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doi: 10.1097/01.NT.0000431950.00762.ee
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Hippocampal Bursts Linked to Memory Problems in Epilepsy Patients

Samson, Kurt

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ARTICLE IN BRIEF

Investigators reported that interictal epileptiform discharges (IEDs) on the EEGs of epilepsy patients were associated with lower scores on memory retrieval and maintenance tests. They say the the cognitive impact of IEDs in the hippocampus may be substantially more important than has been previously documented.

The cognitive difficulties experienced by many epilepsy patients may be due, in part, to brief “silent” epileptic discharges in the hippocampus that occur between seizures and affect certain short-term memory processes, according to new research published online May 17 in Neurology.

Researchers at Dartmouth-Hitchcock Medical Center in Lebanon, NH, and the UCL Institute of Child Health in London, UK, used intracranial electrodes to investigate whether interictal epileptiform discharges (IEDs) in the hippocampus impair specific memory processes.

IEDs appear on electroencephalography (EEG) as “spikes” of various intensity and duration, and while they resemble the EEG signature of an epileptic seizure, they are much shorter and occur without any physical symptoms.

Although there were no controls in the new study, in ten patients, IEDs were associated with lower scores in both memory retrieval and maintenance tests, but not in information encoding — the taking in of information — with longer EEG “spikes” associated with greater impairment, said lead author Barbara C. Jobst, MD, who directs the Dartmouth Epilepsy Program.

“The cognitive impact of IEDs in the hippocampus may be substantially more important than has been previously documented,” she told Neurology Today in a telephone interview.

The new study built upon earlier research by the team — published in 2010 in Annals of Neurology — in a rodent model of temporal lobe epilepsy that linked hippocampal IEDs to impairment in short-term memory retrieval, but not in memory encoding or maintenance.

“This is important because it is a direct translation from an animal model to humans,” said Dr. Jobst. “The big question remains how and why is memory so badly affected, and what factors and processes are involved.”

IEDs in the cortex measured using scalp EEG have been associated with transient cognitive impairment, and earlier research has found that working memory is somewhat reduced with IEDs in the medial temporal lobe. In one earlier study, discharges lasting as little as one second impaired performance in 61 percent of patients asked to perform a simple choice reaction time test. But the precise timing of the IEDs and specific components involved in memory processing have until now not been considered.

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EFFECTS LATERAL, NOT GLOBAL

In the study, the researchers implanted electrodes in patients for preoperative seizure localization, and EEGs were recorded during 2,070 total trials of a short-term memory tasks. Memory processing was broken down into information encoding, maintenance, and retrieval; and the influence of hippocampal IEDs on each process was analyzed and adjusted for individual differences between patients.

The researchers found that hippocampal IEDs during memory retrieval decreased the likelihood of a correct response when they were contralateral (p<0.05) or bilateral (p<0.001) to the seizure focus, while bilateral IEDs during the memory maintenance period had a similar effect (p<0.01), especially longer spike-wave complexes (p<0.01).

“This demonstrates that IEDs are not a global brain phenomenon, but that bilateral IEDs, and IEDs originating at the opposite side of the hippocampus that cause the seizure zone, affect cognition and memory processes on the opposite side, perhaps due to a neural compensatory mechanism,” Dr. Jobst said.

“For clinicians, if spikes are on the side where a seizure originates they may be clinically insignificant, but if they are occuring contralateral of the seizure onset zone, they may have an impact on memory processing. The duration of spikes is also important,” she said. “The larger and longer the spike, the more dramatic the impact on memory retrieval and maintenance tasks.”

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IMPLICATIONS FOR PRACTICE

“I think this is something that everyone has suspected,” commented Selim Benbadis, MD, professor of neurology and director of the Comprehensive Epilepsy Program at the University of South Florida in Tampa, who was not involved with the study. “It has always been postulated that 'micro-impairment' plays some role, but it is very difficult to investigate the cognitive impact of fleeting discharges, so it is very nice to see these data.”

He told Neurology Today that the findings may change the way patients' cognitive complaints are viewed and, perhaps, treated.

“Interictal discharges are so brief and so localized that evaluating their effects on tasks is very tricky. This study provides a better understanding of why frequent discharges may affect cognition, especially when they are bilateral,” he said. “Maybe we should not be so complacent about these discharges. Now we can see that patients with more discharges are likely to have greater impairment that should perhaps be treated more aggressively.”

“We have always questioned what to do when patients complain about memory problems,” said Orrin Devinsky, MD, professor of neurology, neurosurgery and psychiatry at New York University School of Medicine, and director of the NYU Comprehensive Epilepsy Center.

“Although many patients consider medications as the sole cause, recurrent tonic-clonic seizures can impair memory, analagous to recurrent concussions,” Dr. Devinsky said. “For milder seizures and epilepsy waves, it is probable that some patients are vulnerable to their effects. This study shows that even epilepsy waves can transiently impair cognition. Future studies need to assess their cummulative effects.”

He told Neurology Today that the standard has been to ignore them rather than trying to treat them. “But this study and others indicate that these discharges can affect patient function and behavior. In the hippocampi, where memory processing takes place, it turns out that IEDs do have an impact.”

Future challenges will be not just monitoring IEDs, but also suppressing them somehow. “The caveat is that whether controlling them involves stimulation or pharmaceutical intervention, there are always certain risks,” he said.

“Overall, medications are most effective in stopping seizures and often do not suppress all IEDs. If the goal is treating all, there is a risk of overtreating patients. You do not want to become what we call a ‘spike chaser,’” he said. “You could get a spike-free EEG, but the patient may be sleeping all the time.”

And while there is a need for better medications to better control such epileptiform activity, there is an even larger issue — the tendency to think of epilepsy as simply a disorder of recurrent seizures, Dr. Devinsky noted.

“This is a disorder of neurological function, and we need to think about it more broadly. Spikes affect nerve cells even when there the patient is not seizing. And in many cases, there is an impairment of neuronal function even when there are no spikes.”

Further research is needed to understand memory complaints in this population and ways to address them, Drs. Devinsky and Benbadis agreed.

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LINK UP FOR MORE INFORMATION:

•. Rugland AL. Neuropsychological assessment of cognitive functioning in children with epilepsy. Epilepsia. 1990;31[Suppl 4]:S41–S44.

•. Kleen JK, Scott RC, Holmes GL. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology. 2013; E-pub 2013 May 17.

•. Kucewicz MT, Worrell GA, Gotman J. Pathological brain network activity: memory impairment in epilepsy. Neurology. 2013;E-pub 2013 May 17.

•. Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol. 2010; 67:250–257.

•. Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG. Lancet Neurol. 2003; 2:725–730.

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