Brenda Talavera was pretty matter-of-fact when her doctor suggested that they implant a stimulator the size of a small cell phone inside her brain.
"If it was going to make me better, do it," the Seattle woman said while standing in her living room filled with hockey memorabilia. "If it didn't work, they could remove it."
Talavera, 39, had suffered from debilitating seizures since she was 13. They were so violent that she never remembered having them. Her only proof to herself was the same bite mark on the same part of her tongue after each one. She estimates that she suffered more than 10 a month. Medication alone didn't help.
As she reached adulthood, her only solace was knowing the grocery store where she worked was near a fire station. The firefighters who were called every time she had a seizure knew her well.
In 2006, she became the second patient enrolled in the pivotal trial (or final phase) at Swedish Medical Center that would implant a Responsive Neurostimulator System underneath her scalp. The trial, which is being conducted at 28 U.S. sites, will determine whether the Food and Drug Administration approves the treatment.
It works like a pacemaker for the brain, and is designed to detect abnormal electrical activity and deliver small amounts of electrical stimulation to prevent seizures, said Dr. Ryder Gwinn, director of epilepsy and functional neurosurgery at the Swedish Neuroscience Institute. Swedish enrolled 11 patients in Seattle and at Oregon Health Sciences University, where it is jointly conducting the trial.
The RNS is connected to one or two wires containing electrodes that are placed within the brain or rest on the brain surface where doctors determine the seizures start. It's different for each patient, and physicians use MRI scans to figure out where to place the electrodes. Gwinn said there is a period of adjustment as the device regulates to each patient's seizure activities.
The device stores about four seizures' worth of information, which is downloaded to a laptop computer using a hand-held wand Talavera hovers over her head every night. Then she hits a button and all of her seizure information for the day is sent directly to Gwinn.
"She can have a seizure and I can see it on my computer an hour later," he said.
The gold standard for treating epileptic seizures that can't be controlled by medication alone is to find the source of the seizure and remove that part of the brain, Gwinn said. But physicians want to be able to treat seizures without removing tissue and believe the implant is less dangerous.
From previous studies, "there were very few side effects and any effects (such as flashes of light or extra stimulations) can be adjusted to each patient. With permanent tissue removal, once it's done, it's done," Gwinn said.
Gwinn doesn't have specific numbers yet to prove how well the implants are working, but anecdotally, he sees that many of his patients' seizures have diminished.
Dr. John Miller, director of the University of Washington Regional Epilepsy Center at Harborview, calls the approach "very interesting research," but said the university declined to participate in the trial several years ago, partly because there was little experimental work done on animals before going directly to human trials. He also said there hasn't yet been enough evidence of significantly decreasing seizures to justify the risk of the surgical implant.
"It's not yet clear that the device makes people seizure-free and taking patients from 10 seizures to five doesn't really change their life that much," Miller said. "We're not at that point, but that may change -- the device is still under development and improving, but I'm reluctant to consider it for my patients at this time."
Gwinn expects the FDA to approve the epilepsy implant. A similar brain implant to help control tremors in Parkinson's disease patients was approved in 2002. While he doesn't know how much the device will eventually cost patients if approved, he said it would likely be cost-effective compared with how much patients pay now for weekly or monthly hospital visits and expensive medications.
"This is really just a first-generation device to treat epilepsy," Gwinn said. "It will take another five years to be perfected, but just the effectiveness I've see so far warrants its introduction."
Talavera keeps a diary of how many seizures she has and how severe they are. At 73 weeks into the trial, she said she is down to fewer than six a month, and they are much smaller and less severe.
When asked about how she feels about the good results so far with the implant, she's still matter-of-fact about the process, simply saying, "That's something good, less seizures."
EPILEPSY
What is a seizure? A seizure happens when a brief, strong surge of electrical activity affects part or all of the brain. It can last from a few seconds to a few minutes and have many symptoms, including convulsions and loss of consciousness.
How common are they? One in 10 adults will have a seizure. More than 3 million people in the U.S. have some form of epilepsy. About 200,000 new cases of seizure disorders and epilepsy are diagnosed each year.
What causes them? Seizures are symptoms of abnormal brain function, but the causes are usually unknown. Head trauma or genetic factors can be causes.
Source: Epilepsy Foundation
Friday, November 27, 2009
Thursday, November 12, 2009
Cause of severe pediatric epilepsy disorder discovered
Researchers at the University of California, San Diego School of Medicine have discovered that convulsive seizures in a form of severe epilepsy are generated, not on the brain's surface as expected, but from within the memory-forming hippocampus.
The scientists hope that their findings - based on a mouse model of severe epilepsy - may someday pave the way for improved treatments of childhood epilepsy, which affects more than two percent of children worldwide. Their study will be published online by the Proceedings of the National Academy of Science ( PNAS ) the week of March 16.
"A parent of an epileptic child will tell you that they think their child is going to die during their attacks," said senior author Joseph Gleeson, MD, director of the Neurogenetics Laboratory at the UC San Diego School of Medicine, professor in the department of neurosciences and Howard Hughes Medical Institute Investigator. "Parents of children with epilepsy, especially the most severe types of epilepsy, are desperate for a deeper understanding of the causes of the problems and for the development of new treatments."
One of the major causes of epilepsy in children is an alteration in the development of the cerebral cortex. The cerebral cortex is the main folded part of the brain, containing a large percentage of brain cells, and is integral to purposeful actions and thoughts. However, this complex structure is subject to all kinds of defects in development, many of them due to defective genes and many associated with epilepsy.
Cortical dysplasia, meaning disordered development of the cerebral cortex, is identified in 25 to 40 percent of children with the most severe and difficult-to-treat forms of epilepsy. These children often come to the attention of specialists due to stagnation in the acquisition of language and balance skills and accompanying epilepsy. The symptoms displayed by these children can range from very subtle - such as small muscle jerks or eyelid fluttering - to dramatic whole body, tonic-clonic spasms (a series of contractions and relaxations of the muscle) that can affect basic bodily function.
The Gleeson team, led by researchers Geraldine Kerjan, PhD and Hiroyuki Koizumi, PhD, has been studying a disorder called "lissencephaly." (In Greek, leios means smooth, and kephale means brain or head.) Children with lissencephaly have a smooth brain surface that lacks the normal hills and valleys that are characteristic of the human brain. The researchers were recently successful in developing a mouse model that showed some of the features of this disorder, usually the first step toward understanding the cause of a genetic disorder. But the severe epilepsy that is associated with lissencephaly was never displayed in any of the previous animals, so the team kept removing gene after gene until they hit upon a strain that showed epilepsy.
"We study the gene "doublecortin," which is defective in some forms of epilepsy and mental retardation in humans," said Kerjan, lead author of the study. "However, only after we removed a combination of two of the genes in the doublecortin family did we uncover epilepsy."
According to Gleeson, the findings were dramatic, as almost none of the mice in this strain survived to adulthood. Thinking that the deaths might be due to epilepsy, the scientists recorded electroencephalograms, which measure electrical activity produced by the firing of neurons in the brain, and found severe epilepsy in all of the mice tested. Even more surprising was the site of the epileptic focus - or site from which the seizures were generated - which was located beneath the surface of the brain, in the hippocampus.
"Researchers had thought that the cause of the seizures in this disease must be the brain surface, since this is the part that looks the most abnormal on brain MRI scans," said Gleeson. "However, we found that the epilepsy focus was actually deeper in the brain, within the hippocampus, the main memory-forming site."
The research team intends to continue studying in studying the mice, to explore potential mechanisms and utilize this model to test new treatments.
The scientists hope that their findings - based on a mouse model of severe epilepsy - may someday pave the way for improved treatments of childhood epilepsy, which affects more than two percent of children worldwide. Their study will be published online by the Proceedings of the National Academy of Science ( PNAS ) the week of March 16.
"A parent of an epileptic child will tell you that they think their child is going to die during their attacks," said senior author Joseph Gleeson, MD, director of the Neurogenetics Laboratory at the UC San Diego School of Medicine, professor in the department of neurosciences and Howard Hughes Medical Institute Investigator. "Parents of children with epilepsy, especially the most severe types of epilepsy, are desperate for a deeper understanding of the causes of the problems and for the development of new treatments."
One of the major causes of epilepsy in children is an alteration in the development of the cerebral cortex. The cerebral cortex is the main folded part of the brain, containing a large percentage of brain cells, and is integral to purposeful actions and thoughts. However, this complex structure is subject to all kinds of defects in development, many of them due to defective genes and many associated with epilepsy.
Cortical dysplasia, meaning disordered development of the cerebral cortex, is identified in 25 to 40 percent of children with the most severe and difficult-to-treat forms of epilepsy. These children often come to the attention of specialists due to stagnation in the acquisition of language and balance skills and accompanying epilepsy. The symptoms displayed by these children can range from very subtle - such as small muscle jerks or eyelid fluttering - to dramatic whole body, tonic-clonic spasms (a series of contractions and relaxations of the muscle) that can affect basic bodily function.
The Gleeson team, led by researchers Geraldine Kerjan, PhD and Hiroyuki Koizumi, PhD, has been studying a disorder called "lissencephaly." (In Greek, leios means smooth, and kephale means brain or head.) Children with lissencephaly have a smooth brain surface that lacks the normal hills and valleys that are characteristic of the human brain. The researchers were recently successful in developing a mouse model that showed some of the features of this disorder, usually the first step toward understanding the cause of a genetic disorder. But the severe epilepsy that is associated with lissencephaly was never displayed in any of the previous animals, so the team kept removing gene after gene until they hit upon a strain that showed epilepsy.
"We study the gene "doublecortin," which is defective in some forms of epilepsy and mental retardation in humans," said Kerjan, lead author of the study. "However, only after we removed a combination of two of the genes in the doublecortin family did we uncover epilepsy."
According to Gleeson, the findings were dramatic, as almost none of the mice in this strain survived to adulthood. Thinking that the deaths might be due to epilepsy, the scientists recorded electroencephalograms, which measure electrical activity produced by the firing of neurons in the brain, and found severe epilepsy in all of the mice tested. Even more surprising was the site of the epileptic focus - or site from which the seizures were generated - which was located beneath the surface of the brain, in the hippocampus.
"Researchers had thought that the cause of the seizures in this disease must be the brain surface, since this is the part that looks the most abnormal on brain MRI scans," said Gleeson. "However, we found that the epilepsy focus was actually deeper in the brain, within the hippocampus, the main memory-forming site."
The research team intends to continue studying in studying the mice, to explore potential mechanisms and utilize this model to test new treatments.
Sunday, November 8, 2009
Agony, Hope And Resolve
Epilepsy entered our lives more than 25 years ago, and unless things change, I fear that outcomes for families in the future won't be any better than they were for us.
