Post-Traumatic Epilepsy: from Trauma to Therapy

By: Claudio Perino, MD and Silvia Calzoni, MD, TBI Rehabilitation Unit, Ausiliatrice-Don Gnocchi Foundation, Turin, Italy

Traumatic brain injury (TBI)  poses a common and well-recognized risk of developing epilepsy.for over a million people in the United States who experience a TBI each year (Langlois et al., 2006)1. The resulting neurological deficits from open and closed head injury range in severity: from severe paralysis and major mental impairment to a high incidence of behavioral disturbances or post-traumatic stress disorder (PTSD)2. Epilepsy is another neurologic consequence of TBI, and  seizures are reported in up to 50% of survivors (Lowenstein, 2009)3. More importantly, post-traumatic epilepsy (PTE) is a major factor in the inability of survivors of brain injury to return to their preexisting lifestyle and employment2.

Traumatic brain injury (TBI) is a major cause of acquired epilepsy; not surprisingly, the association of epilepsy and head injury has been recognised since antiquity4. In ‘The Edwin Smith Surgical Papirus’, Breasted described patients with skull fractures which developed epilepsy, referring to observations made as far back as 3,000 B.C4. During the Reinassance in Italy, Berengarius da Carpi described a patient with a severe wound of the head who developed  seizures 60 days after the injury. But it was not until Duretus (1527-1586) that we have the first clinical description of posttraumatic epilepsy (PTE). In the modern era, William Spratling noted that TBI was the cause of epilepsy in 6.7% of 1,323 patients who had come under his observation5.

The literature is filled with a variety of definitions for posttraumatic epilepsy.  Therefore, a common set of definitions adopted by many researchers is the following: immediate seizures, which occur less than 24 h after injury;  early seizures, which occur less than 1 week after injury; and  late seizures, which occur more than a week after injury and constitute the diagnosis of posttraumatic epilepsy. The other set of definitions that needs to be accounted for  studies related to posttraumatic epilepsy concerns the degree of head trauma and consequent brain injury. A variety of  classifications can be found in the literature, but many investigators currently use the following: (a) Mild TBI (loss of consciousness less than 30 min and no skull fracture); (b) Moderate TBI (loss of consciousness more than 30 min and less than 24 h, with or without skull fracture); and (c) Severe TBI (loss of consciousness greater than 24 h, with contusion, hematoma, or skull fracture)3.

Epidemiologic studies have found that PTE accounts for approximately 20% of symptomatic epilepsy in the general population, and 5% of all patients seen at specialized epilepsy centers (Agrawal et al., 2006)6. The relative risks (RRs) for developing epilepsy after various brain insults have been summarized in an article published by Susan Herman in Neurology in 2002. This provides an excellent overview of the place of TBI as a risk factor relative to other acquired factors (Herman, 2002)7. Patients with TBI have a 29-fold increased risk of developing epilepsy compared to the general population. This RR is exceeded only by brain tumor (RR = 40) and subarachnoid hemorrhage (RR =34). Not surprisingly, the RR for epilepsy after TBI is strongly related to the severity of head injury—there is a 4-fold increased risk after moderate TBI and only a 1.5-fold increased risk after mild TBI.

Numerous studies have looked at the incidence of early and late posttraumatic seizures in the civilian population.  In population-based studies, the incidence is approximately 2%, whereas in studies of patients admitted to the hospital, the incidence is approximately 10–13%3. Moreover, many clinical studies have provided observations on the type of late seizures developing after TBI, but the data are variable (Haltiner et al., 1997; Diaz-Arrastia et al., 2000)8,9. In one study of 60 patients with moderate to severe TBI, 31 patients developed generalized seizures, 20 had focal seizures, and 9 had focal seizures with secondary generalization (Haltiner et al., 1997). Mesial temporal lobe epilepsy after TBI appears to be relatively uncommon and may have a predilection for children (Mathern et al., 1994)10.

