Epileptogenesis
Encyclopedia
Epileptogenesis is a process by which a normal brain
develops epilepsy
, a chronic condition in which seizure
s occur. The process, which is gradual, occurs in symptomatic epilepsy, in which seizures are caused by an identifiable lesion
in the brain. It results from acute brain insults such as traumatic brain injury
(physical trauma
to the brain), stroke
, or infection. Epileptogenesis is a series of events that occur between the event that causes epilepsy and the first spontaneous seizure. In epileptogenesis, an array of events occur on molecular
and cell
ular levels that cause neuron
s to fire in a disordered manner, resulting in seizure
s.
, stroke
, brain tumor
, infections of the central nervous system
, and status epilepticus
(a prolonged seizure or a series of seizures occurring in quick succession).
called this time between injury and seizure "a silent period of strange ripening". During this latent period, changes occur in the structure and physiology of the brain that result in the development of epilepsy. It is this process in which hyperexciatble neural networks form that is referred to as epileptogenesis, and it is during this latent period that symptoms of epilepsy first occur. If researchers come to better understand epileptogenesis, the latent period may provide a chance for healthcare providers to interfere with the development of epilepsy or reduce its severity.
. These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures.
Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe
structures such as the hippocampus
, the amygdala
, and the piriform cortex
.
In acquired epilepsy in both humans and animal models, pyramidal neurons are lost, and new synapse
s are formed.
Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural network
s will be activated is increased, may be due to loss of inhibitory neurons that would normally balance out the excitability of other neurons, such as GABA
ergic interneuron
s. Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it). In addition, the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease, resulting in less inhibition.
Another proposed mechanism for epileptogenesis in TBI is that damage to white matter
causes hyperexcitability by effectively undercutting the cerebral cortex
.
receptor and both ionotropic glutamate receptor
s and metabotropic glutamate receptor
s (those that are directly linked to an ion channel
and those that are not, respectively). Each of these types of receptor may, when activated, cause an increase in the concentration of calcium
ion
s (Ca2+) within the area of the cell on which the receptors are located, and this Ca2+ can activate enzymes such as Src
and Fyn
that may lead to epileptogenesis.
, including in humans. Excessive release of glutamate results in excitotoxicity
, in which neurons are excessively depolarized
, intracellular Ca2+ concentrations increase sharply, and cellular damage or death results. Excessive glutamatergic activity is also a feature of neuronal circuits after epilepsy has developed, but glutamate does not appear to play an important role in epileptogenesis during the latent period. Another factor in hyperexcitability may include a decrease in the concentration
of Ca2+ outside cells (i.e. in the extracellular space) and a decrease in the activity of ATPase
in glial cell
s.
or iron
into the tissue. Iron from hemoglobin
, a molecule in red blood cells, can lead to the formation of free radicals that damage cell membrane
s; this process has been linked to epileptogenesis.
s and cell culture
models. Epileptogenesis is poorly understood, and increasing understanding of the process may aid researchers in preventing seizures, diagnosing epilepsy, and developing treatments to prevent it.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
develops epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, a chronic condition in which seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s occur. The process, which is gradual, occurs in symptomatic epilepsy, in which seizures are caused by an identifiable lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
in the brain. It results from acute brain insults such as traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
(physical trauma
Physical trauma
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
to the brain), stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, or infection. Epileptogenesis is a series of events that occur between the event that causes epilepsy and the first spontaneous seizure. In epileptogenesis, an array of events occur on molecular
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
and cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
ular levels that cause neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s to fire in a disordered manner, resulting in seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s.
Causes
A variety of conditions can result in epileptogenesis, including neurodegenerative diseases, traumatic brain injuryTraumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, brain tumor
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
, infections of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, and status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
(a prolonged seizure or a series of seizures occurring in quick succession).