By Susan Axelrod | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
Twenty-three mind-numbing medications. Brain stimulation. Special diets. Countless hospitalizations, emergency-room visits and procedures. Drug-induced comas to temporarily halt relentless, brain-damaging and life-threatening clusters of seizures. This describes the first 18 years of my daughter's life. One night, when she was just 7 months old, I put Lauren to sleep in her crib. The next morning I found her blue and limp—the result, I was soon to discover, of a night filled with seizures. Seizures that defied explanation, resisted treatments and have defined her life ever since. All I wanted, from that day on, was to be able to make the seizures stop. But that goal remained elusive. She could have 25 or more seizures a day. She would wake up after a seizure just long enough to feel the next one coming on and scream out in terror, begging me, "Mommy … NO … make it stop…" I never could. As all parents know, your child looks to you to explain the world, help put things in order and to make things better. There is nothing worse than seeing that look of terror in your child's eyes when you are completely helpless to make things better. When she was 15, Lauren underwent a seven-hour neurosurgical procedure, which, at the time, was our last hope. Surgeons bored holes in her skull and implanted electrodes directly onto the surface of her brain in an attempt to pinpoint the area responsible for the seizures, in hopes of being able to surgically remove it.
When we learned that we had subjected her to this horrific procedure only to come up empty-handed once again, it was the lowest moment of my life. Any remaining hope that we could ever stop the torrents of seizures and the brain damage they were causing dissolved. After 24 hours, my tears gave way to a new resolve. It was no longer OK to sit back and accept that answers could not be found.
Empowered by a few other families, I became an advocate for change, and soon learned that epilepsy, the most common neurological disorder of childhood, was not getting the amount or the type of attention it deserved. The investment in research by the federal government and the investment of private dollars in epilepsy research have simply not been proportional to the burden of this disease. Yes, of course we want to try to control seizures, but that's not enough. Most of those involved in the field were not thinking about a cure. And there was no sense of urgency, no groundswell of support for increased research efforts, even as so many of us sat by helplessly, watching our loved ones deteriorate—sometimes as much from the treatments as the seizures—and even lose their lives. Where were the rallying cries of advocates and patients banding together for a cure that are so common with other devastating diseases and conditions?
This is what compelled us to come together and found CURE, Citizens United for Research in Epilepsy. As parents and patients, together with the scientific community, we are raising money, spearheading the search for a cure and supporting the critical, cutting-edge research needed to unravel the mysteries of this disorder.
When Lauren was 18, a new drug, Keppra, was approved. It turned out to be her magic bullet. She continues to take three daily medications and, miraculously, has been seizure-free for the past nine years. Despite the irreversible damage to her brain, we see steady improvement in her cognitive skills and her ability to function independently. No longer haunted by recurrent seizures, she is able to live life fully and it is a true joy to witness.
I don't allow myself to look back and wonder "what if." But when I receive calls from parents of newly diagnosed children who are beginning to travel the same path—for whom available treatments are failing, for whom seizures are so destructive—I can't help but relive it. Epilepsy entered our lives more than 25 years ago and yet, far too often, I have no confidence that outcomes today will be any better than they were for Lauren. That is unacceptable.
We must accelerate research efforts in the field now and address this age-old problem with the urgency and intensity that it merits. Despite the broad public impression, seizures are not a trivial inconvenience. Each and every seizure carries with it the risk of brain damage, physical harm or even death. Until society accepts this and recognizes epilepsy as the serious health problem that it truly is, progress will continue to lag. Too many young brains will be forever affected. Too many lives will be lost.
By Susan Axelrod | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
Twenty-three mind-numbing medications. Brain stimulation. Special diets. Countless hospitalizations, emergency-room visits and procedures. Drug-induced comas to temporarily halt relentless, brain-damaging and life-threatening clusters of seizures. This describes the first 18 years of my daughter's life. One night, when she was just 7 months old, I put Lauren to sleep in her crib. The next morning I found her blue and limp—the result, I was soon to discover, of a night filled with seizures. Seizures that defied explanation, resisted treatments and have defined her life ever since. All I wanted, from that day on, was to be able to make the seizures stop. But that goal remained elusive. She could have 25 or more seizures a day. She would wake up after a seizure just long enough to feel the next one coming on and scream out in terror, begging me, "Mommy … NO … make it stop…" I never could. As all parents know, your child looks to you to explain the world, help put things in order and to make things better. There is nothing worse than seeing that look of terror in your child's eyes when you are completely helpless to make things better. When she was 15, Lauren underwent a seven-hour neurosurgical procedure, which, at the time, was our last hope. Surgeons bored holes in her skull and implanted electrodes directly onto the surface of her brain in an attempt to pinpoint the area responsible for the seizures, in hopes of being able to surgically remove it.
When we learned that we had subjected her to this horrific procedure only to come up empty-handed once again, it was the lowest moment of my life. Any remaining hope that we could ever stop the torrents of seizures and the brain damage they were causing dissolved. After 24 hours, my tears gave way to a new resolve. It was no longer OK to sit back and accept that answers could not be found.
Empowered by a few other families, I became an advocate for change, and soon learned that epilepsy, the most common neurological disorder of childhood, was not getting the amount or the type of attention it deserved. The investment in research by the federal government and the investment of private dollars in epilepsy research have simply not been proportional to the burden of this disease. Yes, of course we want to try to control seizures, but that's not enough. Most of those involved in the field were not thinking about a cure. And there was no sense of urgency, no groundswell of support for increased research efforts, even as so many of us sat by helplessly, watching our loved ones deteriorate—sometimes as much from the treatments as the seizures—and even lose their lives. Where were the rallying cries of advocates and patients banding together for a cure that are so common with other devastating diseases and conditions?
This is what compelled us to come together and found CURE, Citizens United for Research in Epilepsy. As parents and patients, together with the scientific community, we are raising money, spearheading the search for a cure and supporting the critical, cutting-edge research needed to unravel the mysteries of this disorder.
When Lauren was 18, a new drug, Keppra, was approved. It turned out to be her magic bullet. She continues to take three daily medications and, miraculously, has been seizure-free for the past nine years. Despite the irreversible damage to her brain, we see steady improvement in her cognitive skills and her ability to function independently. No longer haunted by recurrent seizures, she is able to live life fully and it is a true joy to witness.
I don't allow myself to look back and wonder "what if." But when I receive calls from parents of newly diagnosed children who are beginning to travel the same path—for whom available treatments are failing, for whom seizures are so destructive—I can't help but relive it. Epilepsy entered our lives more than 25 years ago and yet, far too often, I have no confidence that outcomes today will be any better than they were for Lauren. That is unacceptable.
We must accelerate research efforts in the field now and address this age-old problem with the urgency and intensity that it merits. Despite the broad public impression, seizures are not a trivial inconvenience. Each and every seizure carries with it the risk of brain damage, physical harm or even death. Until society accepts this and recognizes epilepsy as the serious health problem that it truly is, progress will continue to lag. Too many young brains will be forever affected. Too many lives will be lost.
In the Grip of the Unknown
"It's OK, they know. I came home intoxicated the other night at 5 a.m."
Thus begins another skirmish in Devinsky's long-standing war on the fecklessness of youth, their natural tendency to forget their medication, stay up all night working on a term paper and propel themselves into a hypernormal state by swilling vodka or cough medicine. The human brain, for all its marvels, has one glaring fault, the tendency to discount future losses—such as the risk of a fatal seizure—relative to present pleasure, if that's the right word for how 15 Benadryls makes you feel. This psychological quirk has cost the lives of more than 150 of his patients, mostly in their teens and 20s. "I had a patient who hadn't had a seizure in two years," Devinsky tells her. "Last fall I got a call. He went off to college, stayed up late one night at a party and never got up the next morning.
"Do you want to be the mother of two children wondering when your next seizure is coming?"
Striking the right balance of medication is especially important in children as they pass through the critical years for learning. Devinsky raises this with the father of a fourth-grade girl who suffers from brief absence seizures, just five seconds at a time, a few times a day. She has already been on Topamax, Keppra and Zarontin, and is now being treated with Lamictal. Devinsky is hesitant to give her more drugs, but he worries that the absence seizures, which seem so benign, might be causing subtle damage to her learning and behavior. "It's like you're trying to read something," he says, "and I keep tapping you on the arm, like this. For an adult it might not be such a big deal. But if you have this constant distraction during a critical learning window, you miss out, and you don't ever get that back." After talking it over with her father, he decides to up the dosage of Lamictal, and asks the father to let him know of any changes.
Devinsky doesn't disdain technology, but he has a keen sense of its limits. He has all the latest scanners and imagers at his disposal, but knows that most of the time whatever is causing a seizure won't show up on them, at least not definitively. The most important tool in his lab is the EEG machine, which monitors brain activity through electrodes on the scalp, a technology that was invented in 1929.
There are, at this time, only a few ways to treat epilepsy, and applying them is still an art as much as it is a science. What works for one patient often has no benefit for another with identical symptoms. Researchers still don't understand, 80 years after it was discovered, why some children can control seizures with a ketogenic diet, high in fat but so low in carbohydrates that even the amount of sugar in toothpaste can be too much. Nor do they know why two thirds of patients can control their seizures with drugs, but not the rest. Since the 1960s about 30 different compounds have been approved to treat epilepsy, although most neurologists, says Devinsky, have a stable of around 10 that they generally rely on. New ones are being developed and put into use regularly, but that progress is deceptive, says Michael Rogawski, a neurologist at University of California, Davis, who studies epilepsy therapies. The new drugs may have fewer side effects or less toxicity than older ones, but by and large they work only for the same percentage of patients who were already being helped; the number of refractory cases hasn't changed much over the years. And it's still impossible to know in advance which patients will benefit, and from which drugs. "I can look at a person, do all the testing, even see their seizure, and I can't tell which drug they'll respond to," says Carl Bazil, who heads Columbia's Comprehensive Epilepsy Center. "There must be something about their action in the brain, but we don't know what it is." Many researchers believe that the next important breakthrough won't be a new drug at all, but the development of a subcutaneous pump that can deliver medication directly to the right spot in the brain, bypassing both the organs of the rest of the body, and a delivery mechanism that relies on a teenager late for the school bus to remember where he left the bottle.
