bill. 

The Lost Prince: Epilepsy on the Screen

Daniel Williams as Prince John

Tom Hooper's excellent film, The King's Speech focuses on the stammering of King George VI. In the film, George's speech therapist asks the king about his younger brother, Prince John. George says that   "Johnny was a sweet boy who died of epilepsy at 13." Never having heard of a British prince with epilepsy, I looked up Prince John and found my way to a very good 2003 BBC production about his short life, The Lost Prince. While The King's Speech focuses on the years just prior to WWII, The Lost Prince is set two decades earlier at the outset of WWI. Both films use the personal disabilities of princes, brothers, to shed royally-tinted light on those times and wars.

The Lost Prince's direct portrayal of seizures is hard to watch... but worth it. Few things are more scary to see for the first time than a child having a seizure. But by the third or fourth time, compassion starts to eclipse horror. Every family living with epilepsy reaches that point, but it would be great if society at large could as well. The horror response, and the fear those with epilepsy have of evoking it, conserves epilepsy's persistent stigma and bolsters its aura of shame.  Exposure to realistic portrayals of seizures may help.

The Lost Prince also captures the remarkable resilience of children with epilepsy and the perspective they bring to those around them. As the royal family struts and wrings their hands over picayune protocol and the "horrors" of perceived and real slights, Prince John opts out and instead draws funny and incisive portraits of the family's follies. He is the only one brave enough to speak up when the emperor has no clothes. Having a child with epilepsy--and, in the case of John, learning disabilities as well--can bring a quick and corrective perspective shift in families. But that was a shift the royal family wasn't prepared to make. At least not until the death of the delightful young prince, probably from status epilepticus--a seizure that won't stop--at age 13.

After the funeral, Prince George, still a teenager, tells John's devastated nanny that his brother "was the only one of us who was really allowed to be himself." It is no small consolation. As for Prince George, his stammering is not portrayed in The Lost Prince. One royal disability at a time, I guess. A good excuse to see both films.

PNES: A Seizure by Any Other Name is Just as *Bleep*!

 

Is "non-epileptic seizure" an oxymoron? 

To quote Bill Clinton, "Words matter."
Last night, at the American Epilepsy Society conference in San Antonio, I saw a debate between Salim Benbadis, a neurologist from Tampa, and Curt LaFrance, a psychiatrist and neurologist from Providence. These doctors were wrestling over whether the word "seizures" belongs in the diagnosis of "psychogenic non-epileptic seizures." (Also known as PNES.) These are seizure-like events on the outside, with no corresponding epileptic EEG activity on the inside. They are considered a kind of conversion disorder, usually caused by a trauma suffered by a patient who can't effectively process the associated emotions or express them verbally. PNES patients often end up in emergency departments where they're typically prescribed antiepileptic drugs, not to be properly diagnosed unless lucky enough to be seen by an epileptologist (often years after onset) who can definitively reach a PNES diagnosis with a video-monitored EEG. Even after getting properly diagnosed, the patients often get punted back and forth between neurologists--who say the patient's problems are psychological and not in the neuro bailiwick--and psychiatrists who see the seizures as neurological events and thus outside their domain. 

Given that they aren't epileptic in any way, should these events be called "seizures" at all?  Benbadis opened the argument saying that the word "seizure" creates confusion in his newly-diagnosed PNES patients. "I talk to them for half-an-hour explaining what they have and at the end they say, 'But do I still have seizures?' If I answer 'yes,' it can wipe out everything I've just explained." Better to call them "attacks" or "spells" or "episodes," he said.

Benbadis also argued that English dictionaries, both medical and non, associate "seizure" with epilepsy in the first or second definition. The association is a fact of modern usage, he said, and it is "very misleading" to use it to describe a non-epileptic event. It misleads the patient, certainly, but also the medical community.

LaFrance countered that the word "seizure" originally meant  "to be taken hold of" and did not imply epilepsy. PNES patients are indeed "taken hold of" by their seizure-like events, he said. We should not surrender to the modern usage, he argued, simply because it's popular. More essential, though, was LaFrance's point that at first re-diagnosis, the PNES patient is being evicted from both the epilepsy and neurology communities. To kick the patient out of the "seizure" community at the same time, could leave them homeless, so to speak, and feeling still more vulnerable and betrayed.

