Prolonged Status Epilepticus Linked to Brain Atrophy

Pauline Anderson

September 12, 2016

Patients with very prolonged "super refractory" status epilepticus (SRSE), defined as seizures that continue or recur for at least 24 hours after initiation of general anesthetic therapy, develop brain atrophy, and some quite pronounced atrophy, a new retrospective study suggests.

The analysis showed that atrophy was more likely to develop in patients with a longer hospitalization and duration of anesthetic treatment, but surprisingly, atrophy did not correlate with functional outcome.

"Our main finding was that the development of atrophy seems to be widespread; it seems to be more the rule than the exception," said lead author Sara Hocker, MD, associate professor, neurology, Mayo Clinic, Rochester, Minnesota.

Dr Sara Hocker

However, Dr Hocker stressed that the study was small and had several limitations.

"Until we know more about who develops atrophy and why, where the atrophy is, and what it means for the long-term outcome of the patient, we should not be making life and death decisions based on the presence of atrophy alone," she told Medscape Medical News.

Their findings were published online August 15 in JAMA Neurology.

The study included 19 adult patients with SRSE (median age, 41 years) who were treated at the Mayo Clinic. They had undergone initial brain MRI within 2 weeks of SRSE onset and a second MRI at least a week after the original scan and within 6 months of the resolution of SRSE.

The most common cause of SRSE (6 cases) was central nervous system infection, with other cases linked to a variety of other causes, including fever or systemic infection, and stroke.

Anesthetic agents were required for a median of 13 days in study patients. Hospital length of stay extended for a median of 40 days.

All patients underwent continuous electroencephalographic monitoring from the time of status epilepticus diagnosis to the time of its resolution, transition to palliative care, or death.

Atrophy Assessment

To assess cerebral atrophy, researchers used ventricular brain ratio (VBR), which is calculated as the area of the lateral ventricles divided by total area of the brain. They used a percentage change in VBR to quantify change in brain volume between the two scans.

The median VBR in study patients was 0.06 on the initial scan and 0.08 on the follow-up scan. In all 19 patients, brain atrophy developed between the two scans. The median change in VRB was 23.3%.

The researchers were unable to sort out the cause of the atrophy, but according to Dr Hocker, it could have been due to "disuse" (the brain is just not being used) or the anesthesia used to treat the SRSE "having a toxic effect on cells over time."

The study showed that the amount of brain atrophy was positively correlated with duration of anesthetic therapy (P = .02) and the duration of hospital stay (P =.003), but it was too small to detect a difference in atrophy between the different anesthesia drugs used to control SRSE.

Atrophy was negatively associated with patient age (P = .04), the researchers note.

Functional outcome was measured with the modified Rankin Scale (mRS). The median mRS score was 1 before admission, 5 at hospital discharge, and 6 at the last available follow-up. The amount of atrophy was not correlated with mRS score.

However, Dr Hocker pointed out that the mRS is "a very rudimentary measure of function" and that many other variables, for example, withdrawal of care, were not controlled for.

"I wonder whether in future, within a large group of patients in a prospective study where MRIs are done at regular prespecified time points and other variables, like what type of drug is used, for how long, and at what dose, are documented, we might be able to sort those things out," said Dr Hocker.

"We might see that that there is a relationship between the functional outcome in survivors and the degree of atrophy."

Among the 19 patients, 6 were transferred to palliative care during their hospital stay. At the 1-year follow-up, 8 patients had died, 5 were lost to or unavailable for follow-up, and 6 were alive.

Missing Pieces

One of the "missing pieces" in this and other studies of SRSE is information on cognitive outcome, said Dr Hocker. "So we don't know how many patients are going back to work or have problems with, for example, anxiety or depression."

Although the finding regarding atrophy "is preliminary and has limitations and needs validation," Dr Hocker sees her study a "launching pad" for further research.

She and her colleagues are in the early stages of planning a prospective multicenter study of atrophy in SRSE.

In an accompanying editorial, Andrew J. Cole, MD, Epilepsy Service, Massachusetts General Hospital, Boston, said he found it curious that the authors didn't provide a table of case-wise data. This, he writes, makes it difficult for readers "to inspect the case-by-case association" between the degree in change in VBR and duration, etiology, treatment, "or even age of the specific patients."

Dr Cole thought it "particularly surprising" that there was a poor correlation of VBR change with mRS score.

"Two possibilities are that extrinsic variables such as etiology or specific anesthetics used, or intrinsic patient-specific characteristics are more powerful determinates of functional outcome than the degree of observed apparent relative brain atrophy compared with baseline assessment."

Dr Cole pointed out that although the approximate 25% change in VBR is "striking," it does not imply a 25% loss of brain volume. VBR, he said, may change as the result of an increase in ventricular area, a decrease in whole brain area, or a combination of both.

"It would have been instructive for the authors to provide a table listing the actual measured ventricular and whole brain areas, along with some measurement of interobserver variability, to allow the reader to better consider the significance" of the observed changes in VBR," he writes.

Another limitation of the study is the lack of serial scans, beyond the requisite acute and post-treatment studies.

"Because the primary outcome measure is dependent on the assessment of lateral ventricle area on a single slice, assessing the possibility that increased ventricular area is transient, perhaps due to altered cerebrospinal fluid pressure dynamics, would be important," Dr Cole concluded. "Equally interesting is the question of whether whatever process underlies the apparent atrophy acquired during treatment progresses beyond the acute phase."

Dr Hocker reports serving as a coinvestigator and consultant for a clinical trial involving allopregnanolone for SRSE, sponsored by SAGE Therapeutics. Dr Cole reports serving as the chairman of the clinical advisory board and a paid consultant to SAGE Therapeutics.

JAMA Neurol. Published online August 15, 2016. Abstract, Editorial

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