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Morris Scantlebury, MD
Areas of Research
Febrile Seizures
Febrile seizures are the most common seizure disorder to affect children who are at a high risk of developing intractable epilepsy. The mechanisms of febrile seizures are unknown which has limited the development of prophylactic treatments. There is strong evidence supporting that febrile seizures occur when children have fever-induced increases in breathing associated with an infection that leads to respiratory alkalosis and subsequent decreased seizure thresholds. Indeed, shifts in acid-base balance are well recognized to alter brain function such that alkalosis leads to hyperexcitability and decreased seizure thresholds, and acidosis producing the opposite effect. Given this link between fever, respiration and febrile seizures, it is important to determine the precise mechanisms by which fever leads to increases in breathing and subsequent respiratory alkalosis. Transient receptor potential vanilloid type 1 receptors (TRPV1) are heat sensitive receptors that play an important role in thermoregulation and responses to inflammation. Importantly, TRPV1 has been localized in the vagus nerve which is a key driver of the fever-induced increases in breathing linked to respiratory alkalosis. The overall goal of this proposal is to test, in an inflammation-based model of febrile seizures established in my laboratory, the link between TRPV1, inflammation and fever-induced increases in breathing accounting for respiratory alkalosis and consequent increased risk of febrile seizures. The results of this study will provide a molecular target upon which, currently unavailable, prophylactic treatments for febrile seizures can be developed and made available for use in clinical practice.
Febrile seizures are the most common seizure disorder to affect children who are at a high risk of developing intractable epilepsy. The mechanisms of febrile seizures are unknown which has limited the development of prophylactic treatments. There is strong evidence supporting that febrile seizures occur when children have fever-induced increases in breathing associated with an infection that leads to respiratory alkalosis and subsequent decreased seizure thresholds. Indeed, shifts in acid-base balance are well recognized to alter brain function such that alkalosis leads to hyperexcitability and decreased seizure thresholds, and acidosis producing the opposite effect. Given this link between fever, respiration and febrile seizures, it is important to determine the precise mechanisms by which fever leads to increases in breathing and subsequent respiratory alkalosis. Transient receptor potential vanilloid type 1 receptors (TRPV1) are heat sensitive receptors that play an important role in thermoregulation and responses to inflammation. Importantly, TRPV1 has been localized in the vagus nerve which is a key driver of the fever-induced increases in breathing linked to respiratory alkalosis. The overall goal of this proposal is to test, in an inflammation-based model of febrile seizures established in my laboratory, the link between TRPV1, inflammation and fever-induced increases in breathing accounting for respiratory alkalosis and consequent increased risk of febrile seizures. The results of this study will provide a molecular target upon which, currently unavailable, prophylactic treatments for febrile seizures can be developed and made available for use in clinical practice.
Infantile Spasms
Infantile spasms is a rare but devastating epilepsy for which treatment oftentimes do not work. Because of this, children with infantile spasms frequently develop other seizure types and do not learn to talk, walk or care for themselves. Moreover one third of children with infantile spasms will die due to the uncontrolled seizures. A high fat low carbohydrate diet known as the ketogenic diet is emerging as an effective treatment for infantile spasms even in those patients who do not respond to current first-line treatments. The diet however is fraught with side effects and difficult for patients tolerate. It is important to determine how the diet works in infantile spasms so that safe, effective and tolerable treatments can be developed. This timely proposal is directed at uncovering precisely how the ketogenic diet works in infantile spasms. We've discovered in a model of infantile spasms that the ketogenic diet works by making the brain acidic. Correcting this acidity significantly attenuated the antiseizure effects of the ketogenic diet. We hypothesized that the acidity in the brain induced by the ketogenic diet works to control seizures by activating acid sensing ion channels. Our preliminary results show that deleting these channels in the brain using advanced gene editing techniques abolished the antiseizure effects of the ketogenic diet. This proposal describes important experiments to 1) determine how acid sensing ion channels are involved in the anti-seizure effects of the ketogenic diet, 2) determine whether acid sensing ion channels in all brain cells are involved in the ketogenic diet's antiseizure effects or a subtype thereof 3) to test new treatments that will strengthen the ability of acidosis to activate acid sensing ion channels for the treatment of infantile spasms. The goal is to identify a treatment strategy for infantile spasms that will bring us one step closer to eliminating this catastrophic form of epilepsy from the pediatric population.
