Conference Coverage

Hippocampal abnormalities seen in epilepsy subtypes may be congenital



NEW ORLEANS – Abnormalities of hippocampal volume and morphology in children with temporal lobe or juvenile myoclonic epilepsy (JME) are also present in the brains of their unaffected siblings, although to a lesser extent, based on findings from two studies presented at the annual meeting of the American Epilepsy Society.

While the studies suggest an imaging endophenotype associated with these disorders, it’s unclear if a larger degree of abnormality causes disease manifestation, or whether there are other predisposing actors at work.

“What our study tells us is that hippocampal abnormalities can occur in the absence of seizure,” Marian Galovic, MD, said in an interview. “It may be that, in some cases, hippocampal abnormalities could be the cause, rather than the consequence, of seizures.”

Dr. Galovic of University College London was on hand to discuss the work of his colleague, Lili Long, MD, PhD, of the Xiangya Hospital of Central South University, Changsha, China. Visa issues prevented her from attending the meeting.

The study included 18 sibling pairs in which the affected siblings had sporadic, nonlesional temporal lobe epilepsy (TLE), involving the right lobe in 12 and the left in 6. The patients, siblings, and 18 healthy, age-matched controls underwent clinical, electrophysiologic, and high-resolution structural neuroimaging.

The researchers compared overall hippocampal volumes between groups and determined the subregional extent of hippocampal abnormalities using shape analysis. They also looked at whole-brain differences in cortical thickness and folding complexity.

As expected, median hippocampal volumes were largest in the healthy controls (left = 2.82 mL, right = 2.94 mL), and smallest in patients. Patients with left TLE had a median left hippocampal volume of 2.23 mL, while those with right TLE had a median right hippocampal volume of 1.92 mL.

However, volume in the unaffected siblings was a surprise. Like the patients, these subjects also had significant reductions in hippocampal volume when compared with controls (left = 2.47 mL, right = 2.65 mL). “The atrophy was relatively similar in siblings and patients, although not as pronounced in siblings,” Dr. Galovic said. “It was mostly unilateral in the siblings and bilateral in the patients, but it was still more pronounced on the side where the epilepsy of the affected sibling was coming from.”

The hippocampi of patients with TLE and their nonaffected siblings show similar morphology and reductions in volume. Dr. Marian Galovic

The hippocampi of patients with TLE and their nonaffected siblings show similar morphology and reductions in volume.

Patients and siblings also shared morphologic variations of the hippocampus, with atrophy more pronounced on the right than the left. The right lateral body and anterior head of the hippocampus were most affected, Dr. Galovic said, with reductions in the right cornu ammonis 1 subfield and subiculum.

Widespread cortical thinning was present in patients, including the pericentral, frontal, and temporal areas. Unaffected siblings also showed cortical thinning, but this was mostly restricted to the right postcentral gyrus. Patients and siblings also demonstrated increased cortical folding complexity, but in different areas: predominantly frontal in patients, but predominantly parieto-occipital in siblings. Both were significantly different than healthy control subjects.

Patients with TLE and their unaffected siblings show similarities in cortical thinning and folding. Dr. Marian Galovic

Patients with TLE and their unaffected siblings show similarities in cortical thinning and folding.

The study didn’t examine any association with memory, which is often impaired in patients with TLE. However, Dr. Galovic said, “We have just submitted for publication a study in which we did find an association between focal hippocampal atrophy and memory performance.”

A different study by a team at University College London looked at hippocampal structure and function in patients with juvenile myoclonic epilepsy (JME) and their unaffected siblings. The imaging study, lead by Lorenzo Caciagli, MD, of the university comprised 37 patients with JME, 16 unaffected siblings, and 20 healthy controls. It employed multimodal MRI and neuropsychological measures to examine the form and function of the mesiotemporal lobe.

The subjects were matched for age, sex, handedness, and hemispheric dominance, which was assessed with language lateralization indices. This measures the number of active voxels on functional MRI, showing which hemisphere is dominant for language.

Both patients and their siblings showed reductions in left hippocampal volume on the order of 5%-8%, significantly smaller than the volumes seen in healthy controls. About half of patients and half of siblings also showed either unilateral or bilateral hippocampal malrotation. This was present in just 15% of controls, another significant difference. The structural differences weren’t associated with seizure control or age at disease onset, or with any impairments in verbal or visual memory. But when the investigators performed functional mapping, they found unusual patterns of hippocampal activation in both patients and siblings, pointing to a dysfunction of verbal encoding. In patients, there appeared to be distinct patterns of underactivation along the hippocampal long axis, regardless of whether malrotation was present. But among patients who had malrotation, the left posterior hippocampus showed more activation during visual memory.

The team concluded that the hippocampal abnormalities in volume, shape, and positioning in patients with JME and their siblings are related to functional reorganization. The abnormalities probably occur during prenatal neurodevelopment, they noted.

“Cosegregation of imaging patterns in patients and their siblings is suggestive of genetic imaging phenotypes, and independent of disease activity,” Dr. Caciagli and his coinvestigators wrote in their abstract.

Funding for the TLE study came from the National Natural Science Foundation of China, the Ministry of Science and Technology of China, and Xiangya Hospital. Funding for the JME study came from a variety of U.K. charities and government agencies.

SOURCES: Long L et al. AES 2018, Abstract 2.183; Caciagli L et al. AES 2018, Abstract 2.166.

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