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group_2_presentation_2_-_epilepsy [2017/11/02 23:24] morgal |
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| + | Link to presentation: https://docs.google.com/a/mcmaster.ca/presentation/d/1dW15LKA4tzy2A1yKkckc6njZKW-URDgH05njQZ8UVXI/edit?usp=sharing | ||
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| ====== Introduction ====== | ====== Introduction ====== | ||
| Epilepsy is a chronic condition that affects the central nervous system and is characterized by a disruption in the normal functioning of neuronal signaling and activity. Epilepsy is characterized by the presence of unprovoked or spontaneously recurring epileptic seizures ranging in severity and occur within a short span of time. There is often no immediately identifiable trigger for epileptic seizures and two or more seizures occurring within a span of 24 hours is considered an isolated event. Seizures that occur during the neonatal period of life, and acute symptomatic seizures linked to substance abuse are not considered epileptic. (Banerjee, Filippi, & Hauser, 2009) (Scharfman, 2007). The spectrum of epileptic seizures range from a lapse in concentration to unconsciousness with regards to severity. In addition, the World Health Organization defines epilepsy as a prevalent and major health concern world wide, and statistics show that over 50 million individuals world-wide present the disorder (World Health Organization, 2015). | Epilepsy is a chronic condition that affects the central nervous system and is characterized by a disruption in the normal functioning of neuronal signaling and activity. Epilepsy is characterized by the presence of unprovoked or spontaneously recurring epileptic seizures ranging in severity and occur within a short span of time. There is often no immediately identifiable trigger for epileptic seizures and two or more seizures occurring within a span of 24 hours is considered an isolated event. Seizures that occur during the neonatal period of life, and acute symptomatic seizures linked to substance abuse are not considered epileptic. (Banerjee, Filippi, & Hauser, 2009) (Scharfman, 2007). The spectrum of epileptic seizures range from a lapse in concentration to unconsciousness with regards to severity. In addition, the World Health Organization defines epilepsy as a prevalent and major health concern world wide, and statistics show that over 50 million individuals world-wide present the disorder (World Health Organization, 2015). | ||
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| **Excitatory Neurotransmission** | **Excitatory Neurotransmission** | ||
| - | The brain’s primary excitatory neurotransmitter is glutamate. The influx of Ca2+ following depolarization of the terminal axon prompts vesicles to release glutamate into the synaptic cleft where it can bind either NMDA (N-methyl-D-aspartate) or non-NMDA (kainate and AMPA) receptors (Stafstrom, 1998). The binding of glutamate to non-NMDA receptors causes the influx of Na+ into the post synaptic neuron via the rector’s pore. This brings the membrane potential inside the postsynaptic neuron closer to firing threshold and is called an excitatory postsynaptic potential (EPSP). Non-NMDA receptors mediate a fast-EPSP, which is often followed by an action potential once firing threshold is reached. To activate a NMDA receptor, glutamate must bind to the NMDA receptor, a glycine co-agonist must bind to the NMDA receptor complex and a Mg2+ ion that blocks the channel pore of the NMDA receptor complex must be expelled (Stafstrom, 1998). At resting membrane potential the Mg2+ ion blocks the pore and prevents the influx of ions into the postsynaptic neuron. Once the postsynaptic neuron has been depolarized by a non-NMDA mediated fast-EPSP the Mg2+ ion is relieved, permitting the flow of Na+ and Ca2+ into the postsynaptic neuron, this results in a NMDA-mediated prolonged-EPSP. During the longer NMDA-mediated depolarization several action potential may fire (Stafstrom, 1998). | + | The brain’s primary excitatory neurotransmitter is Glutamate. The influx of Ca2+ following depolarization of the terminal axon prompts vesicles to release Glutamate into the synaptic cleft where it can bind either NMDA (N-methyl-D-aspartate) or non-NMDA (kainate and AMPA) receptors (Stafstrom, 1998). The binding of Glutamate to non-NMDA receptors causes the influx of Na+ into the post synaptic neuron via the rector’s pore. This brings the membrane potential inside the postsynaptic neuron closer to firing threshold and is called an excitatory postsynaptic potential (EPSP). Non-NMDA receptors mediate a fast-EPSP, which is often followed by an action potential once firing threshold is reached. To activate a NMDA receptor, Glutamate must bind to the NMDA receptor, a glycine co-agonist must bind to the NMDA receptor complex and a Mg2+ ion that blocks the channel pore of the NMDA receptor complex must be expelled (Stafstrom, 1998). At resting membrane potential the Mg2+ ion blocks the pore and prevents the influx of ions into the postsynaptic neuron. Once the postsynaptic neuron has been depolarized by a non-NMDA mediated fast-EPSP the Mg2+ ion is relieved, permitting the flow of Na+ and Ca2+ into the postsynaptic neuron, this results in a NMDA-mediated prolonged-EPSP. During the longer NMDA-mediated depolarization several action potential may fire (Stafstrom, 1998). |
| {{ :excite.png |}} | {{ :excite.png |}} | ||
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| **Inhibitory Neurotransmission** | **Inhibitory Neurotransmission** | ||
| - | The brain’s primary inhibitory neurotransmitter is gamma-amino-butyric acid (GABA). Glucose is the primary precursor of GABA, but it can also be produced from pyruvate and glutamine. Tricarboxylic acid cycle enzymes convert glucose to glutamate which is then converted to GABA via glutamic acid decarboxylase (GAD). GABA is eventually degraded into succinate by GABA transaminase and is free to enter the Krebs cycle (Purves, 2012). The influx of Ca2+ following the depolarization of the terminal axon causes vesicles to release GABA into the synaptic cleft. Once GABA is in the synaptic cleft it can bind to three receptors: GABA-A, GABA-C, GABA-B. The former two are ionotropic receptors and therefore, the activation of these two receptors leads to an influx of Cl-, which inhibits postsynaptic neurons. Receptor GABA-B is a G-coupled protein, therefore when GABA binds to the receptor it activates the G-subunit of the receptor. Stimulation of the G-protein subunit leads to the recruitment of secondary messengers to activate downstream ion channels. In the case of GABA-B, downstream K+ channels are activated so K+ flows out of the neuron and Ca2+ channels are blocked so they cannot flow into the neuron, resulting in hyperpolarization of the postsynaptic neuron (Treiman, 2001). Essentially, the binding of GABA to any of its respective receptors results in a greater negative charge inside the postsynaptic neuron, this change in membrane potential is called an inhibitory postsynaptic potential (IPSP), which reduces the firing frequency of a neuron by keeping the membrane potential away from firing threshold (Stafstrom, 1998). | + | The brain’s primary inhibitory neurotransmitter is Gamma-Amino-Butyric Acid (GABA). Glucose is the primary precursor of GABA, but it can also be produced from pyruvate and glutamine. Tricarboxylic Acid Cycle enzymes convert glucose to Glutamate which is then converted to GABA via Glutamic Acid Decarboxylase (GAD). GABA is eventually degraded into succinate by GABA transaminase and is free to enter the Krebs cycle (Purves, 2012). The influx of Ca2+ following the depolarization of the terminal axon causes vesicles to release GABA into the synaptic cleft. Once GABA is in the synaptic cleft it can bind to three receptors: GABA-A, GABA-C, GABA-B. The former two are ionotropic receptors and therefore, the activation of these two receptors leads to an influx of Cl-, which inhibits postsynaptic neurons. Receptor GABA-B is a G-coupled protein. When GABA binds to the receptor it activates the G-subunit of the receptor. Stimulation of the G-protein subunit leads to the recruitment of secondary messengers