Post-traumatic epilepsy
Encyclopedia
Post-traumatic epilepsy is a form of epilepsy
that results from brain damage
caused by physical trauma
to the brain (traumatic brain injury
, abbreviated TBI). A person with PTE suffers repeated post-traumatic seizure
s (PTS, seizure
s that result from TBI) more than a week after the initial injury. PTE is estimated to constitute 5% of all cases of epilepsy
and over 20% of cases of symptomatic epilepsy (in which seizures are caused by an identifiable organic brain condition).
It is not known how to predict who will develop epilepsy after TBI and who will not. However, the likelihood that a person will develop PTE is influenced by the severity and type of injury; for example penetrating injuries and those that involve bleeding within the brain confer a higher risk. The onset of PTE can occur within a short time of the physical trauma
that causes it, or months or years after. People with head trauma may remain at a higher risk for seizures than the general population even decades after the injury. PTE may be caused by several biochemical processes that occur in the brain after trauma, including overexcitation of brain cell
s and damage to brain tissues by free radicals.
Diagnostic measures include electroencephalography
and brain imaging techniques such as magnetic resonance imaging
, but these are not totally reliable. Antiepileptic drugs do not prevent the development of PTE after head injury, but may be used to treat the condition if it does occur. When medication does not work to control the seizures, surgery may be needed. Modern surgical techniques for PTE have their roots in the 19th century, but trepanation
(cutting a hole in the skull) may have been used for the condition in ancient cultures.
s (PTS). However, not everyone who has post-traumatic seizures will continue to have post-traumatic epilepsy, because the latter is a chronic condition. However, the terms PTS and PTE are used interchangeably in medical literature. Seizures due to post-traumatic epilepsy are differentiated from non-epileptic post-traumatic seizures based on their cause and timing after the trauma.
A person with PTE suffers late seizures, those occurring more than a week after the initial trauma. Late seizures are considered to be unprovoked, while early seizures (those occurring within a week of trauma) are thought to result from direct effects of the injury. A provoked seizure is one that results from an exceptional, nonrecurring cause such as the immediate effects of trauma rather than a defect in the brain; it is not an indication of epilepsy. Thus for a diagnosis of PTE, seizures must be unprovoked.
Disagreement exists about whether to define PTE as the occurrence of one or more late, unprovoked seizures, or whether the condition should only be diagnosed in people with two or more. Medical sources usually consider PTE to be present if even one unprovoked seizure occurs, but more recently it has become accepted to restrict the definition of all types of epilepsy to include only conditions in which more than one occur. Requiring more than one seizure for a diagnosis of PTE is more in line with the modern definition of epilepsy, but it eliminates people for whom seizures are controlled by medication after the first seizure.
As with other forms of epilepsy, seizure types
in PTE may be partial (affecting only part of one hemisphere
of the brain) or generalized (affecting both hemispheres and associated with loss of consciousness). In about a third of cases, people with PTE have partial seizures; these may be simple or complex. In simple partial seizures, level of consciousness is not altered, while in complex partial seizures consciousness is impaired. When generalized seizures occur, they may start out as partial seizures and then spread to become generalized.
It is not clear why some patients get PTE while others with very similar injuries do not. However, possible risk factors have been identified, including severity and type of injury, presence of early seizures, and genetic factors.
may play a role in the risk that a person will develop PTE; people with the ApoE-ε4 allele may be at higher risk for PTE. The haptoglobin
Hp2-2 allele may be another genetic risk factor, possibly because it binds hemoglobin poorly and thus allows more iron to escape and damage tissues. However, most studies have found that having family members with epilepsy does not significantly increase the risk of PTS, suggesting that genetics are not a strong risk factor.
Severity of trauma
The more severe the brain trauma is, the more likely a person is to suffer late PTE. Evidence suggests that mild head injuries do not confer an increased risk of developing PTE, while more severe types do. In simple mild TBI, the risk for PTE is about 1.5 times that of the uninjured population. By some estimates, as many as half of sufferers of severe brain trauma experience PTE; other estimates place the risk at 5% for all TBI patients and 15–20% for severe TBI. One study found that the 30-year risk of developing PTE was 2.1% for mild TBI, 4.2% for moderate, and 16.7% for severe injuries, as shown in the chart at right.
. In addition, the chances of developing PTE differ by the location of the brain lesion: brain contusion that occurs on in one or the other of the frontal lobe
s has been found to carry a 20% PTE risk, while a contusion in one of the parietal lobes carries a 19% risk and one in a temporal lobe carries a 16% chance. When contusions occur in both hemispheres, the risk is 26% for the frontal lobes, 66% for the parietal, and 31% for the temporal.
