News Category: CURE Epilepsy Discovery

CURE Epilepsy Discovery: Investigating Spreading Depolarization in SUDEP

Key Points:

  • Dr. Stuart Cain’s CURE Epilepsy Taking Flight Award received while at the University of British Columbia, explored the mechanisms underlying Sudden Unexpected Death in Epilepsy (SUDEP).
  • SUDEP occurs when the heart and respiration both stop in a process called “cardiorespiratory arrest.” An area of the brain called the brainstem is critical in maintaining both heart function and respiration and is, therefore, an important brain area for researchers to study in order to understand the biological process through which SUDEP occurs. The brainstem is also connected to areas called the superior and inferior colliculus.
  • A phenomenon known as “spreading depolarization” is known to contribute to respiratory arrest. Dr. Cain’s team investigated mechanisms underlying spreading depolarization in the areas of the brain connected to the brain stem called the superior and inferior colliculus. Their research showed the specific role of the superior colliculus in spreading depolarization to the brainstem, causing SUDEP.
  • This study establishes a foundation for continued study on the superior colliculus to ultimately develop preventative approaches for SUDEP.

 


Deep Dive:

Sudden Unexpected Death in Epilepsy (SUDEP) is one of the most tragic consequences of epilepsy. SUDEP occurs when a seemingly healthy person with epilepsy dies unexpectedly for no known reason. The biological causes of SUDEP are still not fully understood [1, 2]. Research suggests that SUDEP occurs because of the effects of seizures on the cardiovascular and respiratory systems resulting in “cardiorespiratory arrest”. Given that the brainstem is the part of the brain that controls heart rate and respiration, scientists have investigated the role of this region of the brain in causing SUDEP [3]. One phenomenon that has emerged as a possible explanation for SUDEP is called “spreading depolarization.” Spreading depolarization can be described as a wave of abnormal brain activity that travels through the layers of the brain in an organized fashion. Earlier work done by Dr. Cain and other researchers showed that spreading depolarization that engages the brainstem can be fatal. They also observed that additional areas in the brain called the superior and inferior colliculus are susceptible to spreading depolarization, but only during seizures, and that spreading depolarization that traveled into the brainstem during seizures was fatal [4]. 

Past research studies have shown that the superior and inferior colliculus may be involved in epilepsy [5]. Dr. Cain’s research, funded by the CURE Epilepsy Taking Flight Award, sought to investigate if the superior and inferior colliculus may play a role in spreading depolarization to the brainstem [6]. In this study, Dr. Cain’s team used a genetic mouse model that is susceptible to seizures and SUDEP and has been previously shown to be a good model to understand activity in the brainstem during fatal seizures [4]. The team did several experiments using these mice, called Cacna1aS218L mice, and state-of-the-art techniques. Using these techniques, Dr. Cain’s team first showed that when they stimulated the superior or the inferior colliculus, the mice experienced severe seizures, interrupted breathing (respiratory depression), and ultimately, death. Stimulation of the superior or the inferior colliculus started a wave of spreading depolarization that reached the brainstem in Cacna1aS218L mice, but not in normal mice. This wave of spreading depolarization that started in the superior and inferior colliculus traveled to several other brain regions, and then finally to the brainstem. Previous work done by Dr. Cain and other researchers also suggested the potential role of an additional brain structure called the thalamus in spreading depolarization that reaches the brainstem [4, 7]. By performing an additional experiment, the team observed that while stimulation of the thalamus initiated spreading depolarization in the Cacna1aS218L mice, the wave of activity did not reach the brainstem, and hence, was not associated with arresting breathing. The thalamus, therefore, does not appear to be involved in  spreading depolarization that leads to SUDEP.

To dive deeper into whether the superior or the inferior colliculus is important in spreading depolarization in the brainstem, Dr. Cain’s team used electrophysiology to measure electrical signals in these regions. They found that brain cells (neurons) of the superior colliculus of the Cacna1aS218L mice were inherently more excitable compared to superior colliculus neurons from normal mice. This finding suggests that the superior colliculus is what is critical for the brainstem spreading depolarization to occur which may in turn lead to SUDEP.  

Taken together, these novel results suggest the critical role of the superior colliculus in seizures that may lead to SUDEP. The results also strengthen the understanding of the sequence of events that may cause SUDEP. Spreading depolarization in the superior and inferior colliculus reaching the brainstem was associated with respiratory arrest, followed by cardiac arrest that is seen in SUDEP (as seen in the chart below). While more studies are necessary to understand the role of these brain structures in SUDEP, these data help envision methods to target and address brainstem spreading depolarization as a way to prevent SUDEP.

Literature Cited:

  1. Buchanan, G.F., Impaired CO(2)-Induced Arousal in SIDS and SUDEP. Trends Neurosci, 2019. 42(4): p. 242-250.
  2. Massey, C.A., et al., Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol, 2014. 10(5): p. 271-82.
  3. Ryvlin, P., et al., Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol, 2013. 12(10): p. 966-77.
  4. Loonen, I.C.M., et al., Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1aS218L mice. Brain, 2019. 142(2): p. 412-425.
  5. Faingold, C.L., Neuronal networks in the genetically epilepsy-prone rat. Adv Neurol, 1999. 79: p. 311-21.
  6. Cain, S.M., et al., Hyperexcitable superior colliculus and fatal brainstem spreading depolarization in a model of sudden unexpected death in epilepsy. Brain Communications, 2022: p. fcac006.
  7. Cain, S.M., et al., In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures. Proc Natl Acad Sci U S A, 2017. 114(9): p. 2401-2406.

