Puzzle of Impaired Consciousness in Absence Epilepsy Solved?

Pauline Anderson

December 28, 2016

Intense abnormal activity in well-known brain networks that occurs early in a seizure may be the key to impaired consciousness in children with absence epilepsy, new research suggests.

Results of a new study indicate that seizures with behavioral impairment are not limited to focal areas and show intense widespread physiologic activity in the brain's networks. Furthermore, investigators found these seizures show more intense physiologic changes at seizure initiation.

These findings, investigators note, represent a fundamental shift from prevailing views of impaired consciousness in absence seizures.

"It was thought that loss of consciousness in absence seizures is related to a particular spot in the brain, a localized or focal area, that might be critical for the impairment that children have," study investigator Hal Blumenfeld, MD, PhD, Yale University School of Medicine, New Haven, Connecticut, told Medscape Medical News.

"We found that it's not just a localized area of the brain that's different when children can and can't respond; it's the whole brain," Dr Blumenfeld added.

Dr Blumenfeld added that the analysis showed that changes in the brain, seen with both functional MRI (fMRI) and electroencephalography (EEG), are more severe when children can't respond compared to when they can. "The fMRI and EEG changes are larger everywhere when children can't respond," said Dr Blumenfeld.

The study was published in the December issue of The Lancet.

Disorder of Consciousness

Characterized by brief episodes of impaired consciousness, absence epilepsy affects up to 17% of children and adolescents with epilepsy. The seizures are composed of low-frequency (3 to 4 Hz) waves and high-frequency (greater than 10 Hz) spikes.

The seizures meet the definition of a disorder of consciousness because they cause transient deficits on a broad range of tests, including those on verbal, visuo-motor, auditory-motor, memory, and attention vigilance tasks.

Although all absence seizures show similar-appearing spike-wave discharges on EEG, some impair consciousness while others spare consciousness, even in the same patient.

For the study, researchers recruited patients from 59 pediatric neurology practices in the United States. They enrolled 93 children aged 6 to 19 years with absence epilepsy and an EEG with typical 3- to 4-Hz bilateral spike-wave discharges and normal background.

Study outcomes included behavioral responsiveness and amplitude of fMRI and EEG signals during absence seizures.

The behavioral measures of attention during seizures included a continuous performance task (patients pressed a button every time they saw a target letter X out of a random letter sequence) and an easier repetitive tapping task (patients pressed a button every time they saw any letter on the screen).

Both tasks were alternated with a "fixation" period (when patients were not being tested) for a total run duration of 640 seconds. Patients did three to six runs of task as tolerated.

Of the 93 enrolled patients, 39 had absence seizures during testing — and had a total of 1032 seizures. Over half (59%) of these 39 were girls; their mean age was 9.9 years and their duration of epilepsy was about 3 years. These characteristics were similar to those of patients without seizures.

fMRI changes during seizures occurred sequentially in three functional brain networks.

In the default mode network, fMRI amplitude was 0.57% for seizures with impaired and 0.40% for seizures with spared behavioral responses (mean difference, 0.17 percentage points; 95% confidence interval [CI], 0.11 - 0.23; P < .0001).

In the task-positive network, fMRI amplitude was 0.53% for seizures with impaired and 0.39% for seizures with spared behavioral responses (mean difference, 0.14 percentage points; 95% CI, 0.08 - 0.21; P < .0001).

Finally, in the sensorimotor-thalamic network, fMRI amplitude was 0.41% for seizures with impaired and 0.34% for seizures with spared behavioral responses (mean difference, 0.07 percentage points; 95% CI, 0.01 - 0.13; P = .02).

Abnormal, Widespread Activity

The mean fractional EEG power in the frontal leads was 50.4 for seizures with impaired and 24.8 for seizures with spared behavioral responses (mean difference, 25.6; 95% CI, 21.0 - 30.3).

In the middle leads, it was 35.4 for seizures with impaired and 13.3 for seizures with spared behavioral responses (mean difference, 22.1; 95% CI, 20.0 - 24.1). And in the posterior leads, it was 41.6 for seizures with impaired, 24.6 for seizures with spared behavioral responses (mean difference, 17.0; 95% CI, 14.4 - 19.7; P < .0001 for all comparisons).

Researchers also examined the timing of fMRI and EEG changes in seizures with impaired compared with spared behavioral responses. Mean seizure duration was longer for seizures with impaired behavior (7.9 seconds compared with 3.8 seconds for seizures with spared behavior; P <  .0001). However, larger-amplitude fMRI and EEG signals occurred at the outset or even preceding seizures with behavioral impairment.

Previously, experts believed that longer seizures cause more problems because they have more time to accumulate abnormal activity and lead to a more severe seizure.

"We were surprised to find that it wasn't that the longer the seizure lasts, the more abnormal the brain becomes during the course of the seizure," said Dr Blumenfeld. "It turns out that at the beginning of the seizure — right at the outset, right when it starts, and even possibly before it starts, we see a bigger signal on fMRI activity, and the EEG activity starts at bigger rates."

Researchers don't understand why some seizures and not others cause the abnormal, intense brain activity in widespread areas of the brain.

"But we do know that something happens at the triggering point, at the beginning of the seizure, that leads some seizures to be more severe than others," said Dr Blumenfeld. "It may be something about the state of the brain or it may be something about the networks and their synchrony that's different right at the very beginning."

Furthermore, there may be periods when patients are more vulnerable to loss of consciousness during seizures than at other times, he said.

Being able to distinguish which seizures alter consciousness has implications in clinical practice.

"For example, if we can learn enough about which seizures based on EEG or fMRI are the ones that do or don't impair consciousness, when kids reach driving age, this might help guide us. But we're going to have to learn more to get to that point," said Dr Blumenfeld.

Eventually, he said, neurologists may be able to bypass behavioral tests and rely solely on EEG to determine whether a patient is fit to drive.

Comprehensive Study

Commenting on the findings for Medscape Medical News, Robert S. Fisher, MD, PhD, director, Stanford Comprehensive Epilepsy Center, Stanford University, California, said the researchers have "delivered a carefully done and very valuable study correlating behavior, fMRI, and EEG during absence seizures. Aspects of these correlations have previously been addressed, but never comprehensively in a large and unbiased sample."

Dr Fisher agreed that the findings alter the traditional view of absence seizures. "It's no longer plausible to view 'generalized' epilepsy as whole-brain epilepsy but rather as engagement of specific networks involving both sides of the brain.  The resting state default mode, the task-oriented and the thalamo-sensory networks are all impaired during seizures with behavioral deficits, whereas in normal behavior these networks often operate reciprocally."

The networks are more suppressed, after a brief period of activation, during seizures with behavioral impairment, and the fMRI changes may even precede behavior and EEG alterations, said Dr Fisher.

This new study also challenges the notion that duration determines impairment during absence seizures, he added.

"The relationship apparently is not that simple, in that both short and long absence seizures divide into those with significant and insignificant impairment."

Dr Fisher also agreed that further characterization of the networks involved in impairment of behavior during absence seizures might point to therapies that could partially normalize network activity and minimize the negative impact of absence seizures.

The authors have disclosed no relevant financial relationships.

Lancet. 2016;15:1336-1345. Abstract

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