, a continuous seizure or multiple seizures in rapid succession, is especially strongly correlated with the development of PTE; status seizures occur in 6% of all TBIs but are associated with PTE 42% of the time, and quickly halting a status seizure reduces chances of PTE development.
and axon
s, undergo apoptosis
or necrosis
, and experience altered gene expression
. In addition, damage to particularly vulnerable areas of the cortex such as the hippocampus may give rise to PTE.
Blood that gathers in the brain after an injury may damage brain tissue and thereby cause epilepsy. Products that result from the breakdown of hemoglobin
from blood may be toxic to brain tissue. The "iron hypothesis" holds that PTE is due to damage by oxygen free radicals, the formation of which is catalyzed by iron from blood. Animal experiments using rats have shown that epileptic seizures can be produced by injecting iron into the brain. Iron catalyzes the formation of hydroxyl radical
s by the Haber-Weiss reaction; such free radicals damage brain cells by peroxidizing lipids
in their membranes
. The iron from blood also reduces the activity of an enzyme
called nitric oxide synthase
, another factor thought to contribute to PTE.
After TBI, abnormalities exist in the release of neurotransmitter
s, chemicals used by brain cell
s to communicate with each other; these abnormalities may play a role in the development of PTE. TBI may lead to the excessive release of glutamate and other excitatory neurotransmitters (those that stimulate brain cells
and increase the likelihood that they will fire
). This excessive glutamate release can lead to excitotoxicity
, damage to brain cells through overactivation of the biochemical receptors that bind and respond to excitatory neurotransmitters. Overactivation of glutamate receptor
s damages neurons; for example it leads to the formation of free radicals. Excitotoxicity is a possible factor in the development of PTE; it may lead to the formation of a chronic epileptogenic focus. An epileptic focus is the part of the brain from which epileptic discharges originate.
In addition to chemical changes in cells, structural changes that lead to epilepsy may occur in the brain. Seizures that occur shortly after TBI can reorganize neural networks and cause seizures to occur repeatedly and spontaneously later on. The kindling hypothesis
suggests that new neural connections are formed in the brain and cause an increase in excitability. The word kindling is a metaphor: the way the brain's response to stimuli increases over repeated exposures is similar to the way small burning twigs can produce a large fire. This reorganization of neural networks may make them more excitable. Neurons that are in a hyperexcitable state due to trauma may create an epileptic focus in the brain that leads to seizures. In addition, an increase in neurons' excitability may accompany loss of inhibitory neurons that normally serve to reduce the likelihood that other neurons will fire; these changes may also produce PTE.
To be diagnosed with PTE, a person must have a history of head trauma and no history of seizures prior to the injury. Witnessing a seizure is the most effective way to diagnose PTE. Electroencephalography (EEG) is a tool used to diagnose a seizure disorder, but a large portion of people with PTE may not have the abnormal "epileptiform" EEG findings indicative of epilepsy. In one study, about a fifth of people who had normal EEGs three months after an injury later developed PTE. However, while EEG is not useful for predicting who will develop PTE, it can be useful to localize the epileptic focus, to determine severity, and to predict whether a person will suffer more seizures if they stop taking antiepileptic medications.
Magnetic resonance imaging
(MRI) is performed in people with PTE, and CT scanning can be used to detect brain lesions if MRI is unavailable. However, it is frequently not possible to detect the epileptic focus using neuroimaging
.
For a diagnosis of PTE, seizures must not be attributable to another obvious cause. Seizures that occur after head injury are not necessarily due to epilepsy or even to the head trauma. Like anyone else, TBI survivors may suffer seizures due to factors including imbalances of fluid or electrolyte
s, epilepsy from other causes, hypoxia
(insufficient oxygen), and ischemia
(insufficient blood flow to the brain). Withdrawal from alcohol
is another potential cause of seizures. Thus these factors must be ruled out as causes of seizures in people with head injury before a diagnosis of PTE can be made.
and carbamazepine
. Antiepileptic drugs are recommended to prevent late seizures only for people in whom PTE has already been diagnosed, not as a preventative measure. On the basis of the aforementioned studies, no treatment is widely accepted to prevent the development of epilepsy. However, it has been proposed that a narrow window of about one hour after TBI may exist during which administration of antiepileptics could prevent epileptogenesis
(the development of epilepsy).
Corticosteroid
s have also been investigated for the prevention of PTE, but clinical trials revealed that the drugs did not reduce late PTS and were actually linked to an increase in the number of early PTS.
