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Acute traumatic brain injury and seizures

Head trauma from blunt force or from penetration of the skull causes a sequence of
pathophysiologic changes in brain that correlates with the severity of injury. Acute injury
precipitates a cascade of changes in brain metabolism, blood flow, and homeostasis that is a
threat to survival.
Seizures may occur because of the acute injury and are liable to complicate management. They
may be immediate, requiring initiation of treatment at the injury scene, or they may occur later,
within the first 24 hours after the injury.1 Phenytoin is an anticonvulsant that is effective in
preventing seizures that occur in the acute injury period.2
Of course, the occurrence of a seizure in a patient with a head injury requires immediate brain
imaging to define a possible cause, such as the accumulation of blood within the cranium.
Risks
Author: LJ Willmore

Incidence
The risk of developing post-traumatic epilepsy (PTE) is related to the severity of injury.35
Within the first year after head trauma, the incidence of seizures is 12 times as great as for the
population.3 Patients with severe head trauma and cortical injury with neurologic deficits on
physical examination, but with the dura mater remaining intact, have an incidence of epilepsy
from 7% to 39%. Increased severity of trauma, as indicated by dural penetration and neurologic
abnormalities, yields a range of epilepsy incidence of 2057%.3,6 Guidelines for identifying
patients at risk for late epilepsy (see Table: Factors of Late Epilepsy) include those factors
associated with the severity of neocortical contusion, including presence of an intracerebral
hematoma and the need for surgical repair of a depressed skull fracture.1

Risk factors
An attempt was made to improve the prediction of who might be liable to develop PTE, applying
a formula using weighted trauma categories.7 The formula included the brain location, the agent
of injury, severity, complications, and the presence of focal neurologic deficits.7 The highest
numeric values of risk were associated with:

missile wound with dural penetration

central-parietal location

an early seizure

intracerebral hematoma

Predictive factors associated with epilepsy risk in the Vietnam Head Injury Survey8 included:

cortical involvement

moderate volume of brain tissue loss

intracerebral hematoma

retained metal fragments

Other studies of patients with PTE showed prolonged post-traumatic amnesia, the presence of a
cortical laceration occurring with a depressed skull fracture with dural laceration, and
intracerebral hematoma to be predictive.9,10 The risk of development of seizures is increased
after hemorrhagic cerebral infarction11,12 and spontaneous intracerebral hematoma.13 These
data resulted in the development of a hypothesis by Willmore and colleagues that suggested that
trauma-induced hemorrhage with blood in contact with the neuropil is an important etiologic
factor in the development of PTE.1416
Latency from head injury to the development of epilepsy varies, although 57% of patients have
onset of seizure within 1 year of injury.8 Whether a seizure occurs immediately after injury,
within the first week, or beyond the first week may have prognostic significance for the
development of epilepsy.1
Immediate seizures, occurring within hours after trauma, or a sequence of seizures with
development of post-traumatic status epilepticus complicates management of an injured patient
by causing hypoxia, hypertension, and metabolic changes. An immediate seizure may be a
nonspecific reaction to head trauma, but an intracranial hematoma also may present this way and
must be excluded. An early seizure, occurring during the first week after injury, increases the
incidence of late epilepsy.1
Closed head injury of such severity to cause hospitalization results in an overincidence of PTE of
47%.1,17 The incidence of PTE is considerably higher among patients undergoing
rehabilitation for head injury.1820 Patients with penetrating head injury have an epilepsy
incidence of 3550%.3,8,2123 Not all factors are understood, however, because trivial head
injury also has been associated with development of PTE.24
Occurrence of a seizure after head injury is not always predictive for development of epilepsy,
nor does such a complication predict an eventual enduring problem with chronic epilepsy.
Between 50% and 65% of patients who have seizures do so within 12 months of injury.8,23,25
Approximately 80% have seizures by 2 years after injury.26,27
About half of all patients have single seizures, without recurrence, and another 25% have just
two or even three seizures followed by abatement of that clinical problem. Timing of a seizure in
relationship to head injury provides some predictive information. Of patients with a seizure
within 1 week of injury, 2030% have late seizures, beyond 1 week of injury.8,26,28,29 Such
later seizure recurrence seems better correlated with seizure frequency during the first year.

