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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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| {{::focalseizures.png|}} | {{::focalseizures.png|}} | ||
| - | Figure 2: visual representation of partial, primary and secondary generalized seizures. | + | **Figure 2**: visual representation of partial, primary and secondary generalized seizures. |
| **Describing Awareness** | **Describing Awareness** | ||
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| ====== EEG patterns and behaviour ====== | ====== EEG patterns and behaviour ====== | ||
| - | Electroencephalogram (EEGs) is a diagnostic test conducted to detect any irregularities in neuronal activity in the brain. There 5 main types of EEG rhythms, each associated with different states of consciousness (refer to Figure_). Beta rhythms occur during thinking and wakeful periods and are characterized by low amplitudes and high frequencies. This pattern is due to the complex firing of neurons needed for thinking. There are many inputs being processed simultaneously and these signals can be excitatory and inhibitory (Bear, 2007). However, when they fired asynchronously the waves destructively interfere and cancel each other out, leading to low amplitudes. Delta and Theta rhythms fire during deep sleep periods and are characterized by high amplitudes and low frequencies. When there is no real active processes occurring, firing is controlled by the thalamus which is regarded as the rhythmic pace maker in the brain. These neurons fire synchronously and constructively interfere with each other leading to the superimposition of brain waves (Bear, 2007). | + | Electroencephalogram (EEGs) is a diagnostic test conducted to detect any irregularities in neuronal activity in the brain. There 5 main types of EEG rhythms, each associated with different states of consciousness (refer to Figure 4). Beta rhythms occur during thinking and wakeful periods and are characterized by low amplitudes and high frequencies. This pattern is due to the complex firing of neurons needed for thinking. There are many inputs being processed simultaneously and these signals can be excitatory and inhibitory (Bear, 2007). However, when they fired asynchronously the waves destructively interfere and cancel each other out, leading to low amplitudes. Delta and Theta rhythms fire during deep sleep periods and are characterized by high amplitudes and low frequencies. When there is no real active processes occurring, firing is controlled by the thalamus which is regarded as the rhythmic pace maker in the brain. These neurons fire synchronously and constructively interfere with each other leading to the superimposition of brain waves (Bear, 2007). |
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| - | Figure 4: EEG rhythms and associated behaviours. Beta waves occur during thinking periods and are characterized by low amplitudes. Delta waves occur during sleeping periods and are characterized by larder amplitudes. | + | **Figure 4**: EEG rhythms and associated behaviours. Beta waves occur during thinking periods and are characterized by low amplitudes. Delta waves occur during sleeping periods and are characterized by larder amplitudes. |
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| {{:eeg.png?300|}} | {{:eeg.png?300|}} | ||
| - | Figure 5: EEG recording field potential in pyramidal cells. | + | **Figure 5**: EEG recording field potential in pyramidal cells. |
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| {{:action_potential_ap_.png|}} | {{:action_potential_ap_.png|}} | ||
| - | Figure 5: The steps of action potential | + | **Figure 6**: The steps of action potential |
| {{:snare_pic.png|}} | {{:snare_pic.png|}} | ||
| - | Figure 7: Mechanisms of vesicle fusion with axonal membrane leading to the release of neurotransmitters | + | **Figure 7:** Mechanisms of vesicle fusion with axonal membrane leading to the release of neurotransmitters |
| **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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| {{::loss_of_hyperpol.png|}} | {{::loss_of_hyperpol.png|}} | ||
| - | Figure 10: Loss of hyper polarization leads to propagation of seizure. | + | **Figure 10**: Loss of hyper polarization leads to propagation of seizure. |
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| 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) | 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**: | ||
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| Abnormal synchronization of neurons in the brain results in an epileptic seizure. These seizure present various symptoms, which depend on the origin of the seizure and the connections in the brain. Seizure develop from either increased excitation or decreased inhibition (Moshé et al. 2015) | Abnormal synchronization of neurons in the brain results in an epileptic seizure. These seizure present various symptoms, which depend on the origin of the seizure and the connections in the brain. Seizure develop from either increased excitation or decreased inhibition (Moshé et al. 2015) | ||
| {{ :2stepepi.png |}} | {{ :2stepepi.png |}} | ||
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| + | **Figure 12**: | ||
| **Increased Excitability** | **Increased Excitability** | ||
