War Between the Lines of “The Dry Salvages”

146

Severe head injury results in a sequence of patho-physiological changes in brain that tend to corre-late with the severity of injury.¹² Acute traumatic brain injury causes changes in brain metabolism, blood flow, and homeostasis that are a threat to survival. Seizures occur because of the acute injury and are liable to complicate management. Such immediate seizures⁵⁰ that occur either acutely or within the first 24 hours of injury may require ini-tiation of treatment at the injury scene or may occur later in the course of treating the injured pa-tient. Phenytoin is an anticonvulsant that is effec-tive in preventing seizures that occur in the period following an acute injury.⁹³ However, occurrence of a seizure in a head-injured patient requires im-mediate brain imaging to define a possible cause, including the accumulation of blood within the cranium.

Risks for Development of Epilepsy The risk of developing of posttraumatic epilepsy (PTE) is related to the severity of injury.^17,106,107 Within the first year after severe head injury, the incidence of seizures exceeds 12 times the popu-lation risk for the development of epilepsy.^17,38 Patients with severe head trauma and cortical in-jury with neurological deficits on physical

exami-nation, but with the dura mater remaining intact, have an incidence of epilepsy ranging from 7% to 39%. However, increased severity of trauma, with dural penetration and neurological abnormalities, yields an incidence range of epilepsy of 20% to 57%^4,17 Guidelines identifying patients at risk for late epilepsy (Table 7.1) include factors associated with the severity of neocortical contusion, includ-ing the presence of an intracerebral hematoma and the need for surgical repair of a depressed skull fracture.⁵⁰

To improve the prediction of who might be li-able to develop PTE,³⁴ refinement of risk factors was attempted by using a formula with weighted trauma categories. Variables included brain

loca-Table 7.1. Factors Associated with Increased Incidence of Late Epilepsy

Factor n %

No early epilepsy 29/868 3%

Early epilepsy 59/238 25%^*

No hematoma 27/854 3%

Hematoma 45/128 35%^*

No depressed fracture 27/832 3%

Depressed fracture 76/447 17%*

*p < .001.

Source: Modified from Jennett and Teasdale,⁵⁰ with permission.

Posttraumatic Epilepsy 147 tion, the agent of injury, severity, complications,

and the presence of focal neurological deficits.³⁴ The highest numeric values of risk were associated with missile wound with dural penetration, central-parietal location, occurrence of an early seizure, and the presence of an intracerebral hematoma.

Predictive factors for the risk of epilepsy in the Vietnam Head Injury Survey included cortical involvement, moderate volume of brain tissue loss, intracerebral hematoma, and retained metal frag-ments.⁸¹ Other studies of patients with PTE showed prolonged posttraumatic amnesia, the presence of a cortical laceration from a depressed skull fracture with dural laceration, and intracerebral hematoma to be predictive.^48,52,91 The risk of developing sei-zures is increased following hemorrhagic cerebral infarction^24,77 and spontaneous intracerebral he-matoma.³³ These facts resulted in the development of a hypothesis by Willmore et al. suggesting that trauma-induced hemorrhage with blood in contact with the neuropil is an important etiological factor in the development of PTE.^1,56,114

Latency from injury to the development of epi-lepsy varies, although 57% of patients have onset of seizures within the first year after injury.⁸¹ 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.⁵⁰ Immediate seizures, occurring within hours after trauma, or a sequence of seizures with development of posttraumatic status epilepticus will complicate management of an injured patient by causing hypoxia, hypertension, and metabolic changes. Although an immediate seizure may be a nonspecific reaction to head trauma, an intracra-nial hematoma may present this way and must be excluded. An early seizure, occurring during the first week after injury, is associated with increased incidence of late epilepsy.⁵⁰

Closed head injury in the civilian population of such severity to cause hospitalization results in an overincidence of PTE of 4% to 7%.^3,38,50 The inci-dence of PTE is considerably higher among patients undergoing rehabilitation for head injury.^10,51,82 Pa-tients with penetrating head injury have an epilepsy incidence of 35% to 50%.^5,17–19,81 However, not all factors are understood since trivial head injury has been associated with the development of PTE.²⁵ Occurrence of a seizure after head injury is not always predictive for the development of epilepsy, nor does such a complication predict an eventual

enduring problem with chronic epilepsy. Between 50% and 65% of patients with a seizure will have that event within 12 months of injury.^19,23,81 Ap-proximately 80% who seize will have done so by 2 years after injury.^102,103 Of interest, approximately 50% of all patients will have a single seizure, with-out recurrence, while another 25% will have only two or three seizures. Although the risk of recur-rence following a single seizure without trauma as the etiology is 30% at 5 years,⁴⁶ at least 80% of those with a single seizure will have a second seizure by 2 years after injury, supporting the practice of label-ing a patient as havlabel-ing PTE after only one seizure.³⁸ Timing of a seizure in relation to head injury provides some predictive information. From 20%

to 30% of patients with a seizure within 1 week of injury will have late seizures, that is, beyond 1 week of injury.49,81,102,105 Such later seizure recurrence seems better correlated with seizure frequency during the first year. While these observations sug-gest that the overall prognosis is good,¹⁰⁴ intracta-bility becomes a major clinical problem for some patients.