CURE Epilepsy Discovery: Multi-Disciplinary Approach to Uncover New Strategies to Prevent Epilepsy

Key Points:

  • For their CURE Epilepsy Multi-disciplinary grant, Dr. Audrey Yee, an epilepsy researcher and clinical neurologist based at the University of Colorado (now at the National Institute of Allergy and Infectious Disease), and Dr. Amy Yee, a breast cancer and Wnt signaling pathway researcher at Tufts University, used their different expertise to investigate novel mechanisms underlying epileptogenesis.  
  • Utilizing learnings from studies in cancer, the team was able to show that two different biological pathways, the Wnt pathway and the mTOR signaling pathway, are altered during epileptogenesis. Changes in these pathways contribute to an increased susceptibility to seizures. This study is the first to demonstrate the potential relevance of the Wnt signaling pathway in epileptogenesis and epilepsy. 
  • By revealing biological changes that happen during epileptogenesis, this work provides tangible therapeutic strategies that can be used to block epileptogenesis and the development of epilepsy.


Deep Dive:

In acquired epilepsies, a brain injury following head trauma or status epilepticus (a prolonged seizure) can be followed by a latent period called epileptogenesis. During this period, seizures are not occurring, but the brain is undergoing many changes that render it susceptible to seizures [1]. Scientists want to better understand what happens in the brain during this process with the goal of stopping it and ultimately preventing epilepsy. CURE Epilepsy funded two such scientists, Drs. Amy and Audrey Yee (cousins), who focused their research on two cell signaling pathways and changes that take place during epileptogenesis [2].  

Previous studies have shown that the cellular signaling pathway known as mTOR is widely implicated in some epilepsies [3]. The focus of the current study was to explore both mTOR’s role and biochemical integration with a second biological pathway called the Wnt pathway together as part of the process of epileptogenesis. The Wnt pathway is implicated in cancer [4] so the CURE Epilepsy grant allowed these two cousins to leverage their individual research foci in this innovative study, which led to the discovery of the role Wnt signaling plays in epileptogenesis [2].

For their study, the researchers used two types of mouse models, one in which status epilepticus had been chemically induced and the other in which Wnt signaling had been genetically enhanced. To create a complete picture of the mTOR and Wnt signaling pathways during epileptogenesis, the scientists used state-of-the-art techniques to examine the levels of mRNA (molecules that carry the genetic code for protein) and the relevant proteins themselves, including where in the brain they are expressed. The scientists also looked at the balance of chemical messengers known as neurotransmitters [2] and focused on an area of the brain called the hippocampus because of its role in seizure generation and propagation [5].

The researchers first showed that epileptogenesis was associated with activation of the Wnt and mTOR signaling pathways. Next, they investigated the basis for enhanced signaling through these pathways and found that there were accompanying changes associated with the way glucose is metabolized in brain cells during epileptogenesis. The changes in the way glucose is metabolized were also associated with an altered balance of neurotransmitters in the brain. Finally, the investigators showed that Wnt signaling is critical to epileptogenic changes that produce seizures. Using the genetically modified mice with enhanced Wnt pathway activation, they found enhanced seizure susceptibility (that is, the mice had stronger seizures) through the same processes described above [2].

This study demonstrates the interaction between the mTOR and Wnt pathways in epileptogenesis, which was previously unknown. By combining knowledge from the fields of cancer and epilepsy, Drs. Amy Yee and Audrey Yee were able to use cross-disciplinary techniques to better understand epileptogenesis. The hope is that by better understanding changes in the Wnt and mTOR pathways following a brain injury, scientists can create safe therapeutic approaches that can be used during the epileptogenic period to prevent epilepsy. Notably, the mechanisms elaborated by these investigators also have implications for genetic epilepsies, such as tuberous sclerosis complex in which the mTOR pathway is disrupted [6]. Thus, the findings from this study may have significant implications for genetic epilepsies as well.  

Research to define the processes that happen during epileptogenesis is critical to the discovery of better therapeutic strategies to prevent epilepsy following a brain injury. This CURE Epilepsy-funded study revealed that changes in the Wnt and mTOR signaling pathways, and the changes in glucose metabolism and neurotransmitter balance may lead to the progression of epileptogenesis and the development of epilepsy [2]. While further research is needed to define these changes in detail, this study provides hope that targeting the mTOR and Wnt pathways by medications such as sirolimus (rapamycin) or specific inhibitors of the Wnt pathway may be effective in halting the progression of epileptogenesis.

 

Literature Cited:

  1. Lukawski, K. et al. Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. Pharmacol. Rep. 2018; 70(2): 284-293.
  2. Alqurashi, R.S. et al. A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis. PLoS One 2021; 16(8): e0252282.
  3. Meng, X.F. et al. Role of the mTOR signaling pathway in epilepsy. J Neurol Sci, 2013; 332(1-2): 4-15.
  4. Zhan, T., Rindtorff, N. and Boutros, M. Wnt signaling in cancer. Oncogene 2017; 36(11): 1461-1473.
  5. Avoli, M. The epileptic hippocampus revisited: back to the future. Epilepsy currents, 2007. 7(4): p. 116-118.
  6. Curatolo, P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr. Neurol. 2015; 52(3): 281-289. 

CURE Epilepsy Impact: Investing in Early-Stage Investigators Advances Careers & Leads to Groundbreaking Epilepsy Treatments

Key Points:

  • Gregory Worrell, MD, PhD (Mayo Clinic, Rochester, MN) recalls that the first grant that he received was from CURE Epilepsy and credits it with having a tremendous impact on both his career path and his groundbreaking contributions to epilepsy research.
  • According to Dr. Worrell, the initial one-year grant, awarded almost 20 years ago, was a catalyst for his research to improve devices for monitoring brain activity and forecasting seizures. 
  • The CURE Epilepsy grant, along with an NIH career developmental award, and subsequently additional ongoing NIH and foundation grants, has firmly established Dr. Worrell as an important investigator in the fields of brain neurophysiology, seizure detection, seizure forecasting, and neural modulation. 

