Seizures, Epilepsy Linked to Immune Reaction

by Aalok Mehta

April 2, 2009

An immune reaction gone awry may exacerbate the progression of epilepsy by making the blood-brain barrier more “leaky,” scientists suggest.

In studies of mice reported in the journal Nature Medicine, seizures caused blood vessels in the brain to attract immune cells called leukocytes. The resulting inflammatory response, the researchers say, may allow harmful molecules into the brain that affect neural activity and make additional seizures more likely.

In separate research, the researchers found increased leukocyte migration in the brains of people with epilepsy, suggesting that the process might work the same way in humans. If so, targeting the immune reaction might offer a new way to treat or possibly cure some cases of the chronic disease.

“Our results demonstrate that immune cells and immune cell functions are involved in seizure generation and in the pathogenesis of epilepsy,” says lead researcher Gabriela Constantin of the University of Verona. “Our data suggest that inflammation mechanisms may favor the development of seizures also in humans.”

‘Sticky’ factor

Constantin and her team found that, in particular, seizures make brain blood vessels “sticky” by increasing the generation of adhesion molecules. These in turn latch onto leukocytes, a type of white blood cell that normally circulates freely in the blood.

When researchers blocked this interaction, either with antibodies or through genetic manipulation of the mice, the number of seizures dropped significantly. Reducing the number of circulating neutrophils—a type of immune cell that starts to release damaging oxygen radicals when it encounters adhesion molecules—had the same effect.

Blocking leukocyte binding also reduced the damage in the brain from the inflammatory response, Constantin says. By increasing the permeability of the blood-brain barrier, she points out, inflammation could let in molecules that cause neuronal hyperexcitability, the hair-trigger firing of brain cells that can spark new seizures.

“Anti-adhesion therapies block eliptogenesis [seizure generation] in an experimental mouse model,” Constantin says, and suggest that for human brain association with inflammation—such as infection, head trauma, stroke and multiple sclerosis—therapies that block this leukocyte adhesion may prevent epilepsy and lifelong treatment with an anti-epileptic drug.

Targeted treatments

The new research is “very important in terms of bringing to the attention of the epilepsy community the importance of inflammation,” says Jacqueline French, a professor of neurology at New York University.

Chronic seizures can occur for various reasons, and the new work may provide a glimpse into a common mechanism behind them. “This might be a strategy for treatment for the future,” she says, “not by adding a ‘blanket’ over the brain, which many anti-epilepsy drugs do, but [by] attacking a piece of the pathology.”

But the study is only a small piece of a much larger area of research into how inflammation is involved in epilepsy’s development and persistence, she adds. For instance, treatments that block interleukin pathways—in which white blood cells release signaling molecules to help stimulate a full-blown immune reaction—also seem to help stop seizures.

“These therapies already exist” for other diseases and in animal models, she adds. “So the question is, when should one try them in human beings with epilepsy?”