Grand+Mal+Seizure

=Grand Mal Seizures=
 * Seizures** are defined as when the brain experiences abnormal electrical brain activity. There are a wide range different types of seizures, from small localized or **focused** seizures, to large grand scale or **generalized** seizures. **Grand mal** seizures are they classic form of generalized seizures, where there is excessive twitching, convulsing, and loss of consciousness. Grand mal seizures affect a large part of the brain and affect many different structures leading to generalized effects and a large array of symptoms caused by grand mal seizures.

Anatomy:
Grand mal seizures in short are due to abnormalities in the physiology of neurons. Neurons have a resting membrane potential that is due to the potassium and sodium ion channels that are open during rest of a neuron. The permeability and concentration of the potassium in the cell causes a polarization of the membrane potential of the cell in regards to the extracellular potential. The cell has a slightly negative charge, which is important for propagating an action potential. When the cell is stimulated by either an external stimulus or another neuron causing lipid gated ion channels to open, there is a large influx of positive sodium ions into the cell, which causes the membrane potential to depolarize. The influx of sodium causes voltage gated ion channels adjacent to the channel that just opened to open as well, which causes a chain reaction of adjacent voltage gated ion channels to open. This chain reaction is the action potential that is propagated down an axon. When an action potential reaches the terminal ending of the axon, the action potential causes calcium ion channels to open. Calcium causes vesicles filled with neurotransmitter in the synaptic ending of the axon to release their contents into the synaptic cleft, the junction between two neurons.

Neurons in the cortex are organized into two categories: principal cells and interneurons. **Principal cells** are neurons that carry information across longer distances, such as from one cortical area to another or to motor neurons in the spinal cord. **Interneurons** are neurons that have local connections with principal cells. In general, principal cells have an excitatory effect and interneurons are more likely to have an excitatory effect. The basal ganglia works this way, where input principal cells synapse on a series of interneurons which synapse on a select group of principal cells. The interneurons in the basal ganglia "select" certain actions and inhibits others through the interneurons.

The connections between many neurons develop into networks within the brain. When there is a disturbance in the network of neurons, there is a chance for a seizure. Disturbances that can lead to a grand mal seizure are theorized to form in a few key structures in the central nervous system. One the main structures where grand mal seizures might originate is the corpus callosum. The **corpus callosum** connects the two brain hemispheres and connects many structures, which is why it is thought to be one of the main causes in grand mal seizures.The corpus callosum is organized into segments organized anterior to posterior and project to the frontal cortex, motor and premotor ares, somatosensory areas, and visual cortex. The corpus is located superior to the lateral ventricle and posterior to the thalamus.

Fig. 1 Tracking of fibers in the corpus callosum The **thalamus** is another structure that is theorized to be involved in grand mal seizures. The thalamus is located superior to the pons and inferior to the lateral ventricle and is made up of a variety of nuclei. The main function of the thalamus is to receive input from the nervous system, both the central and peripheral, organize and redirect the information to the appropriate cortical structures. Projections include to the motor and premotor areas, somatosensory cortex, visual cortex, and the superior colliculus.

Fig. 2 Thalamic Nuclei and Projections The **basal ganglia** is another structure that is thought to have a major role in the propagation of generalized seizures. The striatum is made up of the caudate and the putamen, which are the main receiving areas from the various cortical structures. The caudate is located jus t lateral to the lateral ventricle and superior to the thalamus. The caudate has a main body, which loops to connect to the putamen in the anterior portion, and a tail that loops posterior and inferior of the caudate body. Interior of the caudate lies the putamen. The basal ganglia receives input from the entirety of the cerebral cortex and some of the thalamus. The cortical input consists of a variety of different functional systems of the brain such as the motor, sensory and limbic system as well as some input from the thalamus.

Pathophysiology:
A seizure occurs when there is a large increase in activity in the neurons in different areas of the brain. The processes by which seizure activity arises in the brain is called ** ictogenesis **. There are a number of mechanism by which activity is increased; the neuron's membrane can alter, the environment around a focal group of cells can alter, a decrease in the release of inhibitory neurotransmitters or an increase in excitatory neurotransmitters. Changes in individual neuron structures can involve changes in membrane permeability, concentration of ion channels, or changes in the postsynaptic membrane. An alteration in the extracellular environment of neurons can also lead to changes which result in seizure activity. Ion concentration and neurotransmitter concentrations surrounding the cell can make cells in a given area can make a cell hyper excitable. The rewiring of the neural network also can result in increased excitability and activity. When inhibitory neurons or neurons which excite inhibitory neurons are loss, uncontrolled neural activity can increase. The effects of the increase excitability have a cascading effect that results in a focussed group of neurons firing excessively. The area which the activity increases will dictate the category of seizure.

Grand mal seizures are characterized by an increase activity in almost all areas of the brain. This indicates that they must originate in areas that connect different cortical and subcortical structures together. Areas like the corpus callosum, basal ganglia and thalamus are extensive in connections throughout the central nervous system. The integration of many different functional systems creates an expansive list of symptoms for grand mal seizures.

