Post-traumatic epilepsy

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Post-traumatic epilepsy Classification and external resources
eMedicine	NEURO/318
MeSH	D004834

Post-traumatic epilepsy (PTE) 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 seizures (PTS, seizures that result from TBI) more than a week after the initial injury.^[1] A person who has a seizure or seizures due to trauma does not necessarily have PTE, which is a chronic condition. However, the terms PTS and PTE may be used interchangeably in medical literature.^[2] Medical articles usually define PTE as "one or more unprovoked seizures occurring after head trauma", but more recently the definition of all types of epilepsy has been narrowed to include only conditions in which more than one unprovoked seizure occur.^[3] PTE is estimated to constitute 5% of all cases of epilepsy and over 20% of cases of symptomatic epilepsy^[4] (in which seizures are caused by an identifiable brain lesion).^[5]

It is not known how to predict who will develop epilepsy after TBI and who will not.^[6] 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.^[7] PTE may be caused by several biochemical processes that occur in the brain after trauma, including overexcitation of brain cells and damage to brain tissues by free radicals.^[8] As with other forms of epilepsy, seizures may be generalized or partial.^[9] The condition may be treated with medication, or when medication does not work, surgery. The condition may go into remission, but people with PTE may remain at a higher risk for seizures than the general population even decades after the injury.

Contents 1 Characteristics 2 Pathophysiology 3 Onset 4 Diagnosis 5 Prevention 6 Treatment 7 Prognosis 8 Epidemiology 8.1 Risk factors 9 History 10 Research directions 11 References

[edit] Characteristics

In about a third of cases, people with PTE have simple or complex partial seizures, but seizures may also be generalized, and these may have a focal onset.^[10] In the time period shortly after head trauma, seizures are commonly generalized, while partial seizures increase in prevalence with increasing time after the injury.^[11]

[edit] Pathophysiology

For unknown reasons, trauma can cause changes in the brain that lead to epilepsy.^[7][12] There are a number of proposed mechanisms by which TBI causes PTE, more than one of which may be present in a given person.^[8] In the period between a brain injury and onset of epilepsy, brain cells may form of new synapses and axons, undergo apoptosis or necrosis, and experience altered gene expression.^[13]

The kindling hypothesis suggests that new neural connections are formed in the brain and cause an increase in excitability.^[11] This reorganization of neural networks may make them more excitable.^[4] Seizures that occur shortly after TBI can reorganize neural networks and cause seizures to occur repeatedly and spontaneously later on.^[4] Neurons that are in a hyperexcitable state due to trauma may create an epileptic focus in the brain that leads to seizures.^[2] In addition, inhibitory neurons may be lost.^[4]

Blood that gathers in the brain after an injury may damage brain tissue and thereby cause epilepsy.^[8] Products that result from the breakdown of hemoglobin from blood may be toxic to brain tissue.^[8] The "iron hypothesis" holds that PTE is due to damage by oxygen free radicals, the formation of which is catalyzed by iron from blood.^[11] Animal experiments using rats have shown that epileptic seizures can be produced by injecting iron into the brain.^[8] Iron leads to the formation of hydroxyl radicals by the Haber-Weiss reaction.^[8] Free radicals damage brain cells by peroxidizing lipids in their membranes.^[14] The iron from blood also reduces the activity of an enzyme called nitric oxide synthase, another factor thought to contribute to PTE.^[11]

Excitotoxicity is another possible factor in the etiology of PTE.^[15] TBI causes excessive amounts of the neurotransmitter glutamate to be released, which may be related to seizure development.^[2] In addition, the release of inhibitory neurotransmitters such as GABA may be reduced.^[8] Overactivation of the biochemical receptors that bind and respond to excitatory neurotransmitters like glutamate leads to the formation of free radicals, and it can cause excitotoxicity.^[8] Brain cells are damaged due to overexcitation of the receptors for excitatory amino acids on the membranes of neurons.^[8] A chronic epileptogenic focus may result from excitotoxicity due to the excessive release of excitatory neurotransmitters that occurs during seizures.^[8]

[edit] Onset

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.^[13] The longer a person goes without developing seizures, the lower the chances are that epilepsy will develop.^[4] Most people with PTE have their first seizure within two years of the TBI; the number may be 80 to 90% or more.^[8] People with no seizures within three years of the injury have only a 5% chance of developing epilepsy.^[16] 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.^[17] Since head trauma is fairly common and epilepsy can occur so late after the injury, it can be difficult to determine whether a case of epilepsy resulted from head trauma that occurred earlier or whether the trauma was incidental.^[18]

[edit] Diagnosis

To be diagnosed with PTE, a person must have a history of head trauma and no history of seizures prior to the injury.^[19] Witnessing a seizure is the most effective way to diagnose PTE.^[2] 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.^[2] 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.^[8]

Magnetic resonance imaging (MRI) is performed in people with PTE, and CT scanning can be used if MRI is unavailable to detect brain lesions.^[8] However, it is frequently not possible to detect the epileptic focus using neuroimaging.^[18]

[edit] Prevention

Prevention of PTE involves preventing TBI in general. Antiepileptic drugs can prevent early PTS but clinical studies have failed to show that prophylactic use of antiepileptic drugs prevents the development of PTE.^[1][17] Animal studies have similarly failed to show much protective effect of the most commonly used seizure medications in PTE trials, such as phenytoin and carbamazepine.^[17] Thus, the drugs are recommended to prevent late seizures only for people in whom PTE has already been diagnosed, not as a preventative measure.^[20] No treatment is widely accepted to prevent the development of epilepsy.^[11] 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 and PTE.^[15]

