WASHINGTON, DC — MRI of the brain can detect potentially life-threatening brainstem damage in patients with epilepsy, suggesting the test could be used as a biomarker to identify those at risk for sudden unexpected death in epilepsy (SUDEP), new research shows.
“When we looked at the brain stem of people who died from SUDEP, we saw that they had volume loss in certain regions of the brain stem, and those regions are involved in autonomic control, so control of breathing and heart beats, et cetera”, lead author, Susanne Mueller, MD, associate professor, radiology and biomedical imaging, University of California, San Francisco (UCSF), told Medscape Medical News.
The investigators found similar, but less severe, damage in patients living with epilepsy.
The findings were presented here at the American Epilepsy Society (AES) 71st Annual Meeting 2017.
Structural Damage
A previous smaller MRI study carried out by the same group of researchers showed evidence of structural damage in the mesencephalon that extended into the lower brainstem in patients with focal epilepsy who later died of SUDEP.
The mesencephalon and medulla oblongata are involved in autonomic control — heart rate and breathing. Researchers suspect that ill-controlled seizures may cause damage in this area.
Dr Mueller aimed to get more details of the brain stem involvement and to see whether patients with epilepsy who don’t die of SUDEP also have brain stem changes.
“We wanted to know if this is a feature of normal epilepsy, whether everyone with epilepsy has it, and it has no relationship with SUDEP,” said Dr Mueller.
Researchers studied two populations. The first included 18 patients with focal epilepsy aged 21 to 60 years and 11 healthy age-matched controls who had heart rate variability (HRV) measurements, which is a proxy for autonomic control, and MRI exams. The second group included 27 patients who died of SUDEP at ages 1 to 45 years for whom MRI had been performed 1 to 10 years previously.
The epilepsy group was “across the board” in terms of seizure status, said Dr Mueller. “But most were doing quite well. In some, seizures were completely controlled with medicine, and some had rare seizures.”
Dr Mueller used a complicated series of calculations (sigExcROIs counts) that over a certain statistical threshold indicated volume loss in certain brain areas.
Results showed that patients with epilepsy had mild damage in the mesencephalon.
“We can see changes that indicate that the structure is no longer normal, even though we can’t say exactly what’s going on. Is it some kind of malformation? Is it scarring? That’s still unknown,” said Dr Mueller.
Brain Stem Changes
The brain stem changes in the epilepsy group were a little different from those in the patients who died of SUDEP. The SUDEP patients had more damage and it extended to several parts of the brain, including the medulla oblongata in the brain stem.
Dr Mueller said she was “excited” that her team was able to show “something is going on in the brain stem in humans with epilepsy, and not just in animals.”
In the past, researchers believed that patients with focal epilepsy have a problem in the specific region of the brain where the seizure arises, said Dr Mueller. “The idea was to find the focus because you could resect it and patients would then become seizure free.”
But over the last few years, as imaging has progressed, “we found that even focal epilepsy is not really focal,” she added. “When you have epilepsy, other regions are also altered, and the brain stem is obviously one of those regions.”
It could be that uncontrolled seizures affect brain cells, leading to brain volume changes. “So it might be secondary to having seizures; that’s what most of us think is going on,” said Dr Mueller.
An alternative explanation is that patients with epilepsy “have a brain that’s not completely normal” right from the beginning, that it’s “something like a birth defect,” she said.
“I can’t exclude this second possibility even though I personally believe the first, that this is something that develops over the years.”
This research is important as patients with epilepsy want to know what SUDEP risk they face. “What they’re looking for is something that tells them ‘you’re not at risk; you’re doing fine,” said Dr Mueller.
But as it stands, “if you have epilepsy, you’re basically being told your seizures might be killing you.”
Potential Biomarker
These results need to be replicated, but down the road, Dr Mueller envisions some kind of MRI “biomarker” that could signal brain stem damage.
Patients with epilepsy already typically undergo regular MRIs if they’re unresponsive to medication. They may have a type of imaging that can more closely analyze whether brain stem damage is progressing.
“That kind of a dedicated MRI gives us more information about what’s going on in that region,” said Dr Mueller.
She emphasized that the brain stem has to appear on several MR images, and not just on one or two slices.
Speaking “very futuristically,” Dr Mueller said a treatment in the form of a “brain pacemaker” may help protect the brain.
“For whatever reason, after a seizure, this region stops working and is not coming back online, so maybe it’s possible to kick it a little bit, to bring it back to life.”
Research with a mouse model susceptible to SUDEP uncovered an imbalance of potassium, said Dr Mueller. Assuming that’s the case, “if you give some kind of electric impulse to keep the region going, or maybe do some kind of vacuuming to take away this superfluous potassium, you might bridge the time to when the patient dies of SUDEP — or prevent seizures.”
This implanted pacemaker approach, which basically attempts to “kill the seizure when it’s building up” in the brain, is being tested in humans, said Dr Mueller.
Data show that 1 in 1000 adults and 1 in 4500 children with epilepsy die of SUDEP every year.
A Big Step Forward
Commenting on the study for Medscape Medical News, Eli M. Mizrahi, MD, AES president, and chair, Department of Neurology, and professor of neurology and pediatrics, Baylor College of Medicine, Houston Texas, praised the authors for helping move the field from discussion to evidence.
“People who have studied SUDEP have suspected that there may be some brain stem issues, but this takes a step towards actually providing real evidence, and I think that’s important.”
The research also highlights the cooperative effort between institutions, said Dr Mizrahi. Researchers who contributed to the study are based at Thomas Jefferson University, Columbia University, NYU Langone Medical Center, Baylor College of Medicine, and UCSF.
A single institution may not have all the expertise to address a complex problem. New funding mechanisms, said Dr Mizrahi, “allow people to reach out to different centers around the country to create a single center with like-minded folks to bring that expertise together, without having them all be in the same geographic area.”
Other research presented at the AES meeting identified factors that might increase the SUDEP risk. These include prior status epilepticus (odds ratio [OR] of 7.83 for SUDEP cases vs controls matched for age, epilepsy duration, and sex), prior epilepsy surgery (OR, 4.23), and taking several antiepileptic drugs (OR, 4.7).
The study was funded in part by grants from the UCSF Research Evaluation and Allocation Committee fund and the Epilepsy Foundation. Dr Mueller and Dr Mizrahi have disclosed no relevant financial relationships.
American Epilepsy Society (AES) 71st Annual Meeting 2017. Abstract 3.205 and Abstract 3.187. Presented December 4, 2017.
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