http://www.nytimes.com/2003/02/18/science/18EPIL.html
Data on Epilepsy Point to Dangers of Repeated Seizures
By LINDA CARROLL

For years, doctors have reassured epilepsy patients that seizures are relatively benign. While a fall during a seizure may cause injury, the surge of electricity in the brain does no actual damage, patients were told.

But mounting evidence now suggests that repeated seizures can indeed harm the brain — or, in rare cases, even lead to death.

In the past decade, research in epilepsy has exploded. In part, the boom has been driven by advances in biology and technology, like the mapping of the genome and the continuing miniaturization of electronics.

But largely, it has been driven by a new recognition that seizures themselves are harmful. Mounting data point to damage to the hippocampus, the part of the brain responsible for laying down new memories, as the cumulative effect of a lifetime of uncontrolled seizures.

Furthermore, recent studies suggest that seizures beget seizures: each electrical surge in the brain causes changes that make future seizures more likely.

Doctors are also realizing that patients with seizures that are not suppressed by drugs or surgery are at higher risk of dying prematurely. A syndrome called sudden unexpected death in epilepsy patients, or Sudep, appears to be much more common than previously thought. No one is sure exactly what happens in the syndrome, but the suspicion is that an electrical short circuit either turns off respiration or the heart.

Among patients with severe epilepsy, about 10 to 15 of 10,000 die unexpectedly each year, according to Dr. Robert S. Fisher, a professor of neurology at Stanford. Often patients and their families know nothing about the syndrome, until there is a death.

"It's the gorilla in the living room that nobody wants to talk about," said Dr. Marc Dichter, director of the David Mahoney Institute of Neurological Sciences and a professor of neurology and pharmacology at the University of Pennsylvania.

In a commentary published last spring in The Lancet, the London-based medical journal, epilepsy experts pointed to new information on the prevalence of the sudden death syndrome among patients with poorly controlled seizures and said the information should serve as a "wake-up call" to the doctors who treat them.

"Sudep is not rare among patients with uncontrolled epilepsy," wrote Dr. Timothy Pedley, the chairman of the department of neurology and the neurologist in chief at the Columbia-Presbyterian Medical Center in New York.

"Patients at risk should be identified, and they and their families should be educated about this possibility," Dr. Pedley added. "Relatives of patients with Sudep consistently indicate that they wish they had been informed that epilepsy can be fatal."

About 1 percent of Americans have epilepsy, a condition characterized by periodic seizures that originate in the brain. Basically, experts say, normal brain activity is fairly chaotic, with neurons sparking as needed. But in people with epilepsy, neurons occasionally begin to fire in sync. There is a power surge and the finer circuits of the brain are overwhelmed as the seizure progresses.

The seizures themselves can range from a brief loss of consciousness lasting one to 10 seconds to a complete loss of consciousness. It is the seizures that provoke a loss of consciousness that most worry researchers because these seizures appear to be most linked to sudden death and damage to the hippocampus.

Although there were hints in the past that uncontrolled seizures led to hippocampal damage, only in the last few years has strong evidence been accumulated.

In June, Australian researchers reported that a group of epileptic patients with uncontrolled seizures, monitored with magnetic resonance imaging for more than three years, experienced significant decreases in the size of their hippocampi, according to a study published in The Annals of Neurology. On average, the volume of the hippocampus dropped by 9 percent. And the more seizures the patients had, the more their hippocampi shrank.

 Brain changes are also seen in children who experience fever-related seizures, says Dr. Shlomo Shinnar, a professor of neuroscience and the director of the epilepsy management center at the Montefiore Medical Center in the Bronx.

Among a small minority of children who experience seizures that last more than 20 minutes, M.R.I. studies have shown signs of swelling in the hippocampus, Dr. Shinnar said. Dr. Shinnar and his colleagues plan to study whether these long-lasting seizures lead to epilepsy later in life.
Advertisement


Further evidence of damage from seizures comes from a study of epileptic rats, which was published in May in the book "Do Seizures Damage the Brain?"

That study showed memory damage with repeated seizures. Rats that experienced 30 or more seizures had trouble remembering how to get through a maze. Those that had fewer seizures had no problem. When the researchers examined the rats at the end of the study, they found significant loss of nerve cells in the hippocampi of rats that had 30 or more seizures.

"I and others have been really concerned that epilepsy has been minimized," said the study's lead author, Dr. Thomas P. Sutula, the chairman of the department of neurology and the director of the Center for Neuroscience at the University of Wisconsin.

"There's lots of data emerging that suggests it's not benign," Dr. Sutula said. "Even as brief as seizures are, there are consequences that last long, long after."

Seizures can be controlled in most patients. Medications block seizures in two-thirds of patients and surgery controls seizures in another 7 percent to 8 percent. But a full 25 percent of patients must live with the seemingly unpredictable surges of electricity.

Solutions for those 25 percent may come from new research into the genetics of epilepsy.

Because epilepsy often turns up in families only sporadically, it can be difficult to tease out the genetics of the disorder. But researchers are beginning to learn more about the common types of epilepsy by studying families with rare but highly heritable forms of the disorder, said Dr. Jeffrey Noebels, a professor of neurology, neuroscience and molecular genetics at the Baylor College of Medicine in Houston.

Epilepsy genes found in the past few years have pointed to problems with ion channels in nerve cells. Ion channels are basically pores that let ions — charged atoms, like sodium, potassium and calcium — into nerve cells, Dr. Noebels said. Normally the pores open for a millisecond or two, allowing ions to rush in, and then slam shut. The neuron becomes charged and "sparks," sending its signal to the next neuron in line.

When genes that encode the ion channels have a certain kind of defect, the pore does not slam shut, said Dr. Alfred L. George Jr., a professor of medicine and the director of the division of genetic medicine at Vanderbilt University in Nashville.

Dr. George has studied the behavior of neurons with a sodium-channel defect that occurs in a certain type of inherited epilepsy. The ion channels, he and his colleagues found, do not close tightly enough. They allow sodium ions to leak into nerve cells long after the channel should have locked shut, a study published in June in the journal Neuron found.

This leakage leads to cells that are constantly on the brink of sparking, Dr. George said. This may be what allows masses of neurons to get overexcited and fire at the same time, culminating in a seizure.

"All of us can have a seizure if provoked in a severe way," Dr. George said. "This mutation may just increase the susceptibility to seizures."

Dr. George and others suspect that many epilepsy patients have defects in their ion channels. One solid piece of evidence for this hypothesis lies in the channel blocker medications, which are highly successful in treating epilepsy, Dr. George said.

The defects may be the result of several minor genetic mutations rather than the single mutation that produces seizures in the rare, highly heritable forms of epilepsy.

Dr. George said he hoped that new models of seizure susceptibility would help lead to better medications to stem power surges. More effective medicines may help prevent childhood seizure disorders from becoming lifetime problems, he suggested. By stifling seizures early, doctors may be able to prevent changes in the brain that make future seizures more likely, Dr. George said.

In the past decade, studies have also shown that unsuppressed seizures can lead to the development of structures that make it easier for power to surge again and again in the brain.

After repeated seizures, neurons can start to sprout new branches that make the seizure circuit easier to complete.

"The brain is, in a sense, establishing excitability as a permanent feature," Dr. Pedley said.

An article in The Lancet in July, reviewing studies on brain changes linked to seizures, concluded that ample evidence showed that seizures could both change and damage the brain.

"The increasing experimental and human evidence about the adverse effects of repeated seizures, is a compelling argument for urgent treatment that achieves full control," concluded Dr. Sutula and his co-author, Asla Pitkanen of the University of Kuopio in Finland.