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).^[17]

[edit] Treatment

People with PTE may be given antiepileptic drugs to prevent further seizures.^[15] However, though antiepileptics prevent seizures while they are being taken, they do not reduce their occurrence once the patient stops taking the drugs.^[1] PTE is commonly difficult to treat with drug therapy.^[7][21] Antiepileptic drugs may be associated with adverse side effects.^[20]

Antiepileptic medication eliminates seizures for about 35% of people with PTE.^[5] 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, but this may be more difficult than it is for epilepsy due to other causes.^[15] Surgery is less likely to be helpful in PTE than in other forms of epilepsy.^[8] It can be particularly difficult in PTE to localize the epileptic focus, the area of the brain from which seizures originate, in part because TBI may affect diffuse areas of the brain.^[18] However, for people with mesial temporal sclerosis, who comprise about one third of people with intractable PTE, surgery is likely to have good outcome.^[4] 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.^[18]

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.^[8] 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.^[15]

[edit] Prognosis

The prognosis for epilepsy due to trauma is worse than that for epilepsy of undetermined cause.^[22] People with PTE are thought to have shorter life expectancies than people with brain injury who do not suffer from seizures.^[2] One study found that, 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.^[2] This finding may suggest that PTE is an indicator of a more severe brain injury, rather than a complication that itself worsens outcome.^[2] Another study found that PTE was associated with worse social and functional outcomes but did not worsen patients' rehabilitation or ability to return to work.^[8] However, people with PTE may have trouble finding employment if they admit to having seizures, especially if their work involves operating heavy machinery.^[23] PTE may be associated with a higher incidence of stroke.^[2]

The question of how long a person with PTE is still at higher risk for seizures than the general population is controversial.^[17] About half of PTE cases go into remission, but cases that occur later may have a smaller chance of doing so.^[22]

[edit] Epidemiology

Studies have found that the incidence 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.^[17]

Brain trauma is the one of the largest predisposing factors for epilepsy development, and is an especially important factor in young adults.^[5] Young adults, who are at the highest risk for head injury, also have the highest rate of PTE.^[8] Children have a lower risk for developing epilepsy; 10% of children with severe TBI and 16–20% of similarly injured adults develop PTE.^[5] Being older than 65 is also a predictive factor in the development of epilepsy after brain trauma.^[13] One study found PTE to be more common in male TBI survivors than in females.^[2]

[edit] Risk factors

It is not clear why some patients get PTE while others with very similar injuries do not.^[3]

Genetics 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.^[17] 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.^[17] However, most studies have found that having family members with epilepsy does not significantly increase the risk of PTS.^[3]

The more severe the brain trauma is, the more likely a person is to suffer late PTE.^[11] Evidence suggests that mild head injuries do not confer an increased risk of developing PTE, while more severe types do.^[22] In simple mild TBI, the risk for PTE has a standardized incidence ratio of 1.5.^[24] About half of sufferers of severe neurotrauma experience PTE.^[11] Other estimates place the risk of PTE at 5% for all TBI patients and 15–20% for severe TBI.^[25] 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.^[5]

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.^[11] About 50% of patients with penetrating head trauma develop PTE.^[8][22] People with missile injuries and loss of brain volume are highly likely to develop PTE.^[26] Intracranial hematomas, in which blood accumulates inside the skull, are one of the most important risk factors for PTE.^[27] Subdural hematoma confers a higher risk of PTE than does epidural hematoma, possibly because it causes more damage to brain tissue.^[8] 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 lobes 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.^[5] When contusions are bilateral (occurring on both sides), the risk is 26% for the frontal lobes, 66% for the parietal, and 31% for the temporal.^[5]

Injuries that occur in military settings carry higher risk for PTE than those that occur in civilian settings, probably because the former type of injury more commonly involves penetrating brain injury and brain damage over a more widespread area.^[17]

The risk that a person will develop PTE is heightened but not 100% if PTS occur.^[22] 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.^[17] 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.^[13] Status epilepticus, 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.^[5]

Damage to tissues from surgery can cause PTE.^[15] 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 swelling.^[8]

[edit] History

Records of PTE exist from as early as 3000 BC.^[23] Trepanation, in which a hole is cut in the skull, may have been used to treat PTE in ancient cultures.^[28] In the early 19th century, the surgeons Baron Larrey and WC Wells each reported having performed the operation for PTE.^[28] The French-educated 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.^[29] 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.^[29] 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.^[29] 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.^[29] The procedure became more accepted in the late 19th century once antisepsis was available and cerebral localization was a familiar concept.^[29] However in 1890, the prominent German physician Ernest von Bergmann criticized the procedure; he questioned its efficacy except in particular circumstances and suggested that others had declared their operations successful too soon after the procedures to know whether they would confer a long-term benefit.^[28] The late 19th  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.^[28] By 1893, at least 42 intracranial operations had been performed for PTE in the US, with limited success.^[28]

[edit] Research directions

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.^[5] 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.^[13] For example, drugs could be developed to interfere with secondary brain injury, by blocking pathways such as free radical damage to brain tissue.^[18] An increase in understanding of age differences in epilepsy development after trauma may also help researchers find biomarkers of epileptogenesis.^[13] There is also interest in finding more antiepileptic drugs than the ones currently used with the potential to interfere with epileptogenesis.^[30] Neuroimaging techniques such as MRI and PET scanning may allow researchers to identify the specific locations in the brain in which epilepsy develops.^[13] No animal model has all the characteristics of epileptogenesis in humans, so research efforts aim to identify one.^[13][5]

[edit] References