Antiepileptic
drugs may be given to prevent further seizures; these drugs completely eliminate seizures for about 35% of people with PTE. However, antiepileptics only prevent seizures while they are being taken; they do not reduce the occurrence once the patient stops taking the drugs. Medication may be stopped after seizures have been controlled for two years. PTE is commonly difficult to treat with drug therapy, and antiepileptic drugs may be associated with side effect
s. The antiepileptics carbamazepine
and valproate are the most common drugs used to treat PTE; phenytoin
may also be used but may increase risk of cognitive side effects such as impaired thinking. Other drugs commonly used to treat PTE include clonazepam
, phenobarbitol, primidone
, gabapentin
, and ethosuximide
. Among antiepileptic drugs tested for seizure prevention after TBI (phenytoin, sodium valproate, carbamazepine, phenobarbital), no evidence from randomized controlled trial
s has shown superiority of one over another.
People whose PTE does not respond to medication may undergo surgery to remove the epileptogenic focus, the part of the brain that is causing the seizures. However surgery may be more difficult than it is for epilepsy due to other causes, and is less likely to be helpful in PTE than in other forms of epilepsy. It can be particularly difficult in PTE to localize the epileptic focus, in part because TBI may affect diffuse areas of the brain. Difficulty locating the seizure focus is seen as a deterrent to surgery. However, for people with sclerosis
in the mesial temporal lobe
(in the inner aspect of the temporal lobe), who comprise about one third of people with intractable PTE, surgery is likely to have good outcome. When there are multiple epileptic foci or the focus cannot be localized, and drug therapy is not effective, vagus nerve stimulation
is another option for treating PTE.
People with PTE have follow-up visits, in which health care providers monitor neurological and neuropsychological function and assess the efficacy and side effects of medications. As with sufferers of other types of epilepsy, PTE sufferers are advised to exercise caution when performing activities for which seizures could be particularly risky, such as rock climbing.
than people with brain injury who do not suffer from seizures. Compared to people with similar structural brain injuries but without PTE, people with PTE take longer to recover from the injury, have more cognitive and motor problems, and perform worse at everyday tasks. This finding may suggest that PTE is an indicator of a more severe brain injury, rather than a complication that itself worsens outcome. PTE has also been found to be associated with worse social and functional outcomes but not to worsen patients' rehabilitation or ability to return to work. However, people with PTE may have trouble finding employment if they admit to having seizures, especially if their work involves operating heavy machinery.
The period of time between an injury and development of epilepsy varies, and it is not uncommon for an injury to be followed by a latent period with no recurrent seizures. The longer a person goes without developing seizures, the lower the chances are that epilepsy will develop. At least 80–90% of people with PTE have their first seizure within two years of the TBI. People with no seizures within three years of the injury have only a 5% chance of developing epilepsy. However, one study found that head trauma survivors are at an increased risk for PTE as many as 10 years after moderate TBI and over 20 years after severe TBI. Since head trauma is fairly common and epilepsy can occur late after the injury, it can be difficult to determine whether a case of epilepsy resulted from head trauma in the past or whether the trauma was incidental.
The question of how long a person with PTE remains at higher risk for seizures than the general population is controversial. About half of PTE cases go into remission, but cases that occur later may have a smaller chance of doing so.
of PTE ranges between 1.9 to more than 30% of TBI sufferers, varying by severity of injury and by the amount of time after TBI for which the studies followed subjects.
Brain trauma is one of the strongest predisposing factors for epilepsy development, and is an especially important factor in young adults. Young adults, who are at the highest risk for head injury
, also have the highest rate of PTE, which is the largest cause of new-onset epilepsy cases in young people. Children have a lower risk for developing epilepsy; 10% of children with severe TBI and 16–20% of similarly injured adults develop PTE. Being older than 65 is also a predictive factor in the development of epilepsy after brain trauma. One study found PTE to be more common in male TBI survivors than in females.
Records of PTE exist from as early as 3000 BC. Trepanation
, in which a hole is cut in the skull, may have been used to treat PTE in ancient cultures. In the early 19th century, the surgeons Baron Larrey and WC Wells each reported having performed the operation for PTE. The French-educated American surgeon Benjamin Winslow Dudley (1785–1870) performed six trepanations for PTE between the years of 1819 and 1832 in Kentucky
and had good results despite the unavailability of antisepsis
. The surgery involved opening the skull at the site of injury, debriding
injured tissue, and sometimes draining blood or fluid from under the dura mater
. Dudley's work was the largest series of its kind that had been done up to that point, and it encouraged other surgeons to use trepanation for post-traumatic seizures. His reports on the operations came before it was accepted that surgery to relieve excess pressure within the skull was effective in treating epilepsy, but it helped set the stage for trepanation for PTE to become common practice. The procedure became more accepted in the late 19th century once antisepsis was available and cerebral localization was a familiar concept. However in 1890, the prominent German physician Ernest von Bergmann criticized the procedure; he questioned its efficacy (except in particular circumstances) and suggested that operations had been declared successful too soon after the procedures to know whether they would confer a long-term benefit. The late 19th century saw the advent of intracranial surgery, operating on brain lesions believed to be causing seizures, a step beyond cranial surgery which involved just the skull and meninges
. By 1893, at least 42 intracranial operations had been performed for PTE in the US, with limited success.