Although these observations suggest that the overall prognosis is good,30 intractability becomes
a major clinical problem for some patients.
Nonepileptic seizures also have complicated head trauma, with up to 32% of one series of
pseudoseizure patients having a history of head injury.31
History of febrile seizures is found as part of the pattern of risk for development of typical mesial
temporal sclerosis and the clinical problem of complex partial seizures. However, head injury,
particularly during childhood, is a factor in some cases.32 Indeed, the University of California at
Los Angeles series33,34 found head trauma as an associate event in 16% of their cases with
mesial temporal sclerosis. Such an occurrence is not typically dual in pathology35,36 but may
represent the consequences of transmitted forces with selective vulnerability of the hippocampus,
as has been observed in animals.37
Cellular mechanisms of epileptogenesis
Author: LJ Willmore
Interictal epileptiform discharges reflect a stereotyped cellular pattern of depolarization shift.71
Transition from interictal to ictal discharge is characterized by loss of hyperpolarization and by
synchronization of neurons in the focus. Amplification of excitatory postsynaptic potentials that
underlie the patterns of depolarization shift may be produced by mechanisms that include:72

withdrawal of inhibition

frequency potentiation of excitatory postsynaptic potentials

change in the space constant of the dendrites of the postsynaptic neuron

activation of the N-methyl-D-aspartate (NMDA) receptor

potentiation by neuromodulators

Biochemical injury to neurons may cause a sequence of changes, ranging from cellular loss with
replacement gliosis to subtle alterations in neuronal plasma membrane. Membrane changes
initiated by biochemical effects of injury may alter densities and distribution of ion channels on
neuronal membrane. Alteration of membrane ionotophores could affect Na+ and Ca2+ currents,
alter thresholds, and lead to progressive depolarization. Intrinsic cellular bursting may also
develop with an increase in extracellular K+ or reduction of extracellular Ca2+. Development or
recruitment of a critical mass of neurons sufficient to cause clinical manifestations requires
synchronization of a critical mass of cells.71,72
The mechanism or critical physiologic changes causing post-traumatic epileptogenesis remains
unknown. However, several processes may provide useful areas for investigation:

Mechanical shearing of fiber tracts, with loss of inhibitory interneurons after anterograde
transynaptic neuronal degeneration73

Trauma-induced release of aspartate or glutamate, with attendant activation of N-methylD-aspartate (NMDA) receptors74

Elaboration of nerve growth factor75

Enhancement of reactive gliosis76

Assessment of hippocampal tissue obtained during surgical resection for temporal lobe seizures
and stained for identification of acetylcholine esterase shows enhancement of staining in the
outer portion of the molecular layer of the dentate gyrus.77 Histochemical staining of rodent
kindled hippocampus shows abundant mossy fiber synaptic terminals in the supragranular region
and the inner molecular layer of the dentate gyrus.78 Although speculative, synaptic
reorganization may increase recurrent excitation in granule cells, favoring epileptogenesis.
Experimental foci have losses in the number of axosomatic g-aminobutyric acid (GABA)ergic
terminals, as represented by asymmetric synapses. The GABA-ergic pericellular basket plexus
that provides tonic inhibition was thought to be sensitive to hypoxia, given the implied
dependence on aerobic metabolism evidenced by the presence of increased numbers of
mitochondria within the altered synapses.79
Genetic and molecular factors
Cellular responses to the generation of free-radical oxidants after decompartmentalization of
hemoglobin or iron-containing heme compounds may depend on the induction of protective
mechanisms. For example, strains of Escherichia coli may be differentiated on observation of
responses to peroxide. Induction of enzymes to repair DNA damage induced by Fenton-derived
free radicals appears to be critical for cellular survival.80,81 Some speculate that continuing
alterations causing focal epileptiform discharges may result from free-radical injury to neuronal
nuclear or mitochondrial DNA. Differences in susceptibility to developing epilepsy after a given
trauma dose may be related to the ability of repair-response induction after initiation of lipid
peroxidation.
Specific brain genetic factors that cause a liability to develop post-traumatic epilepsy remain
unknown. A possible genetic predisposition has been observed, however, with the detection of
decreased levels of serum haptoglobin in familial epilepsy.82 Haptoglobins are acute phase
glycoproteins in the alpha Lglobulin fraction of serum that form stable complexes with
hemoglobin.83 Because antioxidants such as superoxide dismutase and peroxidases are not
found in high concentrations in extracellular fluid, containment of initiators of oxidation must
depend on binding of reactive metals to carrier proteins, including transferrin, lactoferrin,
ceruloplasmin, and haptoglobins.83 Because one mechanism of protection against the induction
of oxidant stress is sequestration of free hemoglobin with haptoglobins, impairment in the
synthesis of these glycoproteins may produce an inherent susceptibility to the development of
epilepsy after head trauma.