Devinsky tries not to use more than two different drugs on a patient at a time, but even so, the number of ways to combine different dosages of two drugs from among 10 is infinite, especially compared to the time he has to get someone's seizures under control before they fry their synapses beyond repair. When he first treated Wheeless he was on Depakote, which was making him lethargic and fat; Devinsky substituted Felbatol in combination with Lamictal. When that didn't work well, Devinsky switched him to Felbatol with Keppra. The improvement was dramatic—so much so that he kept Wheeless on Felbatol even after reports appeared of deaths from liver failure and aplastic anemia. For the relief Wheeless received, the risks seemed small enough to Devinsky, and manageable as long as he closely monitored his blood chemistry. Up till now, he's been right, but if the Felbatol-Keppra combo is losing its effectiveness, he will have to consider increasing the dosage, or switching him to another medication. He wants to improve Wheeless's sleep schedule and control his mood. Depression works synergistically with epilepsy; it can promote seizures, and seizures, of course, can make you depressed. And if those don't work … well, he'll think of something.
The complexity of managing epilepsy this way has led patients and their parents to agitate for research on a cure. Although "cure" is in the name of the foundation Devinsky founded, he uses the term sparingly, especially around patients; just hearing it can encourage them to stop taking their medications, and after a while they show up back in his office with new seizures. Cures do happen, except they're most often spontaneous and random; about half of all children with epilepsy outgrow their seizures and can be taken off meds after several years. In theory, gene therapy could someday cure some cases of generalized epilepsy. The first step would be to identify the mutations that cause the condition, and thousands of patients are being recruited for a study aimed at doing that. And, also in theory, and sometimes in practice, partial epilepsy can be cured by removing the part of the brain where the seizure originates—although most patients continue to take anti-seizure drugs afterward as a precaution.
The principles of epilepsy surgery have been known since the first operations took place more than a century ago: identify the area where the seizure begins and cut it out, as precisely as you can. Obviously this excludes most patients with generalized epilepsy, since you can't take out an entire brain (although in rare cases, you can remove half a brain; the patients sometimes compensate surprisingly well). Werner Doyle is one of two neurosurgeons at the NYU center; he does around 260 procedures a year, there and at St. Barnabas. In contrast to Devinsky's holistic approach to patient quality of life, Doyle's discipline requires an obsessive focus on brain stuff, on the paper-thin margin between diseased and healthy tissue. Sometimes, he says, he can feel the difference with his dissecting instruments, which cut easily through normal gray matter but meet resistance where the tissue is scarred from repeated seizure.
Like many surgeons, he is matter-of-fact about the manual dexterity he deploys inside the skull. The intellectual challenge for him is to find the focus of the seizure and trace the networks along which it spreads, while also mapping the boundaries of the unaffected areas. The basic tool for that is the EEG, but the standard device, with around 20 external leads, is a clumsy instrument for mapping a three-dimensional brain. That has led to the adoption of intracranial electrodes, which are inserted into the brain and can sample as many as 200 points. Inserting these requires opening the skull and takes as much of Doyle's skill and time—six or seven hours—as the subsequent operation itself. Patients may stay in the hospital for a week or more, trailing a Medusa-head of wires, under continuous monitoring both by EEG and video, while the doctors wait for the iconic seizure. Then Doyle goes to work.
In contrast to many types of neurosurgery—for tumors, notably—epilepsy surgery is generally performed on healthy people, and the risks are not that high. But Doyle believes, and hopes, that the future of his field lies not in the relatively blunt procedure of ablation, or cutting tissue, but in augmenting brain function through electronic devices. The first of these, the vagal nerve stimulator, has been in use since 1997, and more than 50,000 have been implanted. Its purpose is to disrupt an incipient seizure by sending an electrical signal to the brain through the vagus nerve in the neck. Again, no one knows exactly why it works, but it often does. Deep-brain stimulation, which has been successful in treating Parkinson's disease, is meant to do the same thing, by delivering a pulse directly to the brain itself, but clinical trials for its use in epilepsy so far have been disappointing. The VNS, though, is a primitive tool, which delivers a small current for a fixed duration at regular intervals of several minutes. Researchers now are working to develop a responsive device that could be implanted in the brain and "sense when a seizure is beginning, to release a small amount of medication or electrical stimulation where needed," says Harvard neurologist Steven Schachter, president of the American Epilepsy Society.
The key to such a device will be the computer algorithms that can predict a seizure, ideally in the "aura" stage that sets in before it even begins. We are accustomed to the idea that computers can process limitless amounts of data, but the brain, with its 100 billion neurons, each linked to as many as 10,000 others, is pushing the limits of information theory. The effort represents an audacious assault on a devastating disease, just what Devinsky was dreaming of in medical school. To conquer epilepsy we will have to outwit our own brains.
Thus begins another skirmish in Devinsky's long-standing war on the fecklessness of youth, their natural tendency to forget their medication, stay up all night working on a term paper and propel themselves into a hypernormal state by swilling vodka or cough medicine. The human brain, for all its marvels, has one glaring fault, the tendency to discount future losses—such as the risk of a fatal seizure—relative to present pleasure, if that's the right word for how 15 Benadryls makes you feel. This psychological quirk has cost the lives of more than 150 of his patients, mostly in their teens and 20s. "I had a patient who hadn't had a seizure in two years," Devinsky tells her. "Last fall I got a call. He went off to college, stayed up late one night at a party and never got up the next morning.
"Do you want to be the mother of two children wondering when your next seizure is coming?"
Striking the right balance of medication is especially important in children as they pass through the critical years for learning. Devinsky raises this with the father of a fourth-grade girl who suffers from brief absence seizures, just five seconds at a time, a few times a day. She has already been on Topamax, Keppra and Zarontin, and is now being treated with Lamictal. Devinsky is hesitant to give her more drugs, but he worries that the absence seizures, which seem so benign, might be causing subtle damage to her learning and behavior. "It's like you're trying to read something," he says, "and I keep tapping you on the arm, like this. For an adult it might not be such a big deal. But if you have this constant distraction during a critical learning window, you miss out, and you don't ever get that back." After talking it over with her father, he decides to up the dosage of Lamictal, and asks the father to let him know of any changes.
Devinsky doesn't disdain technology, but he has a keen sense of its limits. He has all the latest scanners and imagers at his disposal, but knows that most of the time whatever is causing a seizure won't show up on them, at least not definitively. The most important tool in his lab is the EEG machine, which monitors brain activity through electrodes on the scalp, a technology that was invented in 1929.
There are, at this time, only a few ways to treat epilepsy, and applying them is still an art as much as it is a science. What works for one patient often has no benefit for another with identical symptoms. Researchers still don't understand, 80 years after it was discovered, why some children can control seizures with a ketogenic diet, high in fat but so low in carbohydrates that even the amount of sugar in toothpaste can be too much. Nor do they know why two thirds of patients can control their seizures with drugs, but not the rest. Since the 1960s about 30 different compounds have been approved to treat epilepsy, although most neurologists, says Devinsky, have a stable of around 10 that they generally rely on. New ones are being developed and put into use regularly, but that progress is deceptive, says Michael Rogawski, a neurologist at University of California, Davis, who studies epilepsy therapies. The new drugs may have fewer side effects or less toxicity than older ones, but by and large they work only for the same percentage of patients who were already being helped; the number of refractory cases hasn't changed much over the years. And it's still impossible to know in advance which patients will benefit, and from which drugs. "I can look at a person, do all the testing, even see their seizure, and I can't tell which drug they'll respond to," says Carl Bazil, who heads Columbia's Comprehensive Epilepsy Center. "There must be something about their action in the brain, but we don't know what it is." Many researchers believe that the next important breakthrough won't be a new drug at all, but the development of a subcutaneous pump that can deliver medication directly to the right spot in the brain, bypassing both the organs of the rest of the body, and a delivery mechanism that relies on a teenager late for the school bus to remember where he left the bottle.
Devinsky tries not to use more than two different drugs on a patient at a time, but even so, the number of ways to combine different dosages of two drugs from among 10 is infinite, especially compared to the time he has to get someone's seizures under control before they fry their synapses beyond repair. When he first treated Wheeless he was on Depakote, which was making him lethargic and fat; Devinsky substituted Felbatol in combination with Lamictal. When that didn't work well, Devinsky switched him to Felbatol with Keppra. The improvement was dramatic—so much so that he kept Wheeless on Felbatol even after reports appeared of deaths from liver failure and aplastic anemia. For the relief Wheeless received, the risks seemed small enough to Devinsky, and manageable as long as he closely monitored his blood chemistry. Up till now, he's been right, but if the Felbatol-Keppra combo is losing its effectiveness, he will have to consider increasing the dosage, or switching him to another medication. He wants to improve Wheeless's sleep schedule and control his mood. Depression works synergistically with epilepsy; it can promote seizures, and seizures, of course, can make you depressed. And if those don't work … well, he'll think of something.
The complexity of managing epilepsy this way has led patients and their parents to agitate for research on a cure. Although "cure" is in the name of the foundation Devinsky founded, he uses the term sparingly, especially around patients; just hearing it can encourage them to stop taking their medications, and after a while they show up back in his office with new seizures. Cures do happen, except they're most often spontaneous and random; about half of all children with epilepsy outgrow their seizures and can be taken off meds after several years. In theory, gene therapy could someday cure some cases of generalized epilepsy. The first step would be to identify the mutations that cause the condition, and thousands of patients are being recruited for a study aimed at doing that. And, also in theory, and sometimes in practice, partial epilepsy can be cured by removing the part of the brain where the seizure originates—although most patients continue to take anti-seizure drugs afterward as a precaution.
The principles of epilepsy surgery have been known since the first operations took place more than a century ago: identify the area where the seizure begins and cut it out, as precisely as you can. Obviously this excludes most patients with generalized epilepsy, since you can't take out an entire brain (although in rare cases, you can remove half a brain; the patients sometimes compensate surprisingly well). Werner Doyle is one of two neurosurgeons at the NYU center; he does around 260 procedures a year, there and at St. Barnabas. In contrast to Devinsky's holistic approach to patient quality of life, Doyle's discipline requires an obsessive focus on brain stuff, on the paper-thin margin between diseased and healthy tissue. Sometimes, he says, he can feel the difference with his dissecting instruments, which cut easily through normal gray matter but meet resistance where the tissue is scarred from repeated seizure.
Like many surgeons, he is matter-of-fact about the manual dexterity he deploys inside the skull. The intellectual challenge for him is to find the focus of the seizure and trace the networks along which it spreads, while also mapping the boundaries of the unaffected areas. The basic tool for that is the EEG, but the standard device, with around 20 external leads, is a clumsy instrument for mapping a three-dimensional brain. That has led to the adoption of intracranial electrodes, which are inserted into the brain and can sample as many as 200 points. Inserting these requires opening the skull and takes as much of Doyle's skill and time—six or seven hours—as the subsequent operation itself. Patients may stay in the hospital for a week or more, trailing a Medusa-head of wires, under continuous monitoring both by EEG and video, while the doctors wait for the iconic seizure. Then Doyle goes to work.
