Frontal Lobe Glucose Abnormalities May Flag SUDEP Risk

Pauline Anderson

May 15, 2020

Certain patterns of frontal lobe glucose hypometabolism may be associated with higher risk for sudden unexpected death in epilepsy (SUDEP) among patients with refractory focal epilepsy, new research suggests.

"The data provide initial evidence that hypometabolism in certain parts of the frontal cortex may be associated with higher SUDEP risk," author Maysaa M. Basha, MD, associate professor of neurology and director of the Adult Comprehensive Epilepsy Program, Wayne State University/Detroit Medical Center, in Michigan, told Medscape Medical News.

If this research is validated, "it potentially can be used to screen patients for higher SUDEP risk," said Basha.

The idea is to identify those at high risk and then reduce that risk with more aggressive management of seizures or closer monitoring in certain cases, she added.

The research is being presented on AAN.com as part of the 2020 American Academy of Neurology (AAN) Science Highlights. The meeting, originally planned for April 25 to May 1 in Toronto, Canada, was canceled because of the COVID-19 pandemic.

Hypometabolism

Basha and colleagues were encouraged to pursue this new line of research after a pilot [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) study revealed frontal lobe hypometabolism among patients who subsequently died.

"We wanted to determine if such a metabolic abnormality is associated with SUDEP risk," said Basha. She noted that no PET studies have addressed this question, only MRI studies.

In this new study, researchers aimed to identify specific patterns of objectively detected brain glucose metabolic abnormalities in patients with refractory focal epilepsy who were at risk for SUDEP.

The study included 80 patients (45 female patients) aged 16 to 61 years (mean age, 37 years) who underwent FDG-PET as part of their presurgical evaluation for epilepsy surgery. Patients with large brain lesions, such as an infarct or a large tumor, were excluded from the study; such lesions can affect the accuracy of an objective PET analysis, explained Basha.

The researchers assessed risk for SUDEP using the seven-item SUDEP inventory (SUDEP-7), which was developed as a marker of clinical SUDEP risk. The 0- to 10-point scale is used to evaluate the frequency of tonic-clonic and other seizures, the duration of epilepsy, the use of antiepileptic drugs, and intellectual disability.

The researchers calculated SUDEP-7 inventory scores as closely as possible to FDG-PET assessments. The mean score in the patient population was 3.6.

The investigators divided participants into two subgroups: 22 patients had a SUDEP score of 5 or greater; and 58 had a score of less than 5 (higher scores indicate higher risk for SUDEP).

The researchers compared PET scans of each of these subgroups to PET scans from healthy adults to determine whether they showed common areas of metabolic abnormality. For this, they used an image analytic software program called Statistical Parametric Mapping, which compares group values of metabolic activity measured in small units of the brain (voxels) with statistical methods.

The analysis showed that the higher-risk group displayed a common pattern of hypometabolism in certain brain areas.

"The epilepsy patient subgroup with high SUDEP risk showed areas of decreased metabolism, as compared to the control group, in portions of the frontal cortex," said Basha. "The statistically most significant decreases were in the right frontal lobe area ― both lateral convexity and medial cortex."

Basha added that these group abnormalities were "remarkably similar" to the individual metabolic abnormalities found in the four SUDEP patients in the previous pilot study who underwent PET scanning and who subsequently died.

A similar group analysis showed that the group at low SUDEP risk displayed no common metabolic abnormalities.

MRI findings were normal for 40 patients.

Basha and colleagues believe that "this is the first PET study assessing the metabolic correlates of SUDEP risk on the group level."

Common Feature

Interictal glucose hypometabolism is "common in and around epileptic foci," noted Basha. However, this could extend into nonepileptic regions ― for example, to remote connected regions where seizures can spread from the primary focus and into subcortical gray matter structures, such the thalamus.

Some of these metabolic abnormalities may indicate subtle, microscopic, structural abnormalities in the affected brain, said Basha.

Abnormalities that are induced by epilepsy and that result from purely metabolic changes could be partly or fully reversed if seizures are controlled on a long-term basis, she said. "Some metabolic abnormalities can be reversed after better seizure control with antiepileptic drugs, epileptic surgery, or other antiepileptic treatment," she said.

It's "quite possible" that the same brain pattern would be evident in children with epilepsy, although her team has not performed the same analysis in a younger pediatric group, said Basha.

She noted that it would be unethical to administer PET scans, which involve radiation, to young, healthy control persons.

It's too early to recommend that all epilepsy patients undergo FDG-PET scanning to see whether this pattern of brain glucose hypometabolism is present, said Basha. "But if this is proven to be a good biomarker, the next step would be a prospective study" to see whether this brain marker is a true signal of SUDEP risk.

"I don't think our single study would do that, but ultimately, that would be the goal," she added.

Commenting on the study for Medscape Medical News, William Davis Gaillard, MD, president of the American Epilepsy Society and chief of neurology, Children's National Medical Center, Chevy Chase, Maryland, said this new information provides one more piece of the SUDEP puzzle but doesn't complete the picture.

The study authors assessed PET scans of a group of patients and found common abnormalities that implicate the right medial frontal cortex. "That's a pretty reasonable method" of investigation, said Gaillard.

"The challenge is that they're looking at people they believe have a risk of SUDEP as opposed to people who died," said Gaillard.

But he agreed that the results might signal "a biomarker" that "allows you to identify who's at high risk, and then you may be able to intervene to save them."

It's not clear that people with frontal lobe epilepsy are at greater risk for SUDEP than those with temporal lobe epilepsy, he said.

"What you don't know is whether this represents people with a seizure focus in that area or this represents a common network implicated in people with diverse forms of focal epilepsy; so you need to do some more work," he said.

Gaillard pointed out that other research has implicated regions other than the mesial frontal cortex in SUDEP risk. These regions include the insula, the amygdala, the hippocampus, and the brain stem.

He also noted that the SUDEP-7, which has not been thoroughly validated, is designed for use only in adults.

In his own practice, he asks patients about the frequency of tonic-clonic seizures and whether they occur at night. The number of antiepileptic medications a patient takes reflects the difficulty of controlling seizures and may not be "an independent variable for risk," said Gaillard.

"It's clear one needs a better assessment and better idea of who is at risk," he said.

The researchers have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2020 Annual Meeting. Abstract S59.003.

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