"The practical reason for keeping the word "seizure" is that it validates the patient's experience and forms an alliance with the clinician." That alliance, says LaFrance, will be essential for effective treatment. 

The Stanford psychiatrist moderating the debate, John Barry, synthesized the two positions, arguing that it may not really matter what you call the events, as long as you both 1) clearly convey the message that while they are not epilepsy, they are no less real, and 2)  preserve the therapeutic bond. 

Beneath the linguistics, but revealed by them, is a deeper struggle. Benbadis is not trained to care for these patients, he says, and he doesn't want to. He has enough work to do just tending his epilepsy patients, whom he can help. As long as the "attacks" that plague PNES patients are said to be "seizures," those patients will keep flooding his clinic.  "Seizures" are things neurologists are obliged to treat; while psychological "attacks" or "episodes" are not. 


Tanvir Syed is the exception who proves the rule. The one epileptologist in the audience who argued for keeping the word "seizure," the Cleveland-based Syed actually enjoys treating the many PNES patients who find their way to his clinic. He doesn't bother sending them to psychiatry; he knows they'll just boomerang back. And the psychiatrists don't really know how to help them anyway. 

And how does Syed treat his PNES patients? "With meditation," he says. "Teaching them to meditate gives them the strength of mind to deal with the emotions associated with their trauma."

I'm writing a long-form piece on PNES, so much more about this later. 

Epilepsy as a Spectrum Disorder

“Seizures are often only the tip of the epilepsy iceberg,” says Frances Jensen, M.D., professor of neurology at Harvard Medical School and director of epilepsy research at Children’s Hospital in Boston. “We’re beginning to pay attention to what’s down below. Often that includes other serious problems, too,” she says in my article, Epilepsy as a Spectrum Disorder, in the current issue of EpilepsyUSA.

Depression, migraines, learning disorders, autism, ADHD, and Alzheimer's all have high associations with epilepsy.
Unfortunately, many clinicians only have time--or the inclination, or the expertise--to treat seizures. If they can get a patient's seizures under control, they often consider their jobs complete, while the patients continue to suffer quietly from other less salient conditions.

The upside of recognizing these associations is that with emerging insights into the relationship between epilepsy and other  psychiatric and neurological problems, neuroscientists are getting a more comprehensive picture of the deeper workings  of the whole brain. A consensus is emerging among researchers that epilepsy is better viewed, and treated, not simply as a disorder defined by seizures, but as something more complex and nuanced, more explicitly interrelated with other illnesses.

That's one reason many top neuroscientists argue epilepsy research should be a priority investment. When we  understand what causes seizures, on a deep level, we'll also have keys to the doors of  many other brain-related problems. And to an understanding of the well functioning brain, too.

WE Remember, Because HM Forgot

Henry Gustav Molaison

So many big moments in the history of neuroscience are the products of efforts to understand or treat epilepsy. Look for instance at this fine recent story by Mo Costandi in the Guardian memorializing one of the most important figures in the field, a man who for decades was known simply as HM. Henry Molaison (whose full name was only released upon his death two years ago) had been dogged by seizures since childhood and was so desperate to shake them that, in 1953, he agreed to have his hippocampus removed. His surgeon knew HM's seizures were originating there, but no one knew what the side effects would be. The surgery had its intended effect; his seizures were reduced from dozens a year to about two. But in exchange for that gain, he lost the ability to make new memories, a condition known as severe anterograde amnesia.

The main character in Memento, the excellent movie about an amnesiac driven to keep progressing into the future by preserving his past with Post-Its, annotated Polaroids, and tattoos, was purportedly modeled after Molaison.

Before Molaison, most neuroscientists believed memory to be distributed all through the brain.  The first paper about the case, published by Molaison's  surgeon, William Beecher Scoville, and neuroscientist Brenda Milner (both at the Montreal Neurological Institute) showed that though even without his hippocampus Molaison could still retain small amounts of information for short periods of time, he couldn't store them anywhere before they were supplanted by new ones. This suggested, for the first time, that memory has distinct long- and short-term components. Memory research has never been the same, and today no one doubts the central role of that weird little seahorse-shaped part of the limbic system known as the hippocampus in creating and quickening new memories; it is now arguably the most intensively studied part of the brain.