In contrast to many types of neurosurgery—for tumors, notably—epilepsy surgery is generally performed on healthy people, and the risks are not that high. But Doyle believes, and hopes, that the future of his field lies not in the relatively blunt procedure of ablation, or cutting tissue, but in augmenting brain function through electronic devices. The first of these, the vagal nerve stimulator, has been in use since 1997, and more than 50,000 have been implanted. Its purpose is to disrupt an incipient seizure by sending an electrical signal to the brain through the vagus nerve in the neck. Again, no one knows exactly why it works, but it often does. Deep-brain stimulation, which has been successful in treating Parkinson's disease, is meant to do the same thing, by delivering a pulse directly to the brain itself, but clinical trials for its use in epilepsy so far have been disappointing. The VNS, though, is a primitive tool, which delivers a small current for a fixed duration at regular intervals of several minutes. Researchers now are working to develop a responsive device that could be implanted in the brain and "sense when a seizure is beginning, to release a small amount of medication or electrical stimulation where needed," says Harvard neurologist Steven Schachter, president of the American Epilepsy Society.
The key to such a device will be the computer algorithms that can predict a seizure, ideally in the "aura" stage that sets in before it even begins. We are accustomed to the idea that computers can process limitless amounts of data, but the brain, with its 100 billion neurons, each linked to as many as 10,000 others, is pushing the limits of information theory. The effort represents an audacious assault on a devastating disease, just what Devinsky was dreaming of in medical school. To conquer epilepsy we will have to outwit our own brains.
In the Grip of the Unknown 2
Epilepsy drugs are known for serious side effects, including lethargy, hyperactivity, weight gain, weight loss, dizziness, anemia, osteoporosis—and mental disturbances that may confoundingly mimic the symptoms of epilepsy themselves. Devinsky is continually balancing the unpleasantness of a seizure against the misery of throwing up. "You might have two staring spells a month lasting a couple of minutes, and you're on a high dose of medication," Devinsky says. "Now, I can put you on a second medication and get you down to one a month. So now you've got two extra minutes a month but in exchange it's affecting your quality of life for the 15 hours a day you're awake: it may make you tired, or dizzy, or cause mood changes or memory problems. So do you want to make that trade-off?"
Four days a week, Devinsky, who is 52, with a lean, athletic build and a brisk but friendly demeanor, takes a train from his home in New Jersey—he is married, with two teenage daughters and a dog, whom his patients faithfully inquire about—and arrives in New York by 6 a.m. He works out in the gym for an hour before starting his hospital rounds, and then heads to his office. On Thursdays, he sees patients at St. Barnabas Hospital in Livingston, N.J., where he runs another epilepsy center. In a tie and plaid sports jacket, he strides the narrow halls of his clinic, popping in and out of exam rooms where patients wait in varying degrees of anxiety. Even his adult patients usually come with a parent, or a spouse or sibling; almost no one comes alone.
Over the years Devinsky has found himself becoming deeply involved in the lives of his patients. He is close enough with Dan Wheeless to have been a guest at his wedding in 2006. Devinsky says he's been influenced in this way by Sacks, a close friend, who has an exceptional gift for entering into and describing the mental lives of his patients. "I do let patients into my life, and I let myself get into their lives," Devinsky says. "It's an important part of who I am as a doctor." He knows that Wheeless is discouraged because his seizures—which had disappeared entirely for years at a time—have resumed and are becoming more frequent, twice already since New Year's. Worse, they are happening with no obvious triggers under his control, such as drinking or missing a pill. Although Devinsky has patients from as far away as Italy lined up to see him, during a recent office visit he chats with Wheeless as if he had the whole morning for him. He increases the dosage of his antidepressant, suggests melatonin to help him sleep and schedules him for a home EEG—a brain-wave monitor that can be worn for a day while the patient goes about his routine. Wheeless smiles a wan smile, picks up his helmet—for bicycling, not to protect his head in a seizure—and heads out the door. Later, a reporter asks him how he feels about his seizures starting up again. "It's kind of heartbreaking," he says wearily. "I would love to not have epilepsy."
On the day he sees Wheeless, he also sees a college student who has had more than 100 seizures, the most recent one last fall. It happened, she says, after taking Benadryl, an over-the-counter allergy drug that can promote seizures in susceptible patients.
Devinsky nods sympathetically. "How many?" he asks.
"Fifteen," she mumbles. "It's like Robi-tripping."
Devinsky sighs. "I hate to give you the drugs-and-alcohol lecture in front of your parents."
Four days a week, Devinsky, who is 52, with a lean, athletic build and a brisk but friendly demeanor, takes a train from his home in New Jersey—he is married, with two teenage daughters and a dog, whom his patients faithfully inquire about—and arrives in New York by 6 a.m. He works out in the gym for an hour before starting his hospital rounds, and then heads to his office. On Thursdays, he sees patients at St. Barnabas Hospital in Livingston, N.J., where he runs another epilepsy center. In a tie and plaid sports jacket, he strides the narrow halls of his clinic, popping in and out of exam rooms where patients wait in varying degrees of anxiety. Even his adult patients usually come with a parent, or a spouse or sibling; almost no one comes alone.
Over the years Devinsky has found himself becoming deeply involved in the lives of his patients. He is close enough with Dan Wheeless to have been a guest at his wedding in 2006. Devinsky says he's been influenced in this way by Sacks, a close friend, who has an exceptional gift for entering into and describing the mental lives of his patients. "I do let patients into my life, and I let myself get into their lives," Devinsky says. "It's an important part of who I am as a doctor." He knows that Wheeless is discouraged because his seizures—which had disappeared entirely for years at a time—have resumed and are becoming more frequent, twice already since New Year's. Worse, they are happening with no obvious triggers under his control, such as drinking or missing a pill. Although Devinsky has patients from as far away as Italy lined up to see him, during a recent office visit he chats with Wheeless as if he had the whole morning for him. He increases the dosage of his antidepressant, suggests melatonin to help him sleep and schedules him for a home EEG—a brain-wave monitor that can be worn for a day while the patient goes about his routine. Wheeless smiles a wan smile, picks up his helmet—for bicycling, not to protect his head in a seizure—and heads out the door. Later, a reporter asks him how he feels about his seizures starting up again. "It's kind of heartbreaking," he says wearily. "I would love to not have epilepsy."
On the day he sees Wheeless, he also sees a college student who has had more than 100 seizures, the most recent one last fall. It happened, she says, after taking Benadryl, an over-the-counter allergy drug that can promote seizures in susceptible patients.
Devinsky nods sympathetically. "How many?" he asks.
"Fifteen," she mumbles. "It's like Robi-tripping."
Devinsky sighs. "I hate to give you the drugs-and-alcohol lecture in front of your parents."
In the Grip of the Unknown 1
It takes courage and discipline to live every day with the haunting uncertainty of epilepsy. A good doctor helps, too.
By Jerry Adler and Eliza Gray | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
The worst thing about the epileptic seizure Dan Wheeless suffered on the first day of eighth grade wasn't dropping to the floor in the hallway and awakening with no memory of how he got there. It wasn't even being kicked to get up by his classmates, who thought his collapse and jerking were an act; like, say, piloting a fighter jet, being known as the class clown holds uncommon risk for people with a seizure disorder. The worst thing was how the drugs he took made his brain slow down, so that processing auditory information became painfully difficult. He had to write down what was said to him, break it into clauses and concentrate on the meaning of each one. "Sometimes my mom would have to say something to me five times before I could understand it," he recalls. Switching medications after several months improved his cognitive problems, but the new drugs caused lethargy and weight gain, which disappeared only when a new doctor, Orrin Devinsky of New York University, figured out the right regimen for him. "He saved my life," says Wheeless, who was back to see Devinsky recently at his office in Manhattan. Wheeless, a handsome, strapping 32-year-old, went on to graduate from the University of North Carolina, marry an actress and begin a career in the theater. It may be an overstatement that Devinsky saved his life, because doctors can't predict who will die from epilepsy—although Wheeless, who estimates he has had 50 major seizures in his life and countless smaller ones, was certainly a candidate. Devinsky couldn't even save Wheeless's front teeth, all of which had to be replaced after he broke them falling down with seizures. But it is safe to say that Devinsky saved his mind.
When Devinsky was in medical school in the early 1980s, he was attracted to studying the brain in all its magnificent complexity and subtlety. But he wasn't sure he wanted to be a neurologist, doctors with the reputation of not actually doing much for patients. "In neurology, you'd see strokes, MS, brain tumors and migraine," he recalls. "You pontificated about whether the problem was in the brain, but in those days there wasn't much you could do for them." Then he discovered epilepsy, a disease that provides "a window into the mind." The study of epilepsy drove many of the earliest discoveries about how the brain was organized. But just as important to him, it was a disease doctors could actually treat, and go home at the end of the day having made someone better. Since 1989 he has run one of the largest epilepsy centers in the country, at NYU Langone Medical Center; he is the author of the definitive guide for patients, "Epilepsy," a cofounder of the Web site epilepsy.com and of the Epilepsy Therapy Project annd founder of an organization called FACES (Finding a Cure for Epilepsy and Seizures) that promotes research into new treatments.
Epilepsy is a uniquely human disorder, like psychosis, with which it used to be confused, or demonic possession, another now discredited diagnosis. Depending on the part of the brain affected, seizures can produce hallucinations, anxiety, feelings of religious ecstasy or bizarre psychological tics such as "hyperfamiliarity," a delusional sense that you're already acquainted with everyone you meet. Most often, though, they fall in a well-documented spectrum of mental and somatic anomalies, from the transient episodes of decreased awareness known as absence (formerly called "petit mal") to the tonic-clonic (or "grand mal") attack characterized by loss of consciousness, collapse and spasmodic stiffening and jerking. There is some debate about the long-term risk from repeated seizures; Devinsky maintains they can result in irreversible damage to the brain; some other researchers are less sure. But it's certain that uncontrolled seizures are associated with the risk of lasting memory problems, cognitive deficits, personality changes—and death.
Seizures can be triggered by a baffling array of stimuli, as blatant as a flashing strobe light or as subtle as, literally, thought. There are credible reports of people whose seizures were brought on by doing arithmetic, or by playing mah-jongg, or the sound of the TV personality Mary Hart's voice on television. The neurologist and author Oliver Sacks ("The Man Who Mistook His Wife for a Hat") described a woman, who was also a patient of Devinsky's, who would go into seizures at the sound of Neapolitan music. (Rx: Move to Sicily.) Patients sometimes use this knowledge to their advantage; one woman who never had more than one seizure a day induced one intentionally on the morning of her wedding day, so she could get through the ceremony on her feet. Alcohol, drugs, emotional stress and sleep deprivation are common triggers for seizures. Jet lag, a minor inconvenience for most people, can be catastrophic for someone with epilepsy. In earlier eras, people believed that seizures were influenced by the phases of the moon, something Devinsky doesn't dismiss out of hand. If the tides can feel the moon's gravity, why not the brain?
