• Risks
• Prevention and prophylaxis
• Mechanisms of brain injury
• Biochemical effects
• Cellular mechanisms of epileptogenesis
• Genetic and molecular factors
• Can responses be altered?
• Management guidelines
• References

The risk of developing post-traumatic epilepsy (PTE) is related to the severity of injury.3–5 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 20–57%.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.14–16

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 4–7%.1,17 The incidence of PTE is considerably higher among patients undergoing rehabilitation for head injury.18–20 Patients with penetrating head injury have an epilepsy incidence of 35–50%.3,8,21–23 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, 20–30% 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

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Prevention renders a process impossible by an advanced provision.39 Prophylaxis is the process of guarding against the development of a specific disease by an action or treatment that affects pathogenesis.

One example of prevention is administration of anticonvulsants to patients with severe head trauma to prevent seizures that could cause the complications of hypertension and hypoxia. Such use of antiepileptic medications is intended to prevent the complications that are associated with tonic-clonic seizures, for patients considered at risk for such seizures. Prophylactic use of antiepileptic drugs, on the other hand, has the intention to interfere with epileptogenesis in patients with head trauma or patients undergoing neurosurgical procedures requiring incision of the neocortex.40 Although prevention of acute seizures that occur after head injury is a practical goal,40 such treatment is not likely to have a prophylactic effect against later development of epilepsy.

Clinical observations suggesting the efficacy of antiepileptic drugs as prophylactic against the development of post-traumatic epilepsy (PTE) appeared within a few years of the availability of phenytoin.40 Young et al.41 compared the observed 6% epilepsy occurrence in their treated head-injured patients to historic controls developing post-traumatic seizures. They concluded that early administration of antiepileptic drugs prevented the development of PTE and recommended prophylactic administration of phenytoin to patients with a 15% or greater risk of developing PTE.

Rish and Caveness42 did not detect a difference in early seizure occurrence between phenytoin-treated and untreated patients. However, Wohns and Wyler43 reviewed patients selected with critical trauma indicators, including depressed skull fracture, dural or cortical laceration, or a prolonged period of post-traumatic amnesia. Although the authors acknowledged the selection bias introduced in their study, they concluded that antiepileptic drug (AED) administration prevented the development of PTE.

Because the uncontrolled studies suggested that AEDs might have a prophylactic effect, prospective placebo-controlled assessments were undertaken. Penry and colleagues44 administered phenytoin and phenobarbital to head-injured patients in a double-blind fashion with placebo control. Seizure occurrence in the treated group was 21%, versus 13% in controls. The lack of significant difference between the treatment and control groups suggested that anticonvulsant administration had no effect on the development of PTE in the treated patients.

Young et al.45 used a double-blind prospective study of 179 head-injured patients, of which 85 were treated with phenytoin for 18 months and 74 were placebo controls. Seizures occurred in 12.9% of the treated patients and in 10.8% of the control patients.

Temkin et al.2 reported their experience with 404 patients treated in a prospective fashion. Patients with severe head trauma were assigned to receive either phenytoin or placebo, starting with an intravenous loading dose in the first 24 hours after injury. Serum levels were measured at regular intervals, blood levels of drug were maintained in the therapeutic range, and efforts were made to assure that evaluations were blinded. At 1 year, no difference in incidence of PTE was found between the treatment and control groups. By 2 years, PTE had occurred in 27.5% of phenytoin-treated patients and in 21.1% of controls. (They did observe that phenytoin was effective in preventing seizures during the acute period immediately after injury. Thus, early post-traumatic seizures can be prevented with administration of phenytoin for 1 or 2 weeks, but this result was not associated with a reduction of mortality.46)

Valproic acid had an effect on kindling in animals47 and was evaluated in humans as well.48 Valproic acid was given for 1 month or 6 months, or patients were treated for 1 week with phenytoin as control; 379 patients were enrolled in this study. Patients were followed for 2 years after entry into the study. Phenytoin and valproic acid were effective in preventing early seizures, with 1.5% in the phenytoin arm and 4.5% in the valproic acid arm developing seizures within the first week of injury. Valproic acid failed to prevent the development of post-traumatic seizures, with late seizures developing in 15% in the phenytoin group, 16% in the 1-month valproate group, and 24% in the 6-month valproate group. A trend to higher mortality in the valproate treatment group was noted; no specific cause was reported.48