A history of febrile seizures is found as part of the patterns of risk for development of typical mesial temporal sclerosis (MTS) and the clinical problem of complex partial seizures. However head injury, particularly during childhood, is a factor in some cases.³² The UCLA series^9,61 found head trauma associated in 16% of their cases with MTS. Such an occurrence is not typically dual pathology^16,57 but may represent the consequences of transmitted forces with selective vulnerability of the hippocam-pus, as has been observed in animals.⁵⁹

Patients with PTE may develop intractable epi-lepsy. Since such patients are unresponsive to anti-epileptic drug therapy, the usual strategy is to evaluate the patient for consideration for resective surgery. The challenge of the monitoring process, and of the accompanying planning for potential resective surgery, is the unpredictable nature of the process of lesion formation following head injury.

Head trauma of sufficient intensity to result in the development of PTE causes spatial dispersion of injured cortex in temporal and extratemporal re-gions.⁵⁸ Location of the clinically important regions of injury causing epilepsy may require an intracra-nial electrode array. Knowledge observers, includ-ing family members, must review taped seizures to be sure that the clinical events reflect patient’s typical seizures. The patient must understand the

success rate of resective surgery and the potential need to pursue further assessment should the ini-tial surgical effort fail.

Prevention and Prophylaxis

Prophylaxis is the process of guarding against the development of a specific disease by an action or treatment that affects its pathogenesis. Prevention renders a process impossible by an advanced pro-vision.¹⁰⁹ One example of prevention is administra-tion 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 for patients who are thought to be at risk for tonic-clonic seizures is intended to prevent the complications that are associated with convulsive seizures. Prophylactic use of antiepileptic drugs in patients with head trauma, or for patients undergoing neurosurgical procedures requiring incision of the neocortex, has the intention of interfering with epileptogenesis.⁷³ Although prevention of acute seizures following head injury is a practical goal,⁹³ such treatment has not had a prophylactic effect against later devel-opment of epilepsy.⁸

Clinical observations indicating the efficacy of antiepileptic drugs as prophylactic against the de-velopment of posttraumatic epilepsy appeared within a few years of the availability of phenytoin.⁷³ Young et al.¹¹⁷ compared the observed 6% epilepsy occurrence in their treated head-injured patients to historical controls developing posttraumatic sei-zures. They concluded that early administration of antiepileptic drugs prevented the development of posttraumatic epilepsy, and recommended pro-phylactic administration of phenytoin to patients with a 15% or greater risk of developing posttrau-matic epilepsy.

Rish and Caveness⁷⁸ did not detect a difference in early seizure occurrence between phenytoin-treated and unphenytoin-treated patients. However, Wohns and Wyler¹¹⁶ reviewed patients selected with criti-cal trauma indicators that included depressed skull fracture, dural or cortical laceration, or a prolonged period of posttraumatic amnesia. Although the au-thors acknowledged selection bias they introduced in their study, they concluded that antiepileptic drug administration prevented the development of post-traumatic epilepsy.

Because the uncontrolled studies suggested that antiepileptic drugs might have a prophylactic ef-fect, prospective, placebo-controlled studies were undertaken (Table 7.2). Penry et al.⁷⁰ administered phenytoin and phenobarbital to head-injured pa-tients in a double-blind fashion, with a phenytoin vehicle as the initial placebo control. Seizure prob-ability was 21% in the treated group and 13% in the controls. The lack of significant difference be-tween the treatment and control groups supported the conclusion that anticonvulsant administration had no effect on the development of posttraumatic epilepsy in the treated patients.

Young et al.¹¹⁸ used a double-blind, prospective study of 179 head-injured patients treated with phenytoin or placebo for 18 months. Eighty-five patients were included in the treated group, and 74 patients were enrolled as placebo controls. Sei-zures occurred in 12.9% of the treated patients and in 10.8% of the control patients. Temkin et al.⁹³ reported their experience with 404 pa-tients treated in a prospective fashion. Papa-tients with severe head trauma were assigned to receive an intravenous loading dose of either phenytoin or placebo. Serum levels were measured at regu-lar intervals, blood levels of drug were maintained in the therapeutic range, and efforts were made to ensure that evaluations were blinded. At 1 year, no difference in the incidence of PTE was found between the treatment and control groups. How-ever, the authors did observe that phenytoin was effective in preventing seizures during the acute period immediately after injury. By 2 years, PTE

