CURE Discovery: Safe, Quick Measurement in Epilepsy Monitoring Units (EMUs) Has Potential To Identify SUDEP Risk

When the body detects high carbon dioxide (CO₂) levels in the blood, a condition known as hypercapnia, it responds by moving more air through the lungs. This increased ventilation helps remove the excess CO₂. Research by CURE grantee Dr. Rup K. Sainju and his team at the University of Iowa shows that this response may be weakened in some people with drug-resistant epilepsy, which puts them at an increased risk for severe breathing abnormalities and Sudden Unexpected Death in Epilepsy (SUDEP) following a generalized convulsive seizure.

For their CURE-funded project, Dr. Sainju’s team conducted a study in adults with drug-resistant epilepsy who were admitted to the epilepsy monitoring unit (EMU) at the University of Iowa. In addition to comprehensive heart and breathing monitoring, the team measured the hypercapnic ventilatory response (HCVR) in each patient.^1,2 The HCVR measurement evaluates how the body responds to increased blood CO₂levels. A low HCVR indicates a poor or weakened ability to remove CO₂ from the body.

The study found that patients who had a low HCVR were more likely to have severe breathing abnormalities and a longer period of high, potentially dangerous CO₂ levels in the blood after a generalized convulsive seizure. Long-term follow-up revealed one of the patients in the study with the third lowest HCVR passed away of SUDEP 11 months after the study.²

Importantly, this is the first time HCVR has ever been studied in patients with epilepsy. The team demonstrated that an HCVR measurement can be conducted in the EMU rapidly and safely.² The team also reported that the HCVR measurement was well tolerated by the patients.²

Building on their work, Dr. Sainju’s team also conducted a CURE-funded pilot study to determine if the drug fluoxetine, more commonly known as Prozac, could increase HCVR and reduce seizure-related breathing abnormalities. Fluoxetine increases the availability of serotonin in the brain and there is evidence that the serotonin system increases ventilation in response to hypercapnia. Drugs similar to fluoxetine have been safely tested in mice and humans and shown to increase HCVR. The team hypothesized that giving fluoxetine to patients who have a low HCVR would improve the body’s ability to sense high CO₂ levels and reduce post-seizure breathing abnormalities. The team has finished this study, which shows that patients completed it with good adherence. We are eager to see their final analysis.

Dr. Sainju’s study suggests that HCVR is a key measurement which may be useful in predicting the risk of breathing abnormalities and SUDEP. It can be easily and rapidly performed in the EMU with minimal discomfort to people with epilepsy. Future studies will build on this work, analyzing the usefulness of HCVR as a biomarker for SUDEP. Having demonstrated the feasibility of a randomized trial of fluoxetine versus placebo to improve HCVR, the team plans to continue studying fluoxetine and other therapeutic targets.

¹ Gehlbach BK et. al. Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. Epilepsy Behav. 2018 Aug;85:173-176.
² Sainju R.K. et. al. Ventilatory response to CO2 in patients with epilepsy. Epilepsia. 2019 Mar;60(3):508-517.
³ Hodges MR, Richerson GB. Medullary serotonin neurons and their roles in central respiratory chemoreception. Respir Physiol Neurobiol. 2010 Oct 31;173(3):256-63.

CURE Discovery: Using Patient-Specific Cardiac Cells to Predict SUDEP Risk

CURE-funded researchers are using a novel technique to discover ways to predict patients at an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Lori Isom, her team, and co-investigator Dr. Jack Parent at the University of Michigan are transforming skin cells from patients with developmental and epileptic encephalopathy (DEE) syndromes into induced pluripotent stem cells (iPSCs). The team then generates cardiac cells from the iPSCs which retain the patients’ exact genetic information. These unique, patient-specific cardiac cells are used as models to understand if DEE-associated genes play a role in causing heart abnormalities which may lead to SUDEP. The team also hopes to develop measurable indicators, known as biomarkers, of SUDEP risk.

Severe DEE syndromes, such as Dravet syndrome, are associated with a high incidence of SUDEP. It is estimated that up to 20% of patients with Dravet syndrome die from SUDEP.¹ There is still much to be understood about the mechanisms of SUDEP and how to predict who is at risk for it.

