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EPILEPSY IN THE 21st CENTURY: INTRODUCTION
A Vision of Treatment in the New Millennium
At the dawn of a brand new century, change is in the air. New technologies, medical advances and genetic break–throughs are no longer the stuff of science fiction-we read about them almost daily in our morning newspaper. But what does the future hold for the person with epilepsy?
Epilepsy has been documented by historians for at least 3,000 years. Called "the Sacred Disease" or "the Falling Evil" by the ancients, past "treat–ments" for people with epilepsy have included exorcism, bleedings, castra–tion, as well as drinking the blood of fallen gladiators.
Even though modern epilepsy treatments have advanced considerably from these practices, they can still feel quite primitive to the patient of today. Daily doses of anti–convulsant medications can control most seizures, but these drugs can have cognitive and other side effects that are difficult to live with. Epilepsy brain surgery, our other contemporary treatment, is still a seriously invasive procedure open to very few candidates. Is there hope for better treatment for people with epilepsy in the years ahead?
Epilepsy Toronto decided to ask that question of a number of neurologists who specialize in epilepsy at its conference Epilepsy in the 21st Century: A Vision of Treatment in the New Millennium. Here is a report from that fascinating conference.
FORECASTING SEIZURES
Currently, people with epilepsy must take their anti-convulsant medication round-the-clock, every day, because we simply don't know when the next seizure is coming. But if we could predict when a seizure will occur, and get treatment directly to the brain at the right moment to prevent the seizure, epilepsy treatment could be revolutionized. Is it possible to know in advance when a seizure is going to occur?
Neurologist Dr. Richard Wennberg reported on the status of this exciting area of scientific inquiry.
Researchers now talk about "forecasting" a seizure, much like meteorologists forecast the weather. They look at the neurological system of the brain as a whole and do a "systems level analysis" using an EEG.
We know that the neurological system of the brain is composed of billions of tiny nerve cells, or neurons, which are responsible for trans–mitting, receiving and coordinating messages via electrical impulses. This is how the brain controls everything we do. Like a weather system, networks of neurons form a dynamic system of interactions and activities-a system that is not linear or predictable, but complex and chaotic.
When a person has epilepsy, these neuronal networks have a tendency to change &om their normally complex, chaotic activity to a synchronized state in which all the neurons are doing the same thing at the same time. This abnormal, synchronized firing of neurons is what creates a seizure.
According to Dr. Wennberg, the neuronal system sometimes starts to move towards a seizure, but then moves away and the seizure doesn't happen. A seizure is what systems analysts call a "sudden phase
transition"- a change from one state to another, like the moment when water changes into steam, or into ice. As a sudden phase transition, a mathematical model of a seizure can be made using "non-linear dynamic theory" (such as chaos theory).
A researcher in Germany named Christian Elgers uses complex calculations to measure the synchrony of patients' EEGs and successful–ly forecast- two minutes, five minutes, some say even 30 minutes in advance-their seizures. J.L. Perez Velazquez of Canada has used the EEG to identify the very sensitive state that characterizes the transition into or out of a seizure (called "Type III Intermittency") during which the dynamic system is most susceptible to alteration or treatment.
Obviously, before patients with uncontrolled seizures will be able to forecast their seizures using systems like these, we'll need to improve and further miniaturize our computer technology. But how will the seizures, once forecast, be prevented?
Dr. Wennberg summed up one vision of the future this way: "The person with epilepsy with uncontrolled seizures may one day be able to have a device implanted within their brain in the region that the seizures start from, hooked up to a sensor that detects when the seizure will occur and then will induce either an electrical stimuli, or the local application of a liquid drug to abort the seizure before it happens."
This sensor could be similar to a cardiac pacemaker, only it would detect that brain waves were going to synchronize and give a stimulus that would promote chaos and return the brain to its unsynchronized, non-seizure state.
"Forecasting seizures sounds like science fiction, but it's already in the planning stages and will be in the testing phases within a year or two, although not in routine use for a decade", commented Dr. Wennberg.
THE NEW MEDICATIONS AND HOW THEY WILL BE ADMINISTERED
Neurologist Dr. Jack Schneiderman reviewed an array of exciting new epilepsy medications on the horizon, some much closer to release than others.
Diastat, a new rectal formulation of valium which targets cluster seizures, will soon be released in Canada. Diastat seems quite effective. It also has the advantages of working quickly and being useful to patients who cannot take oral medication.