Table 7.2. Summary of Double-Blind, Placebo-Controlled Prospective Studies of the Efficacy of Antiepileptic Drugs as Prophylaxis of Posttraumatic Epilepsy

Percent Developing Epilepsy

Reference Drug Control Treated

Penry et al.⁷⁰ Phenytoin 13% 23%

Phenobarbital¹¹⁸

Young et al. Phenytoin 10.8% 12.9%

Temkin et al.⁹³ Phenytoin 21.1% 27.5%

Temkin et al.⁹² Valproic acid 15% 24%

Source: From L.J. Willmore: Head trauma and the development of posttraumatic epilepsy. In: Ettinger and Devinsky: Managing epilepsy and co-existing disorders. Butterworth-Heinemann 2002, with permission.

Posttraumatic Epilepsy 149 had occurred in 27.5% of phenytoin-treated

patients and in 21.1% of controls. Thus, early posttraumatic seizures can be prevented with ad-ministration of phenytoin for 1 or 2 weeks, but reduction in seizure occurrence is not associated with reduction of mortality.⁴⁵

Valproic acid had an effect on kindling in ani-mals⁸³ and was evaluated in humans as well.⁹² It was given for 1 month or 6 months, or patients were treated for 1 week with phenytoin as controls; 379 patients were enrolled in this study. Patients were followed for 2 years. Both phenytoin and valproic acid were effective in preventing early seizures, with 1.5% in the phenytoin group and 4.5% in the valproic acid group developing seizures within the first week of injury. Valproic acid failed to prevent the development of posttraumatic seizures, with late seizures developing in 15% of the phenytoin group, 16% in the 1-month valproic acid group, and 24% in the 6-month valproic acid group. A trend toward higher mortality in the long-term valproic acid treatment group was noted; no spe-cific cause was reported.⁹²

Mechanisms of Brain Injury

Blunt impact to the head with deformation of the skull causes transmission of a pressure wave through the brain that results in abrupt, and transient cavi-tation in brain tissue. Mechanical forces propagate a pressure wave through the brain.^58,72 Mechanical forces of head injury cause the brain to accelerate, with induction of rotation and shearing injury to fi-ber tracts and blood vessels and contusion.⁴¹ Con-tusion results in hemorrhage that is an admixture of red blood cells, coagulation necrosis, and edema caused by mechanical disruption of blood vessels or by cellular diapedesis. Histopathological studies of material obtained from traumatized brain show for-mation of axonal retraction balls, reactive gliosis, Wallerian degeneration, and microglial star forma-tion within cystic white matter lesions.^54,94,100 Me-chanical effects cause bulk displacement of tissue, with secondary responses that include alterations in cerebral vasomotor regulation, vasospasm, altered cerebral blood flow, changes in intracranial pres-sure, and altered vascular permeability.¹⁰⁸ Immedi-ate effects include increased extracellular calcium and glutamate from transporter failure and free radi-cal formation. Delayed effects of acute head trauma

include focal or diffuse brain edema, ischemia, ne-crosis, gliosis, and neuronal loss.

Biochemical Effects of Brain Injury Contusion or cortical laceration causes bleeding fol-lowed by hemolysis of red blood cells and deposition of hemoglobin within the neuropil. Iron liberated from hemoglobin and transferrin and deposited as hemosiderin is found within the brains of patients with PTE.⁶⁹ Iron is critical to biological functions, but the two stable oxidation states and the redox prop-erties of iron pose a biological hazard. Although oxi-dation of ferrous iron to ferric iron 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.¹ Addition of iron salts or heme com-pounds to solutions containing polyunsaturated fatty acids (PUFA) or to suspensions of subcellular or-ganelles results in the formation of highly reactive free radical oxidants, including perferryl ions, su-peroxide radicals, singlet oxygen, and hydroxyl radi-cals.1,36,37,86,111 Although free radical species may form by iron-catalyzed Haber-Weiss reactions,^22,53 these oxidants are also actively generated by iron in biologically chelated forms in heme or with ADP.^6,37 Free radicals react with methylene groups ad-jacent to double bonds of PUFA and lipids within cellular membranes, causing hydrogen abstrac-tion and subsequent propagaabstrac-tion of peroxidaabstrac-tion reactions.³⁷ This nonenzymatic initiation and propa-gation of lipid peroxidation causes disruption of membranes of subcellular organelles, degrades deoxyribose and amino acids, and yields diene conjugates and fluorescent chromophores.^7,65,95 In-organic iron salts, hematin, and hemoproteins stimulate peroxidation of lipids of microsomes and mitochondria, as well as changing cellular thiodi-sulfide function.⁸⁴ Alkyl hydroxyl and peroxyl species of fatty acids propagate until a termination reaction occurs with a membrane constituent capable of electron donation without formation of a free radical. Such constituents include tocopherol, cho-lesterol, proteins, and the sulfhydryl group of gluta-thione.^2,6,96,113 Histopathological alterations following injection of aqueous iron into neural tissue can be prevented by pretreatment of animals with alpha-tocopherol and selenium, further supporting the

contention that peroxidative reactions are important in trauma-induced brain injury responses.2,96,112,113