Deep Dive:

Dr. Gregory Worrell’s path towards ultimately engaging in epilepsy research did not follow a direct road. He first trained and worked as a PhD-level physicist before entering medical school and then completed a neurology residency followed by an epilepsy fellowship. It took several additional years to reach his current role as a physician-scientist caring for epilepsy patients while simultaneously maintaining a productive research laboratory. Nevertheless, Dr. Worrell’s unique training in engineering and physics, along with the computational analyses, gave him the expertise required to understand and develop devices to monitor and modulate electrical activity of the brain.

Dr. Worrell credits his mentors, including Dr. Gregory Cascino, also at the Mayo Clinic, and Drs. Marc Dichter (a former advisor to CURE Epilepsy) and Brian Litt (a former CURE Epilepsy grantee), both at the University of Pennsylvania, with influencing his career direction. They provided the model, encouragement, and opportunity for a career as a clinician-scientist. Dr. Worrell’s first research grant was from CURE Epilepsy, and he attributes this critical funding for getting him started in epilepsy research. Even though he was also awarded an NIH training award, he feels that, in many ways, the CURE Epilepsy grant was more important because it introduced him to the community of epilepsy researchers

Dr. Worrell’s grant from CURE Epilepsy focused on high-frequency oscillations (HFO), brain waves with a frequency of greater than approximately 80 Hz that are often associated with seizure activity in specific regions of the brain [1]. This electrical activity can be detected on an electroencephalogram (EEG), but at the time (approximately 20 years ago), HFOs were rarely observed simply because the range of a typical EEG was limited to no greater than 70 Hz, biased by then-accepted practice [2]. Basic research with animal models, however, had suggested that an epileptic brain exhibits a much wider dynamic range of activity, sometimes out to frequencies greater than 1,000 Hz, and so Dr. Worrell focused his early efforts on broadening the spatial and temporal sampling of brain waves [2-4]. These so-called “wide-bandwidth” recordings have now become standard in the field. 

The early learnings achieved through the CURE Epilepsy funded research have carried over into the development of “next-generation” implantable therapeutic devices [5], done as part of an NIH Brain Initiative public-private partnership with Medtronic, a company with a long history of creating medical devices. The “public” component is funded through two NIH grants awarded to Dr. Worrell. The aims are to develop new device technology that will permit the tracking of a patient’s brain state, identify periods of increased seizure probability, and adaptively intervene to modulate the brain, moving it to a state of low seizure probability to prevent seizures from ever occurring. Importantly, it has the potential of providing something akin to a “daily weather report”, giving the patient a sense of when a seizure might occur. This is particularly crucial given that one of the most disabling aspects of epilepsy is not necessarily the seizures themselves but their unpredictability. With this type of technology, there is an opportunity to administer therapies, e.g., anti-seizure medications and/or brain stimulation, both of which have considerable side effects, in a time-limited way instead of a continual process. Creating the next generation of electrical stimulation and sensing devices for epilepsy has remained a focus of Dr. Worrell’s research. 

While Dr. Worrell is proud of his individual achievements, he notes that consequential advances in medicine are usually the outcome of team efforts, with dozens perhaps even hundreds of clinicians and scientists collaborating [5,6] To this end, he has participated in numerous clinical trials to test novel devices, including the FDA approved responsive neurostimulator (RNS®) manufactured by Neuropace Inc, to control seizures, and he derives considerable satisfaction from these collective undertakings. Dr. Worrell enthusiastically admits that he receives additional joy in life from taking care of his patients, following their progress over time, and being able to improve their quality of life through the neurophysiology/neuroengineering research performed in his own lab and through collaborations with other clinicians and scientists. In his mind, there is no greater reward than having the ability to help patients in this way

CURE Epilepsy is proud to have played a role in the illustrious career of Dr. Gregory Worrell in advancing research so that we, as a society, will one day be truly able to say that we live in a world of “no seizures and no side effects.” 

Literature Cited

  1. Chen, Z., Maturana, M.I., Burkitt, A.N., Cook, M.J., and Grayden, D.B. High-frequency oscillations in epilepsy: what have we learned and what needs to be addressed. Neurology 2021; 96(9): 439-448. 
  2. Worrell, G.A., Parish, L., Cranstoun, S.D., Jonas, R., Baltuch, G., and Litt, B. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004; 127: 1496-1506. 
  3. Worrell, G.A., Gardner, A.B., Stead, S.M., Hu, S., Goerss, S., Cascino, G.J. et al. High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings. Brain 2008; 131: 928-937.
  4. Stead, M., Bower, M., Brinkmann, B.H., Lee, K., Marsh, W.R., Meyer, F.B., Litt, B., Van Gompel, J.V., and Worrell, G.A. Microseizures and the spatiotemporal scales of human partial epilepsy. Brain 2010; 133(9): 2789-2797.  
  5. Kremen, V., Brinkman, B.H., Kin, I., Guragain, H., Nasseri, M., Magee, A.L. et al. Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J. Transl. Eng. Health Med. 2018; 6: 2500112. 
  6. Brinkmann, B. H., Wagenaar, J., Abbot, D., Adkins, P., Bosshard, S.C., Chen, M., Tieng, Q.M. et al. Crowdsourcing reproducible seizure forecasting in human and canine epilepsy. Brain 2016; 139(6): 1713-1722. 