Molaison died two years ago, at 82, but his brain (still being studied at the Brain Observatory UC San Diego) is still revealing secrets about the nature of memory and what makes it work--and cease working.

It's hard to say where memory research would be today if it weren't for Molaison and his epilepsy; possibly decades behind where it is now.  Let's not forget him...or the many other courageous and generous patients with epilepsy who shed so much light on this field.

What's That Movie Called?: Memory in Film

There’s a movie I can never remember the name of. It’s about a man who has no short-term memory. It begins with the letter “M,” but it isn’t a person’s name. "Manifest?" No, it has something to do with memory. I know it! I know it! I’ve seen the film twice and it is excellent, a tour de force, but I can’t remember the name!  "Manifest!" No! Damn!

In this movie—it’s on the tip of my tongue--Guy Pearce plays Leonard, who suffers from anterograde amnesia, which is a loss of the ability to create new memories. Memories from before the trauma that caused the amnesia remain intact and accessible. New memories never make it from the hippocampus, where memories first form, to wherever they’d be stored for long-term retrieval. Leonard earned his amnesia by interrupting two men who were attacking his wife; he gets a hard whack on the head. He can recall events from before the accident, but nothing new sticks.

To compensate, Leonard surrounds himself with mnemonic aids, fills his pockets with annotated Polaroid photographs and Post-Its. His most striking device, though, for those bits he really can't afford to forget, is the drawing of rich-text tattoos all over his body.
It’s a murder mystery, told in reverse, that is stunningly, delightfully, reelingly complex. The plot gets less and less clear the more you learn. Until the end, when everything becomes clear...or at least coherent.

Leonard's memory loss is so poignant, maybe, because it's a caricature of the normal human condition. Our experience leaks through the sieves of our memories,  while only a few rare bits make their way to long-term storage. It's hard not to mourn the extravagant waste of that. But it's also the secret to our sanity and the coherence of our lives; the trick to memory is not just knowing what to preserve, it's the ability to drop whatever dilutes and confuses the story without adding value. And as this movie reveals, the forces that determine what we preserve, and the stories we weave with that material, are not always conscious. Or honest. You can play the film instantly on Netflix and if you’re interested in memory you should.

Of course, there’s an epilepsy angle: one of the most common causes of anterograde amnesia is temporal lobe surgery, usually for epilepsy with a focus in the medial temporal lobe. Also, some kinds of temporal lobe seizures themselves mess with the same brain areas, and can cause temporary bouts of anterograde amnesia. The hippocampus, and all of the stuff surrounding it, regulates the acquisition of short-term memory. Damaging it is like firing the librarian who files the books to the shelves. New volumes keep coming in, and you can see them as they do, but they quickly get lost in the pile and are impossible track, let alone read.

Memento! Of course, the movie is called Memento!

My next blog should be about TOT (tip of the tongue), a bonafide neurological phenomenon. It's also called Presque vu, from the French for “almost seen.” You know the feeling, it’s when a word or name you know well is right there, but not accessible. "Memento" is one that I, for some reason, have a hell of a time accessing. William James described TOT, back in 1890, as “a (memory) gap that is intensely active.” It feels like there’s a repulsive force involved, not just a lack of connection.  That’s why we sometimes need to Jerry-rig our own memories, to overwhelm those "intensely active" gaps. Maybe I should have “Memento” tattood on my thumb. What do you think?

Exposing Sudden Death from Epilepsy

A thought provoking and disturbing story in Tuesday’s Times focuses on sudden death from epilepsy (Sudep), describing it as epilepsy’s “silent killer.” “Silent” may be a stretch, but it is certainly under-discussed in clinical settings and under-studied in labs. I’m writing a book about epilepsy and I had no idea that it was as pervasive a killer of epileptics as Aliyah Baruchin reports. According to the piece, “Sudep accounts for up to 18 percent of all deaths in people with epilepsy, by most estimates; those with poorly controlled seizures have an almost 1 in 10 chance of dying over the course of a decade.”

