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.

CURE Discovery: Genetic Research Finds Potential Alternatives to Brain Surgery for Children with Cortical Dysplasia

A Potential Alternative is Already in Clinical Trial

Recent research by CURE grantee Dr. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology has shed important light on the genetic mutations that lead to focal cortical dysplasia, a severe form of pediatric epilepsy that inadequately responds to available treatment options. Genetic mutations were found in the brain tissue of individuals affected by a particular subtype of focal cortical dysplasia (focal cortical dysplasia type II) that is characterized by brain abnormalities, leading to seizures and epilepsy.

Conventional genetic testing methods to identify genetic mutations in those with epilepsy often use blood or saliva from patients. However, these latest results from Dr. Lee and his team suggest that certain epilepsy-related gene mutations may only be detectable when brain tissue is analyzed.

Brain-Only Mutations in Genes that Cause Focal Cortical Dysplasia

By comparing blood and saliva samples to samples of brain tissue from a group of 40 individuals who had previously undergone brain surgery for focal cortical dysplasia type II, Dr. Lee and his team found that a significant number of these individuals (12.5%) had brain-only mutations in genes TSC1 and TSC2. Together with the previous pioneering work of his team to identify brain-only mutations in the MTOR gene in individuals with focal cortical dysplasia type II, they revealed that brain-only mutations in genes within the mTOR brain signaling pathway (including the genes TSC1, TSC2 and MTOR) are found in up to 30% of individuals with focal cortical dysplasia. The fact that these mutations were found only in the brain means that these mutations would be undetectable by conventional genetic testing methods, suggesting that investigation of brain-only mutations should be explored to a greater extent.

In addition to identifying brain-only mutations leading to focal cortical dysplasia, Dr. Lee and his team also addressed the current lack of adequate animal models to better study the disorder. The team was able to successfully recreate the brain-only mutations in genes TSC1 and TSC2 in developing mice, providing a much-needed animal model for further examination of the ways in which gene mutations can lead to focal cortical dysplasia type II.

Clinical Trials for the Treatment of Focal Cortical Dysplasia

Furthermore, the team provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia.

As noted by Dr. Lee, because focal cortical dysplasia is a drug-resistant epilepsy, many children with the disorder require invasive brain surgery as treatment. However, even in cases where surgery is performed, up to 40% of these children may still have seizures. By identifying genes associated with focal cortical dysplasia as well as creating a new way of studying the genetic mechanisms behind the disorder, Dr. Lee and his team have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this devastating form of drug-resistant childhood epilepsy.

[1] Lim et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Human Genet 2017; 100(3):454-472.
[2] Guerrini et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 2015; 56(11):1669-86.
[3] Gaitanis and Donahue. Focal cortical dysplasia. Ped Neurol 2013; 49:79-87.
[4] Poduri et al. Genetic testing in the epilepsies – developments and dilemmas. Nat Rev Neurol 2014; 10(5):293-299.
[5] Lim et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4):395-400.

CURE Discovery: Preventing Post-Traumatic Epilepsy with 2-Deoxy-D-Glucose Treatment

The latest results from a CURE-funded grant represent a promising advance in the quest to prevent post-traumatic epilepsy. Dr. Thomas Sutula from the University of Wisconsin and his team have found that the administration of 2-Deoxy-D-Glucose (2DG) following a traumatic brain injury can significantly reduce the subsequent development of post-traumatic epilepsy in a rodent model.

The finding that 2DG can prevent the development of post-traumatic epilepsy in rats is exciting for several reasons. 2DG is a sugar-like molecule that has been proposed to mimic the ketogenic diet – a diet that is highly effective in the treatment of difficult-to-treat epilepsies. Therefore, like the ketogenic diet, 2DG may also have therapeutic effects for individuals that have already developed epilepsy (in this case, post-traumatic epilepsy). 2DG is also already being used in the treatment of other illnesses, including cancer, and can likely progress rapidly to a clinical trial for post-traumatic epilepsy. Furthermore, with this research, Dr. Sutula and his team have successfully utilized a novel rat model that more readily develops a post traumatic-epilepsy-like syndrome with frequent seizures following traumatic brain injury, providing a great research tool in the quest for treatments and a cure for post-traumatic epilepsy.

Post-traumatic epilepsy is a type of epilepsy that develops following a traumatic brain injury such as a bump or blow to the head. Post-traumatic epilepsy accounts for nearly 20% of all symptomatic epilepsies in the general population, and is one of the most common causes of acquired epilepsy. Post-traumatic epilepsy can be particularly devastating because no known prevention or cure for the disorder currently exists.

Because post-traumatic epilepsy can develop months or even years after an initial traumatic brain injury, there is a critical window of time during which the development of post-traumatic epilepsy might be prevented, if only a preventative measure were in existence. For these reasons, Dr. Sutula’s finding that 2DG significantly reduces the development of post-traumatic epilepsy in his novel breed of rat within this critical window is an important one.

In the future, Dr. Sutula and his team plan on taking strategic steps to push their research forward towards an Investigational New Drug trial to test the effectiveness of this drug in the prevention of post-traumatic epilepsy in humans. In this way, Dr. Sutula hopes that his research will impact the lives of individuals suffering from post-traumatic epilepsy, or those with the potential to develop post-traumatic epilepsy, as soon as possible.

CURE-funded grant yields Dravet syndrome discovery

A recent CURE-funded grant has taken a step forward in the search for therapeutic mechanisms to combat Dravet syndrome, a type of epilepsy that is currently difficult to treat and has no known cure.[1] A CURE-funded team has discovered that RNA-stimulators have the capability of fully restoring functionality to the Scn1a gene (in rodents), which may in turn prevent or reverse the symptoms of Dravet syndrome.

CURE researcher Dr. Antonello Mallamaci of the Scuola Internazionale Superiore di Studi Avanzati is leading the team that seeks to restore functionality to Scn1a, by creating “Scn1a-stimulating RNA devices” to stimulate Scn1a activity.

The team sees great potential in being able to use these devices to compensate for the reduction in Scn1agene functionality. Next steps include plans to test these RNA-stimulators in the Dravet syndrome mouse that has similar symptoms to humans with Dravet syndrome and in human tissue from individuals with Dravet syndrome. There are also plans to create a specialized “tool” called a viral vector that can deliver these RNA-stimulators directly into affected brain areas, pushing this research ever closer to achieving a viable human therapy.

Dravet syndrome is a rare epilepsy that begins in infancy, is lifelong and often leads to developmental disability.[2] It is most often caused by a mutation or deletion in the Scn1a gene, a gene that codes for an important sodium channel whose function is essential in normal transmission of electrical signals within the brain.[3],[4] The loss of functionality of this gene can lead to brain activity and hyperexcitability that characterizes seizures and epilepsy.[5]

Through the critical work of researchers like Dr. Mallamaci, new therapeutic approaches for epilepsy are within our reach. This exciting research has been made possible by funding from CURE as we strive ever closer to our goal of producing treatments and cures for epilepsy to achieve “no seizures, no side effects.”


[1] Wirrel EC. Treatment of Dravet syndrome. Can J Neurol Sci 2016: 43 Suppl 3:S13-18.

[2] Dravet C. The core Dravet syndrome phenotype. Epilepsica 2011; 52(2):3-9.

[3] Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; Suppl 2:24-9

[4] Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 2005; 115(8): 2010-2017.

[5] Chopra R, Isom LL. Untangling the Dravet syndrome seizure network: The changing face of a rare genetic epilepsy. Epilepsy Curr 2014; 14(2):86-89.