Surgery was the standard treatment for PTE until the years following World War II, when the condition received more attention as soldiers who had survived head trauma developed it. The increased need for drugs to treat PTE led to trials with antiepileptics; these early trials suggested that the drugs could prevent epileptogenesis (the development of epilepsy). It was still thought that antiepileptic drugs could prevent epileptogeneis in the 1970s; in 1973, 60% of physicians surveyed used them to prevent PTE. However, the clinical trials which had supported a protective effect of antiepileptics were uncontrolled; in later, controlled trials the drugs failed to demonstrate an antiepileptogenic effect. Studies did show that antiepileptics prevented seizures occurring within a week after injury, and in 1995 the task force of the Brain Trauma Foundation published a recommendation suggesting their use to protect against seizures early after trauma. However, recommendations were published against the prophylactic use of antiepileptic drugs more than a week after injury by the Brain Injury Special Interest group of the American Academy of Physical Medicine and Rehabilitation in 1998 and by the American Association of Neurological Surgeons
in 2000.
, gabapentin
, and lamotrigine
have already been developed and have shown promise in treatment of PTE. No animal model
has all the characteristics of epileptogenesis in humans, so research efforts aim to identify one. Such a model may help researchers find new treatments and identify the processes involved in epileptogenesis.
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...
that results from brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
caused by 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 (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...
, abbreviated TBI). A person with PTE suffers repeated post-traumatic seizure
Post-traumatic seizure
Post-traumatic seizures are seizures that result from traumatic brain injury , brain damage caused by physical trauma. PTS may be a risk factor for post-traumatic epilepsy , but a person who has a seizure or seizures due to traumatic brain injury does not necessarily have PTE, which is a form of...
s (PTS, 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 that result from TBI) more than a week after the initial injury. PTE is estimated to constitute 5% of all cases of 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...
and over 20% of cases of symptomatic epilepsy (in which seizures are caused by an identifiable organic brain condition).
It is not known how to predict who will develop epilepsy after TBI and who will not. However, the likelihood that a person will develop PTE is influenced by the severity and type of injury; for example penetrating injuries and those that involve bleeding within the brain confer a higher risk. The onset of PTE can occur within a short time of the 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...
that causes it, or months or years after. People with head trauma may remain at a higher risk for seizures than the general population even decades after the injury. PTE may be caused by several biochemical processes that occur in the brain after trauma, including overexcitation of brain cell
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 and damage to brain tissues by free radicals.
Diagnostic measures include electroencephalography
Electroencephalography
Electroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
and brain imaging techniques such as magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
, but these are not totally reliable. Antiepileptic drugs do not prevent the development of PTE after head injury, but may be used to treat the condition if it does occur. When medication does not work to control the seizures, surgery may be needed. Modern surgical techniques for PTE have their roots in the 19th century, but trepanation
Trepanation
Trepanning, also known as trephination, trephining or making a burr hole, is a surgical intervention in which a hole is drilled or scraped into the human skull, exposing the dura mater in order to treat health problems related to intracranial diseases. It may also refer to any "burr" hole created...
(cutting a hole in the skull) may have been used for the condition in ancient cultures.
Classification
Seizures may occur after traumatic brain injury; these are known as post-traumatic seizurePost-traumatic seizure
Post-traumatic seizures are seizures that result from traumatic brain injury , brain damage caused by physical trauma. PTS may be a risk factor for post-traumatic epilepsy , but a person who has a seizure or seizures due to traumatic brain injury does not necessarily have PTE, which is a form of...
s (PTS). However, not everyone who has post-traumatic seizures will continue to have post-traumatic epilepsy, because the latter is a chronic condition. However, the terms PTS and PTE are used interchangeably in medical literature. Seizures due to post-traumatic epilepsy are differentiated from non-epileptic post-traumatic seizures based on their cause and timing after the trauma.
A person with PTE suffers late seizures, those occurring more than a week after the initial trauma. Late seizures are considered to be unprovoked, while early seizures (those occurring within a week of trauma) are thought to result from direct effects of the injury. A provoked seizure is one that results from an exceptional, nonrecurring cause such as the immediate effects of trauma rather than a defect in the brain; it is not an indication of epilepsy. Thus for a diagnosis of PTE, seizures must be unprovoked.