Cellular Mechanisms of Epileptogenesis Interictal epileptiform discharges reflect stereo-typed cellular patterns of depolarization shift (PDS).⁷¹ Transition from interictal to ictal discharge is characterized by loss of hyperpolarization and by synchronization of neurons in the focus. Amplifica-tion of excitatory postsynaptic potentials (EPSP) that underlie the PDS may be produced by mechanisms that include withdrawal of inhibition, frequency potentiation of EPSPs, change in the space constant of the dendrites of the postsynaptic neuron, activa-tion of N-methyl-D-aspartate (NMDA) receptors, and potentiation by neuromodulators.²⁶

Biochemical injury to neurons may cause a se-quence of changes ranging from cellular loss with replacement gliosis to subtle alterations in the neu-ronal plasma membrane. Membrane changes ini-tiated by biochemical effects of injury may alter the densities and distribution of ion channels on the neuronal membrane. Alteration of membrane ionotophores could affect Na⁺ and Ca²⁺ currents, alter thresholds, and lead to progressive depolar-ization. Intrinsic cellular bursting may also develop with an increase in extracellular K⁺ or a reduction of extracellular Ca²⁺. Development or recruitment of a critical mass of neurons sufficient to cause clini-cal manifestations requires synchronization of a critical mass of cells.^26,71

The mechanism or critical physiological changes causing posttraumatic epileptogenesis remains un-known. However, several processes may provide useful areas for investigation. Trauma may cause mechanical shearing of fiber tracts with loss of inhibitory interneurons following anterograde trans-synaptic neuronal degeneration.⁸⁰ Trauma-induced release of aspartate or glutamate, with at-tendant activation of NMDA receptors,³¹ elabora-tion of nerve growth factor,⁴⁰ or enhancement of reactive gliosis may be operant as well.⁶⁶ Assessment of hippocampal tissue obtained during surgical re-section for temporal lobe seizures and stained for identification of acetylcholine esterase shows en-hancement of staining in the outer portion of the molecular layer of the dentate gyrus.⁴² Histochemi-cal staining of rodent kindled hippocampus shows abundant mossy fiber synaptic terminals in the

supragranular region and the inner molecular layer of the dentate gyrus.⁸⁵ Expression of the immedi-ate early gene proteins c-Fos, c-Jun, and Zif/268 does not appear to be critical to the development of mossy fiber sprouting.⁶⁴ Although speculative, synaptic reorganization may increase recurrent ex-citation in granule cells, favoring epileptogenesis.

Experimental foci experience the loss of axosomatic GABAergic terminals, as represented by asymmet-ric synapses. The GABAergic peasymmet-ricellular basket plexus that provides tonic inhibition was thought to be sensitive to hypoxia, given the implied depen-dence on aerobic metabolism evidepen-denced by the pres-ence of increased numbers of mitochondria within the altered synapses.⁷⁵ Intrinsic membrane changes with enhanced NMDA synaptic conductances sug-gest a potential mechanism as well.¹³

Genetic and Molecular Factors

Cellular responses to the generation of free radi-cal oxidants following decompartmentalization of hemoglobin- or iron-containing heme compounds may depend upon the induction of protective mechanisms. For example, strains of Escherichia coli may be differentiated observing responses to peroxide. Induction of enzymes to repair DNA damage induced by Fenton-derived free radicals appears to be critical for cellular survival.^15,47 Al-though speculative, sustained membrane changes that are associated with continuing alterations caus-ing focal epileptiform discharges may result from free radical injury to neuronal nuclear or mitochon-drial DNA. Differentiation of the susceptibility to develop epilepsy after a given trauma dose may be related to the ability of repair response induction following initiation of lipid peroxidation.

Specific brain genetic factors that cause a liabil-ity to the development of PTE remain unknown. A possible genetic predisposition has been observed with the detection of decreased levels of serum hap-toglobin in familial epilepsy.⁶⁸ Haptoglobins are acute phase glycoproteins in the alpha-1-globulin fraction of serum that form stable complexes with hemoglobin.⁴³ Since antioxidants such as superox-ide dismutase and peroxidases are not found in high concentration in extracellular fluid, containment of factors that initiate oxidation must depend upon binding of reactive metals to carrier proteins, includ-ing transferrin, lactoferrin, ceruloplasmin, and

hap-Posttraumatic Epilepsy 151

hap-Posttraumatic Epilepsy 151