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Blunt impact to the head that deforms the skull causes transmission of a pressure wave through the brain that results in abrupt and transient cavitation in brain tissue. Mechanical forces propagate a pressure wave through the brain.38,49 Mechanical forces of head injury cause the brain to accelerate with induction of rotation and shearing injury to fiber tracts and blood vessels and contusion.50 Contusion results in hemorrhage, with an admixture of red blood cells, necrotic brain caused by coagulation necrosis, and edema caused by mechanical disruption of blood vessels or by cellular diapedesis.

Histopathologic studies of material obtained from traumatized brain show:51–53

• formation of axonal retraction balls
• reactive gliosis
• wallerian degeneration
• microglial star formation within cystic white matter lesions

Mechanical effects cause bulk displacement of tissue with secondary responses that include alterations in cerebral vasomotor regulation, vasospasm, altered cerebral blood flow, changes in intracranial pressure, and altered vascular permeability.54

Delayed effects of acute head trauma include focal or diffuse brain edema, ischemia, necrosis, gliosis, and neuronal loss.

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Contusion or cortical laceration causes bleeding within the neuropil, followed by red blood cell hemolysis and deposition of hemoglobin within the neuropil. Iron, liberated from hemoglobin and transferrin and deposited as hemosiderin, is found within the brain of patients with PTE.55 Iron is critical to biological functions, but the two stable oxidation states and the redox properties of iron pose a biological hazard. Oxidation of ferrous iron to ferric is a simple reaction yielding insoluble hydroxide complexes. Autoxidation reactions in aqueous solution, or biological fluids, with or without chelators, causes a complicated series of one-electron transfer reactions yielding free-radical intermediates. Addition of iron salts or heme compounds to solutions containing polyunsaturated fatty acids or to suspensions of subcellular organelles results in the formation of highly reactive free-radical oxidants, including perferryl ions, superoxide radicals, singlet oxygen, and hydroxyl radicals.14,56–59 Although free-radical species may form by iron-catalyzed Haber-Weiss reactions,60,61 these oxidants are also actively generated by iron in biologically chelated forms in heme or with adenosine 5'-diphosphate.57,62

Free radicals react with methylene groups adjacent to double bonds of polyunsaturated fatty acids and lipids within cellular membranes, causing hydrogen abstraction and subsequent propagation of peroxidation reactions.57 This nonenzymatic initiation and propagation of lipid peroxidation disrupts membranes of subcellular organelles, degrades deoxyribose and amino acids, and yields diene conjugates and fluorescent chromophores.63–65 Inorganic iron salts, hematin, and hemoproteins stimulate peroxidation of lipids of microsomes and mitochondria and change cellular thiodisulfide function.66

Alkyl hydroxyl and peroxyl species of fatty acids propagate until a termination reaction occurs with a membrane constituent capable of donating an electron without forming a free radical. Such constituents include tocopherol, cholesterol, proteins, or the sulfhydryl group of glutathione.62,67–69 Pretreatment of animals with a-tocopherol and selenium prevented histopathologic alterations after injection of aqueous iron into neural tissue, further supporting the contention that peroxidative reactions are important in responses to brain injury.67–70

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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-methyl-D-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

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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 L–globulin 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 Down-regulation 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.93–95 Alterations in GABA uptake may be important to the process of chronic epileptogenesis after head trauma.96

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Antiperoxidants may be of value in modulating brain injury responses. The actions of enzymes such as catalase, peroxidase, and superoxide dismutase quench hydroxyl radicals, superoxide radicals, and peroxides generated in biological systems by oxidative chemistry or by the actions of heme-containing compounds liberated within lipid systems.97 Glutathione peroxidase, using glutathione as a co-substrate and selenium as a metallic co-factor, reduces intracellular formation of hydrogen peroxide and free radicals. Oxidative stress increases activity of glutathione reductase, glucose-6-phosphate dehydrogenase, and glutathione peroxidase.98,99 Selenium, a metallic cofactor of glutathione peroxidase, also seems to act synergistically with ƒnalpha-tocopherol in preventing peroxidation of structural membrane components.