Infantile spasms is a rare but devastating epilepsy for which treatment oftentimes do not work. Because of this, children with infantile spasms frequently develop other seizure types and do not learn to talk, walk or care for themselves. Moreover one third of children with infantile spasms will die due to the uncontrolled seizures. A high fat low carbohydrate diet known as the ketogenic diet is emerging as an effective treatment for infantile spasms even in those patients who do not respond to current first-line treatments. The diet however is fraught with side effects and difficult for patients tolerate. It is important to determine how the diet works in infantile spasms so that safe, effective and tolerable treatments can be developed. This timely proposal is directed at uncovering precisely how the ketogenic diet works in infantile spasms. We've discovered in a model of infantile spasms that the ketogenic diet works by making the brain acidic. Correcting this acidity significantly attenuated the antiseizure effects of the ketogenic diet. We hypothesized that the acidity in the brain induced by the ketogenic diet works to control seizures by activating acid sensing ion channels. Our preliminary results show that deleting these channels in the brain using advanced gene editing techniques abolished the antiseizure effects of the ketogenic diet. This proposal describes important experiments to 1) determine how acid sensing ion channels are involved in the anti-seizure effects of the ketogenic diet, 2) determine whether acid sensing ion channels in all brain cells are involved in the ketogenic diet's antiseizure effects or a subtype thereof 3) to test new treatments that will strengthen the ability of acidosis to activate acid sensing ion channels for the treatment of infantile spasms. The goal is to identify a treatment strategy for infantile spasms that will bring us one step closer to eliminating this catastrophic form of epilepsy from the pediatric population.
Pediatric Epilepsy Outcomes and Informatics Project
The PEOIP is a world leading bioinformatics program of the Alberta Children’s Hospital Comprehensive Children Epilepsy Center (CCEC); the latter serves as the primary referral for seizures in southern Alberta. The mission statement of the CCEC is- “To create a system of excellence to provide comprehensive clinical care and research that leads to improved outcomes & education for all stakeholders in a manner that optimizes societal resources.” Central to accomplishing our mission we created a data structure by which common data elements are entered by physicians and nurses into an electronic note available in our EHR (Sunrise Clinical Manager), soon to be transitioned to EPIC. The data for the entire population of patients of epilepsy is then organized into a dashboard using the data visualization tool Tableau. The population dashboard contains many filterable fields and thus is a powerful tool that allows clinicians to receive answers to important clinical questions and notably the answers can be received within minutes to seconds. A summary of the patient’s history is also provided as a patient specific dashboard. All dashboards are updated at least weekly and made available to the physician for use at the point of care. The data collected with the epilepsy note can also be combined with data from other provincial data sources to enrich our understanding of our patients with epilepsy. Thus far we have prospectively collected longitudinal standardized data on 3753 unique patients with pediatric epilepsy comprising ~ 17,541 notes (patient encounters) which is one of the largest such repository of standardized data collection for pediatric epilepsy patients in North America. We aim to leverage and enhance the data-capture and infrastructure within the PEOIP to achieve our goal to improve outcomes for our children with epilepsy.
The PEOIP is a world leading bioinformatics program of the Alberta Children’s Hospital Comprehensive Children Epilepsy Center (CCEC); the latter serves as the primary referral for seizures in southern Alberta. The mission statement of the CCEC is- “To create a system of excellence to provide comprehensive clinical care and research that leads to improved outcomes & education for all stakeholders in a manner that optimizes societal resources.” Central to accomplishing our mission we created a data structure by which common data elements are entered by physicians and nurses into an electronic note available in our EHR (Sunrise Clinical Manager), soon to be transitioned to EPIC. The data for the entire population of patients of epilepsy is then organized into a dashboard using the data visualization tool Tableau. The population dashboard contains many filterable fields and thus is a powerful tool that allows clinicians to receive answers to important clinical questions and notably the answers can be received within minutes to seconds. A summary of the patient’s history is also provided as a patient specific dashboard. All dashboards are updated at least weekly and made available to the physician for use at the point of care. The data collected with the epilepsy note can also be combined with data from other provincial data sources to enrich our understanding of our patients with epilepsy. Thus far we have prospectively collected longitudinal standardized data on 3753 unique patients with pediatric epilepsy comprising ~ 17,541 notes (patient encounters) which is one of the largest such repository of standardized data collection for pediatric epilepsy patients in North America. We aim to leverage and enhance the data-capture and infrastructure within the PEOIP to achieve our goal to improve outcomes for our children with epilepsy.
Supervising degrees
Neuroscience - Masters: Accepting Inquiries
Neuroscience - Doctoral: Accepting Inquiries
Working with this supervisor
The principal foci of our laboratory are 1) to find a cure for infantile spasms and 2) to prevent the development of epilepsy following atypical febrile seizures in children.
My research has focused on the development and characterization of models of pediatric epilepsy syndromes. I have so far developed a model of temporal lobe epilepsy following atypical febrile seizures and a model of symptomatic infantile spasm syndrome. In a collaborative approach, our laboratory utilizes long-term EEG and behavioral assessments in conjunction with molecular, biochemical, pharmacological and electrophysiological techniques to understand the factors underlying seizure/epileptogenesis in the animal models. Our overall goal is to use this increased understanding derived from the animal models to guide the discovery of novel targets for therapeutic intervention that can be rapidly translated to clinical practise.
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