Disagreement exists about whether to define PTE as the occurrence of one or more late, unprovoked seizures, or whether the condition should only be diagnosed in people with two or more. Medical sources usually consider PTE to be present if even one unprovoked seizure occurs, but more recently it has become accepted to restrict the definition of all types of epilepsy to include only conditions in which more than one occur. Requiring more than one seizure for a diagnosis of PTE is more in line with the modern definition of epilepsy, but it eliminates people for whom seizures are controlled by medication after the first seizure.
As with other forms of epilepsy, seizure types
Seizure types
The numerous epileptic seizure types are most commonly defined and grouped according to the scheme proposed by the International League Against Epilepsy in 1981...
in PTE may be partial (affecting only part of one hemisphere
Cerebral hemisphere
A cerebral hemisphere is one of the two regions of the eutherian brain that are delineated by the median plane, . The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres has an outer layer of grey matter called the cerebral cortex that is...
of the brain) or generalized (affecting both hemispheres and associated with loss of consciousness). In about a third of cases, people with PTE have partial seizures; these may be simple or complex. In simple partial seizures, level of consciousness is not altered, while in complex partial seizures consciousness is impaired. When generalized seizures occur, they may start out as partial seizures and then spread to become generalized.
Causes
Genetics
GeneticsGenetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
may play a role in the risk that a person will develop PTE; people with the ApoE-ε4 allele may be at higher risk for PTE. The haptoglobin
Haptoglobin
Haptoglobin is a protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system...
Hp2-2 allele may be another genetic risk factor, possibly because it binds hemoglobin poorly and thus allows more iron to escape and damage tissues. However, most studies have found that having family members with epilepsy does not significantly increase the risk of PTS, suggesting that genetics are not a strong risk factor.
Severity of trauma
The more severe the brain trauma is, the more likely a person is to suffer late PTE. Evidence suggests that mild head injuries do not confer an increased risk of developing PTE, while more severe types do. In simple mild TBI, the risk for PTE is about 1.5 times that of the uninjured population. By some estimates, as many as half of sufferers of severe brain trauma experience PTE; other estimates place the risk at 5% for all TBI patients and 15–20% for severe TBI. One study found that the 30-year risk of developing PTE was 2.1% for mild TBI, 4.2% for moderate, and 16.7% for severe injuries, as shown in the chart at right.
Nature of trauma
The nature of the head trauma also influences the risk of PTE. People who suffer depressed skull fractures, penetrating head trauma, early PTS, and intracerebral and subdural haematomas due to the TBI are especially likely to suffer PTE, which occurs in more than 30% of people with any one of these findings. About 50% of patients with penetrating head trauma develop PTE, and missile injuries and loss of brain volume are associated with an especially high likelihood of developing the condition. Injuries that occur in military settings carry higher-than-usual risk for PTE, probably because they more commonly involve penetrating brain injury and brain damage over a more widespread area. Intracranial hematomas, in which blood accumulates inside the skull, are one of the most important risk factors for PTE. Subdural hematoma confers a higher risk of PTE than does epidural hematoma, possibly because it causes more damage to brain tissue. Repeated intracranial surgery confers a high risk for late PTE, possibly because people who need more surgery are more likely to have factors associated with worse brain trauma such as large hematomas or cerebral swellingCerebral edema
Cerebral edema or cerebral œdema is an excess accumulation of water in the intracellular or extracellular spaces of the brain.-Vasogenic:Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier...
. In addition, the chances of developing PTE differ by the location of the brain lesion: brain contusion that occurs on in one or the other of the frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
s has been found to carry a 20% PTE risk, while a contusion in one of the parietal lobes carries a 19% risk and one in a temporal lobe carries a 16% chance. When contusions occur in both hemispheres, the risk is 26% for the frontal lobes, 66% for the parietal, and 31% for the temporal.
Post-traumatic seizures
The risk that a person will develop PTE is heightened but not 100% if PTS occur. Because many of the risk factors for both PTE and early PTS are the same, it is unknown whether the occurrence of PTS is a risk factor in and of itself. However, even independent of other common risk factors, early PTS have been found to increase the risk of PTE to over 25% in most studies. A person who has one late seizure is at even greater risk for having another than one who has early PTS; epilepsy occurs in 80% of people who have a late seizure. Status epilepticusStatus 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 continuous seizure or multiple seizures in rapid succession, is especially strongly correlated with the development of PTE; status seizures occur in 6% of all TBIs but are associated with PTE 42% of the time, and quickly halting a status seizure reduces chances of PTE development.