Alpha-tocopherol prevents peroxidative injury of sulfhydryl groups of glycolipids and glycoproteins, apparently augmenting the antioxidant effects of enzyme systems such as glutathione peroxidase. Tocopherol also prevents peroxidation of unsaturated fatty acids and lipids by reaction of phenolic hydroxyl groups with propagating lipid radicals that were initiated by oxidative carbonyl hydrogen abstraction.100-103 Furthermore, the phytyl side chain of tocopherol may intercalate within the acyl chains of polyunsaturated phospholipids, causing lipid membrane stabilization and a reduction in membrane permeability.104,105 Tocopherol may also act as a free-radical scavenger and singlet oxygen-quenching agent.103 A novel nonglucocorticoid 21 Vaminosteroid, with properties of inhibiting iron-dependent lipid peroxidation, had a salutary effect on concussive injury to mice.106,107

Superoxide radicals induce cellular and vasogenic edema.108-110 Initiation of focal edema by cold-induced injury to the cerebral cortex of rodents causes increased levels of superoxide radicals.108 Administration of liposome-entrapped copper-zinc superoxide dismutase interferes with the development of cold-induced edema, suggesting that super- oxide dismutase interruption of oxygen free-radical¡Vinduced fatty acid injury may have the potential for interruption of trauma-induced brain injury.108

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229¡V238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

As with other forms of epilepsy, those patients with few seizures that are easily controlled tend to have the best prognosis. Walker and Erculei30 observed that 50% of patients identified as having post-traumatic epilepsy would be in complete remission by 15 years after injury.

Assessment and decisions about discontinuation of medication after a long seizure-free interval should be governed by guidelines that apply to any patient who is a candidate for a trial off of medication.111,112

5. Patients with intractable epilepsy

Patients with post-traumatic epilepsy may develop intractable epilepsy. Because such patients are unresponsive to antiepileptic drug therapy, the usual strategy is to evaluate the patient for resective surgery. The patient must understand the success rate of resective surgery and the potential for the need to pursue further assessment should the initial surgical effort fail.

The challenge of the monitoring process and accompanying planning for potential resective surgery is the unpredictable nature of the process of lesion formation after head injury. Head trauma of sufficient intensity to result in the development of post-traumatic epilepsy causes spatial dispersion of injured cortex in temporal and extratemporal regions.38 Location of the clinically important regions of injury causing epilepsy requires careful planning of intracranial electrode arrays. Knowledgeable observers, such as family members, should review videotaped seizures captured during epilepsy monitoring to ensure that the clinical events reflect the patient’s typical seizures.

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

1. Jennett B, Teasdale G. Management of Head Injuries. Philadelphia: FA Davis Co, 1981:271.

2. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497–502.

3. Caveness WF. Epilepsy, a product of trauma in our time. Epilepsia 1976;17:207–215.

4. Weiss GH, Feeney DM, Caveness WF, et al. Prognostic factors for the occurrence of posttraumatic epilepsy. Arch Neurol 1983;40:7–10.

5. Weiss GH, Salazar AM, Vance SC, et al. Predicting posttraumatic epilepsy in penetrating head injury. Arch Neurol 1986;43:771–773.

6. Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338:20–24.

7. Feeney DM, Walker AE. The prediction of posttraumatic epilepsy. A mathematical approach. Arch Neurol 1979;36:8–12.

8. Salazar AM, Jabbari B, Vance SC, et al. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury study. Neurology 1985;35:1406–1414.

