Brain research, neurosurgical care focus on seizures
By Jennifer Brown
A random, electrical “hiccup” from a few neurons triggers a chain reaction of uncontrolled electrical discharges that can spread throughout the brain, disrupting areas that control vital functions like moving, thinking, and breathing.
This is a brain caught in a seizure. When it happens, the body’s response can range from an almost imperceptible lapse of awareness to a dramatic loss of body control, including spasms and unconsciousness—frightening to witness, let alone experience. Yet even in a physically severe seizure, the brain generally self-corrects, eventually calming the electrical storm. The common advice for managing a seizure is to ensure the individual is safe and simply let the seizure run its course.
“Most people think of seizures as relatively benign,” says George Richerson (’87 MD/PhD), chair and department executive officer of neurology at the University of Iowa Carver College of Medicine. “The seizure itself is not considered dangerous unless it progresses into status epilepticus—defined as a single prolonged seizure or frequent seizures without recovery in between—which can be deadly and requires urgent treatment.”
Because of its physical effects, a major seizure can create potentially dangerous situations—injuries from falls or accidents while driving, for example—but another, more insidious consequence of seizures can be even more devastating and is much less well-known: sudden unexpected death in epilepsy (SUDEP).
Despite estimates that up to six people in America die each day from SUDEP, the condition remains under-recognized, even among physicians who treat patients with epilepsy, according to Richerson, the Roy J. Carver Chair in Neuroscience who is internationally known for his research on brain pathways that control breathing.
Overlooked cause of death
Epilepsy, or chronic seizure disorder, is diagnosed when a person has two or more unprovoked seizures. It affects almost 3 million people in the United States and 60 million worldwide. The condition can arise early in childhood, often due to brain infections or genetic abnormalities, or it can start later in life, often following brain trauma. In about two-thirds of cases, epilepsy can be successfully managed with medications or a special diet. However, about a third of patients (about 15,000 people in Iowa) have refractory epilepsy that cannot be well controlled with two or more medications. These patients may be helped by surgery to remove the brain tissue where the seizures start, or with implanted devices that disrupt the abnormal electrical activity that causes seizures.
SUDEP is a significant cause of premature death in people with epilepsy, with estimates that it causes up to 17 percent of all deaths in patients with epilepsy and up to half of all deaths in patients with refractory epilepsy. Yet SUDEP, which primarily strikes young, seemingly healthy adults, was formally defined as a cause of death only about 20 years ago. Understanding of the condition is still very limited.
The risk of SUDEP is higher in people who have frequent, uncontrolled seizures or generalized convulsive (tonic-clonic or “grand mal”) seizures. And a recent study of mortality in epilepsy monitoring units provided the first clear evidence that death in these cases is caused by seizure-induced disruption of life-sustaining respiratory or cardiac function.
There are only two ways to die: The heart stops beating or a person stops breathing. Much of published research investigating SUDEP has focused on seizure-related cardiac abnormalities, which clearly have the potential to be fatal. However, evidence is building that also implicates seizure-induced breathing abnormalities as another likely cause of SUDEP.
The concept that seizures interrupt breathing is not new. British physician Hughlings Jackson noted in 1899 that patients turned blue during an epileptic seizure. But what hasn’t been appreciated until much more recently is how common this apnea is and that it can occur even with mild seizures.
“It turns out that even a small, benign, ‘bland-looking’ partial seizure—where a person just pauses and stares off and maybe smacks their lips a little—can also stop breathing and allow a patient’s blood oxygen levels to drop dangerously low,” says Mark Granner (’87 MD), UI professor of neurology and neurosurgery and director of the Epilepsy Monitoring Unit at UI Hospitals and Clinics. “It is much more common than we previously realized.”
Breathing, serotonin, and SUDEP
Richerson has a long-standing interest in the neural mechanisms that control respiration. His work has shown that neurons in the brainstem that make and release the neurotransmitter serotonin are required for normal breathing responses. These serotonin neurons, which are positioned close to the major artery serving the brainstem, monitor and respond to increased carbon dioxide and decreased pH levels in blood.
Under normal circumstances, accumulation of too much carbon dioxide in the blood triggers increased respiration. Studies in mice show that when carbon dioxide levels increase, serotonin neurons fire more rapidly and breathing rates increase. Richerson’s research showed that mice with near complete loss of serotonin neurons in the brainstem had a 50 percent lower ventilation response to high carbon dioxide as compared to “control” mice.
