Epilepsy after head injury: An overview

Transcription

1 POSTTRAUMATIC EPILEPSY Epilepsia, 50(Suppl. 2): 4 9, 2009 Epilepsy after head injury: An overview Daniel H. Lowenstein Department of Neurology, University of California, San Francisco, California, U.S.A. SUMMARY Traumatic brain injury (TBI) has been recognized as a cause of epilepsy since antiquity, and it remains one of the most common and important causes of acquired epilepsy today. Epidemiologic studies have demonstrated a clear relationship between the severity of injury and the likelihood of developing epilepsy, with the risk approaching 50% in TBI cases associated with direct injury to brain parenchyma. Importantly, many TBI victims develop epilepsy months or years following the initial injury, making this patient population a prime target for the development of antiepileptogenesis therapies. However, progress in this area of clinical research is hindered by the lack of reliable and valid biomarkers. Given current events in the Middle East and elsewhere, the importance of TBI and epilepsy deserves special attention due to the increase in severe head trauma associated with modern warfare. KEY WORDS: Epilepsy, Seizures, Traumatic brain injury, Epileptogenesis, Biomarkers. Epilepsy that develops after traumatic brain injury (TBI) has a number of features that make it particularly deserving of study. First, it is universally recognized as among the most common forms of acquired epilepsies, and patients with posttraumatic epilepsy are a regular part of the care provided by epilepsy specialists, as well as general neurologists and primary care physicians throughout the world. Second, posttraumatic epilepsy can be particularly difficult to treat, both medically and surgically, thereby increasing the burden of the illness on patients and family members. Third, the likelihood of developing epilepsy after severe TBI is as high as 40 50% in some settings. Therefore, patients with significant head injury would derive enormous benefit from antiepileptogenesis therapy, that is, treatment instituted after the TBI that would prevent the subsequent development of epilepsy. Finally, in recent years there have been a number of interesting and potentially important experimental studies of posttraumatic epilepsy using animal models. Given the relative lack of progress in this arena previously, the recent studies finally raise the possibility that a better understanding of the underlying pathogenesis of this important clinical problem may be closer at hand. Address correspondence to Daniel H. Lowenstein, M.D., Box 0114, University of California, San Francisco, CA 94143, U.S.A. lowenstein@medsch.ucsf.edu. Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy This article is meant to provide an overview of posttraumatic epilepsy to help place the articles that follow in this volume into the general context of the clinical problem. I start with a brief discussion of some of the historical observations made about epilepsy following head injury, followed by the definitions commonly used for clinical studies of posttraumatic epilepsy. This is followed by a description of some of the important epidemiologic studies that have identified major risk factors for the development of posttraumatic epilepsy, the clinical types of seizures following TBI, and the limited knowledge of biomarkers for this disease process. Finally, given the importance of TBI in the current conflicts in the Middle East, some of the special considerations of TBI in the setting of war are discussed. Historical Notes Not surprisingly, the association of epilepsy and head injury has been recognized since antiquity. Given the descriptions of skull fractures in the Edwin Smith surgical papyrus, written in the 17th century B.C. but referring to observations made as far back as 3,000 B.C., it is almost certain that patients surviving severe head injury went on to develop epilepsy (Breasted, 1930). Curiously, however, there is no mention of posttraumatic epilepsy among the medical writings at the time of Hippocrates. Temkin, in The Falling Sickness, notes that the Hippocratic physicians observed that seizures in the setting of head injury or surgery were a bad prognostic sign (Temkin, 1945). 4

2 Epilepsy after Head Injury 5 However, in all cases, the writings only describe convulsions within a few days after the injury, and there is no description of chronic seizures. In fact, according to Temkin, it was not until the early Renaissance that clear descriptions of epilepsy following head injury can be found. Berengarius da Carpi, in 1518, described a patient with a severe wound of the head who developed seizures 60 days after the injury. But it was not until Duretus, who lived from , that we have a convincing clinical description of posttraumatic epilepsy: A bone of the skull of a twelve-year old youth had been broken and depressed by a fall and had by negligence not been restored. The brain was therefore hindered in its growth, since the injured bone itself could not grow so as to become able to hold a larger brain. Consequently in his eighteenth year the youth suffered from epilepsy because of the oppression of the brain. He was, however, cured by perforation of the depressed bone, for thus the oppression of the brain was removed. (Temkin, 1945) Given our current understanding of the epidemiology of posttraumatic epilepsy (see below), the fact that this patient had experienced severe head injury, as indicated by the depressed skull fracture with direct impingement on cerebral structures, makes it very likely that his epilepsy was a consequence of the injury. Nonetheless, it appears that brain injury as an important and common cause for epilepsy was underappreciated until the latter part of the 19th century. For example, among the etiologic diagnoses assigned to a group of 67 patients by the French physician Leuret in 1843, identified a fall was identified as the cause in two patients and injuries of the head as the cause in one patient. In contrast, fear was the most common cause and accounted for 35 cases (Temkin, 1945). The observations by William Spratling in his 1904 textbook on epilepsy (Epilepsy and Its Treatment), a document the evolution of thinking about posttraumatic epilepsy in the modern era (Spratling, 1904). Spratling noted that trauma was the cause of epilepsy in 88 (or 6.7%) of 1,323 patients who had come under his observation. Seizures began before age 20 in 73 (83%) of the 88 cases, a fact that perhaps induced the author to add the following editorial comment: Most of the [injuries were] received by the young, whose fear of liability to injury is overbalanced by a lack of judgment and a healthy excess of animal life that leads them into perilous positions. follow TBI) is to be distinguished from repeated seizures in the early stages following TBI. Therefore, a common set of definitions adopted by many researchers is the following: (1) Immediate seizures, which occur less than 24 h after injury; (2) Early seizures, which occur less than 1 week after injury; and (3) 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 in studies related to posttraumatic epilepsy concerns the degree of head trauma. Again, a variety of definitions can be found in the literature, but many investigators currently use the following: (1) Mild TBI (loss of consciousness less than 30 min and no skull fracture); (2) Moderate TBI (loss of consciousness more than 30 min and less than 24 h, with or without skull fracture); and (3) Severe TBI (loss of consciousness greater than 24 h, with contusion, hematoma, or skull fracture). Epidemiology and Risk Factors Epidemiologic studies have found that posttraumatic epilepsy 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). Fig. 1 shows the relative proportion of etiologies identified in a large population-based study out of Rochester, Minnesota, U.S.A., where head trauma was identified as the cause of epilepsy in 6% of the population (Hauser et al., 1993). Consistent with the observations of Spratling mentioned earlier, there are important differences among age groups: Trauma is the cause of epilepsy in almost 30% of individuals who develop epilepsy between ages 15 and 34 years, whereas it is a cause in approximately 14% in children younger than 14 years and 8% in adults older than 65 years (Hauser et al., 1993). In addition, as will be emphasized later, there are substantial differences in incidence when Definitions The literature is filled with a variety of definitions for posttraumatic epilepsy, and this variation must be taken into account when interpreting the results of clinical studies. Nonetheless, most investigators agree that posttraumatic epilepsy (i.e., recurrent, spontaneous seizures that Figure 1. Proportion of incidence cases of epilepsy by etiology in Rochester, