Thursday, December 7, 2017

Brainstem network disruption in focal epilepsy and sudden unexplained death in epilepsy

 AES [2017] Abstract 3.205: Mueller SG, Nei M, Bateman L, et al. Evidence for a brainstem network disruption in focal epilepsy and sudden unexplained death in epilepsy: A first validation study.

The symptoms in witnessed Sudden Unexplained Death in Epilepsy (SUDEP) suggest a breakdown of the central autonomic control. A previous MR study found evidence for structural damage in the mesencephalon in focal epilepsy that was more severe and extended into the lower brainstem in two patients who later died of SUDEP. Mesencephalon and medulla oblongata are both involved in autonomic control. The purpose of this study was 1. to expand the previous study by demonstrating an association between brainstem damage in focal epilepsy and reduced heart rate variability (HRV) as a proxy of autonomic control. 2. to replicate the findings of more extensive brainstem damage in a larger population of SUDEP patients.
Two populations were studied: 1. Autonomic population (18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3T MR exams. 2. SUDEP population (27 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion (sigExcROIs).
The total sigExcROIs counts in the autonomic population were negatively correlated with HRV (r=-0.37, p=0.03), sigExcROis counts in periventricular gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r2=-0.82/0.67, p2=-0.60/0.35,p=0.001).
These findings confirm those of the previous study and suggest that MRI can detect potentially life threatening brainstem damage years before SUDEP and thus might be used as biomarker to identify patients at risk of SUDEP due to epilepsy-associated brainstem m damage.
Supported by U01NS090406-02 to AMG and UCSF REAC and Epilepsy Foundation award 325981 to SGM

Patients who died of sudden unexplained death in epilepsy (SUDEP) had magnetic resonance imaging (MRI) suggesting widespread loss of volume in the brainstem compared to healthy controls, and more extensive volume loss correlated with the survival time of the patients, according to findings presented here at the annual meeting of the American Epilepsy Society.

"It's the first study to show in humans who died of SUDEP that they actually have something going on in their brainstem," said Susanne G. Mueller, MD, associate professor in the department of radiology and biomedical imaging at the University of California, San Francisco (UCSF), who presented the findings.

Despite research that has found potential biological pathways involved in SUDEP, the critical triggers for SUDEP are still unclear and few biomarkers can be used to pinpoint the mortality risk of individual patients.

Researchers from UCSF and other centers studied the brain MRIs of 18 patients with seizures of focal temporal or fronto-temporal onse, 11 healthy controls, and 27 SUDEP cases for whom a suitable MRI had been done within the previous 10 years before death.

At the time of analysis, the patients with epilepsy were on average 40 years old and the healthy controls, 31 years old.

Those who had SUDEP were on average 23 years old at the time of their last MRI, with a median time from the last MRI to SUDEP of 4.2 years. Their MRIs showed they had volume loss in the autonomic nuclei and raphe nuclei, primarily responsible for serotonin production. They also found that brainstem volume loss in regions of autonomic control was associated with lower heart-rate variability (p=0.03) — a sign that focal epilepsy could lead to brainstem changes that cause problems with autonomic control.

Widespread brainstem volume loss was evident in the last MRIs before the SUDEP patients had died compared with healthy controls.

"The combined structural change as detected on the imaging in regions encompassing autonomic and raphe nuclei explained most of the variation of time to SUDEP," researchers wrote. "These observations suggest that focal epilepsy is associated with structural changes in the mesencephalic region and expansion of this structural change into the medulla oblongata may affect nuclei involved in autonomic control."

Dr. Mueller said the eventual goal should be an ability to stratify patients as low-risk, moderate-risk, which might require occasional MRI monitoring, and high-risk who, ideally, would get medical intervention to lower their SUDEP risk.

Dr. Mueller acknowledged that, due to the nature of SUDEP, there are limitations with the comparisons — the MRIs were not all conducted using the same machines and the imaging is just an approximation of volume loss, for instance.

She also noted that there is "probably not just one type of SUDEP," but several, including some types with more of a distinct genetic underpinning.

Jeffrey R. Buchhalter, MD, PhD, FAAN, the director of the Comprehensive Children's Epilepsy Center at Alberta Children's Hospital, who has studied SUDEP, said the study is an important step forward.

"These findings are of potentially great importance as the results provide a link between SUDEP, heart rate variation, and brainstem damage," he said. "As SUDEP is a fortunately rare event, it is particularly difficult to demonstrate physiological and/or anatomic changes in life that may identify who is at greatest risk of premature mortality."

He said the study is limited by its small numbers of patients, but it shows that the presence of age-adjusted heart-rate variation with or without brainstem changes could serve as biomarkers of SUDEP.

"The importance of biomarkers cannot be understated," Dr. Buchhalter said, "as these could lead to more aggressive therapeutic interventions, implementation of seizure detection devices, and targets for SUDEP prevention other than seizure control."

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