9. Jennett B. Epilepsy and acute traumatic intracranial haematoma. J Neurol Neurosurg Psychiatry 1975;38:378–381.

10. Kaplan HA. Management of craniocerebral trauma and its relation to subsequent seizures. Epilepsia 1961;2:111–116.

11. DeCarolis P, D’Alessandro R, Ferrara R, et al. Late seizures in patients with internal carotid and middle cerebral artery occlusive disease following ischaemic events. J Neurol Neurosurg Psychiatry 1984;47:1345–1347.

12. Richardson EP, Dodge PR. Epilepsy in cerebrovascular disease. Epilepsia 1954;3:49–74.

13. Faught E, Peters D, Bartolucci A, et al. Seizures after primary intracerebral hemorrhage. Neurology 1989;39:1089–1093.

14. Aisen P. Some Physicochemical Aspects of Iron Metabolism. In Ciba Foundation Symposium (51st ed). New York: Elsevier, 1977:1–14.

15. Levitt P, Wilson WP, Wilkins RH. The effects of subarachnoid blood on the electrocorticogram of the cat. J Neurosurg 1971;35:185–191.

16. Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of post-traumatic epilepsy. Ann Neurol 1978;4:329–336.

17. Annegers JF, Grabow JD, Grover RV, et al. Seizures after head trauma: a population study. Neurology 1980;30:683–689.

18. Bontke CF, Lehmkuhl LD, Englander J, et al. Medical complications and associated injuries of patients treated in TBI Model System programs. J Head Trauma Rehabil 1993;8(2):34–46.

19. Kalisky Z, Morrison P, Meyers CA, Von Laufen AV. Medical problems encountered during rehabilitation of patients with head injury. Arch Phys Med Rehabil 1985;66:25–29.

20. Sazbon L, Groswasser Z. Outcome in 134 patients with prolonged posttraumatic unawareness. Part 1: parameters determining late recovery of consciousness. J Neurosurg 1990;72:75–80.

21. Ascroft PB. Traumatic epilepsy after gunshot wounds of the head. BMJ 1941;1:739–744.

22. Caveness WF, Liss HR. Incidence of post-traumatic epilepsy. Epilepsia 1961;2:123–129.

23. Caveness WF, Meirowsky AM, Rish BL, et al. The nature of posttraumatic epilepsy. J Neurosurg 1979;50:545–553.

24. Devinsky O. Epilepsy after minor head trauma. J Epilepsy 1996;9:94–97.

25. da Silva AM, Vaz AR, Riberiro I, et al. Controversies in posttraumatic epilepsy. Acta Neurochir (Wien) 1990;50:48–51.

26. Walker AE. Posttraumatic epilepsy in World War II veterans. Surg Neurol 1989;32:235–236.

27. Walker AE, Blumer D. The fate of World War II veterans with posttraumatic seizures. Arch Neurol 1989;46:23–26.

28. Walker AE, Jablon S. A follow-up of head injured men of World War II. J Neurosurg 1959;16:600–610.

29. Jennett WB, Lewin W. Traumatic epilepsy after closed head injuries. J Neurol Neurosurg Psychiatry 1960;23:295–301.

30. Walker AE, Erculei F. Posttraumatic epilepsy 15 years later. Epilepsia 1970;11:17–26.

31. Westbrook LE, Devinsky O, Geocadin B. Nonepileptic seizures after head injury. Epilepsia 1998;39:978–982.

32. Falconer MA, Serafetinides EA, Corsellis JA. Etiology and pathogenesis of temporal lobe epilepsy. Arch Neurol 1964;10:233–248.

33. Betz P, Eisenmenger W. Traumatic origin of a meningioma? Int J Legal Med 1995;107:326–328.

34. Mathern GW, Babb TL, Armstrong DL. Hippocampal Sclerosis. In J Engel Jr, TA Pedley (eds), Epilepsy: a Comprehensive Textbook. Philadelphia: Lippincott–Raven, 1997:133–155.

35. Cascino GD, Jack CR, Parisi JE, et al. Operative strategy in patients with MRI-identified dual pathology and temporal lobe epilepsy. Epilepsy Res 1993;33:639–644.

36. Li LM, Cendes F, Watson C, et al. Surgical treatment of patients with single and dual pathology: relevance of lesion and of hippocampal atrophy to seizure outcome. Neurology 1997;48:437–444.