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| There are elevated levels of glutamate in the brain of patients with epilepsy, which is known as glutamate-induced excitotoxicity. Glutamate is normally degraded by an enzyme called glutamine synthetases (GS). However, GS has been shown to be deficient in patients with acquired epilepsy, also known as TLE. The GS deficiency causes high glutamate levels in astrocytes and in extracellular areas such as the synaptic cleft. This leads to prolonged effects of glutamate. Furthermore, GTL-1 is a major glutamate uptake molecule found in the brain, and its downregulation causes increased glutamate levels, leading to more excitability (Cho 2013). Glutamate itself and glutamate receptors, such as NMDA, cause high excitability as characterized in epilepsy. The cell death and tissue damage which occur in the initial stage of acquired epilepsy leads to the high concentrations of glutamate leakage into the extracellular space. Furthermore, tissue reorganization, occurring in epileptogenesis impairs high efficiency uptake of glutamate from the synaptic cleft. The decreased uptake of glutamate, allows for prolonged excitation of postsynaptic neurons (Brandford 1995). | There are elevated levels of glutamate in the brain of patients with epilepsy, which is known as glutamate-induced excitotoxicity. Glutamate is normally degraded by an enzyme called glutamine synthetases (GS). However, GS has been shown to be deficient in patients with acquired epilepsy, also known as TLE. The GS deficiency causes high glutamate levels in astrocytes and in extracellular areas such as the synaptic cleft. This leads to prolonged effects of glutamate. Furthermore, GTL-1 is a major glutamate uptake molecule found in the brain, and its downregulation causes increased glutamate levels, leading to more excitability (Cho 2013). Glutamate itself and glutamate receptors, such as NMDA, cause high excitability as characterized in epilepsy. The cell death and tissue damage which occur in the initial stage of acquired epilepsy leads to the high concentrations of glutamate leakage into the extracellular space. Furthermore, tissue reorganization, occurring in epileptogenesis impairs high efficiency uptake of glutamate from the synaptic cleft. The decreased uptake of glutamate, allows for prolonged excitation of postsynaptic neurons (Brandford 1995). | ||
| {{ :glutame_epilepsy.png |}} | {{ :glutame_epilepsy.png |}} | ||
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| + | **Figure 13**: Sustained excitatory behaviour via glutamate release results in propagation of seizure. | ||
| As mentioned before, voltage gated Na+ channels play a vital role in axon depolarization and therefore it can be assumed that dysregulation in their function can lead to epileptic symptoms. The voltage gated Na+ channels are composed of four homologous subunits (I-IV) and each subunit is composed of 6 transmembrane segments (Escayg, 2010). Subunits III and IV are connected by an intracellular loop which forms the inactivation gate. The channels are also connected to accessory beta units; 1, 2, 3, 4 which help modulate voltage dependence. Voltage gated Na+ channels are encoded by nine genes, SCN1A to SCN11A which gives rise to nine distinct channel isoforms. These isoforms differ in their location, ranging from CNS to embryonic heart muscle and also their threshold for activation. Mutations in these SNCA genes lead to increased frequency of depolarization of neurons and can even lead to excitotoxicity. For example, alterations in SCN1A and SCN2A lead to disorders such as genetic epilepsy with febrile seizures plus (Escayg, 2010). | As mentioned before, voltage gated Na+ channels play a vital role in axon depolarization and therefore it can be assumed that dysregulation in their function can lead to epileptic symptoms. The voltage gated Na+ channels are composed of four homologous subunits (I-IV) and each subunit is composed of 6 transmembrane segments (Escayg, 2010). Subunits III and IV are connected by an intracellular loop which forms the inactivation gate. The channels are also connected to accessory beta units; 1, 2, 3, 4 which help modulate voltage dependence. Voltage gated Na+ channels are encoded by nine genes, SCN1A to SCN11A which gives rise to nine distinct channel isoforms. These isoforms differ in their location, ranging from CNS to embryonic heart muscle and also their threshold for activation. Mutations in these SNCA genes lead to increased frequency of depolarization of neurons and can even lead to excitotoxicity. For example, alterations in SCN1A and SCN2A lead to disorders such as genetic epilepsy with febrile seizures plus (Escayg, 2010). | ||
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| {{::na_channels_.png|}} | {{::na_channels_.png|}} | ||
| - | Figure_: Visual representation of voltage gated Na+ channels, composed of four subunits which are each made up of 6 transmembrane proteins to form the channel and inactivation gate. | + | **Figure 14:** Visual representation of voltage gated Na+ channels, composed of four subunits which are each made up of 6 transmembrane proteins to form the channel and inactivation gate. |
| **Decreased Inhibition** | **Decreased Inhibition** | ||