CURE Epilepsy Discovery: Targeting Infantile Spasms After Disease Onset

Key Points:

  • CURE Epilepsy awardee, Dr. Aristea Galanopoulou and colleagues at Albert Einstein College of Medicine in New York sought a way to prevent the devastating consequences of already-established infantile spasms (IS). 
  • They used a novel, more clinically relevant IS rat model [1] to test the effect of a specific substance known as rapamycin on motor seizures, spasms, and sleep wave patterns, both immediately and over time.  
  • Data show that rapamycin appears to be an effective treatment for IS and that short-term administration early in life and during the peak of spasms can prevent future seizures in adulthood and even improve cognitive outcomes.  

Deep Dive:

Infantile spasms (IS) is a rare (~0.03% of all live births) and catastrophic type of epilepsy that usually first manifests between 3 to 7 months of age [2,3], and infants with poor response to first-line treatment are at an increased risk for a more serious form of epilepsy known as Lennox-Gastaut syndrome (LGS) [4]. Because one of the symptoms includes stereotypical jerks resembling colic, IS is difficult for parents and sometimes even pediatricians to recognize. Conclusive diagnosis is made by the spasms themselves, developmental delay, and often an abnormal, disorganized electroencephalographic (EEG) pattern known as hypsarrhythmia. This chaotic EEG pattern is observed between seizures and characterized by irregular, nonrhythmic waves and spikes of electrical activity [2,3].

IS is commonly treated with a combination of one or two specific steroids (adrenocorticotropic hormone [ACTH] and/or prednisone) and/or the antiseizure medication (ASM) vigabatrin [3,5,6]. These treatments are only effective in approximately 50% of patients [7] and, for those who do respond, diagnosis must be made early enough to minimize significant cognitive deterioration. However, these therapies do not reduce the incidence of future epilepsy and almost two-thirds of these infants continue to have seizures that do not respond to existing therapies [6]. Unfortunately, at present there is no consistent way of predicting who will respond to these treatments. Moreover, the optimal therapy would not only acutely arrest seizure activity but would also possess a “permanent” disease-modifying effect and perhaps even reverse any cognitive decline that had already taken place.

More severe and most frequent causes of IS stem from structural abnormalities in specific regions of the brain [2]. To understand the underlying biology of this form of IS and identify effective treatments, Dr. Aristea Galanopoulou, a member of CURE Epilepsy’s Infantile Spasms Initiative [8], at the Albert Einstein College of Medicine, and colleagues Drs. Solomon Moshé and Morris Scantlebury, developed a rat model known as the “multiple-hit model.” This model has brain lesions that closely mirror those observed in the brains of infants with IS, along with more visible traits such as developmental delay, behavior problems, poor social skills, drug resistance, EEG abnormalities, and potential emergence of other seizure types [1].

Using this model, Dr. Galanopoulou’s team created a platform for screening the potential for various drugs to treat IS. The investigators first used the model to test the ability of the drug rapamycin, an inhibitor of a neuronal signaling pathway linked to epilepsy, to affect IS symptoms [9]. Importantly, rapamycin was given in a 3-day pulse (as opposed to continuous administration) and only after the onset of spasms. This strategy of drug delivery is meaningful since it mimics what happens in clinical practice. A previous study from this group [9] had shown that the rapamycin stopped the spasms and was able to partially restore learning and memory deficiencies, which suggests that the rapamycin was able to modify the progression of IS. However, rapamycin did not diminish any of the other seizure types or reduce the size of the structural lesions.

To better understand the long-term effects of the pulse rapamycin treatment, the researchers then examined [10] whether it reduced the rate of epilepsy in adult rats with IS. The same 3-day pulse of rapamycin was given to the “multiple-hit” rats and investigated in greater detail. In the absence of rapamycin, and similar to the clinical picture of some severe cases of IS in humans, rats eventually exhibited LGS-like features such as motor seizures during sleep and a distinct EEG pattern termed “slow spike-wave discharges”. Importantly, the pulse rapamycin treatment that had been used to stop spasms early in life significantly reduced the rate of epilepsy with motor seizures in adult rats with IS. Furthermore, rapamycin also reversed the sleep disorder seen in these rats, suggesting an interesting relationship between sleep and epilepsy. These preclinical findings raise hope that drugs like rapamycin may be developed for treatment of IS, to both stop spasms and prevent lifelong epilepsy and associated comorbidities, filling a current gap in the clinical management of IS.

Literature Cited

  1. Scantlebury, M.H. et al. A model of symptomatic infantile spasms syndrome. Neurobiol. Dis. 2010; 37(3): 604-612. 
  2. Pellock, J.M et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010; 51: 2175-2189. 
  3. D’Alonzo et al. West syndrome: a review and guide for paediatricians. Clin. Drug. Investig. 2018; 38: 113-124. 
  4. Nelson, J.A. et al. Evolution of infantile spasms to Lennox-Gastaut Syndrome: what is there to know J. Child Neurol. 2021; 36(9): 752-759. 
  5. Riikonen, R. Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs 2014; 28(4): 279-290. 
  6. Riikonen, R. Infantile spasms: outcome in clinical studies. Pediatr. Neurol. 2020; 108: 54-64. 
  7. Knupp, K.G. et al. Response to treatment in a prospective national infantile spasms cohort. Ann. Neurol. 2016; 79(3): 475-484 
  8. CURE Infantile Spasms Consortium, Lubbers, L., & Iyengar, S.S. A team science approach to discover novel targets for infantile spasms. Epilepsia Open 2020; 6(1): 49-61. 
  9. Raffo, E. et al. A pulse rapamycin therapy for infantile spasms and associated decline.Neurobiol. Dis. 2011;43: 322-329. 
  10. Akman, O. et al. Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions. Epilepsia 2021; 62(8): 1985-1999. 