Pathophysiology
For unknown reasons, trauma can cause changes in the brain that lead to epilepsy. There are a number of proposed mechanisms by which TBI causes PTE, more than one of which may be present in a given person. In the period between a brain injury and onset of epilepsy, brain cells may form of new synapsesSynaptogenesis
Synaptogenesis is the formation of synapses. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development...
and axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s, undergo apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
or necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, and experience altered gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. In addition, damage to particularly vulnerable areas of the cortex such as the hippocampus may give rise to PTE.
Blood that gathers in the brain after an injury may damage brain tissue and thereby cause epilepsy. Products that result from the breakdown of 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...
from blood may be toxic to brain tissue. The "iron hypothesis" holds that PTE is due to damage by oxygen free radicals, the formation of which is catalyzed by iron from blood. Animal experiments using rats have shown that epileptic seizures can be produced by injecting iron into the brain. Iron catalyzes the formation of hydroxyl radical
Hydroxyl radical
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...
s by the Haber-Weiss reaction; such free radicals damage brain cells by peroxidizing lipids
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
in their membranes
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...
. The iron from blood also reduces the activity of an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
called nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
, another factor thought to contribute to PTE.
After TBI, abnormalities exist in the release of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, chemicals used by brain cell
Brain Cell
Brain Cell is a mail art project begun by Ryosuke Cohen in June 1985. The project is basically a networked art project where individual artists create their own 30x42cm work of art with stamps, drawings, stickers and so forth. This is sent to Cohen, who prints each cell - 150 copies each - with a...
s to communicate with each other; these abnormalities may play a role in the development of PTE. TBI may lead to the excessive release of glutamate and other excitatory neurotransmitters (those that stimulate brain cells
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
and increase the likelihood that they will fire
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
). This excessive glutamate release can lead to 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...
, damage to brain cells through overactivation of the biochemical receptors that bind and respond to excitatory neurotransmitters. Overactivation of glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s damages neurons; for example it leads to the formation of free radicals. Excitotoxicity is a possible factor in the development of PTE; it may lead to the formation of a chronic epileptogenic focus. An epileptic focus is the part of the brain from which epileptic discharges originate.
In addition to chemical changes in cells, structural changes that lead to epilepsy may occur in the brain. Seizures that occur shortly after TBI can reorganize neural networks and cause seizures to occur repeatedly and spontaneously later on. The kindling hypothesis
Kindling model
Kindling is a commonly used model for the development of seizures and epilepsy in which the duration and behavioral involvement of induced seizures increases after seizures are induced repeatedly. The kindling model was first proposed in the late 1960s by Goddard and colleagues...
suggests that new neural connections are formed in the brain and cause an increase in excitability. The word kindling is a metaphor: the way the brain's response to stimuli increases over repeated exposures is similar to the way small burning twigs can produce a large fire. This reorganization of neural networks may make them more excitable. Neurons that are in a hyperexcitable state due to trauma may create an epileptic focus in the brain that leads to seizures. In addition, an increase in neurons' excitability may accompany loss of inhibitory neurons that normally serve to reduce the likelihood that other neurons will fire; these changes may also produce PTE.
Diagnosis
Magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI) is performed in people with PTE, and CT scanning can be used to detect brain lesions if MRI is unavailable. However, it is frequently not possible to detect the epileptic focus using neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
.
For a diagnosis of PTE, seizures must not be attributable to another obvious cause. Seizures that occur after head injury are not necessarily due to epilepsy or even to the head trauma. Like anyone else, TBI survivors may suffer seizures due to factors including imbalances of fluid or electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s, epilepsy from other causes, hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
(insufficient oxygen), and ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
(insufficient blood flow to the brain). Withdrawal from alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
is another potential cause of seizures. Thus these factors must be ruled out as causes of seizures in people with head injury before a diagnosis of PTE can be made.
Prevention
Prevention of PTE involves preventing brain trauma in general; protective measures include bicycle helmets and child safety seats. No specific treatment exists to prevent the development of epilepsy after TBI occurs. In the past, antiepileptic drugs were used with the intent of preventing the development of PTE. However, while antiepileptic drugs can prevent early PTS, clinical studies have failed to show that prophylactic use of antiepileptic drugs prevents the development of PTE. Why antiepileptic drugs in clinical trials have failed to stop PTE from developing is not clear, but several explanations have been offered: for example, the drugs may simply not be capable of preventing epilepsy, or the drug trials may have been set up in a way that did not allow a benefit of the drugs to be found (e.g. drugs may have been given too late or in inadequate doses). Animal studies have similarly failed to show much protective effect of the most commonly used seizure medications in PTE trials, such as phenytoinPhenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
. Antiepileptic drugs are recommended to prevent late seizures only for people in whom PTE has already been diagnosed, not as a preventative measure. On the basis of the aforementioned studies, no treatment is widely accepted to prevent the development of epilepsy. However, it has been proposed that a narrow window of about one hour after TBI may exist during which administration of antiepileptics could prevent epileptogenesis
Epileptogenesis
Epileptogenesis is a process by which a normal brain develops epilepsy, a chronic condition in which seizures 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...