The brain, of course, is unique among the organs of the body both in its susceptibility to outside stimuli, and the variety of things that can go wrong with it. By contrast, a heart can fail in only so many ways. Conceptually, the job of the cardiologist is straightforward: he needs to restore a damaged heart to its normal rhythm. But epilepsy is the opposite. A normal brain is governed by chaos; neurons fire unpredictably, following laws no computer, let alone neurologist, could hope to understand, even if they can recognize it on an EEG. It is what we call consciousness, perhaps the most mathematically complex phenomenon in the universe. The definition of a seizure is the absence of chaos, supplanted by a simple rhythmic pattern that carries almost no information. It may arise locally (a "partial" seizure), perhaps at the site of an old injury, a tumor or a structural malformation. A network of neurons begin firing in unison, enlisting their fellows in a synchronous wave that ripples across the brain. Or it may begin everywhere at once ("generalized" epilepsy), with an imbalance of ions across the cell membrane, usually the result of an inherited mutation. At a chemical signal, whose origin is still a mystery, billions of neurons drop the mundane business of running the body and join in a primitive drumbeat, drowning out the murmur of consciousness. And so in contrast to the cardiologist, the epilepsy doctor must attempt to restore not order, but chaos.
Seizures can be fatal, especially the rare status epilepticus, a continuous convulsion lasting longer than 10 minutes. One of Devinsky's patients is a teenage boy who showed up at the hospital in December with status epilepticus of unknown origin, although Devinsky suspects a brain lesion from an undiagnosed infection. The only way to stop his convulsions was to induce a coma, and he has been in one ever since. Devinsky keeps looking for the right combination of drugs to save his life. Occasionally people with epilepsy will go to bed at night, apparently healthy, and die in their sleep; the autopsy may be inconclusive and the death is chalked up to SUDEP—Sudden Unexplained Death in Epilepsy. Among patients with refractory seizures—ones that can't be controlled with medication—the risk factor for SUDEP is a little less than 1 percent a year—small, but not negligible. Some of these patients may be candidates for surgery. But in general Devinsky spends more time thinking about the quality of a patient's life than the length of it. "Imagine you come to see me after a single seizure, just one," he says. "I examine you and do an EEG, an MRI and everything looks good, so I say, you're in luck, there's only a 20 percent chance you'll have another one." That is roughly the same risk a middle-aged man or woman runs of having a second heart attack within five years of the first. "But that could affect your life tremendously. Say you're a truckdriver, or a surgeon. Or if you're a commercial pilot—well, that's done." The biggest quality-of-life issue for most people with seizure disorders is driving; every state restricts, to varying degrees, the licenses of people who have had seizures. Most require them to be seizure-free for a certain number of months or years before restoring driving privileges—but only six require doctors to report seizures, so presumably a lot of people are getting away with it. "You say, 20 percent, that's terrible, I want you to tell me I won't have another one. And I can't. And then if you have two, your chance of a third goes up to 70 or 80 percent."
By Jerry Adler and Eliza Gray | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
The worst thing about the epileptic seizure Dan Wheeless suffered on the first day of eighth grade wasn't dropping to the floor in the hallway and awakening with no memory of how he got there. It wasn't even being kicked to get up by his classmates, who thought his collapse and jerking were an act; like, say, piloting a fighter jet, being known as the class clown holds uncommon risk for people with a seizure disorder. The worst thing was how the drugs he took made his brain slow down, so that processing auditory information became painfully difficult. He had to write down what was said to him, break it into clauses and concentrate on the meaning of each one. "Sometimes my mom would have to say something to me five times before I could understand it," he recalls. Switching medications after several months improved his cognitive problems, but the new drugs caused lethargy and weight gain, which disappeared only when a new doctor, Orrin Devinsky of New York University, figured out the right regimen for him. "He saved my life," says Wheeless, who was back to see Devinsky recently at his office in Manhattan. Wheeless, a handsome, strapping 32-year-old, went on to graduate from the University of North Carolina, marry an actress and begin a career in the theater. It may be an overstatement that Devinsky saved his life, because doctors can't predict who will die from epilepsy—although Wheeless, who estimates he has had 50 major seizures in his life and countless smaller ones, was certainly a candidate. Devinsky couldn't even save Wheeless's front teeth, all of which had to be replaced after he broke them falling down with seizures. But it is safe to say that Devinsky saved his mind.
When Devinsky was in medical school in the early 1980s, he was attracted to studying the brain in all its magnificent complexity and subtlety. But he wasn't sure he wanted to be a neurologist, doctors with the reputation of not actually doing much for patients. "In neurology, you'd see strokes, MS, brain tumors and migraine," he recalls. "You pontificated about whether the problem was in the brain, but in those days there wasn't much you could do for them." Then he discovered epilepsy, a disease that provides "a window into the mind." The study of epilepsy drove many of the earliest discoveries about how the brain was organized. But just as important to him, it was a disease doctors could actually treat, and go home at the end of the day having made someone better. Since 1989 he has run one of the largest epilepsy centers in the country, at NYU Langone Medical Center; he is the author of the definitive guide for patients, "Epilepsy," a cofounder of the Web site epilepsy.com and of the Epilepsy Therapy Project annd founder of an organization called FACES (Finding a Cure for Epilepsy and Seizures) that promotes research into new treatments.
Epilepsy is a uniquely human disorder, like psychosis, with which it used to be confused, or demonic possession, another now discredited diagnosis. Depending on the part of the brain affected, seizures can produce hallucinations, anxiety, feelings of religious ecstasy or bizarre psychological tics such as "hyperfamiliarity," a delusional sense that you're already acquainted with everyone you meet. Most often, though, they fall in a well-documented spectrum of mental and somatic anomalies, from the transient episodes of decreased awareness known as absence (formerly called "petit mal") to the tonic-clonic (or "grand mal") attack characterized by loss of consciousness, collapse and spasmodic stiffening and jerking. There is some debate about the long-term risk from repeated seizures; Devinsky maintains they can result in irreversible damage to the brain; some other researchers are less sure. But it's certain that uncontrolled seizures are associated with the risk of lasting memory problems, cognitive deficits, personality changes—and death.
Seizures can be triggered by a baffling array of stimuli, as blatant as a flashing strobe light or as subtle as, literally, thought. There are credible reports of people whose seizures were brought on by doing arithmetic, or by playing mah-jongg, or the sound of the TV personality Mary Hart's voice on television. The neurologist and author Oliver Sacks ("The Man Who Mistook His Wife for a Hat") described a woman, who was also a patient of Devinsky's, who would go into seizures at the sound of Neapolitan music. (Rx: Move to Sicily.) Patients sometimes use this knowledge to their advantage; one woman who never had more than one seizure a day induced one intentionally on the morning of her wedding day, so she could get through the ceremony on her feet. Alcohol, drugs, emotional stress and sleep deprivation are common triggers for seizures. Jet lag, a minor inconvenience for most people, can be catastrophic for someone with epilepsy. In earlier eras, people believed that seizures were influenced by the phases of the moon, something Devinsky doesn't dismiss out of hand. If the tides can feel the moon's gravity, why not the brain?
The brain, of course, is unique among the organs of the body both in its susceptibility to outside stimuli, and the variety of things that can go wrong with it. By contrast, a heart can fail in only so many ways. Conceptually, the job of the cardiologist is straightforward: he needs to restore a damaged heart to its normal rhythm. But epilepsy is the opposite. A normal brain is governed by chaos; neurons fire unpredictably, following laws no computer, let alone neurologist, could hope to understand, even if they can recognize it on an EEG. It is what we call consciousness, perhaps the most mathematically complex phenomenon in the universe. The definition of a seizure is the absence of chaos, supplanted by a simple rhythmic pattern that carries almost no information. It may arise locally (a "partial" seizure), perhaps at the site of an old injury, a tumor or a structural malformation. A network of neurons begin firing in unison, enlisting their fellows in a synchronous wave that ripples across the brain. Or it may begin everywhere at once ("generalized" epilepsy), with an imbalance of ions across the cell membrane, usually the result of an inherited mutation. At a chemical signal, whose origin is still a mystery, billions of neurons drop the mundane business of running the body and join in a primitive drumbeat, drowning out the murmur of consciousness. And so in contrast to the cardiologist, the epilepsy doctor must attempt to restore not order, but chaos.
Seizures can be fatal, especially the rare status epilepticus, a continuous convulsion lasting longer than 10 minutes. One of Devinsky's patients is a teenage boy who showed up at the hospital in December with status epilepticus of unknown origin, although Devinsky suspects a brain lesion from an undiagnosed infection. The only way to stop his convulsions was to induce a coma, and he has been in one ever since. Devinsky keeps looking for the right combination of drugs to save his life. Occasionally people with epilepsy will go to bed at night, apparently healthy, and die in their sleep; the autopsy may be inconclusive and the death is chalked up to SUDEP—Sudden Unexplained Death in Epilepsy. Among patients with refractory seizures—ones that can't be controlled with medication—the risk factor for SUDEP is a little less than 1 percent a year—small, but not negligible. Some of these patients may be candidates for surgery. But in general Devinsky spends more time thinking about the quality of a patient's life than the length of it. "Imagine you come to see me after a single seizure, just one," he says. "I examine you and do an EEG, an MRI and everything looks good, so I say, you're in luck, there's only a 20 percent chance you'll have another one." That is roughly the same risk a middle-aged man or woman runs of having a second heart attack within five years of the first. "But that could affect your life tremendously. Say you're a truckdriver, or a surgeon. Or if you're a commercial pilot—well, that's done." The biggest quality-of-life issue for most people with seizure disorders is driving; every state restricts, to varying degrees, the licenses of people who have had seizures. Most require them to be seizure-free for a certain number of months or years before restoring driving privileges—but only six require doctors to report seizures, so presumably a lot of people are getting away with it. "You say, 20 percent, that's terrible, I want you to tell me I won't have another one. And I can't. And then if you have two, your chance of a third goes up to 70 or 80 percent."
A STORM IN THE BRAIN
A STORM IN THE BRAIN
The toll of epilepsy has been overlooked—and the research underfunded—for too long. A call to action.
By Jon Meacham | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
The statistics are stark and sobering— and for the uninitiated (which is to say most of us), startling. Epilepsy in America is as common as breast cancer, and takes as many lives. A mysterious and widely misunderstood affliction, epilepsy is a disorder in which the brain produces sudden bursts of electrical energy that can interfere with a person's consciousness, movements or sensations. Up to 50,000 Americans die each year from seizures and related causes, including drownings and other accidents; one in 10 people will suffer a seizure in their lifetimes. By some estimates, the mortality rate for people with epilepsy is two to three times higher—and the risk of sudden death is 24 times greater—than that of the general population. There are 200,000 new cases each year, and a total of more than 3 million Americans are affected by it—more than multiple sclerosis, cerebral palsy, muscular dystrophy and Parkinson's disease combined. Between 1 and 3 percent of the population will develop some form of epilepsy before age 75.