Clinical studies reveal that TBI is one of only a few undisputed examples of epileptogenesis in the human brain. Experimental animal models and human observations have revealed that there is often a ‘‘latent’’ period following the initial insult, during which there are no acute seizures, prior to the eventual emergence of spontaneous seizures. In TBI, the latency can be up to several years (Lowenstein, 2009)3. The existence of a latent period prior to onset of epilepsy raises multiple important issues for diagnosis and treatment in the TBI population. Identification of the cellular and molecular changes involved in the cascade of events leading up to epilepsy might reveal new therapeutic targets. Multiple experimental models are showing that there may be stepwise changes that occur in neuronal network over days to weeks or even months and years following an epileptogenic insult. Early changes include the induction of immediate early genes and post-translational modifications of neurotransmitter receptor and ion channel/transporter proteins (McNamara et al., 2006; Cornejo et al., 2007; Rakhade et al., 2008)11,12,13. Within days, neuronal death, initiation of an inflammatory cascade, and new gene transcription has been reported to occur (Vezzani & Granata, 2005; Scharfman, 2007)14,15. Later changes occurring over days to weeks include morphological changes including axonal sprouting and dendritic modifications, such as mossy fiber sprouting, that is commonly observed as a hallmark of chronic epileptic brain (Dudek& Sutula, 2007)16.

Despite these encouraging observations, there are no pharmacological or nonpharmacological therapies available today that are truly antiepileptogenic. Clinical trials show that treatment with conventional antiepileptic drugs (AEDs) following TBI does not protect against later development of epilepsy (Temkin, 2009)17.

Advances in therapy for TBI will likely arise from a better understanding of the pathophysiological processes triggered by trauma to the central nervous system . Posttraumatic epilepsy is a common and frequently disabling complication of TBI. Because so much is known. about the epidemiology and natural history of posttraumatic epilepsy, it represents a near-ideal clinical model in which to test  antiepileptogenic therapy (D’Ambrosio & Perucca, 2004)18.

Phenytoin (PHT) is the drug that has been most frequently tested for an antiepileptogenic effect. It was first used in the 1940s (Hoff & Hoff, 1947)19, with early trials reporting a positive effect. A meta-analysis of all trials using PHT showed its substantial effect on early seizures, and a lack of positive effect on late seizures (Temkin, 2001)20. Phenobarbital (PB) alone has been evaluated in two studies [(Manaka, 1992)21 and the study by Locke summarized in (Temkin et al., 1996)22]. Confidence intervals are wide and results for late seizures inhibition are not encouraging. Carbamazepine (CBZ) has been evaluated in one study (Glçtzner et al., 1983)23, with results similar to those for PHT (a reduction in early seizures, but no effect on epilepsy even during the period of treatment). Valproate (VPA) has been evaluated in only one study (Temkin et al., 1999)24, and the comparator was 1 week of PHT, making the effect on early seizures difficult to interpret. The early seizure rate was higher on VPA than on PHT, although with the small number of early seizures, the difference is not statistically significant. VPA showed no positive effect on late seizure.

According to our clinical experience, we do not suggest to use PTH or PB in TBI patients with epilepsy, because of their side effects on the central nervous system (i.e. cognitive impairment).  We, alternatively, prefer to use Levetiracetam (LVT) as it tends to have a relatively clean side effect profile, work with both partial and generalized epilepsy, and have minimal drug drug interactions.  That being said, there is still no clear evidence of a single preferred agent to use in PTE based on the available literature.

Finally, little is known about the subjective ictal phenomenology of PTE. In our TBI Rehabilitation Unit, we set out to quantitatively assess the general level of awareness and the subjective contents of consciousness during post-traumatic seizures using the Ictal Consciousness Inventory (ICI)25 scale, a new self-report 20 item specifically developed to quantify the level of general awareness/responsiveness (items 1-10) and the ‘vividness’ of ictal experiential phoenomena (items 11-20) during epileptic seizures. The ICI was performed in 15 patients with PTE, who also underwent MRI, EEG and cognitive and behavioral examinations, which included a clinical interview and psychometric tests. Our initial data suggest the existence of significant differences in ictal alterations of consciousness during epileptic seizures following brain lesions affecting different brain regions. Both the general level of responsiveness and the subjective experiences appear to be stronger in post-traumatic patients with a temporal epileptic focus, compared to patients with a frontal epileptic focus on EEG. These are only preliminary findings, but are potentially relevant to ascertain the impact of different types of PTE on patient’s health-related quality of life.

References

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