(the development of epilepsy).
Corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s have also been investigated for the prevention of PTE, but clinical trials revealed that the drugs did not reduce late PTS and were actually linked to an increase in the number of early PTS.
Treatment
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
drugs may be given to prevent further seizures; these drugs completely eliminate seizures for about 35% of people with PTE. However, antiepileptics only prevent seizures while they are being taken; they do not reduce the occurrence once the patient stops taking the drugs. Medication may be stopped after seizures have been controlled for two years. PTE is commonly difficult to treat with drug therapy, and antiepileptic drugs may be associated with side effect
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s. The antiepileptics carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
and valproate are the most common drugs used to treat PTE; phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
may also be used but may increase risk of cognitive side effects such as impaired thinking. Other drugs commonly used to treat PTE include clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
, phenobarbitol, primidone
Primidone
Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, and ethosuximide
Ethosuximide
Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures.-Approved:It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence...
. Among antiepileptic drugs tested for seizure prevention after TBI (phenytoin, sodium valproate, carbamazepine, phenobarbital), no evidence from randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s has shown superiority of one over another.
People whose PTE does not respond to medication may undergo surgery to remove the epileptogenic focus, the part of the brain that is causing the seizures. However surgery may be more difficult than it is for epilepsy due to other causes, and is less likely to be helpful in PTE than in other forms of epilepsy. It can be particularly difficult in PTE to localize the epileptic focus, in part because TBI may affect diffuse areas of the brain. Difficulty locating the seizure focus is seen as a deterrent to surgery. However, for people with sclerosis
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
in the mesial 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....
(in the inner aspect of the temporal lobe), who comprise about one third of people with intractable PTE, surgery is likely to have good outcome. When there are multiple epileptic foci or the focus cannot be localized, and drug therapy is not effective, vagus nerve stimulation
Vagus nerve stimulation
Vagus nerve stimulation is an adjunctive treatment for certain types of intractable epilepsy and treatment-resistant depression.- Mechanism of action :...
is another option for treating PTE.
People with PTE have follow-up visits, in which health care providers monitor neurological and neuropsychological function and assess the efficacy and side effects of medications. As with sufferers of other types of epilepsy, PTE sufferers are advised to exercise caution when performing activities for which seizures could be particularly risky, such as rock climbing.
Prognosis
The prognosis for epilepsy due to trauma is worse than that for epilepsy of undetermined cause. People with PTE are thought to have shorter life expectanciesLife expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
than people with brain injury who do not suffer from seizures. Compared to people with similar structural brain injuries but without PTE, people with PTE take longer to recover from the injury, have more cognitive and motor problems, and perform worse at everyday tasks. This finding may suggest that PTE is an indicator of a more severe brain injury, rather than a complication that itself worsens outcome. PTE has also been found to be associated with worse social and functional outcomes but not to worsen patients' rehabilitation or ability to return to work. However, people with PTE may have trouble finding employment if they admit to having seizures, especially if their work involves operating heavy machinery.
The period of time between an injury and development of epilepsy varies, and it is not uncommon for an injury to be followed by a latent period with no recurrent seizures. The longer a person goes without developing seizures, the lower the chances are that epilepsy will develop. At least 80–90% of people with PTE have their first seizure within two years of the TBI. People with no seizures within three years of the injury have only a 5% chance of developing epilepsy. However, one study found that head trauma survivors are at an increased risk for PTE as many as 10 years after moderate TBI and over 20 years after severe TBI. Since head trauma is fairly common and epilepsy can occur late after the injury, it can be difficult to determine whether a case of epilepsy resulted from head trauma in the past or whether the trauma was incidental.
The question of how long a person with PTE remains at higher risk for seizures than the general population is controversial. About half of PTE cases go into remission, but cases that occur later may have a smaller chance of doing so.
Epidemiology
Studies have found that the incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of PTE ranges between 1.9 to more than 30% of TBI sufferers, varying by severity of injury and by the amount of time after TBI for which the studies followed subjects.
Brain trauma is one of the strongest predisposing factors for epilepsy development, and is an especially important factor in young adults. Young adults, who are at the highest risk for head injury
Head injury
Head injury refers to trauma of the head. This may or may not include injury to the brain. However, the terms traumatic brain injury and head injury are often used interchangeably in medical literature....