to activate downstream ion channels. In the case of GABA-B, downstream K+ channels are activated so K+ flows out of the neuron and Ca2+ channels are blocked so they cannot flow into the neuron, resulting in hyperpolarization of the postsynaptic neuron (Treiman, 2001). Essentially, the binding of GABA to any of its respective receptors results in a greater negative charge inside the postsynaptic neuron, this change in membrane potential is called an Inhibitory Postsynaptic Potential (IPSP), which reduces the firing frequency of a neuron by keeping the membrane potential away from firing threshold (Stafstrom, 1998). |
| {{ :inhibit.png |}} | {{ :inhibit.png |}} | ||
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| Epileptogenesis is the process in which a normally functioning brain changes toward a brain that produces an abnormal amount of electrical activity known resulting in seizures. Epilepsy occurs due to any biological feature that results in the brain’s production of unprovoked seizure. These can include anatomical, molecular, or circuit level alterations. For example, neuron death, or abnormality in ion channels or neurotransmitter receptors. | Epileptogenesis is the process in which a normally functioning brain changes toward a brain that produces an abnormal amount of electrical activity known resulting in seizures. Epilepsy occurs due to any biological feature that results in the brain’s production of unprovoked seizure. These can include anatomical, molecular, or circuit level alterations. For example, neuron death, or abnormality in ion channels or neurotransmitter receptors. | ||
| The process of epileptogenesis occurs in three steps. The first one being a brain injury. The second step, categorized by a latent period in which the brain changes to an epileptic brain due to the injury. The third and final phase is known as chronic, characterised by epilepsy (Goldberg et al. 2013). | The process of epileptogenesis occurs in three steps. The first one being a brain injury. The second step, categorized by a latent period in which the brain changes to an epileptic brain due to the injury. The third and final phase is known as chronic, characterised by epilepsy (Goldberg et al. 2013). | ||
| - | During the second phase, there is both rapid and slower progressive changes. Rapid changes include modifications to pre-existing proteins, and neuronal death. Slower responses include growth such as; axon outgrowth, synaptogenesis, angiogenesis, leading to synaptic reorganization. These slow and fast response changes ultimately decrease the threshold in which the a seizure can occur. Therefore, genes, development, and the responses to the initial insult are likely to act together to result in a state of chronic seizures (Scharfman 2007) | + | During the second phase, there is both rapid and slower progressive changes. Rapid changes contain neuronal excitation and calcium influx, which triggers events that such as second messenger and immediate early gene responses, modifications to pre-existing proteins, and protein synthesis. Immediately, there is cell death and proliferation as well as inflammatory, glia, and vascular responses. Slower responses include growth such as; axon outgrowth, synaptogenesis, angiogenesis, leading to synaptic reorganization. Over a period of time, there is a growing increase in excitability, and thus the risk of a seizure increases. Therefore, genes, development, and the responses to the initial insult are likely to act together to result in a state of chronic seizures (Scharfman 2007) |
| {{ :steps_of_epilepsy.png |}} | {{ :steps_of_epilepsy.png |}} | ||
| - | **Figure 11**: Three steps which occur to change a normal functioning brain, into an epileptic brain. | + | **Figure 11**: |
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| - | **Figure 12**: The two major pathways in which seizure can occur in the brain for an epileptic patient. | + | **Figure 12**: |
| **Increased Excitability** | **Increased Excitability** | ||
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| {{ :aeds_mechanims_epi.png |}} | {{ :aeds_mechanims_epi.png |}} | ||