37. Lowenstein DH, Thomas MJ, Smith DH, McIntosh TK. Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 1992;12:4846–4853.

38. Lingren SO. Experimental studies of mechanical effects in head injury. Acta Chir Scand 1966;132[Suppl 360]:1–32.

39. Willmore LJ. Prophylactic Use of Anticonvulsant Drugs. In SR Resor Jr, H Kutt (eds), Medical Treatment of Epilepsy. New York: Dekker, 1992:73–77.

40. Rapport RL, Penry JK. Pharmacologic prophylaxis of post-traumatic epilepsy: a review. Epilepsia 1972;13:295–304.

41. Young B, Rapp R, Brooks WH, et al. Post-traumatic epilepsy prophylaxis. Epilepsia 1979;20:671–681.

42. Rish BL, Caveness WF. Relation of prophylactic medication to the occurrence of early seizures following craniocerebral trauma. J Neurosurg 1973;38:155–158.

43. Wohns RN, Wyler AR. Prophylactic phenytoin in severe head injuries. J Neurosurg 1979;51:507–509.

44. Penry JK, White BG, Brackett CE. A controlled prospective study of the pharmacologic prophylaxis of posttraumatic epilepsy. Neurology 1979;29:600–601.

45. Young B, Rapp RP, Norton JA, et al. Failure of prophylactically administered phenytoin to prevent late post- traumatic seizures. J Neurosurg 1983;58:236–241.

46. Haltiner AM, Newell DW, Temkin NR, et al. Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis. J Neurosurg 1999;91:588–592.

47. Silver JM, Shin C, McNamara JO. Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilepsy. Ann Neurol 1991;29:356–363.

48. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg 1999;91:593–600.

49. Pudenz RH, Shelden CH. The lucite calvarium—a method for direct observation of the brain. J Neurosurg 1946;3:487–505.

50. Gennarelli TA, Thibaulat LE, Adams JH, et al. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:564–574.

51. Langfitt TW, Weinstein JD, Kassell NF. Vascular Factors in Head Injury. Contribution to Brain-Swelling and Intracranial Hypertension. In WE Caveness, AE Walker (eds), Head Injury. Philadelphia: Lippincott, 1966:172–194.

52. Tornheim PA, Liwnicz BH, Hirsch CS, et al. Acute responses to blunt head trauma. J Neurosurg 1983;59:431–438.

53. Unterharnscheidt F, Sellier K. Mechanisms and pathomorphology of closed head injuries. In WF Caveness, AE Walker (eds), Head Injury. Philadelphia: Lippincott, 1966:321–341.

54. Willmore LJ. Posttraumatic epilepsy: cellular mechanisms and implications for treatment. Epilepsia 1990;31[Suppl 3]:S67–S73.

55. Payan H, Toga M, Berard-Badier M. The pathology of post-traumatic epilepsies. Epilepsia 1970;11:81–94.

56. Fong KL, McCay BP, Poyer JL, et al. Evidence that peroxidation of lysosomal membranes is initiated by hydroxyl free radicals produced during flavin enzyme activity. J Biol Chem 1973;248:7792–7797.

57. Fong KL, McCay PB, Poyer JL, et al. Evidence of superoxide-dependent reduction of Fe3+ and its role in enzyme-generated hydroxyl radical formation. Chem Biol Interact 1976;15:77–89.

58. Svingen BA, O’Neal FO, Aust SD. The role of super- oxide and singlet oxygen in lipid peroxidation. Photo- chem Photobiol 1978;28:803–809.

59. Willmore LJ, Hiramatsu M, Kochi H, Mori A. Formation of superoxide radicals, lipid peroxides, and edema after FeCl3 injection into rat isocortex. Brain Res 1983;277:393–396.

60. Czapski G, Ilan YA. On the generation of the hydroxylation agent from superoxide radical. Can the Haber- Weiss reaction be the source of OH radicals? Photo- chem Photobiol 1978;28:651–653.