While serotonin neurons in the brainstem seem to be critical for normal breathing, Richerson’s work also suggests that serotonin neurons in a different part of the brain play a role in another mechanism that can restore normal breathing.
“Our current model for what is happening is this: Carbon dioxide causes serotonin neurons to be activated in the medulla in the base of the brain, which causes you to increase breathing. At the same time, midbrain serotonin neurons are also activated, which activates the cortex and wakes you up—that’s arousal,” he explains. “Both mechanisms protect against suffocation. If either is disrupted, it would increase the risk of death from asphyxiation.”
Serotonin abnormalities have also been linked to another syndrome involving sudden unexpected death. Work by Hannah Kinney, MD, at Harvard, one of Richerson’s colleagues from his time at Yale, showed that sudden infant death syndrome (SIDS) is associated with serotonin abnormalities.
In both SUDEP and SIDS, deaths often occur at night during sleep and with the individual lying face down. Additionally, the two conditions occur in seemingly healthy individuals, and the exact cause of death is difficult to determine.
Animal models are helping Richerson’s team and others unlock these neural mechanisms that might contribute to SUDEP and SIDS. However, a rare intersection of brain research and neurosurgical care for patients with epilepsy exists at the UI that may help move the studies beyond mice and allow researchers to test, in humans with epilepsy, ideas generated in the animal studies.
The UI is home to the Human Brain Research Laboratory (HBRL), led by Matthew Howard, MD, chair and department executive officer of neurosurgery. Comprised of a multidisciplinary group of scientists and physicians, including members from universities across the country and around the world, the HBRL team uses direct recordings of neural activity from inside humans’ brains to investigate sensory, perceptual, and cognitive processes related to hearing, speech, language, and emotion.
Only a few groups in the world have the expertise and collaborative infrastructure to conduct these experiments. It is possible because patients undergoing invasive brain mapping in preparation for epilepsy surgery also volunteer to participate in research studies. Howard and his team at the UI conduct their research with about 15 such epilepsy surgery patients each year.
Brain surgery to remove the seizure focus can sometimes be used to treat refractory epilepsy. A subset of these patients requires specialized electrodes to be inserted into their brains to identify the location of the seizure and ensure that removal of the abnormal tissue will not damage vital brain functions. Once the electrodes are placed, the patient spends a week or more in the UI Epilepsy Monitoring Unit as neural activity is continuously recorded. During this brain-mapping period, there is a good deal of “down time,” so many of the patients volunteer to participate in studies that allow HBRL researchers to piggyback on the implanted electrodes’ unique recording capabilities.
“We are putting a recording platform into the patient’s brain for clinical purposes and we can modify it without changing the risk of the surgery. This allows us to understand functions in the brain in a way that is impossible to do with any other approach,” Howard says.
“The patients are the real heroes of the research program,” he adds. “They need the operation, but participating in the research aspect is completely voluntary. Almost all the information gathered helps mankind but doesn’t help the patient directly. It requires a generosity of spirit to participate, because many of the experiments involve hard work on the part of the patient, participating in different (cognitive) tasks for an extended period of time.”
Howard and his team, along with Granner and his colleagues in the UI Epilepsy Monitoring Unit and Brian Gehlbach, MD, of the pulmonary division of internal medicine, are now collaborating with Richerson to test his ideas regarding possible causes of SUDEP.
By monitoring patients with the specialized electrodes, the team has learned that when a seizure affects a particular region of the temporal lobe, breathing is interrupted.
“We think there are neurons in this location that have direct projections to the medulla and cause inhibition of serotonin neurons. The serotonin neurons are shut down, which stops their normal function of stimulating breathing,” Richerson says.
The evidence is still preliminary, but the team is excited by the new findings and what they might mean for understanding SUDEP.
Evolving monitoring units
Evidence is accumulating from UI studies in both animal models and human patients suggesting that inhibited breathing coupled with an abnormal arousal response to increased carbon dioxide may be involved in SUDEP. Richerson hopes that a better understanding of the effect of seizures on breathing and arousal will ultimately help physicians identify which patients are most at risk for SUDEP and even suggest interventions or therapies that may prevent it.
For now, though, the UI physicians are taking what they’ve already learned and using it to raise awareness of the dangers of SUDEP among physicians treating epilepsy and among families affected by the condition. They also aim to change care practices in epilepsy monitoring units to improve patient safety.