CURE Epilepsy Discovery: Identification of Environmental Contributors to SUDEP

Key Points:

  • CURE Epilepsy awardee Dr. Franck Kalume and colleagues at the Seattle Children’s Research Institute and New York University sought to identify simple environmental factors that may increase the risk of SUDEP. 
  • The team examined the effects of increased temperature and moderate exercise on several basal involuntary bodily functions of an established mouse model of Dravet syndrome (DS), a severe form of epilepsy with an increased incidence of SUDEP. 
  • When compared to normal mice, DS mice showed diminished regulation of core body temperature as well as cardiac and respiratory function.
  • Understanding the mechanisms behind these impairments might help develop effective approaches to reduce the risk of and perhaps even prevent SUDEP.

Deep Dive:

Sudden unexpected death in epilepsy (SUDEP) is a devasting event that occurs in approximately 1 in 1,000 people with epilepsy [1,2]. It appears to be related to seizure-induced dysfunction of the autonomic nervous system (ANS) [3].  The ANS controls body functions essential for survival and is responsive to environmental changes. Some of these functions include maintenance of core body temperature as well as tight regulation of heart and breathing rates. Previous research has revealed that disruptions in ANS function related to a seizure event are marked by diminished control of these three body processes, but the precise nature and mechanisms of these weakened responses are not clear.

Dr. Franck Kalume, a recipient of CURE Epilepsy’s Sleep and Epilepsy Award, generously funded by the BAND Foundation, explored this important area of research by utilizing his mouse model of Dravet syndrome (DS). [4] DS is a treatment-resistant form of epilepsy with a high risk of SUDEP, and an increased prevalence of ANS dysfunction. This particular mouse model was developed by deleting the gene linked to most cases of DS in humans (known as SCN1A), which is also one of the many genes responsible for propagating electrical signals in the brain.

The first set of experiments involved assessing the ability of DS mice to regulate 1) core body temperature, 2) heart rate, and 3) breathing rate in response to an increase in surrounding temperature, i.e., to 86-90°F. Responses from the DS mice and control mice were subsequently compared [5].  

Before elevating the external temperature, the internal body temperatures of both DS and control mice were similar. In the first 15 min after heat exposure, the core body temperature in both groups increased, although the absolute temperature and rate of this increase was much smaller in DS versus control mice. As exposure to heat was reduced, the core body temperature returned to baseline in control animals, but in DS mice, body temperature remained elevated. These observations suggest that DS mice have deficits in thermoregulation (an ability to control core body temperature).  

Dr. Kalume and his team developed another set of DS mice in which the SCN1A gene had been deleted only in neurons responsible for transmitting inhibitory electrical signals in the brain [5]. The same responses were observed in this second group of DS mice, indicating that thermoregulation is most likely mediated by these inhibitory neurons. 

Along with deficits in controlling core body temperature, the DS mice also had problems regulating cardiac and respiratory function in response to elevated temperature. Specifically, although the heart rate of DS mice increased to only half that of control mice, the rate of recovery was much slower after the heat source had been removed. Likewise, even though the breathing rates decreased in both DS and control mice in response to higher temperatures, it recovered partially in control mice but not at all in DS mice.  

The effect of moderate exercise (running on a treadmill) on heart rate as well as heart rate variability was also assessed [5]. During this exercise challenge, the highest heart rate level reached was much lower in DS than in control mice, and it took much longer for DS mice to reach their peak values. Similar responses were observed for heart rate variability, all of which suggest impaired cardiac function in DS. 

Together, these findings imply that there are clear abnormalities within the ANS of DS mice and, by extension, in people with DS and possibly other intractable epilepsies. Understanding the biological bases of these irregularities and how environmental changes may adversely affect them will likely assist in the development of novel methods to reduce seizure-related health consequences as well as the high risk of SUDEP.   

This work was conducted in collaboration with Dr. Orrin Devinsky of New York University. 

Read more about Dr. Kalume’s research in sleep and epilepsy here

 

 

Literature Cited

  1. Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088. 
  2. Devinsky, O. & Sisodiya, S.M. SUDEP: Advances and challenges. Epilepsy Curr. 2020; 20(6 Suppl): 29S-31S. 
  3. Kalume, F. Sudden unexpected death in Dravet syndrome: respiratory & other physiological dysfunctions. Respir. Physiol. Neurobiol. 2013; 189: 324-328. 
  4. Kalume, F. et al. Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 2013; 123: 1798-1808. 
  5. Sahai, N. et al. Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome. Neurobiol. Dis. 2021; 147: 105154. 

CURE Epilepsy Discovery: Optimizing Brain Stimulation for People with Drug-Resistant Epilepsy

Key Points:

• Taking Flight grantee Dr. Ankit Khambhati and colleagues at the University of California – San Francisco sought to understand why some people with drug-resistant epilepsy respond better than others to responsive neurostimulation (RNS) therapy.

• After examining the pattern of brain waves of approximately 50 patients, the investigators identified a new biomarker that could predict which people would most benefit from RNS therapy.

• This important finding has the potential to help neurologists decide which patients would benefit the most from an RNS device before it is actually implanted in the brain.

Deep Dive:

Of the millions of people who are impacted by epilepsy, approximately one-third do not respond to currently available antiseizure medications [1], adversely affecting their quality of life. Among those with drug-resistant focal epilepsy (seizures that start from a single area in the brain, formerly known as partial seizures), one of the more effective treatment options involves brain stimulation [2], including the Neuropace Responsive Neurostimulation System® (RNS) [3]. The RNS is a ‘smart’ device implanted on the surface of the brain, with two thin wires placed where the seizures begin. It monitors brain waves recorded from the wires to produce what is called an intracranial electroencephalogram (iEEG). When the RNS device senses abnormal neural activity, it responds with subtle electrical pulses to either terminate or suppress an emerging seizure. The iEEG data can also be mined for research purposes to identify changing patterns in the brain waves as a patient’s condition improves.

The RNS is effective at reducing seizures in many patients with focal epilepsy, but it does not work for every patient, and it is not clear why. Dr. Khambhati and his colleagues, Drs. Edward Chang and Vikram Rao, thought that the lack of response in some people may be related to some seemingly inconsistent observations from numerous clinical trials of the RNS System. As mentioned above, the RNS device was designed to send electrical pulses to terminate a developing seizure only when abnormal electrical activity was detected, but the researchers found actual stimulation often occurred more than 1,000 times a day. This did not correlate with the actual number of seizures reported suggesting a significant amount of abnormal activity between seizures. In addition, clinically significant improvements, i.e., reduction in seizure frequency, occurred gradually over time, often years rather than just immediately after electrical stimulation by RNS [4]. Together, these observations suggested that there is abnormal electrical activity that occurs between seizures, possibly exacerbating them, and that the RNS device both terminates seizures and may also slowly modify how they are generated.

To explore this possibility, Dr. Khambhati and colleagues capitalized on the availability of many years’ worth of iEEG data from approximately 50 patients with an implanted RNS device [5]. Upon close examination of the data, they found a wide range of RNS response effectiveness among these patients and categorized them in three separate groups: super, intermediate, and poor responders based on the percent reduction in seizures.

Comparing the iEEG patterns from each of these groups allowed the researchers to conclude that RNS therapy, in addition to suppressing an emerging seizure, was also inducing a rewiring of the epileptic network, essentially disrupting it. This, in turn, dramatically decreased the brain’s tendency to generate excessive excitatory electrical activity sufficient to trigger a seizure. More importantly, the researchers found that much of this rewiring was a result of stimulation that occurred between seizures rather than just before the “buildup” of electrical activity indicative of seizure onset. Furthermore, since each of the three responder groups exhibited different iEEG “fingerprints”, the researchers were also able to consolidate these data to generate a powerful algorithm that could examine iEEG patterns and pinpoint unique biomarkers reflecting a prospective patient’s likely response to an implanted RNS device.

With this critical advancement, clinical care of patients with focal epilepsy being treated with RNS therapy may be improved beyond the typical adjustment of stimulation parameters. Neurologists may now be able to predict how a patient will respond to RNS, better counsel patients on their prognosis, and adjust stimulation parameters accordingly. Ideally, this discovery will help determine if a patient will even benefit from RNS therapy before the device is even implanted in the brain, thereby reducing unnecessary treatment risks for patients with focal epilepsy.

Literature Cited
1. Chen, Z. et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018; 75: 279-286.
2. Foutz, T. & Wong, M. Brain stimulation treatments in epilepsy: basic mechanisms and clinical advances. Biomed. J 2021; in press
3. Morrell, M.J. RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011; 77: 1295-1304.
4. Nair, D.R. et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology 2020; 95: e1244-e1256.
5. Khambhati, A.N. et al. Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy. Sci. Transl. Med. 2021; 13(608): eabf6588.

CURE Epilepsy Discovery: Beyond Pharmacological Therapy for the Treatment of Epilepsy: Creating Electrodes to Prevent Seizures by Stimulating the Brain

Dr. Brian Litt at the University of Pennsylvania has dedicated his research career to the creation and improvement of flexible, active, implantable electrodes to monitor and stimulate the brain with the goal of curing epilepsy.

Key Points:

Dr. Brian Litt, MD, Professor in both the Departments of Neurology and Bioengineering at the University of Pennsylvania, obtained a research grant from CURE Epilepsy in 2011 to develop active, flexible, implantable electrodes to treat epilepsy by stimulating the brain.

  • The flexible electrodes are ideal to insert into brain tissue and are able to record brain activity as well as stimulate specific brain areas when a seizure arises, thereby mitigating it.
  • Dr. Litt considers the CURE Epilepsy grant that he received to be pivotal to the development of his laboratory. His laboratory has since grown tremendously and has proven to be a very fertile environment, especially for the training of young researchers who have gone on to work on various research strategies to cure epilepsy.

Deep Dive:

Dr. Litt studied Engineering and Applied Sciences at Harvard University and obtained his medical degree at Johns Hopkins University. When he started treating patients as a neurologist, he realized that the treatments that were available for patients with drug-resistant epilepsy were mostly based on traditional pharmacological interventions and had limited capacity to significantly change the course of the disease. The lack of alternatives for patients who were resistant to pharmacological treatments inspired him to research electrical stimulation as a new method to treat epilepsy, with the goal of preventing seizures to control the disease.

A research grant from CURE Epilepsy in 2011 for “Flexible Implantable Devices for Epilepsy” was instrumental in the development of these technologies, and in defining Dr. Litt’s research trajectory when he started his laboratory at the University of Pennsylvania.

Dr. Litt´s laboratory collaborated with Dr. John Rogers, also at the University of Pennsylvania, who had developed the first flexible electrodes but had not tried implanting them in live tissue at the time. Together, their laboratories developed and tested the first brain implants incorporating active electronics for recording seizure activity and stimulating the brain to control seizures.

Dr. Litt’s research has always been on the forefront of advancing the relationship between medicine and engineering, and he has actively fostered collaborations between these two areas at his university. Dr. Litt belongs to both the Departments of Neurology and Bioengineering and collaborates extensively with research groups with varied areas of expertise and at different institutions all over the country.  

Dr. Litt believes the CURE Epilepsy grant he received many years ago had a great impact on his career. In addition to contributing to epilepsy research in an essential way, it has enabled him to train the next generation of epilepsy researchers. Over the years, he has trained over 50 PhD students and post-doctoral researchers with the majority of them still successfully working on epilepsy today. Several of his trainees have started their independent research careers in epilepsy and secured NIH funding for their projects. 