| - | **Figure 16**: Certain AEDs can increase inhibition by potentiating GABA's effect whereas others inhibit excitatory by decreasing Glutamatergic effects. Both pathways decrease the likelihood of an epileptic episode. | + | **Figure 16**: Certain AEDs can increase inhibition by potentiating GABA's effect whereas others inhibit excitatory by decreasing Glutamatergic effects. |
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| **Brain Surgery** | **Brain Surgery** | ||
| - | The goal of surgery is to find the epileptogenic focus which is not eloquent cortex and resect it without causing any neurological deficits. The most common focus point in adults is the temporal lobe (mainly the hippocampus). There are many ways to discover the area of epileptogenic focus: Video and scalp EEG, fMRI, MEG (magnetoencephalography), or seizure semiology. | + | The goal of surgery is to find the epileptogenic focus which is not eloquent cortex and resect it without causing any neurological deficits. The most common focus point in adults is the temporal lobe (mainly the hippocampus). There are many ways to discover the area of epileptogenic focus: Video and scalp EEG, fMRI, MEG (magnetoencephalography), or seizure semiology. (Kawai, 2015) |
| Surgery can be divided into either palliative or curative procedures. Curative procedures include lesional resection, lobectomy, and multiple subpial transections. For the treatment of temporal love epilepsy a gamma knife radiosurgery is used. | Surgery can be divided into either palliative or curative procedures. Curative procedures include lesional resection, lobectomy, and multiple subpial transections. For the treatment of temporal love epilepsy a gamma knife radiosurgery is used. | ||
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| Surgery is either used to define and resect an area of epileptogenic focus or disrupt the spread of seizure activity which in turn reduces the likelihood of seizures. Electrodes are used to record from the surface of the brain. One of the most common procedures is for medial temporal lobe epilepsy where the hippocampus is the main target for surgery. | Surgery is either used to define and resect an area of epileptogenic focus or disrupt the spread of seizure activity which in turn reduces the likelihood of seizures. Electrodes are used to record from the surface of the brain. One of the most common procedures is for medial temporal lobe epilepsy where the hippocampus is the main target for surgery. | ||
| - | + | (Bromfield, 2006) | |
| - | (Bromfield, 2006) (Kawai, 2015) | + | |
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| Banerjee, P. N., Filippi, D., & Hauser, W. A. (2009). The descriptive epidemiology of epilepsy-a review. Epilepsy Research, 85(1), 31–45. http://doi.org/10.1016/j.eplepsyres.2009.03.003 | Banerjee, P. N., Filippi, D., & Hauser, W. A. (2009). The descriptive epidemiology of epilepsy-a review. Epilepsy Research, 85(1), 31–45. http://doi.org/10.1016/j.eplepsyres.2009.03.003 | ||
| - | Bhalla, D., Godet, B., Druet-Cabanac, M., Preux, P.M. (2011). Etiologies of epilepsy: a comprehensive review. Expert Review of Neurotherapeutics. 11(6):861-76 | + | Bhalla, D., Godet, B., Druet-Cabanac, M., Preux, P.M. (2011). Etiologies of epilepsy: a comprehensive review. Expert Review of Neurotherapeutics. 11(6):861-76. Retrieved from https://journals-scholarsportal-info.libaccess.lib.mcmaster.ca/pdf/14737175/v11i0006/861_eoeacr.xml |
| - | https://journals-scholarsportal-info.libaccess.lib.mcmaster.ca/pdf/14737175/v11i0006/861_eoeacr.xml | + | |
| BRADFORD, H.F. (1995). Glutamate, GABA and epilepsy. Prog. Neurobiol., 47, 477–511. | BRADFORD, H.F. (1995). Glutamate, GABA and epilepsy. Prog. Neurobiol., 47, 477–511. | ||
| - | Bromfield EB, Cavazos JE, Sirven JI, editors. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; 2006. Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy.Available from: https://www.ncbi.nlm.nih.gov/books/NBK2510/ | + | Bromfield EB, Cavazos JE, Sirven JI, editors. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; 2006. Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK2510/ |
