BOSTON—Effective treatment of patients with epilepsy requires understanding and addressing a myriad of issues that extend well beyond seizures, including cognitive, behavioral, psychiatric, and other neurologic comorbidities, as well as higher mortality rates, according to Anne T. Berg, PhD.
“When we talk about epilepsy, we are referring to a large group of disorders that involve seizures certainly, but there is far more to epilepsy than seizures alone,” said Dr. Berg, Research Professor in the Department of Biological Sciences, Northern Illinois University, in DeKalb.
Episodic, Transient, and Progressive Effects of Epilepsy
Seizures also cause chronic and progressive effects on brain structure and cognition. “This is best studied in regional temporal lobe epilepsy, where we see a relatively healthy hippocampus turn into a small bright gliotic scar,” said Dr. Berg. “Other areas in the limbic system are involved, but recently we’re becoming aware that it may be beyond the limbic system.”
Recent data have demonstrated a progressive thinning of the neocortex with an increasing duration of epilepsy, after the general effects of aging have been controlled for. Other research has shown that patients with chronic temporal lobe epilepsy have a greater loss of cognitive function compared with healthy controls.
Encephalopathic Effects of Epilepsy One possible explanation is that whatever causes the epilepsy independently causes the autism and mental retardation. “If we think about underlying structural metabolic lesions of the brain in children, approximately a quarter of children will have a recognizable insult,” said Dr. Berg.
The developmental and encephalopathic effects of seizure activity is a developing concept, noted Dr. Berg. “But it is based on the very old recognition that the severest forms of epilepsy begin in the first few years of life,” she said. Severe brain disorders occurring in early age have been collectively dubbed epileptic encephalopathies and include such symptoms as EEG paroxysmal activity, intractable seizures, and cognitive, behavioral, and neurologic deficits. Examples include Dravet syndrome, early myotonic encephalopathy, and Lennox-Gastaut syndrome. About three-fourths of children with one of these syndromes are mentally retarded, compared with 15% of children with all other epilepsies combined.
In terms of episodic and transient effects, seizures—especially severe ones—disrupt a patient’s daily behavior. Even subtle seizures, such as those in childhood absence epilepsy, can adversely affect a child’s ability to pay attention in school. Transient cognitive impairments can occur during interictal discharges, which may affect cognitive function. In addition, depending on seizure severity, longer-term transient impairment may occur, “sort of a subclinical postictal period,” noted Dr. Berg.
A study of young children with seizure onset before age 1 found that 18% also had autism. An inverse relationship between epilepsy and autism has also been observed. For example, one study found that 16% of children with autism developed epilepsy. “That’s phenomenal, if you consider that in the population overall, fewer than 1% of children develop epilepsy,” commented Dr. Berg. “These sorts of observations suggest that epilepsy, mental retardation, and autism form a trio of encephalopathy. I sometimes call it the unholy trinity. And the question is ‘why?’”
“To the extent that the integrity of brain structure is necessary for the integrity of brain function, you will not be surprised to find out that these children have more difficulties than other children with epilepsy,” she continued. “Those with structural metabolic lesions [more frequently have] low IQ. They are the ones with abnormal neurologic exams, they are pharmaco-resistant, and they also have a higher death rate.”
The premise behind epileptic encephalopathy “is that the epileptic activity itself contributes to severe cognitive behavioral impairments, above and beyond what might be expected from the underlying pathology alone,” Dr. Berg explained. “And what we are particularly concerned with is that this happens during critical periods of brain development. It can derail development permanently.
“So in theory, epileptic encephalopathy should be a continuum and should potentially occur virtually in anyone,” Dr. Berg continued. “It should affect any form of epilepsy—not just those that we identify as epileptic encephalopathies—and its severity of expression should depend on age at onset, current age, duration of epilepsy, frequency of seizures, and perhaps other factors that we have not yet identified. In fact, that is what’s going on, and particularly in a young brain.”
In a study of children presenting for epilepsy surgery, researchers found a strong correlation between young age of seizure onset and lower IQ scores. Among children who had onset of daily seizures younger than age 2, two-thirds were mentally retarded. Among those younger than 2 with less frequent seizures, 22% were mentally retarded, versus 3% of those who were older. Other investigators have found a very strong correlation between degree of disability and age of seizure onset, with the most disabled patients having the youngest age of onset.