Dravet syndrome and other DEEs are often associated with variants in genes, such as SCN1A, SCN1B, and SCN8A. These genes provide instructions to make sodium ion channels, which are very important proteins that help brain cells transmit electrical signals. The same genes are also expressed in the heart; thus, the team hypothesizes that any variants in these genes that disrupt electrical signaling in the brain would affect normal electrical function of the heart as well. In support of this hypothesis, the investigators’ previous work in mouse models of Dravet syndrome and DEEs showed that these mice exhibited irregular heartbeat, which in some cases preceded SUDEP-like events.^2-4

In this CURE-funded project, the investigators expanded upon their previous work by testing their hypothesis in heart muscle cells called cardiac myocytes, generated in the laboratory from skin cells of patients with Dravet syndrome or other DEEs using iPSC technology. This Nobel Prize-winning technology involves obtaining skin or blood cells from patients and converting them to iPSCs. These are stem cells that can be converted into almost any specialized cell type in the body, such as heart, muscle, pancreatic, or neuronal cells. The cells are patient-specific, meaning they retain the unique genetic make-up of the patient they originated from, allowing investigators to study cell types which would otherwise be very difficult or impossible to obtain from a living patient.

Dr. Isom, Dr. Parent, and their colleagues previously used iPSC technology to generate heart muscle cells from four patients with variants in the SCN1A gene and found increased sodium currents and spontaneous contraction rates in these cells, suggesting cardiac electrical dysfunction.⁵ Cardiac abnormalities were subsequently found in the patient with the highest increase in sodium current.⁵ These data suggest that iPSC-cardiac cells may be useful models for identifying and developing biomarkers, such as increased sodium current, as indicators of SUDEP risk.

The investigators used the same technique to study variants in the SCN1B and SCN8A genes. The team observed that iPSC-cardiac myocytes derived from a patient with SCN1B Dravet syndrome had increased sodium currents similar to those seen in iPSC-cardiac myocytes from the patient with SCN1A Dravet syndrome, suggesting that variants in these two different genes could cause heart abnormalities through similar mechanisms. Preliminary data in iPSC-cardiac myocytes from patients with DEE caused by variants in SCN8A, suggest that these cells have altered beating rates but no change in sodium current, which is aligned with their observations in a mouse model with a variant in SCN8A.

Taken together, these results reveal mechanisms by which different epilepsy-related genes can affect heart function and SUDEP. Future research will investigate the impact of variants of a specific non-ion channel gene to see if it causes altered cardiac beating. Patient-specific iPSC cardiac myocytes are a very useful model to study SUDEP mechanisms and could be developed as diagnostic biomarkers to identify SUDEP risk in patients.

¹ Cooper MS et al. Mortality in Dravet Syndrome. Epilepsy Res. 2016 Dec; 128:43-47.
² Auerbach DS et al. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10).
³ Lopez-Santiago LF et al. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5):636-47.
⁴ Frasier CR et al. Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. Proc Natl Acad Sci U S A. 2016; in press.
⁵ Frasier CR et al. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient Derived Cardiac Myocytes. Stem Cell Reports. 2018 Sep 11;11(3):626-634.

CURE Discovery: Potential Genetic Link Between Epilepsy and Sudden Unexpected Death in Children

This grant is generously supported by the Isaiah Stone Foundation.

A potential link between epilepsy- and SUDEP-associated SCN1A gene variants and Sudden Infant Death Syndrome (SIDS) has been discovered by CURE Grantee Dr. Annapurna Poduri of Boston Children’s Hospital.¹ Her work, generously supported by the Isaiah Stone Foundation, may provide insight into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. In Dr. Poduri’s analysis of 10 infants who died of SIDS, two children were found to have disease-associated variants in the SCN1A gene. Despite finding variants in an epilepsy-related gene and hippocampal lesions that are commonly associated with temporal lobe epilepsy, these children had no history of seizures or epilepsy.

SIDS occurs when a seemingly healthy baby dies suddenly. The sudden death of a child is a tragic occurrence and even more distressing when there is no known cause. There are several categories of this type of death: SIDS if the child is less than one year old; Sudden Unexplained Death in Childhood (SUDC) if the child is greater than one year old; and Sudden Unexpected Death in Epilepsy (SUDEP) if the child has epilepsy.

These types of childhood death are traditionally thought of as separate entities and the causes behind them are largely unknown. However, by finding a link between SIDS and SCN1A mutations,^2,3 Dr. Poduri and her colleagues have deepened our understanding of the potential genetic factors behind sudden death in children. This research also suggests epilepsy genes may be more widely important in cases of sudden death in children than originally thought.