Dr. Litt wants donors to know how important CURE Epilepsy has been to his successful career.  “I can’t tell you how grateful I am to the organization and the donors. […] Probably the biggest impact of CURE Epilepsy is that the organization doesn’t spend dollars foolishly. You carefully bet on the people as well as the projects. You’re very good stewards of the money.” Additionally, he commented, “Research is incremental. It builds on itself with time. Getting the result of the research is just one piece of the puzzle, but what’s even more important is getting a lot of smart young people to think about epilepsy and work on it, so you build this critical mass and this community.”  

The CURE Epilepsy grant allowed Dr. Litt to start his research to develop implantable electrodes to stimulate the brain. Considering the limitations of pharmacological therapy for many epilepsy patients, it is essential to increase the range of available treatments, and the work from Dr. Litt’s laboratory makes a cure for epilepsy closer to becoming a reality. Dr. Litt and his group members, past and present, are at the frontline of this fascinating and fundamental endeavor, and CURE Epilepsy is a proud supporter of this enterprise. 

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A special thank you to Irene Sanchez Brualla, PhD, for her assistance with this article. 

2021 Curing the Epilepsies Conference: The Epilepsy Community at an Inflection Point

Key Points:

  • The 2021 Curing the Epilepsies conference assembled diverse stakeholders from the epilepsy community to discuss the status of epilepsy research and transformative research priorities.
  • During the 2021 conference, participants identified several key topics as indispensable for advancing epilepsy research and improving the lives of those impacted by epilepsy, including integrating epilepsy care and research, improving measurement and tracking of health outcomes, and reducing health disparities for underserved communities.
  • In an editorial published after the conference, members of the epilepsy advocacy community, co-led by CURE Epilepsy’s Chief Scientific Officer Dr. Laura Lubbers, proposed development of a National Plan to address the epilepsies. This plan would include a comprehensive strategy, the infrastructure, and the expanded partnerships to rapidly translate scientific discoveries into better health outcomes for people with epilepsy.

Deep Dive:  

The Curing the Epilepsies conference has been held approximately every seven years since the first one in 2000.  The initial conference was established with the help of CURE Epilepsy, with governmental funding agencies, professional societies, and other patient advocates also contributing.  As in the past, the 2021 conference included stakeholders such as clinicians, researchers, and especially patients and caregivers, to review scientific discoveries and transformative research priorities with the ultimate goals of 1) curing epilepsy with no side effects and 2) preventing epilepsy in people at risk. Research progress, documented in an editorial recently published in the journal Epilepsy Currents [1], has led to an enhanced understanding of: 

  •  epileptogenesis, the processes by which epilepsy develops  
  • increased risk of premature death, especially from sudden unexpected death in epilepsy (SUDEP)  
  • epilepsy-associated comorbidities such as depression 
  • technologically– based diagnostics, especially in neuroimaging and genetic testing  
  • non-pharmacological treatment options, particularly for surgery and implantable devices for treating seizures [1].  

It was also recognized that despite such compelling scientific strides, these exciting developments have yet to significantly improve health outcomes for people with epilepsy.  

To truly accelerate progress and cure the epilepsies, leaders in the epilepsy advocacy community propose development of a comprehensive research strategy as part of a National Plan [2] to address the epilepsies. A National Plan would bring together the necessary infrastructure and expanded partnerships needed to rapidly translate scientific discoveries into better health outcomes. A key goal of the plan would include improving patient care and the quality of patient-centered data, both key to catalyzing the following four transformative priorities:  

1) consolidation of research and clinical care  

2) lessening of health disparities faced by underserved populations 

3) consistent monitoring of patient outcomes  

4) creation of a nationwide database with statistics on epilepsy burden, prevalence, incidence, epidemiology, and mortality categorized according to distinct criteria such as age, race, ethnicity, and socioeconomic status.   

Carrying out the National Plan will require the combined efforts of many stakeholder groups, including researchers, clinicians, advocacy groups, and, most importantly, people with epilepsy and their families. It is crucial that the courageous voices of patients and their families and their lived experiences, are incorporated into all steps of the research planning process. Working together, we can chart the course for aligning the infrastructure, incentives, research needs, and resources to put the nation on a path toward curing the epilepsies.? 

Literature Cited 

  1. Marsh, E.D. et al. The 2021 Epilepsy Research Benchmarks – respecting core principles, reflecting evolving community priorities. Epilepsy Currents 2021; Epub – Online first 
  1. Miller, I.P. et al. Epilepsy community at an inflection point: translating research toward curing the epilepsies and improving patient outcomes. Epilepsy Currents 2021; Epub – Online first 

CURE Epilepsy Discovery: Heart Dysfunction Is a Risk Factor for SUDEP

Key Points:

  • CURE Epilepsy Award grantee Dr. Christopher Reid and his team sought to understand the genetic connection between sudden expected death in epilepsy (SUDEP) and cardiac arrhythmia with the goal of improving treatment for people with epilepsy and reducing the risk of SUDEP.
  • The team focused on KCNH2, a gene whose loss-of-function mutations are linked to cardiac arrhythmias and increased SUDEP risk in humans.
  • Currently, the team is generating laboratory models with genetic mutations comparable to those found in humans, to explore the link between cardiac abnormalities and SUDEP risk with greater precision than is feasible with humans.

Deep Dive:

SUDEP is the most common cause of death among people with treatment-resistant epilepsy [1], but its underlying biological cause remains obscure. There is strong evidence of the association of breathing problems with SUDEP [2,3], but there is also equally strong, if not more so, data for cardiac abnormalities, particularly cardiac arrhythmias (irregular heartbeat). In fact, studies have found mutations in genes associated with cardiac arrhythmias in SUDEP patients [4].