| Cho, C.-H. (2013). New mechanism for glutamate hypothesis in epilepsy. Frontiers in Cellular Neuroscience, 7, 127. http://doi.org/10.3389/fncel.2013.00127 | Cho, C.-H. (2013). New mechanism for glutamate hypothesis in epilepsy. Frontiers in Cellular Neuroscience, 7, 127. http://doi.org/10.3389/fncel.2013.00127 | ||
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| Dostrovsky, J. O. and Lozano, A. M. (2002), Mechanisms of deep brain stimulation. Mov. Disord., 17: S63–S68. doi:10.1002/mds.10143 | Dostrovsky, J. O. and Lozano, A. M. (2002), Mechanisms of deep brain stimulation. Mov. Disord., 17: S63–S68. doi:10.1002/mds.10143 | ||
| - | Epilepsy Support Centre. (2015). Diagnosing Epilepsy. Available at: http://epilepsysupport.ca/seizure-education/about/diagnosing | + | Epilepsy Support Centre. (2015). Diagnosing Epilepsy. Retrieved from http://epilepsysupport.ca/seizure-education/about/diagnosing |
| Fisher, R.S. (2017). The New Classification of Seizures by the International League Against Epilepsy 2017. Current Neurology and Neuroscience Reports, 17(48). https://doi.org/10.1007/s11910-017-0758-6 | Fisher, R.S. (2017). The New Classification of Seizures by the International League Against Epilepsy 2017. Current Neurology and Neuroscience Reports, 17(48). https://doi.org/10.1007/s11910-017-0758-6 | ||
| - | Gilmour, H., Ramage-Morin, P., & Wong, S.L. (2016). Epilepsy in Canada: Prevalence and impact. Statistics Canada. http://www.statcan.gc.ca/pub/82-003-x/2016009/article/14654-eng.htm | + | Gilmour, H., Ramage-Morin, P., & Wong, S.L. (2016). Epilepsy in Canada: Prevalence and impact. Statistics Canada. Retrieved from http://www.statcan.gc.ca/pub/82-003-x/2016009/article/14654-eng.htm |
| Goldberg, E. M., & Coulter, D. A. (2013). Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nature Reviews. Neuroscience, 14(5), 337–349. http://doi.org/10.1038/nrn3482 | Goldberg, E. M., & Coulter, D. A. (2013). Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nature Reviews. Neuroscience, 14(5), 337–349. http://doi.org/10.1038/nrn3482 | ||
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| Banerjee, P. N., Filippi, D., & Hauser, W. A. (2009). The descriptive epidemiology of epilepsy-a review. Epilepsy Research, 85(1), 31–45. http://doi.org/10.1016/j.eplepsyres.2009.03.003 | Banerjee, P. N., Filippi, D., & Hauser, W. A. (2009). The descriptive epidemiology of epilepsy-a review. Epilepsy Research, 85(1), 31–45. http://doi.org/10.1016/j.eplepsyres.2009.03.003 | ||
| - | Sills, G.J.(2006). The mechanisms of action of gabapentin and pregabalin. Current Opinions in Pharmacology.6(1);108-126. https://doi.org/10.1016/j.coph.2005.11.003. (http://www.sciencedirect.com/science/article/pii/S1471489205001906) | + | Sills, G.J.(2006). The mechanisms of action of gabapentin and pregabalin. Current Opinions in Pharmacology.6(1);108-126. https://doi.org/10.1016/j.coph.2005.11.003. |
| - | Stafstrom, C.E. (1998). Back to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians. Pediatrics in Review, 19(10). | + | Stafstrom, C.E. (1998). Back to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians. Pediatrics in Review, 19(10). Retrieved from http://pedsinreview.aappublications.org.libaccess.lib.mcmaster.ca/content/19/10/342.long |
| Treiman DM.(2001). GABAergic mechanisms in epilepsy. Epilepsia;42:Suppl 3:8-12 | Treiman DM.(2001). GABAergic mechanisms in epilepsy. Epilepsia;42:Suppl 3:8-12 | ||
| - | World Health Organization. Epilepsy. Fact Sheet No. 999. Geneva: World Health Organization, 2015. Available at: http://www.who.int/mediacentre/factsheets/fs999/en/index.html | + | World Health Organization. Epilepsy. Fact Sheet No. 999. Geneva: World Health Organization, 2015. Retrieved from http://www.who.int/mediacentre/factsheets/fs999/en/index.html |
| - | Uthman, B. M. (n.d.). (2000). Vagus nerve stimulation for seizures. Retrieved October 27, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/11036181 | + | Uthman, B. M. (n.d.). (2000). Vagus nerve stimulation for seizures. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11036181 |
