It has long been known that children with epilepsy have cognitive problems, but that problem was thought to be caused by chronic seizures. Now, investigators have accumulated evidence that neuropsychological concerns may be there from the very beginning of the seizure disorder.
The findings, reported online Aug. 12 in advance of the print edition of Neurology, suggest that neurologists should identify cognitive problems soon after diagnosis and perhaps even start interventions that could avert academic problems down the road.
“There is ample evidence that children with chronic epilepsy have significant neuropsychological impairments — 50 percent of chronic children meet criteria for learning disability — but we wanted to determine when these problems actually develop,” said Philip S. Fastenau, PhD, professor of neurology and director of clinical neuropsychology at University Hospitals Case Medical Center and Case Western Reserve University School of Medicine in Cleveland. “Since neuropsychological deficits are strongly associated with academic performance in these children, it was critical to track the onset and evolution of the disorders.”
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This is the first large-scale study to identify cognitive problems on the heels of the initial diagnosis and to systematically examine risk factors, Dr. Fastenau said. Only half the children were taking antiepileptic medications at the start of the study, which allowed the researchers to begin studying whether the cognitive problems were the result of the seizure disorder or the drugs used for treatment.
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STUDY PROTOCOLS, RESULTS
The investigators recruited 350 children from Indiana and Ohio, identifying children when they were seen by neurologists, pediatricians, and school nurses with a first recognized seizure. They conducted academic and neuropsychological testing in 282 children (ages 6–14, IQ greater than 70) who had a first recognized seizure as well as 147 of their healthy siblings at entry into the study and again after 18- and 36-months; the current report describes their functioning at the time of onset. The sample included diverse seizure types and epileptic syndromes that mirror epidemiological studies with this population. Twenty-seven percent of the children who had at least one seizure showed neuropsychological deficits — problems in language, processing speed, memory, and an index assessing attention, construction, and executive functioning (such as problem solving skills — compared with 18.2 percent of siblings (p=0.04). [See “Odds Ratios: Neuropsychological Domains, Clinical Risk Factors.”]
Risk factors associated with neuropsychological deficits included multiple seizures (OR=1.96); use of antiepileptic drugs (OR=2.27); symptomatic/cryptogenic etiology (OR=2.15)); and epileptiform activity on the initial EEG (OR=1.90). A child with all four risks was three times more likely than healthy siblings to have neuropsychological deficits by the first clinic visit.
Up to 40 percent of the children with risk factors, including a second unprovoked seizure, had neuropsychological problems. And contrary to the common belief that absence epilepsy is a benign syndrome, these children carried twice the risk for neuropsychological problems.
“This adds to a growing body of evidence that this condition is still affecting the integrity of brain function,” Dr. Fastenau said of absence seizures. “We can no longer consider this condition entirely benign.”
The findings suggest that both seizures and antiepileptic drugs (AEDs) play a role in altering cognitive function. In the study, they compared four subgroups: 77 children who had a single seizure but were not taking AEDs; 18 with a single seizure who were taking AEDs; 63 who had multiple seizures and were not taking AEDs; and 123 who had multiple seizures and were taking AEDs. Those being treated had more cognitive problems than those who had only one seizure and who were not on medications.
The investigators also assessed the combined influence of medications and seizures and did not find that the two risk factors had a compounding effect. Instead, they had independent effects, with the medications altering processing speed (p=0.001), language (p=0.04), and memory (p=0.05), and multiple seizures leading to lower scores on attention, executive, and construction skills (p=0.03).
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These neuropsychological deficiencies worsen over three years for children with incomplete seizure control. Last December at the annual meeting of the American Epilepsy Society, Dr. Fastenau and his colleagues presented preliminary longitudinal findings with this cohort over a three-year period. The children were tested on a neuropsychological battery at baseline, 18 months, and 36 months after the first seizure. In addition, every nine months the investigators obtained information about their clinical status, including seizure recurrence and medication status. They found that children with more seizures experienced more decline than those with infrequent breakthrough seizures; those who did not have any more seizures after the initial one seemed cognitively normal like their siblings.
Because the study captured children in the months following the first seizure, they did not identify any significant differences from siblings in school performance yet. This, said Dr. Fastenau, is important because it “suggests that there is a window of opportunity during which the seizure disorder hasn't affected performance in the classroom yet.”
SUBJECT FOR DEBATE
Here is where the study results are open to debate. Dr. Fastenau and his colleagues contend that the findings make it essential for children with seizures to be evaluated for neurocognitive problems promptly after diagnosis. “We could potentially head things off at the pass,” said Dr. Fastenau. “Typically, children get referred after the fact when they are already having problems in school.”
Studies of children with chronic epilepsy, he said, have found 38 percent also have attention deficit disorder — almost eight times the rate found in the general population. Their primary symptom is inattention, and thus many can get overlooked in the busy classroom where their hyperactive counterpart can get easily picked from the crowd.
While Shlomo Shinnar, MD, PhD, director of the Comprehensive Epilepsy Management Center at Montefiore Medical Center and the Albert Einstein College of Medicine in the Bronx, applauds the much-needed study and its findings, he is not sure whether every newly diagnosed child should be sent to a neuropsychologist for testing. “These findings strongly support the conclusion that the cognitive issues and co-morbidities are part and parcel of the condition and that the cognitive problems are not a consequence of years of epilepsy. This is an important finding,” he said. “We all know that kids with epilepsy have these issues and it is not so straightforward as to what to do.”
“While these children are two times as likely as their siblings to have neuropsychological problems, the majority of children did not. Doctors should be sensitive to the higher rate of these problems but what types of interventions will we do? We are not going to put a 5-year-old on stimulants to boost attention. This is not unlike what happens when children are born premature. Who is going to qualify for early intervention? In the real world, not every child will need it or get it.”
He added: “We have to also be concerned about the reality of labeling children. And before they are having academic problems, what kinds of interventions do we offer?” He suspects that “neurologists should follow the children diagnosed with epilepsy and have a lower threshold for referral. We just don't have the data to know what kinds of interventions would even work. These studies should now be done.”
• Fastenau PS, Johnson CS, Dunn DW, et al. Neuropsychological status at seizure onset in children: Risk factors for early cognitive deficits. Neurology 2009: E-pub 2009 Aug. 12.
• Dunn DW, Austin JK, Ambrosius WT, et al. ADHD and epilepsy in childhood. Dev Med Child Neurol
• Fastenau PS, Shen J, Austin JK, et al. Academic underachievement among children with epilepsy: proportion exceeding psychometric criteria for learning disability and associated risk factors. J Learn Disabil
• Fastenau PS, Shen J, Austin JK, et al. Neuropsychological predictors of academic underachievement in pediatric epilepsy: moderating roles of demographic, seizure, and psychosocial variables. Epilepsia
• Kalnin AJ, Fastenau PS, deGrauw TJ, et al. MR imaging findings in children with first recognized seizure. Pediatr Neurol