Content:
RATIONALE:
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.
METHODS:
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).
RESULTS:
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).
CONCLUSIONS:
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.
FUNDING:
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."
http://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersAESAnnualMeeting/pages/post.aspx?PostID=28&cid=HLRP-Other-2017-SOC-AANConference-Region-Neurology-ProdID-Promo-Email-id=4449104&mkt_tok=eyJpIjoiWVRabU1tVmpOalUzWkRFdyIsInQiOiJhdFE5cWlvZTE5UUJpNG1lclpSN2ZQV20zaEYxUWRWNEtDdUxKSnRwOTFcL0lOZUYwY1R3Tys5RVlzWWhsd2lJY1wvbXRUSHRDUW83Tzl4TEh6TCtWd2ZYMnJaVm9NVXA1ZkVMNnVSa2Y5M1B4cjJZK1VcL25FQTFpbG9xN29qZ3ZLXC8ifQ%3D%3D
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