, also have the highest rate of PTE, which is the largest cause of new-onset epilepsy cases in young people. Children have a lower risk for developing epilepsy; 10% of children with severe TBI and 16–20% of similarly injured adults develop PTE. Being older than 65 is also a predictive factor in the development of epilepsy after brain trauma. One study found PTE to be more common in male TBI survivors than in females.
History
Trepanation
Trepanning, also known as trephination, trephining or making a burr hole, is a surgical intervention in which a hole is drilled or scraped into the human skull, exposing the dura mater in order to treat health problems related to intracranial diseases. It may also refer to any "burr" hole created...
, in which a hole is cut in the skull, may have been used to treat PTE in ancient cultures. In the early 19th century, the surgeons Baron Larrey and WC Wells each reported having performed the operation for PTE. The French-educated American surgeon Benjamin Winslow Dudley (1785–1870) performed six trepanations for PTE between the years of 1819 and 1832 in Kentucky
Kentucky
The Commonwealth of Kentucky is a state located in the East Central United States of America. As classified by the United States Census Bureau, Kentucky is a Southern state, more specifically in the East South Central region. Kentucky is one of four U.S. states constituted as a commonwealth...
and had good results despite the unavailability of antisepsis
Antiseptic
Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction...
. The surgery involved opening the skull at the site of injury, debriding
Debridement
Debridement is the medical removal of a patient's dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue...
injured tissue, and sometimes draining blood or fluid from under the dura mater
Dura mater
The dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. It is derived from Mesoderm. The other two meningeal layers are the pia mater and the arachnoid mater. The dura surrounds the brain and the spinal cord and is responsible for...
. Dudley's work was the largest series of its kind that had been done up to that point, and it encouraged other surgeons to use trepanation for post-traumatic seizures. His reports on the operations came before it was accepted that surgery to relieve excess pressure within the skull was effective in treating epilepsy, but it helped set the stage for trepanation for PTE to become common practice. The procedure became more accepted in the late 19th century once antisepsis was available and cerebral localization was a familiar concept. However in 1890, the prominent German physician Ernest von Bergmann criticized the procedure; he questioned its efficacy (except in particular circumstances) and suggested that operations had been declared successful too soon after the procedures to know whether they would confer a long-term benefit. The late 19th century saw the advent of intracranial surgery, operating on brain lesions believed to be causing seizures, a step beyond cranial surgery which involved just the skull and meninges
Meninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
. By 1893, at least 42 intracranial operations had been performed for PTE in the US, with limited success.
Surgery was the standard treatment for PTE until the years following World War II, when the condition received more attention as soldiers who had survived head trauma developed it. The increased need for drugs to treat PTE led to trials with antiepileptics; these early trials suggested that the drugs could prevent epileptogenesis (the development of epilepsy). It was still thought that antiepileptic drugs could prevent epileptogeneis in the 1970s; in 1973, 60% of physicians surveyed used them to prevent PTE. However, the clinical trials which had supported a protective effect of antiepileptics were uncontrolled; in later, controlled trials the drugs failed to demonstrate an antiepileptogenic effect. Studies did show that antiepileptics prevented seizures occurring within a week after injury, and in 1995 the task force of the Brain Trauma Foundation published a recommendation suggesting their use to protect against seizures early after trauma. However, recommendations were published against the prophylactic use of antiepileptic drugs more than a week after injury by the Brain Injury Special Interest group of the American Academy of Physical Medicine and Rehabilitation in 1998 and by the American Association of Neurological Surgeons
American Association of Neurological Surgeons
The American Association of Neurological Surgeons is a professional body based in the United States with more than 8,000 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public...
in 2000.
Research
How epilepsy develops after an insult to the brain is not fully understood, and gaining such understanding may help researchers find ways to prevent it, or make it less severe or easier to treat. Researchers hope to identify biomarkers, biological indications that epileptogenesis is occurring, as a means to find drugs that can target pathways by which epilepsy develops. For example, drugs could be developed to interfere with secondary brain injury (injury that does not occur at the moment of trauma but results from processes initiated by it), by blocking pathways such as free radical damage to brain tissue. An increase in understanding of age differences in epilepsy development after trauma may also help researchers find biomarkers of epileptogenesis. There is also interest in finding more antiepileptic drugs, with the potential to interfere with epileptogenesis. Some new antiepileptic drugs such as topiramateTopiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, and lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
have already been developed and have shown promise in treatment of PTE. No animal model
Animal 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...
has all the characteristics of epileptogenesis in humans, so research efforts aim to identify one. Such a model may help researchers find new treatments and identify the processes involved in epileptogenesis.