In fact, as an integral part of her CURE-funded work, Dr. Poduri and her colleagues in Robert’s Program on Sudden Death in Childhood set out to understand the genetic basis of these sudden childhood deaths, with the hypothesis that there may be a common mechanism between some cases of SIDS, SUDC, SUDEP, and epilepsy. This hypothesis is based on neuropathological abnormalities seen in the hippocampal region of approximately 40% of cases with SIDS and SUDC.⁴

Although typically considered rare, more children die each year from Sudden Unexplained Death in Pediatrics (SUDP), a category that includes SIDS and SUDC, than from childhood cancer or heart disease.⁵ Understanding the reasons behind these types of death is important in understanding how to prevent them.

Besides finding variants in the SCN1A gene in two children who died of SIDS, Dr. Poduri and her colleagues also found variants in the epilepsy-related SCN1B gene in two siblings who died suddenly and unexpectedly.⁶ These important findings identify additional epilepsy-related genes which may underlie some cases of sudden death in children, supporting the team’s idea that there are shared mechanisms between SIDS, SUDC, and epilepsy.

In the future, Dr. Poduri and her colleagues plan to continue their analysis of potential epilepsy-associated genetic variants, which may contribute to sudden childhood death, to better understand causes of these devastating occurrences. They are hopeful their findings will apply to children with and without epilepsy who may be at risk for sudden death. Their overall goal is to identify not only genetic risk factors for SIDS and SUDC, but also other means of identifying children at risk for sudden death. This work could lay the foundation for strategies which can be systematically implemented to prevent these deaths from occurring.

¹ Brownstein CA et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018; 59(4):e56-e62.
² Escayg A and Golding AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51(9):1650-1658.
³ Goldman AM. Mechanisms of sudden unexpected death in epilepsy. Curr Opin Neurol 2015; 28(2):166-174.
⁴ Kinney HC, Poduri A et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol 2016. 75(10):981-997.
⁶ Poduri, unpublished.

CURE Discovery: Predicting Acquired Epilepsy Following a Brain Infection

A potential method of predicting who will get epilepsy following a brain infection, such as that brought on by malaria, has been discovered. This breakthrough is the result of work by two CURE grantees, Dr. Bruce Gluckman and Dr. Steven Schiff of Pennsylvania State University.

Individuals who contract cerebral malaria (malaria accompanied by a coma, typically spread by mosquitos) are at a substantially increased risk of developing epilepsy.¹ Malaria is especially widespread in non-industrialized areas of the world and often affects children.² Because malaria is so widespread, it may be the most significant cause of post-infection epilepsy in the world today. Currently, there are no methods to predict who will develop epilepsy, or any means of preventing epilepsy after such an infection.

This makes Dr. Gluckman and Dr. Schiff’s discovery so critical. Together with their team members Fatemeh Bahari and Dr. Paddy Sstentongo, they found a combination of brain and heart activity in mice that could accurately predict which animals would develop seizures and epilepsy after infection with malaria.³

Using their CURE grant, Drs. Gluckman and Schiff studied the connection between cerebral malaria and epilepsy by first developing a mouse “model” replicating malaria-induced epilepsy. In addition, they investigated possible ways to determine which mice would go on to develop epilepsy after infection.

Using the mice which developed epilepsy after infection with malaria, the research team measured two important variables often associated with epilepsy: the activity of the brain and heart. They found abnormal brain activity immediately followed by abnormal heart activity – but only in the animals which went on to develop epilepsy.

This discovery represents a possible biomarker for predicting epilepsy following infection with malaria. In other words, these may be measurable indicators to determine the infected individuals who will develop epilepsy. Furthermore, the abnormal brain and heart activity was detectable as early as 14 weeks before the first seizure, opening a potential window during which therapeutic interventions might be used to prevent epilepsy.

Drs. Gluckman and Schiff plan to continue this work, using these findings to develop treatment methods for people who contract cerebral malaria to prevent them from developing epilepsy. They are hopeful their discovery will lead to a means to eliminate not only post-malarial epilepsy, but also epilepsy caused by other types of brain injuries.

¹ Ngoungou and Preux. Cerebral malaria and epilepsy. Epilepsia 2008; 49(s6):19-24.
² World Health Organization. World malaria report 2017. http://www.who.int/malaria/publications/world-malaria-report-2017/report/en/.
³ Bahari et al. A brain-heart biomarker for epileptogenesis. J Neurosci 2018; pii: 1130-18.