There is also a rise expected in the incidence of epilepsy among the veterans of the wars in Afghanistan and Iraq who have sustained traumatic head injuries. Yet public and private funding for research lag far behind other neurological afflictions, at $35 a patient (compared, for instance, with $129 for Alzheimer's and $280 for multiple sclerosis). It is time to remedy that gap, and to raise epilepsy to the front ranks of public and medical concern.
There is cause for hope. Science is unraveling more and more of the mysteries of the brain, and perhaps the source of the cataclysmic electrical storms of epilepsy will yield its secrets. Such, at least, is the aim of Sen. Edward M. Kennedy, who is considering a major bill to support enhanced research that will fund more work toward a cure, and of a resolute band of advocates that includes thhe man who sits nearest the Oval Office in the West Wing. White House senior adviser David Axelrod and his wife, Susan, are the parents of Lauren, a 27-year-old who began suffering seizures when she was 7 months old. Mrs. Axelrod, who contributes a piece in the following pages, is a founding board member and president of CURE—Citizens United for Research in Epilepsy. The group's mission is clear from the acronym: to learn everything we can about epilepsy in search of a cure.
Epilepsy is an ancient brain disorder, and different cultures at different times have veered between considering it a disease or thinking of it as a sign of demonic possession. Around 400 B.C., Hippocrates defined it as a physical, not a spirit, affliction, writing of what was then called "the Sacred Disease": "It appears to me to be nowise more divine nor more sacred than other diseases, but has a natural cause like other affections." Julius Caesar suffered from it; Jesus cured people with epilepsy in Gospel accounts of his ministry. The word itself is derived from the Latin epilepsia, which means "to take hold of." In 1604, Shakespeare has Othello suffer a kind of seizure as Iago works him into a frenzy of jealousy: "My lord is fall'n into an epilepsy," Iago tells Cassius. Seizures played a role in convicting suspected witches through the ages. Well into the 20th century, some states had sterilization laws that applied to people with epilepsy, and several more forbade those with epilepsy from marrying. In 1956, Roscoe L. Barrow and Howard D. Fabing published "Epilepsy and the Law: A Proposal for Legal Reform in the Light of Medical Progress," a book that helped lead to the repeal of many sterilization and antimarriage laws.
Though the most overt examples of discrimination and demonization have faded with time, epilepsy still receives too little attention, either from the medical community or the public at large. Why? One reason is that advances in drug treatments have created the popular impression that epilepsy is now an essentially manageable condition. (Which, for two thirds of patients, it is. But that still leaves a third for whom it is not.) It is thought to be rarely fatal, controllable by medication.
There is a terrible irony here: because most people with epilepsy are not in a constant state of seizure—they are, rather, in perpetual but quiet danger—their condition can appear less serious than it truly is. It is all too human, but all too true, that a problem, including the problem of a serious medical affliction, stays out of mind when it is out of sight.
Because so many of those who must endure it do so valiantly, and with grace and grit, it is more difficult for those not directly affected by it to grasp that epilepsy can kill. Put harshly, we need more of a cancerlike sensibility around epilepsy. We cannot usually see our friends' cancer, but we do not hesitate to invest the search for a cure for different cancers with the utmost cultural and political importance. We must now do the same with epilepsy. "We want complete freedom from seizures," says Susan Axelrod. "We want future families to be spared what so many other families, for so many years, have endured. Lives should not be defined by diseases." No, they should not—which is why all of us must focus on understanding epilepsy. And then we must defeat it.
The toll of epilepsy has been overlooked—and the research underfunded—for too long. A call to action.
By Jon Meacham | NEWSWEEK
Published Apr 11, 2009
From the magazine issue dated Apr 20, 2009
The statistics are stark and sobering— and for the uninitiated (which is to say most of us), startling. Epilepsy in America is as common as breast cancer, and takes as many lives. A mysterious and widely misunderstood affliction, epilepsy is a disorder in which the brain produces sudden bursts of electrical energy that can interfere with a person's consciousness, movements or sensations. Up to 50,000 Americans die each year from seizures and related causes, including drownings and other accidents; one in 10 people will suffer a seizure in their lifetimes. By some estimates, the mortality rate for people with epilepsy is two to three times higher—and the risk of sudden death is 24 times greater—than that of the general population. There are 200,000 new cases each year, and a total of more than 3 million Americans are affected by it—more than multiple sclerosis, cerebral palsy, muscular dystrophy and Parkinson's disease combined. Between 1 and 3 percent of the population will develop some form of epilepsy before age 75.
There is also a rise expected in the incidence of epilepsy among the veterans of the wars in Afghanistan and Iraq who have sustained traumatic head injuries. Yet public and private funding for research lag far behind other neurological afflictions, at $35 a patient (compared, for instance, with $129 for Alzheimer's and $280 for multiple sclerosis). It is time to remedy that gap, and to raise epilepsy to the front ranks of public and medical concern.
There is cause for hope. Science is unraveling more and more of the mysteries of the brain, and perhaps the source of the cataclysmic electrical storms of epilepsy will yield its secrets. Such, at least, is the aim of Sen. Edward M. Kennedy, who is considering a major bill to support enhanced research that will fund more work toward a cure, and of a resolute band of advocates that includes thhe man who sits nearest the Oval Office in the West Wing. White House senior adviser David Axelrod and his wife, Susan, are the parents of Lauren, a 27-year-old who began suffering seizures when she was 7 months old. Mrs. Axelrod, who contributes a piece in the following pages, is a founding board member and president of CURE—Citizens United for Research in Epilepsy. The group's mission is clear from the acronym: to learn everything we can about epilepsy in search of a cure.
Epilepsy is an ancient brain disorder, and different cultures at different times have veered between considering it a disease or thinking of it as a sign of demonic possession. Around 400 B.C., Hippocrates defined it as a physical, not a spirit, affliction, writing of what was then called "the Sacred Disease": "It appears to me to be nowise more divine nor more sacred than other diseases, but has a natural cause like other affections." Julius Caesar suffered from it; Jesus cured people with epilepsy in Gospel accounts of his ministry. The word itself is derived from the Latin epilepsia, which means "to take hold of." In 1604, Shakespeare has Othello suffer a kind of seizure as Iago works him into a frenzy of jealousy: "My lord is fall'n into an epilepsy," Iago tells Cassius. Seizures played a role in convicting suspected witches through the ages. Well into the 20th century, some states had sterilization laws that applied to people with epilepsy, and several more forbade those with epilepsy from marrying. In 1956, Roscoe L. Barrow and Howard D. Fabing published "Epilepsy and the Law: A Proposal for Legal Reform in the Light of Medical Progress," a book that helped lead to the repeal of many sterilization and antimarriage laws.
Though the most overt examples of discrimination and demonization have faded with time, epilepsy still receives too little attention, either from the medical community or the public at large. Why? One reason is that advances in drug treatments have created the popular impression that epilepsy is now an essentially manageable condition. (Which, for two thirds of patients, it is. But that still leaves a third for whom it is not.) It is thought to be rarely fatal, controllable by medication.
There is a terrible irony here: because most people with epilepsy are not in a constant state of seizure—they are, rather, in perpetual but quiet danger—their condition can appear less serious than it truly is. It is all too human, but all too true, that a problem, including the problem of a serious medical affliction, stays out of mind when it is out of sight.
Because so many of those who must endure it do so valiantly, and with grace and grit, it is more difficult for those not directly affected by it to grasp that epilepsy can kill. Put harshly, we need more of a cancerlike sensibility around epilepsy. We cannot usually see our friends' cancer, but we do not hesitate to invest the search for a cure for different cancers with the utmost cultural and political importance. We must now do the same with epilepsy. "We want complete freedom from seizures," says Susan Axelrod. "We want future families to be spared what so many other families, for so many years, have endured. Lives should not be defined by diseases." No, they should not—which is why all of us must focus on understanding epilepsy. And then we must defeat it.
Wednesday, October 14, 2009
Certain Colours More Likely To Cause Epileptic Fits
Researchers have discovered that epileptic brains are more ordered than non-epileptic ones and also that certain flicking colours seem more likely to cause fits.
In 1997, more than seven hundred children in Japan suffered an epileptic attack while watching an episode of Pokemon cartoon. This was later diagnosed as a case of photosensitive epilepsy (a kind of epilepsy caused by visual stimulus) triggered by a specific segment of the cartoon containing a colourful flickering stimulus. Recently in 2007, the animated video footage promoting the 2012 London Olympics faced similar complaint from the viewers.
Because of the widespread usages of television and video games, it is important to detect the crucial visual parameters in triggering an epileptic attack. Common guidelines are available on specific visual parameters of the stimuli like spatial/temporal frequency, stimulus contrast, patterns etc. However, despite the ubiquitous presence of colourful displays and materials, very little is known about the relationship between colour-combinations (chromaticity) and photosensitivity. Further it is also not precisely known how the patients' brain responses differ from healthy brains against such colourful stimuli.
In a study published in the PLoS ONE on September 25, researchers led by Joydeep Bhattacharya at Goldsmiths, University of London, investigated brain rhythms of photosensitivity against combinational chromatic flickering in nine adult controls, an unmedicated patient suffering from photosensitive epilepsy, two age-matched controls, and another medicated patient.
Their results show that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly a chaotic state with a high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further their study has found how complexities underlying brain dynamics could be modulated by certain colour combinations more than the other, for example, red-blue flickering stimulus causes larger cortical excitation than red-green or blue-green stimulus.
Dr. Bhattacharya said, "These findings support the 'decomplexification hypothesis': a healthy brain is more 'complex' than a pathological brain."
However, he added, "It is important to extend the research with larger number of patients to find at what extent these statistical and complexity measures applied in the present paper would have diagnostic potential."
In 1997, more than seven hundred children in Japan suffered an epileptic attack while watching an episode of Pokemon cartoon. This was later diagnosed as a case of photosensitive epilepsy (a kind of epilepsy caused by visual stimulus) triggered by a specific segment of the cartoon containing a colourful flickering stimulus. Recently in 2007, the animated video footage promoting the 2012 London Olympics faced similar complaint from the viewers.