Grand mal seizures, also called **tonic-clonic** seizures are depicted as seiz ures where there is a loss of consciousness, followed by a period of rigidity that lasts up to 10 seconds known as the ** tonic ** phase. The tonic phase is thought to be the large burst of activity in neuronal networks. The large excitation is not regulated and when this occurs in an area that effects the descending pathways, as in the motor cortex, basal ganglia or the pons, the observed effects are contractions which seem to "freeze" the patient. The tonic phase is followed by the ** clonic ** phase, which is a period of full body convulsions or spasms that can last anywhere from 30 seconds to 2 minutes. Clonic phase has a temporal spacing during the convulsions. It is not well understood how the timing of the clonic phase is regulated, but the basal ganglia is predict ed to have some role (Blumfield et. al. 2005). The seizure is followed a latency period known as the postictal state, where the muscle become flaccid and the consciousness is slowly regained. Some evidence in recent research observing the blood flow during grand mal seizures has showed that the cerebellum has some role in the postictal state. While it is not always apparent, other symptoms of grand mal seizures also include gasping at onset of the tonic phase, incontinence or even foaming at the mouth. The most common side effect of a grand mal seizure is injury due to falling or because of the environment which the seizure happened.

Fig. 3 Typical phases of Tonic Clonic Seizures a. Loss of Consciousness b. Rigidity c. Spasms in extremities d. Posictal and flaccidity One period of a grand mal seizure that is not always present is the **aura**, which is the period leading up to the onset of a seizure. During this phase of the seizure, symptoms are extremely diverse and have many different signs depending on the person. Some patients hear different songs or television shows; others see images or visions, both of which indicate to them that a seizure is about to occur.

**Research** Some methods which researches have come to understand seizures and activity involve two major fields. The larges field is electroencephalogram or EEG. EEG uses electrodes placed in specific regions of the head to read the electrical activity of neurons. EEG measure areas of activity in the cortex and can measure synaptic activity between neurons. This is due to the electric potential of neurons at the synaptic cleft. This method is useful for detecting cortical activity, however is not able to detect changes in the subcortical levels because the EEG probes cannot deep structures. The same principle of the EEG can also be applied directly to the cortex. This method is known as an Electrocorticogram, and results in more accurate electrical activity readings and can be placed on specific structures on the cortex and deeper structures.

Fig. 4 Electrocorticogram Placed on Cortex

Fig. 5 EEG Readings in Focal and Generalized Seizures

Other research in seizure activity is using functional MRI machines and dye to observe blood flow during brain activity. Areas with more neural activity, such as in a seizure, will have more blood flow. The MRI research is able to detect the blood flow in cortical levels as well as deep structures in the brain. Research using this method is able to track seizure activity and trace it through a seizure. Another benefit is that the blood flow method also both hyper-fusion and hypo-fusion, showing areas that are more and less active. While this method is useful for tracking propagation of seizures, a major issue of this method is that it does not tract the neural activity directly of seizures. It is not able to reveal the neural pathways and track the physiology of neurons, but rather observes the effects of neural activity.

Fig.6 fMRI Imaging of Blood Flow During Seizure Activity

Grand Mal Pathway Theories
The many symptoms of seizures and the inconsistency in observations of seizure onsets have lead to a few theories of the propagation of seizures. One theory is the **Centrocephalic Theory** that reas ons that seizures originate toward the middle thalamus. Because the thalamus is so heavily integrated with the entirety of the cortex, reasoning that the thalamus is the origin of a seizure worked (Meeren, H. et al 2005). Howeve r an issue with this theory is only one part of the thalamus is activates abnormally and could not cause a propagation which would result in generalized symptoms.

Fig.7 Pathway Theories: Top Left- Centrocephalic, Top Right- Cortical, Bottom Left- Thalamic Clock



Branching off of this theory is the **Thalamic Clock Theory** that argues that the thalamus is the location of origin, and there is a timing component of the firing rate, which causes abnormal firing in the cortex, producing the onset of a seizure. This theory was able to explain how the generalized affects were generated.

Some researchers do not believe that seizures originate in the thalamus but in the cortex instead. The **Cortical Theory** suggests that generalized seizures originate in the cortical levels and spread down to subcortical structures, where they are then distributed to the rest of the brain. This theory explains the presence of an aura because abnormal activity, which would cause unique symptoms such as hallucinations.

Summary
Grand mal seizures are one of the easiest seizure types to diagnose because the effects are widespread and easy to identify. The difficulty with seizures is understanding the pathophysiology because there is no one epidemiology which causes grand mal seizures. The neural networks of the brain are delicate and the slightest alteration in a structure such as the thalamus can have widespread effects. Alterations can be the result of either the microenvironment surrounding neurons or because of the individual neurons. Research in generalized seizures and epilepsy have led to theories about how seizures are propagated, but more is needed to understand the exact physiology of seizure physiology.