Trileptal is on the horizon for the treatment of partial onset seizures, and seems similar to Tegretol but with fewer drug interactions. Another new drug, Tiagabine, seems to be quite effective as an add-on therapy for partial seizures. Tiagabine increases the brain's levels of GABA (the brain's natural anti-convulsant drug), but because it may actually worsen some kinds of seizures, it must be used very carefully.
The drugs of the next generation are in various stages of development. The research is focusing on a host of new mechanisms of action and ways of delivering drugs to the brain. These drugs include ADCI and AWD 131-138 (both in early stages of development), Ganaxsolone (related to sex hormones), Levetiracetam (mainly for partial onset seizures), Losigamone (also an anti–depressant), Pregabalin (similar to Gabapentin but more potent), Remacimide (currently being tested in Canada), Reticabine (increases the production of GABA), Rufinamide, Soretolide, local anaesthetics, TV 1901 (a derivative of GABA) and DP Valproic Acid.
Dr. Schneiderman pointed out that today, our anticonvulsants are limited in their effectiveness more by side effects than by their ability to control seizures. The most important side effects are drowsiness and cognitive problems. However, some of the next generation of epilepsy drugs may actually enhance cognitive function and mood.
Taking anti-epileptic drugs orally means you have to remember to take your medication. And your body has to get the drug to the right place - the brain. Today's drugs are absorbed from the stomach or gut into the bloodstream, where they bind to proteins before passing through the liver and being broken down.
"The drug is distributed to all of the tissues, and we don't want it in all the tissues- in the kidney, liver, skin- we want it in the brain," said Dr. Schneiderman.
But the brain doesn't want the drug: in fact, the blood brain barrier (BBB) is designed to keep things out. (Even the body's own natural anti–convulsant, GABA, can't get into the brain, but has to be manufactured there). A very small percentage of medication actually gets to where it's needed. And if you have focal seizures, the drug is not needed by the whole brain, but only by one part of the brain: the seizure focus.
"If you can get drugs to limited locations in the brain in small amounts, you can virtually guarantee that the side effects are going to be very, very much less, especially the side-effects on the central nervous system."
DP Valproic Acid is an example of the next generation of drugs that uses a different mechanism of action to get around some of these problems. It wraps the anticonvulsant valproic acid in a lipid membrane to create a "bag" of the drug. The drug stays "bagged" and inactive until it meets an enzyme which opens up the vesicles and releases the valproic acid. The idea is that this enzyme is only released when the person's seizure focus becomes activated. The more activity, more valproic acid is released. Eventually, enough is released to block seizures, with the other side of the brain not getting any drug. After the seizure stops, the brain "mops up" the drug.
"It's a clever way to get drug to the right place at the right time," commented Dr. Schneiderman.
Speculating on the future, we can envision a catheter that will inject a drug (perhaps a drug that would not otherwise be able to cross the blood brain barrier) directly into the lobe of the brain having seizures. If the person's seizures do not have a single focus, the drug could be injected into the fluid-filled spaces in the centre of the brain (the ventricles). Getting the drug directly to one small area would lower the body's total drug exposure, reducing organ toxicity and drug side effects. However, this would require surgery, a reloading of the pump, and the risks of possible infection and even brain damage from the catheter
"Seizures are brief and intermittent, and we don't need the drug all the time. Only some of the time." A timed drug delivery system, where a patient who has an aura can push a button to release a drug and stop the progression of the seizure would be advanta–geous. Speculating even further down the road, Dr. Schneiderman envisioned a system similar to Dr. Wennberg's, where a sensor implanted into the brain can automatically detect a seizure, perhaps even before it starts, and inject a drug. The sensor would need to be connected to a computerized controller and a pump. It would be miniaturized so it can be implanted like a pacemaker under the skin.
"I am fully confident that it will be possible one day."
THE FUTURE OF EPILEPSY BRAIN SURGERY
Neurosurgeon Dr. Andrew Parrent performs epilepsy brain surgery today with an eye to the future. He reported on the new surgical breakthroughs for the treatment of epilepsy.
Today, people with temporal lobe epilepsy form the largest group of surgery patients. This type of epilepsy often comes from damage to structures that lie deep in the temporal lobe of the brain- structures called the hippocampus (where memory "resides") and the amygdala. Surgeons treating temporal lobe epilepsy open up the head and cut out or "resect" the "epileptic" parts of the brain, such as the outer layer of the temporal lobe, and/or the hippocampus and amygdala. Between 62 and 66% of these resection patients have favourable outcomes. The goal of surgery in the future is to reduce its side effects-such as transient or permanent speech and memory problems- as well as its discomfort, invasiveness, and the length of the hospital stay and recovery required.