Because of the widespread usages of television and video games, it is important to detect the crucial visual parameters in triggering an epileptic attack. Common guidelines are available on specific visual parameters of the stimuli like spatial/temporal frequency, stimulus contrast, patterns etc. However, despite the ubiquitous presence of colourful displays and materials, very little is known about the relationship between colour-combinations (chromaticity) and photosensitivity. Further it is also not precisely known how the patients' brain responses differ from healthy brains against such colourful stimuli.
In a study published in the PLoS ONE on September 25, researchers led by Joydeep Bhattacharya at Goldsmiths, University of London, investigated brain rhythms of photosensitivity against combinational chromatic flickering in nine adult controls, an unmedicated patient suffering from photosensitive epilepsy, two age-matched controls, and another medicated patient.
Their results show that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly a chaotic state with a high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further their study has found how complexities underlying brain dynamics could be modulated by certain colour combinations more than the other, for example, red-blue flickering stimulus causes larger cortical excitation than red-green or blue-green stimulus.
Dr. Bhattacharya said, "These findings support the 'decomplexification hypothesis': a healthy brain is more 'complex' than a pathological brain."
However, he added, "It is important to extend the research with larger number of patients to find at what extent these statistical and complexity measures applied in the present paper would have diagnostic potential."
Sunday, October 11, 2009
Some Mysteries of Neonatal Seizures Solved in a Study at MassGeneral Hospital for Children
New insights into the mechanism of neonatal seizures, which have features very different from seizures in older children
and adults has been provided in a study
led by MassGeneral Hospital for Children (MGHfC) investigators.
In their report in the Sept. 10 issue of Neuron, the researchers describe finding how neurons in different parts of the brains of newborn mammals respond differently to the neurotransmitter GABA, an observation that may explain why seizure activity in the neonatal brain often does not produce visible convulsions and why the common antiseizure drug phenobarbital can exacerbate the invisible nature of neonatal seizures.
"The incidence of seizures is higher in the newborn period than at any other stage of life," says Kevin Staley, MD, MGHfC chief of Neurology, senior author of the Neuron paper. "This is a time of transition when brain cells begin to switch the way they respond to the neurotransmitter GABA, which increases the activity of immature brain cells but decreases the activity of mature cells. Many of our most powerful seizure medicines work by enhancing the action of GABA, but this treatment may backfire for brain cells that have not yet made that transition."
GABA acts by mediating the flow of chloride ions into and out of neurons, and previous research has shown that neurons in structures deep within the developing mammalian brain change the expression of proteins that pump ions in or out of cells at an earlier stage than do neurons in the neocortex, the outer part of the brain that matures last and where seizures originate. The current study was designed to investigate whether the different expression of chloride pumps in specific regions of the brain might explain why newborns often have seizures not accompanied by convulsions.
The researchers first confirmed in newborn mice that chloride levels in deep-brain structures like the thalamus are much lower than cortical levels, a difference that decreases as the animals mature and cortical chloride levels drop. They then showed that GABA inhibits the activity of thalamic neurons but stimulates cortical neurons in neonatal rats, a difference that was enhanced by the induction of seizures.
Treatment with phenobarbital suppressed seizure activity in subcortical structures but not in the neocortex. That finding could explain the suppression of convulsions, which require the passage of seizure signals from the cortex through subcortical structures and out to the muscles, while a cortical seizure persists. Adding the diuretic bumetanide, which blocks the chloride pump responsible for immature neurons' excitatory response to GABA, to phenobarbital treatment successfully suppressed seizure activity in both cortical and subcortical regions.
"Our study provides a logical mechanism for the clinical invisibility of many neonatal seizures, information that may help determine the best way to monitor newborns with brain injuries for seizures and select the best strategies for anticonvulsant treatment," Staley explains. "For example, by blocking the protein responsible for immature brain cells' excitatory response to GABA, bumetanide essentially converts that immature response to a mature response and allows antiseizure medicines to work properly. We are excited to be participating in a trial of bumetanide as an adjunctive treatment of neonatal seizures currently being carried out in collaboration with colleagues at Childrens Hospital Boston and Brigham and Women's Hospital."
and adults has been provided in a study
led by MassGeneral Hospital for Children (MGHfC) investigators.
In their report in the Sept. 10 issue of Neuron, the researchers describe finding how neurons in different parts of the brains of newborn mammals respond differently to the neurotransmitter GABA, an observation that may explain why seizure activity in the neonatal brain often does not produce visible convulsions and why the common antiseizure drug phenobarbital can exacerbate the invisible nature of neonatal seizures.
"The incidence of seizures is higher in the newborn period than at any other stage of life," says Kevin Staley, MD, MGHfC chief of Neurology, senior author of the Neuron paper. "This is a time of transition when brain cells begin to switch the way they respond to the neurotransmitter GABA, which increases the activity of immature brain cells but decreases the activity of mature cells. Many of our most powerful seizure medicines work by enhancing the action of GABA, but this treatment may backfire for brain cells that have not yet made that transition."
GABA acts by mediating the flow of chloride ions into and out of neurons, and previous research has shown that neurons in structures deep within the developing mammalian brain change the expression of proteins that pump ions in or out of cells at an earlier stage than do neurons in the neocortex, the outer part of the brain that matures last and where seizures originate. The current study was designed to investigate whether the different expression of chloride pumps in specific regions of the brain might explain why newborns often have seizures not accompanied by convulsions.
The researchers first confirmed in newborn mice that chloride levels in deep-brain structures like the thalamus are much lower than cortical levels, a difference that decreases as the animals mature and cortical chloride levels drop. They then showed that GABA inhibits the activity of thalamic neurons but stimulates cortical neurons in neonatal rats, a difference that was enhanced by the induction of seizures.
Treatment with phenobarbital suppressed seizure activity in subcortical structures but not in the neocortex. That finding could explain the suppression of convulsions, which require the passage of seizure signals from the cortex through subcortical structures and out to the muscles, while a cortical seizure persists. Adding the diuretic bumetanide, which blocks the chloride pump responsible for immature neurons' excitatory response to GABA, to phenobarbital treatment successfully suppressed seizure activity in both cortical and subcortical regions.
"Our study provides a logical mechanism for the clinical invisibility of many neonatal seizures, information that may help determine the best way to monitor newborns with brain injuries for seizures and select the best strategies for anticonvulsant treatment," Staley explains. "For example, by blocking the protein responsible for immature brain cells' excitatory response to GABA, bumetanide essentially converts that immature response to a mature response and allows antiseizure medicines to work properly. We are excited to be participating in a trial of bumetanide as an adjunctive treatment of neonatal seizures currently being carried out in collaboration with colleagues at Childrens Hospital Boston and Brigham and Women's Hospital."
Wednesday, October 7, 2009
Diet May Eliminate Spasms For Infants With Epilepsy
Infantile spasms are a severe and potentially devastating epilepsy condition affecting children aged typically 4-8 months. In a new study appearing in Epilepsia, researchers have found that the ketogenic diet, a high fat, low carbohydrate diet more traditionally used for intractable childhood epilepsy, is an effective treatment for this condition before using drugs.
The study is the first description of the ketogenic diet as a first-line therapy for infantile spasms.
ACTH and vigabatrin, medications that are the commonly-used first treatments worldwide, can have potentially-serious side effects such as hypertension, gastric ulceration, cortical atrophy, and visual field constriction. ACTH, though it is effective in 60-70 percent of cases, also costs more than $80,000 for a one-month supply and vigabatrin is not currently available in the U.S. Both drugs have about a 30-40 percent recurrence rate of spasms as well. Other therapies are not yet proven.
"We decided to review our experience at Johns Hopkins using the ketogenic diet to treat infantile spasms before medications were tried and compare this to our use of ACTH over the same time period," says Eric Kossoff, M.D, a pediatric neurologist at Johns Hopkins Hospital and lead author of the study. "We knew that the ketogenic diet worked well for difficult-to-control infantile spasms, so we thought it would also be effective earlier."
If the diet stopped the spasms, infants were kept on it for usually 6 months. The diet worked in 8-of-13 infants within approximately one week. Only 1-of-8 had recurring spasms, and that infant was controlled again with the addition of topiramate to the diet. Side effects were fewer than ACTH in this series and the recurrence rate was also lower with the diet. In the 5 patients in which the diet did not work, ACTH was started immediately; it worked quickly in 4 of the 5 infants. ACTH did lead to a normal EEG quicker, but long-term developmental outcomes were identical.
As a result of the findings, the ketogenic diet is now one of the typically-offered first-line therapies for new-onset infantile spasms at Johns Hopkins. Other hospitals are beginning to use the ketogenic diet similarly. The researchers hope this novel use of the ketogenic diet may be the first step in finding another treatment to control new-onset infantile spasms.
The study is the first description of the ketogenic diet as a first-line therapy for infantile spasms.
ACTH and vigabatrin, medications that are the commonly-used first treatments worldwide, can have potentially-serious side effects such as hypertension, gastric ulceration, cortical atrophy, and visual field constriction. ACTH, though it is effective in 60-70 percent of cases, also costs more than $80,000 for a one-month supply and vigabatrin is not currently available in the U.S. Both drugs have about a 30-40 percent recurrence rate of spasms as well. Other therapies are not yet proven.
"We decided to review our experience at Johns Hopkins using the ketogenic diet to treat infantile spasms before medications were tried and compare this to our use of ACTH over the same time period," says Eric Kossoff, M.D, a pediatric neurologist at Johns Hopkins Hospital and lead author of the study. "We knew that the ketogenic diet worked well for difficult-to-control infantile spasms, so we thought it would also be effective earlier."
If the diet stopped the spasms, infants were kept on it for usually 6 months. The diet worked in 8-of-13 infants within approximately one week. Only 1-of-8 had recurring spasms, and that infant was controlled again with the addition of topiramate to the diet. Side effects were fewer than ACTH in this series and the recurrence rate was also lower with the diet. In the 5 patients in which the diet did not work, ACTH was started immediately; it worked quickly in 4 of the 5 infants. ACTH did lead to a normal EEG quicker, but long-term developmental outcomes were identical.
As a result of the findings, the ketogenic diet is now one of the typically-offered first-line therapies for new-onset infantile spasms at Johns Hopkins. Other hospitals are beginning to use the ketogenic diet similarly. The researchers hope this novel use of the ketogenic diet may be the first step in finding another treatment to control new-onset infantile spasms.
Controversial Medication May Decrease Spasms For Infants With Epilepsy
ScienceDaily (Feb. 3, 2009) — The antiepileptic drug vigabatrin (VGB) has been shown to be one of the best treatments against a special form of epilepsy in infants, called infantile spasm. However, its use has been limited in many countries because it has been shown to cause a permanent narrowing of visual fields in approximately 40percent of adults who have been exposed at school age or later.
A new study published in Epilepsia examined school-aged children who had been treated with VGB in infancy. The findings showed normal visual fields in 15 of the 16 children studied children.