Given that about 50 million people suffer from epilepsy worldwide, we're talking about hundreds of thousands of Sudep deaths each year. And yet, American doctors rarely tell their patients with epilepsy about Sudep. The reason they don’t, Baruchin reports, is that it would pose too heavy a psychological burden on patients who are already hard-hit by the everyday difficulties of seizures. If there isn’t really anything patients can do about it, why tell them, doctors ask. (I suspect, from my own experience, American doctors also fail to discuss Sudep because they don’t have time.) Baruchin’s piece, good as it is, begs an important question here: Is there anything you can do to prevent Sudep even if you know about it? She reports that in Britain anti-Sudep products, like mattress alarms and structured pillows, are sold to ward off Sudep during sleep. But she  presents no evidence that those products do anything at all or are even recommended by doctors in the UK.

Nonetheless, if patients face a heightened risk of dying from their epilepsy, they have a right to know. And doctors have the responsibility to tell them, even if it takes time and causes discomfort. Truth matters. For one thing, without some kind of collective acknowledgement of Sudep, it won’t get the attention it deserves from brain scientists.

Too often, doctors and scientists alike treat epilepsy simply as recurring seizures. But it is so much more. Disabling as they are, “seizures are often only the tip of the epilepsy iceberg,” says Frances Jensen, MD, professor of neurology at Harvard Medical School and director of epilepsy research at Children’s Hospital in Boston. “We’re beginning to pay attention to what’s down below. Often that includes other serious problems, too.” One of those other serious problems is the propensity to die suddenly and without warning. That deserves attention.

Soldiers and their Seizures

Brenda Patoine has written an interesting and ominous piece about the coming tidal wave of seizure disorders among veterans returning from Iraq. Traumatic brain injury (TBI) has always been associated with a high incidence of epilepsy, which may show up months, and often years, after the initial injury. Many soldiers returning from Iraq and Afghanistan have begun to have seizures and many many more will begin to, even as they settle unsuspectingly back in to life at home. The article, on the Epilepsy Foundation's website, cites 1985 study of vets who’d suffered traumatic brain injury in Vietnam found that 50 percent developed seizure disorders within a few years of returning home.
Patoine writes:

"No one knows how many of those troops with brain injuries will eventually develop epilepsy. But with an estimated 1.4 million troops who have served or are currently serving in Iraq, even the most conservative statistics portend a looming crisis of post-TBI neurologic problems.…”

Patoine goes on to quote Marc Dichter at the University of Pennsylvania who pleas for  preventive action for these high-risk soldiers. “Basically, we’ve been waiting for epilepsy to happen and then seeing if we can treat it… Why aren’t we paying attention to the development of epilepsy, as we do for every other medical disease?” he asks.

Pantione then outlines a few trials that look at how well various anti-seizure meds work as prophylactics for seizures if they are administered soon after the initial injury. That’s a worthwhile approach, sure, but is administering anti-seizure meds as a prevention really the whole deal? I don't know, but either the article failed to describe other avenues of research, or they aren’t happening. Have VA docs looked for patterns in the EEGs of soldiers with TBI but still no seizures, for example, to see which ones develop epilepsy and which ones don’t? Some people are more likely to develop seizures after brain injury, while others have more resilience due to, say, greater adaptive plasticity, or some other mechanism. What about the increase of gabapentin after injury and its influence on the growth of new synaptic connections; might that acceleration of healing growth also make brains more susceptible to seize? Or maybe (probably) those soldiers who become epileptic would have been more likely to begin seizing anyway; the injury just pushes them over the line. If that's the case, what made them so? Is there a genetic link? How about the specific kind and location and intensity of the brain injury? Are those details being tracked as determinants of seizure onset? And finally, how many of these seizures are psychogenic non-epileptic seizures (PNES)? Do VA doctors really know?

This would be a great time to study these things, both for the soon-to-be epileptic soldiers with head injuries and for the millions of non combatants who are going to begin having seizures in the years to come but don't know it. If we can identify their propensity, and mitigate it, before the onset of full-blown seizures, that would be a huge advance.