CURE Discovery: New Ultraflexible Electrodes for Minimally Invasive Electrical Recordings

A less invasive yet more accurate, safe, and effective method of recording seizures from deep layers of the brain may now be possible, thanks to the work of CURE grantee Dr. Flavia Vitale.¹

Dr. Vitale, of the University of Pennsylvania, and a team of researchers engineered a method of delivering thin, ultraflexible electrodes deep into neural tissue. The way these electrodes are constructed and inserted limits the brain damage associated with the penetrating electrodes currently used for recording neural signals. This new and improved technology may allow researchers and clinicians to better pinpoint changes in electrical activity in the brains of people with epilepsy.

Recording this electrical activity is essential to understanding the epileptic “map” of a person’s brain. Understanding the map helps doctors locate where seizures originate (the focus) and learn how they spread. With this information, doctors can more effectively treat epilepsy. Knowing the focus of an individual’s epilepsy can, for example, help guide epilepsy surgery or the implantation of an anti-seizure device. This kind of precision isn’t always possible with current clinical mapping tools because of their invasiveness and low-resolution, Dr. Vitale notes.

The thinner, softer, and higher-resolution electrodes can be focused, moved, and adjusted after implantation, reaching deep layers of the brain while causing minimal damage. Thus far, the team has successfully tested this system in the small, fresh-water organism called hydra as well as in rats.

Dr. Vitale is now performing new experiments to demonstrate that this updated electrode technology is safer and less damaging than the placement of stiffer, commercial electrodes.

As a next step in her CURE project, Dr. Vitale will also focus on understanding the safety of her electrode system after it has been implanted for a long period of time. By completing the development of this novel recording system, her overall goal is to increase the understanding of brain activity patterns in individuals with epilepsy, improving the safety and accuracy of recordings and the treatment of epilepsy.

¹ Vitale F, et al. Fluidic microactuation of flexible electrodes for neural recording. Nano Lett 2018; 18(1):326-335.

CURE Discovery: Improving Sleep with Small Environmental Changes May Decrease Seizures

Relatively small changes in environmental factors which improve the ‘internal clock’ (otherwise known as the circadian rhythm) and the quality of sleep lead to decreases in seizures in mice with similarities to Dravet syndrome, a severe form of epilepsy. These promising results are the latest findings from the lab of CURE grantee Dr. Franck Kalume of Seattle Children’s Hospital, whose grant is generously supported through the BAND Foundation.

Individuals with Dravet syndrome have problems with their circadian rhythm and with regulating their sleep.¹ Upon observing that mice with similarities to Dravet syndrome have similar sleep disturbances,² Dr. Kalume and his team set out to determine if improving circadian rhythm and sleep patterns in these mice could reduce the occurrence of seizures.

To improve circadian rhythm in the mice, the team confined either meals or exercise to nighttime, when mice are typically active. The team limited these activities during the day, when mice typically sleep. As a result of these simple changes, the team found that the mice became more active at night and less active during the day, an indication of improved circadian rhythm. The mice also showed improvements in the quality of their sleep.

Significantly, restricting these activities to nighttime led to a decrease in the incidence of irregular brain activity that is characteristic of an epileptic brain, an indication that improvements in sleep practices may improve epilepsy.

Dr. Kalume and his team next plan to confine both exercise and meals to nighttime to see if this leads to an even greater reduction of seizures. They also plan to determine the effect of these changes on the risk of sudden death in these mice, as these mice and humans with Dravet syndrome are more susceptible to Sudden Unexpected Death in Epilepsy (SUDEP).

These important results contribute to our understanding of the relationship between sleep and epilepsy and provide hope for the development of new therapies to improve epilepsy outcomes. Dr. Kalume and his team hope these studies will lead to practical steps not involving medication that individuals with epilepsy can take to improve their circadian rhythm and sleep to reduce seizures and the risk of SUDEP.

¹ Licheni SH et al. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol 2018; 60(2):192-198.
² Kalume F et al. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis. 2015; 77: 141-54.