While VGB is an effective drug for infantile spasms, there have been no previous reports on later visual field testing after treatment in infancy. This study used a form of peripheral vision testing, called kinetic perimetry, which is effective in detecting peripheral field defects typical of VGB toxicity, and produces more reliable results in children.
Vigabatrin treatment began at a mean age of 7.6 months, and the mean duration of therapy was 21 months, with a mean cumulative dose of 655 grams. Three of the children had been previously treated with another anti-epileptic drug (AED), five had received only hormonal treatment, and eight children had never been treated with any form of AED.
The findings show that the risk of permanent visual field defects caused by VGB may be lower for treatments in infants than in adults. Results showed that 15 children had normal visual fields and mild visual field loss was observed in one child who had been treated with VGB for 19 months and received a cumulative dose of 572 grams. This frequency is lower than previous observations using kinetic perimetry in older children or adults.
The cumulative VGB doses and treatment durations in the study were, on average, lower than in previous studies, which correspond to the much younger age and weight of the tested patients.
“Our results may encourage doctors to use vigabatrin to treat infantile spasms as the risk for visual field damage may be relatively low in many children compared to
the risks caused by continuous seizures,” says Dr. Eija Gaily, co-author of the study.
Visual field testing can be carried out in normally developed children from the age of six years. It is important to note that not all children with normal fields manifest normal results at the first visual field testing because good cooperation and attention are required in order to get reliable results. All abnormal findings in children should always be confirmed by repeating the test.
A new study published in Epilepsia examined school-aged children who had been treated with VGB in infancy. The findings showed normal visual fields in 15 of the 16 children studied children.
While VGB is an effective drug for infantile spasms, there have been no previous reports on later visual field testing after treatment in infancy. This study used a form of peripheral vision testing, called kinetic perimetry, which is effective in detecting peripheral field defects typical of VGB toxicity, and produces more reliable results in children.
Vigabatrin treatment began at a mean age of 7.6 months, and the mean duration of therapy was 21 months, with a mean cumulative dose of 655 grams. Three of the children had been previously treated with another anti-epileptic drug (AED), five had received only hormonal treatment, and eight children had never been treated with any form of AED.
The findings show that the risk of permanent visual field defects caused by VGB may be lower for treatments in infants than in adults. Results showed that 15 children had normal visual fields and mild visual field loss was observed in one child who had been treated with VGB for 19 months and received a cumulative dose of 572 grams. This frequency is lower than previous observations using kinetic perimetry in older children or adults.
The cumulative VGB doses and treatment durations in the study were, on average, lower than in previous studies, which correspond to the much younger age and weight of the tested patients.
“Our results may encourage doctors to use vigabatrin to treat infantile spasms as the risk for visual field damage may be relatively low in many children compared to
the risks caused by continuous seizures,” says Dr. Eija Gaily, co-author of the study.
Visual field testing can be carried out in normally developed children from the age of six years. It is important to note that not all children with normal fields manifest normal results at the first visual field testing because good cooperation and attention are required in order to get reliable results. All abnormal findings in children should always be confirmed by repeating the test.
Monday, October 5, 2009
Diagnosing Infantile Spasm
Although the epileptogenic mechanisms of infantile spasms is not well understood, an etiologic diagnosis can be identified in more than 70% of cases (4, 5), which may lead to a specific therapy that can have a dramatic influence on the outcome of the patient. It is, therefore, essential that an appropriate diagnostic evaluation be performed in every patient. Because infantile spasms has such characteristic clinical and electrographic features, it is easy to make the diagnosis if the epileptic nature of the spells is recognized. However, sometimes the spasms are subtle enough that the syndrome is not even considered.
Three key factors lead to the diagnosis. The first factor is age. Infantile spasms is a disorder of the developing nervous system and the spasms typically begin in the first year of life, most commonly between 4 and 8 months of age (6). Occasionally, they may begin in the neonatal period (7) or, rarely, much later in childhood (8). An atypical age of onset may help with etiologic diagnosis. For example, neonatal onset is associated with cortical dysplasia (9), whereas late onset (after 1 year of age) often is associated with genetic anomalies, hypoxic ischemic encephalopathy, and cortical dysplasia.
The second factor is the semiology. Clusters of flexion jerks of the neck, trunk, and extremities lasting 1–2 seconds are typical. Variations occur, such as extension of upper and lower extremities or both. Or, the spells may be very subtle, such as just a brief head drop (so-called Blitz-Nick-Krämpfe or “lightening neck spasms"), and often are misdiagnosed as a Moro reflex or simple startle reflex. In such cases, the epileptic nature of the spells may remain unappreciated for weeks or months. Although the spasms may happen as single jerk event, clusters are more common and often occur on awakening in the morning or after a nap (6). Other seizure types may arise concurrently or sequentially with infantile spasms.
The third factor is a very distinct EEG pattern. It is interesting to note that infantile spasm syndrome was not recognized as an epileptic disorder until the 1950s when Gibbs et al. described the characteristic and pathognomonic EEG abnormality called hypsarrhythmia (13). Hypsarrhythmia is a very high-voltage, disorganized pattern of EEG abnormality. A less chaotic pattern, called modified hypsarrhythmia, actually may be more common than hypsarrhythmia (14). Hypsarrhythmia or modified hypsarrhythmia is seen in about two thirds of cases. Other patterns, such as multifocal independent spike discharges (MISD), are present in the remainder. Although infantile spasms may be associated with other EEG abnormalities, hypsarrhythmia virtually never occurs in other epilepsy syndromes.Because infantile spasm seizures are frequent, it is common to capture the spells on a routine EEG, revealing the characteristic feature of electrodecrement immediately after the individual clinical spasm. If the EEG is normal, the diagnosis of infantile spasms should be reconsidered, as there are benign disorders that may appear clinically similar to infantile spasms (e.g., benign infantile myoclonus (15) or benign familial infantile convulsions.
These three factors are so distinctive that the clinical diagnosis of infantile spasms can be made with certainty in the vast majority of cases. Whereas the diagnosis of infantile spasms syndrome is usually easy, determining an etiologic diagnosis may be difficult. However, the etiologic diagnosis has such a profound impact on treatment and prognosis that an appropriate evaluation is essential in all cases.
Three key factors lead to the diagnosis. The first factor is age. Infantile spasms is a disorder of the developing nervous system and the spasms typically begin in the first year of life, most commonly between 4 and 8 months of age (6). Occasionally, they may begin in the neonatal period (7) or, rarely, much later in childhood (8). An atypical age of onset may help with etiologic diagnosis. For example, neonatal onset is associated with cortical dysplasia (9), whereas late onset (after 1 year of age) often is associated with genetic anomalies, hypoxic ischemic encephalopathy, and cortical dysplasia.
The second factor is the semiology. Clusters of flexion jerks of the neck, trunk, and extremities lasting 1–2 seconds are typical. Variations occur, such as extension of upper and lower extremities or both. Or, the spells may be very subtle, such as just a brief head drop (so-called Blitz-Nick-Krämpfe or “lightening neck spasms"), and often are misdiagnosed as a Moro reflex or simple startle reflex. In such cases, the epileptic nature of the spells may remain unappreciated for weeks or months. Although the spasms may happen as single jerk event, clusters are more common and often occur on awakening in the morning or after a nap (6). Other seizure types may arise concurrently or sequentially with infantile spasms.
The third factor is a very distinct EEG pattern. It is interesting to note that infantile spasm syndrome was not recognized as an epileptic disorder until the 1950s when Gibbs et al. described the characteristic and pathognomonic EEG abnormality called hypsarrhythmia (13). Hypsarrhythmia is a very high-voltage, disorganized pattern of EEG abnormality. A less chaotic pattern, called modified hypsarrhythmia, actually may be more common than hypsarrhythmia (14). Hypsarrhythmia or modified hypsarrhythmia is seen in about two thirds of cases. Other patterns, such as multifocal independent spike discharges (MISD), are present in the remainder. Although infantile spasms may be associated with other EEG abnormalities, hypsarrhythmia virtually never occurs in other epilepsy syndromes.Because infantile spasm seizures are frequent, it is common to capture the spells on a routine EEG, revealing the characteristic feature of electrodecrement immediately after the individual clinical spasm. If the EEG is normal, the diagnosis of infantile spasms should be reconsidered, as there are benign disorders that may appear clinically similar to infantile spasms (e.g., benign infantile myoclonus (15) or benign familial infantile convulsions.
These three factors are so distinctive that the clinical diagnosis of infantile spasms can be made with certainty in the vast majority of cases. Whereas the diagnosis of infantile spasms syndrome is usually easy, determining an etiologic diagnosis may be difficult. However, the etiologic diagnosis has such a profound impact on treatment and prognosis that an appropriate evaluation is essential in all cases.
What is Infantile Spasm?
What are Infantile Spasms?
An infantile spasm (IS) is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood known as West Syndrome. West Syndrome is characterized by infantile spasms, developmental regression, and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). The onset of infantile spasms is usually in the first year of life, typically between 4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other seizure types. Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to spasms, making it important to identify the underlying cause. In some children, no cause can be found.
Is there any treatment?
Treatment with corticosteroids such as prednisone is standard, although serious side effects can occur. Several newer antiepileptic medications, such as topiramate may ease some symptoms. Some children have spasms as the result of brain lesions, and surgical removal of these lesions may result in improvement.
What is the prognosis?
The prognosis for children with IS is dependent on the underlying causes of the seizures. The intellectual prognosis for children with IS is generally poor because many babies with IS have neurological impairment prior to the onset of spasms. Spasms usually resolve by mid-childhood, but more than half of the children with IS will develop other types of seizures. There appears to be a close relationship between IS and Lennox-Gastaut Syndrome, an epileptic disorder of later childhood.
An infantile spasm (IS) is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood known as West Syndrome. West Syndrome is characterized by infantile spasms, developmental regression, and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). The onset of infantile spasms is usually in the first year of life, typically between 4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other seizure types. Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to spasms, making it important to identify the underlying cause. In some children, no cause can be found.
Is there any treatment?
Treatment with corticosteroids such as prednisone is standard, although serious side effects can occur. Several newer antiepileptic medications, such as topiramate may ease some symptoms. Some children have spasms as the result of brain lesions, and surgical removal of these lesions may result in improvement.
What is the prognosis?
The prognosis for children with IS is dependent on the underlying causes of the seizures. The intellectual prognosis for children with IS is generally poor because many babies with IS have neurological impairment prior to the onset of spasms. Spasms usually resolve by mid-childhood, but more than half of the children with IS will develop other types of seizures. There appears to be a close relationship between IS and Lennox-Gastaut Syndrome, an epileptic disorder of later childhood.
Subscribe to:
Posts (Atom)