Regulation of glutamate may be critical in the process of epileptogenesis. Microdialysis


measurements from humans with spontaneous seizures from the hippocampus show transient
release of glutamate.84 Most glutamate is cleared from the extrasynaptic space by the action of
high-affinity transporters called GLAST and GLT-1. These proteins are found predominantly in
glia.85,86 Decreasing GLAST and GLT-1 expression would be the result of down-regulation,
because the messenger RNAs of these proteins were decreased even though progressive gliosis is
a characteristic found in the hippocampus of rats that are spontaneously seizing.87,88 Downregulation of glial glutamate transporter with expected increase in tissue glutamate concentration
contributes to excitatory synaptic transmission, associated occurrence of seizures, and
neurodegeneration in the hippocampus. Animals with spontaneous iron-induced amygdalar
seizures89 have down-regulation of glutamate transporter production as a component of their
chronic epileptogenesis.90,91
Molecular changes appear to correlate with depolarization-induced elevation of extracellular
glutamate levels in the hippocampus, as determined by in vivo microdialysis. A protein called
GAT-1 transports GABA. This transporter protein is reported to be responsible for approximately
85% of GABA reuptake.92 GAT-1 is widely distributed in neurons and astrocytes in
hippocampal and limbic regions.9395 Alterations in GABA uptake may be important to the
process of chronic epileptogenesis after head trauma.96

Biochemical pathogenesis of post-traumatic epilepsy


Abstract
Head trauma is often followed by epilepsy and may be related to the breakdown of red blood
cells and hemoglobin within the CNS. Injection of hemoglobin or iron salts into the rat cortex is
known to induce a chronic epileptic focus. We observed the formation of superoxide anion (O 2)
and hydroxyl radical (OH) after ferric chloride injection into the rat cerebral cortex and suggest
that these radicals, especially OH, may be responsible for the initiation of lipid peroxidation in
neuronal membranes and for the accelerated production of guanidine compounds in the brain,
which may in turn lead to epileptogenicity. Then, we found that treatment with epigallocatechin
(EGC) or a phosphate diester of vitamins E and C (EPC), which are potent OH scavengers,
significantly inhibited the formation of malondialdehyde and epileptic discharges in the ironinduced epileptic focus.
Patof emed
The mechanism by which trauma to brain tissue leads to recurrent seizures is unknown. Cortical
lesions seem important in the genesis of the epileptic activity. Early seizures are likely to have a
different pathogenesis than late seizures; early PTS are thought to be a nonspecific response to
the physical insult.
The PTE kindling model of epilepsy postulates that iron deposition from extravasated blood
leads to damage by free radicals, and the accumulation of glutamate leads to damage by

excitotoxicity. Animal studies suggest that disruption of the blood-brain barrier is likely to
contribute to the generation of seizures in PTE.