Dr. Christopher Reid and his team at the Florey Institute of Neuroscience & Mental Health at the University of Melbourne sought to build upon the known relationship between cardiac abnormalities and SUDEP risk by identifying specific genes involved in proper cardiac function. With the assistance of a CURE Epilepsy Award, they chose to focus on a gene known as KCNH2, which affects the spread of electrical signals in the heart. KCNH2 variants that result in a loss of cardiac function are a well-known cause of long QT syndrome [5], a potentially fatal condition that affects heart function and which has as a distinct pattern on an electrocardiogram.

 Prior research revealed that KCNH2 was one of thirty genes found in an analysis of rare genetic variants in SUDEP patients when compared to controls [6]. Following up on that work and as part of this study, the team characterized the variants, finding that about 8% of SUDEP cases carry a KCNH2 variant that causes the gene to not function (7). As a result of these findings, the team proposed that the risk of SUDEP is significantly higher for a person who experiences seizures and carries a KCNH2 loss-of-function variant than for a person who has seizures but does not carry a loss-of-function variant. This suggests that the presence of loss-of-function mutations of KCNH2 may serve as valuable biomarkers for SUDEP risk [7].

To probe this relationship with greater precision than is possible in humans, Dr. Reid and his team are currently generating laboratory models with mutations in genes that are involved in cardiac arrhythmias and development of epilepsy, comparing their SUDEP risk to those models with either arrhythmia alone or epilepsy alone. Based on the human studies, the expectation is that the combination of cardiac- and epilepsy-related genetic mutations will result in a much greater propensity for sudden death. The eventual goal is to use these data to help understand how cardiac function and epilepsy might intersect and inform clinical guidelines for the treatment of epilepsy patients, hopefully reducing SUDEP risk in the process.

Literature Cited

  1. Thurman, D.J. et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League against Epilepsy. Seizure 2017; 58(1): 17-26.
  2. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
  3. Wenker, I.C. et al. Postictal death is associated with tonic phase apnea in a mouse model of sudden expected death in epilepsy. Neurol. 2021; 89: 1023-1035.
  4. Bagnall, R.D., Crompton, D.E., and Semsarian, C. Genetic basis of sudden unexpected death in epilepsy. Neurol. 2017; 8: 348.
  5. Bleakley, L.E. et al. Are variants causing cardiac arrhythmia risk factors in sudden unexpected death in epilepsy? Neurol. 2020; 11: 925.
  6. Bagnall, R.D. et al. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Neurol. 2016; 79(4): 522-534.
  7. Soh, M.S. et al. Loss-of-function variants in Kv11.1 cardiac channels as a biomarker for SUDEP. Clin. Transl. Neurol. 2021; Epub ahead of print.

CURE Epilepsy Discovery: When Does a Seizure Lead to SUDEP?

Key Points:

  • CURE Epilepsy Taking Flight grantee Dr. Ian Wenker and colleagues used mouse models to determine the series of biological events underlying sudden expected death from epilepsy (SUDEP).
  • Analysis of electrical activity from the brain and heart, along with breathing, revealed that the main cause of death was apnea (breathing cessation), which originated during the tonic phase of a seizure, the stage during which muscles stiffen.
  • Restoration of breathing, either naturally or artificially, soon after the seizure had ended increased the rate of survival, thereby preventing SUDEP.
  • The clinical relevance of these data was reflected in an epilepsy patient whose breathing disruptions were similar to those observed in the mice.

Deep Dive:

SUDEP is a devastating outcome for some people with epilepsy, and the most common cause of death among people with treatment-resistant epilepsy [1]. Despite significant research into the cause of SUDEP [2], including an implication of cardiorespiratory dysfunction [1,3], the precise series of biological events ultimately leading to death is not clear.

With the help of a CURE Epilepsy Taking Flight award, Dr. Ian Wenker and colleagues, working in the laboratory of Dr. Manoj Patel at the University of Virginia School of Medicine, sought to better understand these events. Specifically, they sought to determine the order in which physiological processes occur, the circumstances that lead to death, and what could be done during the seizure to prevent death [4]. The researchers used mouse models of epilepsy wherein seizures were induced either genetically or chemically. They measured breathing and monitored electrical activity from the brain and heart for both fatal and nonfatal seizures.

Dr. Wenker and colleagues found that during the tonic phase of a seizure, the phase in which muscles, including the primary breathing muscle known as the diaphragm, become rigid, breathing disruptions (apnea) were common. However, death only occurred if breathing did not promptly restart after the seizure. This conclusion was then tested by mechanically ventilating those mice whose breathing had not fully recovered after the seizure, and they survived.

To extend these exciting findings from mice to people with epilepsy, the researchers examined the corresponding data from a patient with a harmful genetic mutation similar to that in the mutant mice. The breathing patterns, frequency, and disruptions in this individual were comparable to those from seizure-susceptible mice, suggesting that treating any breathing disruptions in patients post-seizure may prevent SUDEP. Dr. Wenker plans to build on these data and hopes to contribute to the development of a protocol that may one day eliminate SUDEP completely.

Literature Cited

  1. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
  2. Jones, L.A. & Thomas, R.H. Sudden death in epilepsy: Insights from the last 25 years. Seizure 2017; 44: 232-236.
  3. Stewart, M. et al. Causes and effects contributing to sudden death in epilepsy and the rationale for prevention and intervention. Neurol. 2020; 11: 765.
  4. Wenker, I.C. et al. Postictal death is associated with tonic phase apnea in a mouse model of sudden expected death in epilepsy. Neurol. 2021; 89: 1023-1035.