Latent period
After a brain injury occurs, there is frequently a "silent" or "latent period" lasting months or years in which seizures do not occur; Canadian neurosurgeon Wilder PenfieldWilder Penfield
Wilder Graves Penfield, OM, CC, CMG, FRS was an American born Canadian neurosurgeon. During his life he was called "the greatest living Canadian"...
called this time between injury and seizure "a silent period of strange ripening". During this latent period, changes occur in the structure and physiology of the brain that result in the development of epilepsy. It is this process in which hyperexciatble neural networks form that is referred to as epileptogenesis, and it is during this latent period that symptoms of epilepsy first occur. If researchers come to better understand epileptogenesis, the latent period may provide a chance for healthcare providers to interfere with the development of epilepsy or reduce its severity.
Pathophysiology
Changes that occur during epileptogenesis are poorly understood but are thought to include cell death, axonal sprouting, reorganization of neural networks, alterations in the release of neurotransmitters, and neurogenesisNeurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
. These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures.
Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....
structures such as the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, and the piriform cortex
Piriform cortex
In anatomy of animals, the piriform cortex, or pyriform cortex is a region in the brain.-Anatomy and function:The piriform cortex is part of the rhinencephalon situated in the telencephalon....
.
Neural reorganization
In addition to chemical processes, the physical structure of neurons in the brain may be altered.In acquired epilepsy in both humans and animal models, pyramidal neurons are lost, and new synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s are formed.
Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural network
Neural network
The term neural network was traditionally used to refer to a network or circuit of biological neurons. The modern usage of the term often refers to artificial neural networks, which are composed of artificial neurons or nodes...
s will be activated is increased, may be due to loss of inhibitory neurons that would normally balance out the excitability of other neurons, such as GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
ergic interneuron
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
s. Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it). In addition, the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease, resulting in less inhibition.
Another proposed mechanism for epileptogenesis in TBI is that damage to white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
causes hyperexcitability by effectively undercutting the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
.
Receptor activation
It is believed that activation of biochemical receptors on the surfaces of neurons is involved in epileptogenesis; these include the TrkB neurotrophinNeurotrophin
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
receptor and both ionotropic glutamate receptor
Ionotropic glutamate receptor
The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA , AMPA and kainate receptors...
s and metabotropic glutamate receptor
Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...
s (those that are directly linked to an ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
and those that are not, respectively). Each of these types of receptor may, when activated, cause an increase in the concentration of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s (Ca2+) within the area of the cell on which the receptors are located, and this Ca2+ can activate enzymes such as Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
and Fyn
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
that may lead to epileptogenesis.
Glutamate
Excessive release of the neurotransmitter glutamate is widely recognized as an important part of epileptogenesis early after a brain injuryAcquired brain injury
An acquired brain injury is brain damage caused by events after birth, rather than as part of a genetic or congenital disorder such as fetal alcohol syndrome, perinatal illness or perinatal hypoxia. ABI can result in cognitive, physical, emotional, or behavioural impairments that lead to permanent...
, including in humans. Excessive release of glutamate results in excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, in which neurons are excessively depolarized
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
, intracellular Ca2+ concentrations increase sharply, and cellular damage or death results. Excessive glutamatergic activity is also a feature of neuronal circuits after epilepsy has developed, but glutamate does not appear to play an important role in epileptogenesis during the latent period. Another factor in hyperexcitability may include a decrease in the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of Ca2+ outside cells (i.e. in the extracellular space) and a decrease in the activity of ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
in glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s.
Blood
Blood that spills into brain tissue (as may occur in traumatic brain injury or stroke) may play a role in the damage that results in epilepsy, perhaps by depositing hemosiderinHemosiderin
thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...
or iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
into the tissue. Iron from hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, a molecule in red blood cells, can lead to the formation of free radicals that damage cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s; this process has been linked to epileptogenesis.
Research directions
Epileptogenesis that occurs in human brains has been modeled in a variety of animal modelAnimal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s and cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
models. Epileptogenesis is poorly understood, and increasing understanding of the process may aid researchers in preventing seizures, diagnosing epilepsy, and developing treatments to prevent it.