A new type of surgery called "stereotactic" surgery uses a frame attached to the outside of the head to hold the head in place. An MRI scan pinpoints the affected area of the brain to within 1 millimeter. A two–inch cut is sliced just above the ear, and a hole the size of a quarter is made in the head. Through the hole is placed an electrode or probe which is heated up, and an area of the brain is cauterized or lesioned.
People who have had stereotactic surgery appear to recover sooner than patients having temporal lobe resections; they can go back to work after 10 days or two weeks. Their language seems less disturbed, although their memory problems are about the same, probably because the hippocampus is still targeted as the source of the epilepsy. Nine months later, the MRI scan shows that the area has been hollowed out by the cauterization. Of the approxi–mately 20 patients who have had this procedure so far at Dr. Parrent's hospital in London, 60% had a successful outcome.
Radiosurgery is another promising surgical technique of the future. This technique works by concentrating radiation on the epileptic tissue in the brain, without cutting open the head to do so. The radiation can be done either by using a "Linear Accelerator Device," or a "Gamma Knife."
In Gamma Knife radiosurgery, a frame is attached to the head (much like stereotactic surgery), and radiation is projected onto the hippocam–pus and amygdala of the temporal lobe. After this procedure is completed, the person goes home, and their seizures continue unchanged. But gradually, over time, their seizures apparently improve. After about nine months, their seizures cease (at least they did in the 21 research subjects having this new procedure). MRI scans show changes in the patient's brain that progress and then resolve, so that thebrain ends up being substantially the same as it was before the surgery.
"You are left with a person who is seizure-free with an MRI scan that shows nothing has substantially changed inside. But does this structure that has been radiated and no longer produces seizures still function in its normal role of maintaining memory?" asks Dr. Parrent. "Should this be the case, it offers an amazing therapy of removing the bad part of how that brain functions and leaving its normal functions intact."
Dr. Parrent warned that we don't yet know whether this is the case, as detailed memory testing still needs to be done on the patients who have had radiosurgery. Such testing will be very important in influencing whether this technique replaces some of the other techniques we use to treat temporal lobe epilepsy. And what about the risks from radiation itself? The surgeon radiates a very small area to reduce the risk of radiation damage, but we may not know the long-term effects on patients until 15-20 years later.
What new surgeries does the future have to offer the person with generalized epilepsy, whose whole brain is involved in their seizures?
Thalamic stimulation is currently undergoing a multi–centred trial. A stimulator wire with some exposed electrodes at the end is placed deep into a key part of the brain called the thalamus. The wire is attached to a pacemaker implanted in the chest below the collarbone, much like a cardiac pacemaker, and this device sends electrical impulses into the thalamus. Tentative results so far indicate that thalamic stimulation appears to have a beneficial affect on generalized tonic–clonic and partial motor seizures, but not on other types. It has not proven to be a cure–all.
What is on the horizon? Researchers are investigating complex therapies such as transplantation of animal fetal brain cell tissue into human brains to reduce seizures. In mouse and rat models, it apparently can reduce seizures in genetic epilepsies. However, we must first identify the tissue into which it
should be transplanted. Transplanting hippocampus tissue from fetal animals into a lesioned human hippocampus appears to improve epilepsy. However, it may take another decade before this treatment is developed.
Deep Brain Stimulation may be an effective surgical procedure, and will be hotly pursued. It involves stimulation of the sub–thalamic nucleus and basal ganglia, areas which are not usually associated with epilepsy.
VAGAL NERVE STIMULATION
A new type of surgery which does not involve opening the brain is already being performed on a regular basis in the U.S. and elsewhere, although only about 55 Canadians have had the procedure so far. Called Vagal Nerve Stimulation (VNS), it is currently being provided on a limited basis at a number of centers throughout Canada. Neurologist Dr. Richard McLachlan reported on its success.
Vagal Nerve Stimulation consists of a programmable generator resembling a cardiac pacemaker being surgically implanted in the chest wall and attached with wires to the left vagus nerve in the side of the neck. The vagus nerve is an important pathway to the brain that is accessible to us. Typically, the VNS generator sends 30 second bursts of electrical stimulation along the vagus nerve, every five minutes. This treatment is usually tolerated quite well by the patient, although it may temporarily affect the vocal cords, so some patients experience side-effects like hoarseness, coughing and pain.