Sodium valproate (Depakote, Depakene, Depacon, Stavzor)

Valproate is chemically unrelated to other antiseizure drugs. Its mechanism of action has not
been established; it may be related to increased brain levels of gamma-aminobutyric acid
(GABA) or to enhanced GABA action. Valproate may potentiate postsynaptic GABA responses,
affect the potassium channel, or have a direct membrane-stabilizing effect.
For conversion to monotherapy, the concomitant AED dose is ordinarily reduced by about 25%
every 2 weeks. Reduction may start with therapy or delayed 1-2 weeks if seizures are possible
with reduction; closely monitor patients during this time for increased seizure frequency.
As adjunctive therapy, valproate may be added to the regimen at 10-15 mg/kg/d. The dosage may
increase by 5-10 mg/kg/wk for optimal clinical response. Optimal clinical response is usually
achieved at a dose of less than 60 mg/kg/d.
View full drug information

Carbamazepine (Tegretol, Carbatrol, Equetro, Epitol)

Carbamazepine is indicated for complex partial seizures. It may block posttetanic potentiation by
reducing summation of temporal stimulation. After therapeutic response, the dose can be reduced
to the minimum effective level, or discontinued at least once every 3 months.

Phenytoin (Dilantin, Phenytek)

Phenytoin may act in the motor cortex, inhibiting spread of seizure activity; it may inhibit
activity of brainstem centers responsible for the tonic phase of grand mal seizures.
Dosages must be individualized. Administer a larger dose before sleep if the dose cannot be
divided equally. To minimize GI irritation, administer with or immediately after meals. Rapid
injection or direct IV injection may cause severe hypotension or CNS depression.

Topiramate (Topamax)

Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic


activity that may have state-dependent sodium channel blocking action, potentiating the
inhibitory activity of the neurotransmitter gamma-aminobutyrate (GABA). It may block
glutamate activity.

Levetiracetam (Keppra)

Levetiracetam is used as adjunctive therapy for partial seizures and myoclonic seizures. It is also
indicated for primary generalized tonic-clonic seizures. Its mechanism of action is unknown.
For unknown reasons, trauma can cause changes in the brain that lead to epilepsy. [2][25] There are
a number of proposed mechanisms by which TBI causes PTE, more than one of which may be
present in a given person.[7] In the period between a brain injury and onset of epilepsy, brain cells
may form new synapses and axons, undergo apoptosis or necrosis, and experience altered gene
expression.[24] In addition, damage to particularly vulnerable areas of the cortex such as the
hippocampus may give rise to PTE.[3]
Blood that gathers in the brain after an injury may damage brain tissue and thereby cause
epilepsy.[7] Products that result from the breakdown of hemoglobin from blood may be toxic to
brain tissue.[7] The "iron hypothesis" holds that PTE is due to damage by oxygen free radicals,
the formation of which is catalyzed by iron from blood.[18] Animal experiments using rats have
shown that epileptic seizures can be produced by injecting iron into the brain.[7] Iron catalyzes the
formation of hydroxyl radicals by the Haber-Weiss reaction;[7] such free radicals damage brain
cells by peroxidizing lipids in their membranes.[26] The iron from blood also reduces the activity
of an enzyme called nitric oxide synthase, another factor thought to contribute to PTE.[18]
After TBI, abnormalities exist in the release of neurotransmitters, chemicals used by brain cells
to communicate with each other; these abnormalities may play a role in the development of PTE.
[7]
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 receptors damages neurons; for example it leads to the formation of free radicals. [7]
Excitotoxicity is a possible factor in the development of PTE; [12] it may lead to the formation of a
chronic epileptogenic focus.[7] An epileptic focus is the part of the brain from which epileptic
discharges originate.[27]
In addition to chemical changes in cells, structural changes that lead to epilepsy may occur in the
brain.[2] Seizures that occur shortly after TBI can reorganize neural networks and cause seizures

to occur repeatedly and spontaneously later on.[3] The kindling hypothesis suggests that new
neural connections are formed in the brain and cause an increase in excitability.[18] 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. [28] This reorganization of
neural networks may make them more excitable. [3] Neurons that are in a hyperexcitable state due
to trauma may create an epileptic focus in the brain that leads to seizures. [11] 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.[3]