“Just knowing that breathing is affected by seizures changes how we communicate with patients and physicians,” Richerson says. “I want physicians to know that if they have a patient whose seizures are not being well controlled with multiple medications, they should try a different treatment strategy, because that patient is at risk for SUDEP.”
Recognition of breathing problems during even mild seizures has also led to increased monitoring of respiration in the UI Epilepsy Monitoring Unit, as well as testing of different devices for monitoring respiration. The UI team is also working to establish new standards for patient care that reflect the new knowledge about SUDEP.
“We are using this information to design an even safer epilepsy monitoring environment,” Granner says. “We are moving toward an epilepsy monitoring unit that looks a little bit more like an intensive care unit, with the proper number of nurses and specialists who monitor seizures and respiration—not just recording EEGs, but also recording heart and breathing activity.
“I think that’s the future of these monitoring units across the country. It will be a more intensive care environment,” Granner adds. “We are hoping to lead that effort. Developing a much safer, more modern epilepsy monitoring unit is something we are helping to do.”
Multinational teams take unique peek at brain activity
By Jennifer Brown
Glance at a person’s face and your brain makes a near instantaneous assessment: friend or foe. The cognitive processing behind this decision is complex. Information must travel from the eyes to the visual cortex at the back of the brain, then the signals move to neurons in the frontal lobe where the “decision” is made. Despite the complexity, it happens astonishingly fast—on the order of 150 milliseconds.
A University of Iowa team was able to measure the speed so precisely because the researchers had a unique window into real-time neuronal activity—a way to directly record the activity of the neurons responsible for the final decision.
Using specialized electrodes implanted into the brains of patients preparing for epilepsy surgery, researchers at the Human Brain Research Laboratory (HBRL) can make these direct neural recordings from inside the human brain, right down to the level of a single neuron’s firing.
“The clinical recordings involve detecting signals that are generated by thousands of neurons. But with the modified fine wire contacts (on the electrodes), we can also, for research purposes, look in on the firing properties of individual cells. This allows us to understand functions in the brain in a way that is impossible to do with any other approach,” explains Matthew Howard, MD, chair and department executive officer of neurosurgery and director of the HBRL.
Investigators in departments across the UI are members of the HBRL, which also has collaborators at the University of Wisconsin (Madison), California Institute of Technology, Albert Einstein College of Medicine, New York University, Northwestern University, Newcastle University in England, University of London, and National Cheng Kung University and National Chiao Tung University, both in Taiwan.
With these multidisciplinary, multinational teams focused on understanding visual and auditory processing, neuroeconomic decision-making, and sensory-motor integration, the HBRL is already a powerful global research program. Howard plans to increase its impact by providing more scientists access to the UI’s rare neuronal recordings that offer a unique perspective on human brain activity.
“We want to link our direct neuron recordings with (brain imaging) techniques that are more readily available,” Howard says. “I think that will spread the impact of the work when we have patients who participate in noninvasive imaging studies that many groups around the world can do, but then for those same patients, we also do the direct recordings. It will give other research teams insight into how to interpret findings from their noninvasive functional brain imaging studies.”
The National Association of Epilepsy Centers recognizes the Iowa Comprehensive Epilepsy Program (ICEP) as a Level 4 Epilepsy Center with the professional expertise and facilities to provide the highest-level medical and surgical evaluation and treatment for patients with complex epilepsy.
The ICEP offers a full range of diagnostic and treatment options, including initial evaluation, long-term management of drug-resistant cases, and surgical therapy—for infants to older adults, as well as special patient populations including aging, pregnant, and developmentally disabled patients.
The ICEP includes:
- Four clinical adult epileptologists, two pediatric epileptologists, and three epilepsy surgeons
- A large team of scientists studying causes and treatments of epilepsy, including sudden unexpected death in epilepsy (SUDEP)
- One of the first five electroencephalography (EEG) laboratories in the country, which performs more than 1,000 EEG studies a year
- Nine-bed adult and five-bed pediatric epilepsy monitoring units providing continuous 24/7 monitoring of video, EEG, and vital functions, as well as a full range of electrodiagnostic techniques, including intracranial electrodes
- Advanced neuroimaging services, including CT, PET, and 3T MRI with dedicated seizure protocols
- Ketogenic diet program directed by a multidisciplinary team (dietitian, nurse, pharmacist, and physician) that administers this high-fat diet found to reduce and sometimes eliminate seizures
- Researchers who have applied to secure a clinical trial site at the UI for testing cannabidiol (a marijuana-derived compound) as a treatment for epilepsy seizures