It is rare for someone to become seizure-free on VNS. Success is measured as achieving a greater than 50% decrease in seizures. There is a gradual increase in its effectiveness over time. In a Canadian study of 25 VNS patients followed for 6 months, 44% had obtained a reduction in their seizures of more than 50%.
Dr. McLachlan made it clear that VNS is not a cure-all, but does have the potential to decrease the impact of epilepsy in at least 1/3 of people with intractable seizures. It may also improve patients' well-being and quality of life.
Another treatment, Repetitive Transcranial Magnetic Stimulation, seems less promising to Dr. McLachlan. This one involves placing a coil on the outside of the head to generate magnetic pulses. Because a magnetic field means you also have an electrical field, this is an indirect way to produce an electrical stimulus of the brain. Repetitive Transcranial Magnetic Stimulation is supposed to disrupt neuronal mechanisms in the cortex to reduce seizures, but in the past, this technique was known more for producing seizures than for stopping them.
GENE THERAPY FOR EPILEPSY
We've all heard about "gene therapy", but how many of us really know what that means? Dr. Berge Minassian, a neurologist and scientist specializing in epilepsy research, provided a short lesson in genetics before reporting on how gene therapy will be used to treat epilepsy in the years ahead.
Each of us has 20 billion brain cells, and each of these cells contains 100,000 genes. A gene is our DNA: our personal blueprint, the code that makes us who we are. Genes help make the proteins that perform important functions in our bodies.
The absence of a gene or improper gene function can lead to severe, progressive epilepsies like Lafora's disease. If we could replace one kind of gene we could cure the disease. Gene therapy is more likely to be used to treat the most serious kinds of epilepsy, rather than the simpler and more common kinds of seizure disorders
Researchers working on gene therapy for epilepsy face some difficult problems. How do you get a replacement gene to go inside a cell membrane? And how do you get a cell to cross the blood brain barrier that protects the brain? Perhaps we could "package" the gene inside a vehicle that knows how to get across these barriers: a virus like HIV. The contents of the virus are emptied out or "pitted" (so it's not a virus any more) and replaced with the missing gene that you want to get into the brain. HIV has a special "key" protein (TAT) that can go into all the cells of the brain.
"The idea now is to put in our missing protein of interest, get it into the brain and potentially cure our patients. To me this is one of the greatest advances in gene therapy recently and will probably result in a lot of progress in our actually being able to treat patients using this approach," said Dr. Minassian.
"Gene therapy is not in the distant future. Soon we will be treating with it."
Unfortunately, the more common forms of epilepsy, such as absence seizures or juvenile myoclonic epilepsy, are not caused by one gene but by many genes working together. These "polygenic" diseases may require scientists to replace more than one gene. We don't expect to be using gene therapy on such cases, which are otherwise treatable with medication, for a very long time.
Gene therapy may have potential for patients with temporal lobe epilepsy, but success is farther off in the future. The idea is to introduce a GABA receptor gene to act as a "brake" which will prevent excessive firing of the excitatory channels of the brain. The new gene could turn on whenever a seizure is starting, and prevent its development.
THE KETOGENIC DIET
Actually one of the oldest effective treatments for epilepsy (since the 1920's), the Ketogenic Diet was largely ignored after the development of anti-convulsant medications. This is an extremely high-fat diet regime that puts the child's body into a state of "ketosis" which can sometimes control their seizures. Dr. Rosalind Curtis, a pediatric neurologist and director of the largest Ketogenic Diet program in Canada, reported on her experience with the diet to date.
The Ketogenic Diet has already been used on over 100 children who are refractory to medi–cations, with 30-35% of them becoming seizure free and 40% improving their seizure control. A child is also likely to be more alert on the diet. Side effects include renal stones.
According to Dr. Curtis, "Tomorrow is Today" for the Ketogenic Diet, as the diet is already generally accepted as a treatment option for the 15–20% of children with epilepsy that cannot be controlled by medication. The diet works best in young children and doesn't seem to work in adults. In the years ahead it will continue to be used for a very specialized group in intractable children who can tolerate the diet and its rigid regime.
ALTERNATIVE THERAPIES
Dr. Lila Georgevich, a neurologist with the Rouge Valley Health System in Toronto, reported on the "alternative therapies" for epilepsy, everything from biofeedback to marijuana. This is a vast area that needs its own newsletter. Look for our next issue!
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