61. Koppenol WH, Butler J, van Leeuwen JW. The HaberWeiss cycle. Photochem Photobiol 1978;28:655–660.

62. Aust SD, Svingen BA. The role of iron in enzymatic lipid peroxidation. In WA Pryor (ed), Free Radicals in Biology. New York: Academic, 1982:1–28.

63. Baker N, Wilson L. Water-soluble products of UV-irradiated, autoxidized linoleic and linolenic acids. J Lipid Res 1966;7:341–348.

64. Niehaus WG, Samuelsson B. Formation of malonalde- hyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 1968;6:126–130.

65. Triggs WJ, Willmore LJ. In vivo lipid peroxidation in rat brain following intracortical Fe2+ injection. J Neurochem 1984;42:976–980.

66. Smith GJ, Dunkley WL. Initiation of lipid peroxidation by a reduced metal ion. Arch Biochem Biophys 1962;98:46–48.

67. Anderson DK, Means ED. Lipid peroxidation in spinal cord. FeCl2 induction and protection with antioxidants. Neurochem Pathol 1983;1:249–264.

68. Willmore LJ, Rubin JJ. Effects of antiperoxidants on FeCl2-induced lipid peroxidation and focal edema in rat brain. Exp Neurol 1984;83:62–70.

69. Triggs WJ, Willmore LJ. Effect of [dl]-alpha-tocopherol on FeCl2-induced lipid peroxidation in rat amygdala. Neurosci Lett 1994;180:33–36.

70. Willmore LJ, Rubin JJ. Antiperoxidant pretreatment and iron-induced epileptiform discharge in the rat: EEG and histopathologic study. Neurology 1981;31:63–69.

71. Prince DA, Connors BW. Mechanisms of epileptogenesis in cortical structures. Ann Neurol 1984;16[Suppl]:S59–S64.

72. Dichter MA, Ayala GF. Cellular mechanisms of epilepsy: a status report. Science 1987;237:157–164.

73. Saji M, Reis DJ. Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist. Science 1987;235:66–69.

74. Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989;244:798–800.

75. Gall CM, Isackson PJ. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 1989;245:758–761.

76. Nieto-Sampedro M. Astrocyte mitogen inhibitor related to epidermal growth factor receptor. Science 1988;240:1784–1786.

77. Green RC, Blume HW, Kupferschmid SB, Mesulam MM. Alterations of hippocampal acetylcholinesterase in human temporal lobe epilepsy. Ann Neurol 1989;26:347–351.

78. Sutula T, Cascino G, Cavazos J, et al. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 1989;26:321–330.

79. Ribak CE, Harris AB, Vaughn JE, Roberts E. Inhibitory GABAergic nerve terminals decrease at sites of focal epilepsy. Science 1979;205:211–214.

80. Carlsson J, Carpenter VS. The recA+ gene product is more important than catalase and superoxide dismutase in protecting Escherichia coli against hydrogen peroxide toxicity. J Bacteriol 1980;142:319–321.

81. Imlay JA, Linn S. DNA damage and oxygen radical toxicity. Science 1988;240:1302–1309.

82. Panter SS, Sadrzadeh SM, Hallaway PE, et al. Hypohaptoglobinemia associated with familial epilepsy. J Exp Med 1985;161:748–754.

83. Gutteridge JM. The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 1987;917:219–223.

84. During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;341:1607–1610.

85. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675–686.

86. Lehre KP, Levy LM, Ottersen OP, et al. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 1995;15:1835–1853.

87. Tanaka S, Kondo S, Tanaka T, Yonemasu Y. Long-term observation of rats after unilateral intra-amygdaloid injection of kainic acid. Brain Res 1988;463:163–167.

88. Tanaka T, Tanaka S, Fujita T, et al. Experimental complex partial seizures induced by a microinjection of kainic acid into limbic structures. Prog Neurobiol 1992;38:317–334.

89. Ueda Y, Willmore LJ, Triggs WJ. Amygdalar injection of FeCl3 causes spontaneous recurrent seizures. Exp Neurol 1998;153:123–127.