CURE Discovery: Spider Venom Peptide May Reduce Seizures

A new treatment for Dravet syndrome, a rare and catastrophic form of drug-resistant epilepsy, may soon be on the horizon thanks to the work of CURE grantees Dr. Glenn King of the University of Queensland and Dr. Steven Petrou of the Florey Institute of Neuroscience and Mental Health. Drs. King and Petrou identified a peptide found in spider venom which can reduce seizures and mortality in mice modeling the symptoms of human Dravet syndrome.¹

The majority of Dravet syndrome cases are caused by mutations in a gene that lead to too little inhibition and too much excitation in the brain, triggering the hyperexcitability seen with seizures.^2,3 Drs. King and Petrou found that the spider venom peptide works to restore the balance of inhibition and excitation in the brains of Dravet syndrome mice, decreasing hyperexcitability and reducing seizures. Furthermore, the team found that this peptide also decreases mortality in these mice.

Drs. King and Petrou next plan to investigate this peptide’s effects on other symptoms associated with Dravet syndrome, such as anxiety, autistic traits, and sleep disturbance. They will also explore ways to develop this peptide into a treatment for epilepsy, including methods of delivering the peptide into the brain.

Besides providing a potential new treatment for Dravet syndrome, these results are especially important because they highlight the therapeutic power of venomous substances, Dr. King notes. These substances work due to their ability to target the brain and alter its activity. Dr. King is optimistic that venomous substances may also be used in the treatment of types of epilepsy other than Dravet syndrome, as well as other brain disorders.

We at CURE are also hopeful this line of research will open new treatment possibilities for rare and difficult-to-treat epilepsies. As noted by Dr. King, the overall goal of this research is to develop therapeutics that will reverse all symptoms of Dravet syndrome and enable those with the disorder to live normal lives.

¹ Richards et al. Selective Nav1.1 activation rescues Dravet syndrome mice from seizures and premature death. PNAS 2018; 115(34):E8077-E8085.
² Bender et al. SCN1A mutations in Dravet syndrome: Impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 2012; 23(3):177-186.
³ Liautard et al. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia 2013; 54(7):1251-1261.

CURE Discovery: Transplanting Inhibitory Neurons Can Reduce Seizures

CURE Grantee Dr. Janice Naegele of Wesleyan University has been working on harnessing the brain’s own inhibitory power as a treatment to reduce excitability and “quiet” the overly excitable epileptic brain. As a promising first step, she and her team have successfully shown that transplantation of mouse inhibitory neurons into the mouse hippocampus – a brain structure that is often involved in epilepsy – can reduce the number of seizures in mice with temporal lobe epilepsy. (1)

Temporal lobe epilepsy is the most common form of epilepsy, with neuronal loss being one of its hallmark traits. (2,3) The loss of inhibitory neurons can be an important factor in the development or worsening of the disorder, (4) because the balance between excitatory and inhibitory neuronal activity is essential for proper brain function. Fewer inhibitory neurons can decrease inhibitory neurotransmission, in turn leading to excessive neuronal excitation, seizures, and epilepsy. One focus of Dr. Naegele’s epilepsy research has been to find a way to increase inhibition in the hyperexcitable epileptic brain. (5)

Dr. Naegele used her CURE grant to focus on transplanting both mouse and human inhibitory neurons into the hippocampus of mice with temporal lobe epilepsy. She hypothesized that these inhibitory neurons would wire up with existing neurons, increasing inhibitory transmission and decreasing the hyperexcitability that characterizes temporal lobe epilepsy. This type of treatment is called “regenerative medicine” because it uses healthy tissue to restore normal brain functioning. An advantage of regenerative medicine is that the transplanted cells can potentially replace lost or damaged inhibitory neurons and also integrate into the existing brain circuitry. This treatment would provide a cure for seizures by addressing the root cause, unlike standard antiepileptic drugs that simply treat the symptoms of seizures.

Indeed, as shown by advanced imaging techniques, the inhibitory neurons Dr. Naegele’s team transplanted into the brains of mice with temporal lobe epilepsy formed new, functional connections with excitatory neurons already present in the hippocampus, providing the increased inhibition that likely led to fewer seizures in these mice. (1)

Following the success of quieting seizures using the implantation of mouse inhibitory neurons, Dr. Naegele and her team are now focused on a means to quiet seizures by implanting human inhibitory neurons, pushing this research one step closer to being a viable treatment for people with epilepsy. As part of their strategy, they are keeping in mind important potential differences in neuronal generation and transmission between humans and mice. (6)

Dr. Naegele’s research brings an exciting possibility to the future of epilepsy treatment: the transplantation of a type of neuron that already exists in the human brain with the goal of stopping seizures. While work still remains, CURE applauds the progress Dr. Naegele has made thus far. We share Dr. Naegele’s hopes that her approach becomes a non-drug method of treating those affected by not only temporal lobe epilepsy, but other forms of epilepsy as well.