Glossary

 * Seizures**: Abnormal excitatory activity in the brain
 * Focused seizures**: Abnormal seizure activity is localized to one area of the brain
 * Generalized seizures**: Abnormal seizure activity is bilateral and affects multiple functional areas
 * Grand mal seizures**: A type of seizure characterized by loss of consciousness and full body convulsions
 * Principal cells**: Neurons which travel longer distances and connect different neural structures
 * Interneurons**: Neurons that travel short distances and act on adjacent neurons
 * Corpus callosum**: Structure that connects two hemispheres of brain
 * Thalamus**: Collection of nuclei that redirects information the various structures
 * Basal ganglia**: Collection of nuclei that filters and initiates certain cortical areas, especially movement
 * Ictogenesis**: The process which seizure activity is generated
 * Tonic-clonic seizures**: Another name for grand mal seizure; seizure defined by a tonic and clonic phase
 * Tonic phase**: Seizure which the body becomes rigid due to widespread muscle flexion
 * Clonic phase**: Seizure where body experiences spasms and convulsions
 * Aura**: Precursor to seizure activity that manifests as a variety of different symptoms
 * Centrocephalic Theory**: Seizure propagation generates in the middle thalamus
 * Thalamic Clock Theory**: Seizure propagation generates in the thalamus and has a timing component that delays propagation
 * Cortical Theory**: Seizure propagation begins in the cortex and activates other structures that spreads throughout CNS

Questions
1. T/F Grand Mal siezures are a type of focal seizure. 2. T/F Interneurons are more likely to have inhibitory effects than principal cells. 3. T/F Seizure activity is due to excessive excitatory activity in brain. 4. T/F The clonic phase of grand mal seizure convulsions have a timing component. 5. T/F All grand mal seizures are preceded by auras. 6. T/F Grand mal seizures result in partial consciousness.

1. Describe the different neural mechanisms that cause ictogenesis.

2. Describe the different theories about seizure propagation.

3. What is some different research methods that help understand seizure activity.

Answers 1. F 2. T 3. T 4. T 5. F 6. F

Suggested Readings
Epilepsy West Lothian is a charity service that provides services to over 1500 epileptic patients in West Lothian Scotland. http://cyberwebs-wd.co.uk/clients/donated/ewl/Introduction_to_Epilepsy.html

Focus on Epilepsy is a organization designed for health professionals with education and a better understanding the mechanisms of epilepsy. http://focusonepilepsy.com/learning_center

One of the best sources on that one can find about seizures http://kin450-neurophysiology.wikispaces.com/Seizure+-+Cortical+Related

Refrences
Beverlin II, Bryce, & Netoff, Theoden I. (2013). Dynamic control of modeled tonic-clonic seizure states with closed-loop stimulation. //Frontiers in Neural Circuits, 6//. doi: 10.3389/fncir.2012.00126 Blumenfeld, H, Varghese, GI, Purcaro, MJ, Motelow, JE, Enev, M, McNally, KA,. . . Zubal, IG. (2009). Cortical and subcortical networks in human secondarily generalized tonic–clonic seizures. //Brain, 132//(4), 999-1012. Bryce Beverlin, II, & Netoff, Theoden I. (2012). Dynamic control of modeled tonic-clonic seizure states with closed-loop stimulation. //Frontiers in Neural Circuits, 6//. Bromfield EB, Cavazos JE, Sirven JI, editors. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; 2006. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2508/ DeSalvo, Matthew N, Schridde, Ulrich, Mishra, Asht M, Motelow, Joshua E, Purcaro, Michael J, Danielson, Nathan,. . . Blumenfeld, Hal. (2010). Focal BOLD fMRI changes in bicuculline-induced tonic–clonic seizures in the rat. // Neuroimage, 50 // (3), 902-909.

Enev, Miro, McNally, Kelly A., Varghese, George, Zubal, I. George, Ostroff, Robert B., & Blumenfeld, Hal. (2007). Imaging Onset and Propagation of ECT-induced Seizures. //Epilepsia (Series 4), 48//(2), 238-244. doi: 10.1111/j.1528-1167.2007.00919.x Engelborghs, S, D’Hooge, R, & De Deyn, PP. (2000). Pathophysiology of epilepsy. // Acta neurologica belgica, 100 // (4), 201-213. Gursahani, Roop, & Gupta, Namit. (2012). The adolescent or adult with generalized tonic–clonic seizures. // Ann Indian Acad Neurol, 15 // (2), 81. Kramer, Mark A., & Cash, Sydney S. (2012). Epilepsy as a Disorder of Cortical Network Organization. // The Neuroscientist, 18 // (4), 360-372. doi: 10.1177/1073858411422754 Meeren, H., van Luijtelaar, G., Lopes da Silva, F., & Coenen, A. (2005). Evolving concepts on the pathophysiology of absence seizures: The cortical focus theory. // Archives of Neurology, 62 // (3), 371-376. doi: 10.1001/archneur.62.3.371 Weaver, Dr. Donald. (2001). //Epilepsy and Seizures: Everything You Need to Know//. Buffalo, NY: Firefly Books.