90. Doi T, Ueda Y, Tokumaru J, et al. Sequential changes in glutamate transporter mRNA during Fe+++ induced epileptogenesis. Mol Brain Res 2000;75:105–112.

91. Ueda Y, Willmore LJ. Sequential changes in glutamate transporter protein levels during Fe+++ induced epileptogenesis. Epilepsy Res 2000;39:201–219.

92. Borden LA, Smith KE, Hartig PR, et al. Molecular heterogeneity of gamma-aminobutyric acid (GABA) transport system. J Biol Chem 1992;267:21098–21104.

93. Durkin MM, Smith KE, Borden LA, et al. Localization of messenger RNAs encoding three GABA transporters in rat brain: an in situ hybridization study. Mol Brain Res 1995;33:7–21.

94. Minelli A, Brecha NC, Karschin C, et al. GAT-1, a high affinity GABA plasma membrane transporter is localized to neurons and astroglia in the cerebral cortex. J Neurosci 1995;15:7734–7746.

95. Ribak CE, Tong WM, Brecha NC. GABA plasma membrane transporters. GAT-1 and GAT-2 display different distributions in the rat hippocampus. J Comp Neurol 1996;367:595–606.

96. Ueda Y, Willmore LJ. Hippocampal gamma-aminobutyric acid transporter alterations following focal epileptogenesis induced in rat amygdala. Brain Res Bull 2000;52:357–361.

97. Fridovich I. Superoxide dismutase. Adv Enzymol 1974;41:35–97.

98. Orlowski M, Karkowsky A. Glutathione metabolism and some possible functions of glutathione in the nervous system. Int Rev Neurobiol 1976;19:75–121.

99. Tappel AL. Lipid peroxidation damage to cell components. Fed Proc 1973;32:1870–1874.

100. McCay PB, King MM. Vitamin E: Its Role As a Biological Free Radical Scavenger and Its Relationship to the Microsomal Mixed-Function Oxidase System. In LJ Machlin (ed), Vitamin E. New York: Marcel Dekker, 1980;289–317.

101. Rehncrona S, Smith DS, Akesson B, et al. Peroxidative changes in brain cortical fatty acids and phospholipids, as characterized during Fe2+- and ascorbic acid-stimulated lipid peroxidation in vitro. J Neurochem 1980;34:1630–1638.

102. Tappel AL. Vitamin E and free radical peroxidation of lipids. Ann N Y Acad Sci 1972;203:12–28.

103. Witting LA. Vitamin E and Lipid Antioxidants in FreeRadical-Initiated Reactions. In WA Pryor (ed), Free Radicals in Biology (vol 4). New York: Academic, 1980;295–319.

104. Diplock AT, Lucy JA. The biochemical modes of action of vitamin E and selenium: a hypothesis. FEBS Lett 1973;29:205–210.

105. Lucy JA. Functional and structural aspects of biological membranes: a suggested structural role for vitamin E in the control of membrane permeability and stability. Ann N Y Acad Sci 1972;203:4–11.

106. Hall ED, Yonkers PA, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg 1988;68:456–461.

107. Willmore LJ. Post-traumatic epilepsy: mechanisms and prevention [Review]. Psychiatry Clin Neurosci 1995;49:S171–S173.

108. Chan PH, Fishman RA. Transient formation of super- oxide radicals in polyunsaturated fatty acid-induced brain swelling. J Neurochem 1980;35:1004–1007.

109. Fishman RA, Chan PH, Lee J, Quan S. Effects of superoxide free radicals on the induction of brain edema. Neurology 1979;29:546.

110. Wagner FC, Stewart WB. Effect of trauma dose on spinal cord edema. J Neurosurg 1981;54:8802–8806.

111. Callaghan N, Garrett A, Goggin T. Withdrawal of anti- convulsant drugs in patients free of seizures for two years. N Engl J Med 1988;318:942–946.

112. Chadwick D, Reynolds EH. When do epileptic patients need treatment? Starting and stopping medication. BMJ 1985;290:1885–1888.

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier (www.elsevier.com).

Reviewed April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.