1 Henderson et al. Long-term seizure suppression and optogenetic analysis of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci 2014; 34(40):13492-13504.
2 Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Neurol 2002; 1(3):173-181.
3 Engel J Jr, Williamson PD, Weiser HG. Mesial temporal lobe epilepsy. In: Epilepsy: a comprehensive textbook (Engel J Jr, Pedley TA, eds) 1997: 2417-2426.
4 Kumar SS, Buckmaster PS. Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 2006; 26(17):4613-4623.
5 Van Zandt MA, Naegele JR. GABAergic synapse dysfunction and repair in temporal lobe epilepsy. (2017) Synaptic Plasticity Thomas Heinbockel, IntechOpen; DOI: 10.5772/67218. Available from: https://www.intechopen.com/books/synaptic-plasticity/gabaergic-synapse-d….
6 Naegele JR. Controversial brain study has scientists rethinking neuron research. (2018) Available from: https://theconversation.com/controversial-brain-study-has-scientists-ret…

CURE Discovery: New Cause of Severe Childhood Epilepsy Found – Genetic Mutation in the CUX2 Gene

CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.¹

The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.^2,3

Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.

Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.

Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.

Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.

Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.

In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.

Citations

¹ Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
² Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
³ Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.

CURE Discovery: Potential Target Area in the Brain for Prevention of Epilepsy-Related Sudden Death

An area of the brain known as the amygdala may be critical in the conscious control of breathing, making it an important target area for research into epilepsy-related sudden death, according to a study recently published by CURE Grantee Dr. William Nobis of Northwestern University Feinberg School of Medicine.¹ As part of a team led by Dr. Christina Zelano, also of Northwestern University, Dr. Nobis found that stimulation of the amygdala consistently induced apnea, or disrupted breathing, in a group of individuals with temporal lobe epilepsy. This finding is significant because it points to a possible role of the amygdala in what may be the most severe epilepsy-related complication, Sudden Unexpected Death in Epilepsy (SUDEP).

SUDEP occurs when a seemingly healthy person with epilepsy dies for no obvious reason,² most often at night or during sleep. While research suggests that several factors including respiratory and cardiac dysfunction contribute to SUDEP,^3,4 the precise biological processes remain unknown. By implanting electrodes into the brains of seven patients undergoing surgical evaluation for temporal lobe epilepsy, Dr. Nobis and his team were able to pinpoint specific regions of the amygdala that are important in controlling respiration, identifying areas possibly important in the cessation of respiration that characterizes SUDEP. Furthermore, the team found that by instructing patients to inhale during an apnea-inducing stimulation of the amygdala, they were able to prevent apnea providing an area upon which to focus development of therapeutic strategies to prevent SUDEP.

With funding from CURE, Dr. Nobis is now pushing this research to uncover the mechanisms behind SUDEP even further. He and his team think that the amygdala may be activated during seizures, causing it to lead to cessation of respiration and SUDEP. By using a genetic animal model of epilepsy that has a high rate of SUDEP, the team hopes to identify and examine the specific neurons within the amygdala that project to important respiratory centers in other parts of the brain, allowing the amygdala to influence respiratory function – and the loss of respiratory function that occurs in SUDEP.

Early results from Dr. Nobis’s current CURE project have begun to identify populations of neurons in the amygdala that project to areas of the brain important in respiration. The team next plans on examining how these neurons are activated in response to seizures, and how changes in the excitability of these neurons might correspond with changes in respiratory function that could lead to SUDEP.

In the future, Dr. Nobis hopes to be able to determine whether it is possible to target this subset of neurons within the amygdala to prevent SUDEP from occurring, providing a large step forward for SUDEP research and possible therapies for SUDEP prevention. Thanks to CURE-funded researchers like Dr. Nobis, we are moving closer to being able to eliminate the sudden and devastating death of individuals with epilepsy.

¹ Nobis WP et al. Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent. Ann Neurol 2018; 83(3):460-471.
² Nashef. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997; 38(11 Suppl):S6-8.
³ Surges et al. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009; 5(9):492-504.
⁴ Bagnall et al. Genetic basis of sudden unexpected death in epilepsy. Front Neurol 2017; 8:348.

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