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| Deviations in normal GABA synthesis and release has been shown to produce epileptic symptoms. There has been observed abnormalities in GABAergic function found in both genetic and acquired epilepsy. Decreased GABA-mediated inhibition has been observed in epilepsy. There is defective GABA synthesis in humans with genetic epilepsy, which is characterized by seizures in infants (Treiman, 2012). GABA-receptor densities have been shown to be decreased in people with epilepsy. Furthermore, it was also shown that GABA release in epileptic patients were reduced when compared to non-epileptic people. In a particular study, it was shown that there are two main mechanisms in which GABA can be released into the synaptic cleft (Treiman, 2012). The first being vesicular fusion mediated by Ca2+ influx (discussed earlier). The second is non-vesicular secretion which is regulated via Na+ influx. When comparing an epileptic hippocampus to a non-epileptic hippocampus, it was observed that non-vesicular release of GABA in the epileptic hippocampus was not as robust as the control, resulting in a decreased amount of GABA in the synaptic cleft and by extension a decrease in inhibitory effects on postsynaptic neurons (Treiman, 2012). | Deviations in normal GABA synthesis and release has been shown to produce epileptic symptoms. There has been observed abnormalities in GABAergic function found in both genetic and acquired epilepsy. Decreased GABA-mediated inhibition has been observed in epilepsy. There is defective GABA synthesis in humans with genetic epilepsy, which is characterized by seizures in infants (Treiman, 2012). GABA-receptor densities have been shown to be decreased in people with epilepsy. Furthermore, it was also shown that GABA release in epileptic patients were reduced when compared to non-epileptic people. In a particular study, it was shown that there are two main mechanisms in which GABA can be released into the synaptic cleft (Treiman, 2012). The first being vesicular fusion mediated by Ca2+ influx (discussed earlier). The second is non-vesicular secretion which is regulated via Na+ influx. When comparing an epileptic hippocampus to a non-epileptic hippocampus, it was observed that non-vesicular release of GABA in the epileptic hippocampus was not as robust as the control, resulting in a decreased amount of GABA in the synaptic cleft and by extension a decrease in inhibitory effects on postsynaptic neurons (Treiman, 2012). | ||
| {{ :gaba_epi.png |}} | {{ :gaba_epi.png |}} | ||
| + | **Figure 15:** Decreased GABA release results in loss of hyper polarization and transmission of excitatory signals to distal neurons. | ||
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| ====== Treatments ====== | ====== Treatments ====== | ||
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| AEDs also will affect excitation. Phenytoin, carbamazepine, and Lamotrigine all block voltage gated sodium channels, resulting in a reduction of continuation of electric signal. Furthermore, Ethosuximide will block calcium channels to prevent the post synaptic neuron from firing. Felbamate, ketamine, and Mg++ will block NMDA receptors (which bind to glutamate) to prevent an excitatory signal, while topiramate can block both NMDA and non- NMDA receptors to produce the same effect (Stafstrom 1998). | AEDs also will affect excitation. Phenytoin, carbamazepine, and Lamotrigine all block voltage gated sodium channels, resulting in a reduction of continuation of electric signal. Furthermore, Ethosuximide will block calcium channels to prevent the post synaptic neuron from firing. Felbamate, ketamine, and Mg++ will block NMDA receptors (which bind to glutamate) to prevent an excitatory signal, while topiramate can block both NMDA and non- NMDA receptors to produce the same effect (Stafstrom 1998). | ||
| {{ :aeds_mechanims_epi.png |}} | {{ :aeds_mechanims_epi.png |}} | ||
| - | **Vagus Nerve Stimulation (VNS)** | ||
| - | It is a novel therapy that has become available for epilepsy. This is used for patients with partial onset with or without secondary generalization after the age of 12. It is basically a system compromised to battery generators which send intermittent electrical stimuli which is controlled by software and an interrogating wand. The generator is implanted in the left upper chest which connects to the left cervical vagus nerve using two semi-circular helical electrodes. It takes an approximate of 2 hours to complete under general anesthesia. There are some effects that are present during VNS such as vice alteration and tingling sensation in the throat. The intensity of the effects starts to decrease over several weeks. This is one of the less invasive methods for anti-epilepsy. This is however not a replacement for resection surgery which is known to produce seizure-free effects in patients with a chance of 70-90%. | + | **Figure 16**: Certain AEDs can increase inhibition by potentiating GABA's effect whereas others inhibit excitatory by decreasing Glutamatergic effects. |
| - | (Uthman, 2000) | + | |
| + | **Vagus Nerve Stimulation (VNS)** | ||
| + | |||
| + | It is a novel therapy that has become available for epilepsy. This is used for patients with partial onset with or without secondary generalization after the age of 12. It is basically a system compromised to battery generators which send intermittent electrical stimuli which is controlled by software and an interrogating wand (Uthman, 2000). The generator is implanted in the left upper chest which connects to the left cervical vagus nerve using two semi-circular helical electrodes. It takes an approximate of 2 hours to complete under general anesthesia. There are some effects that are present during VNS such as vice alteration and tingling sensation in the throat(Uthman, 2000). The intensity of the effects starts to decrease over several weeks. This is one of the less invasive methods for anti-epilepsy. This is however not a replacement for resection surgery which is known to produce seizure-free effects in patients with a chance of 70-90%. (Uthman, 2000) | ||
| **Deep Brain Stimulation (DBS)** | **Deep Brain Stimulation (DBS)** | ||
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| {{::dbs_procedure.png|}} | {{::dbs_procedure.png|}} | ||
| - | Figure_: | + | **Figure 17**: visual of DBS procedure. |
| **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. |
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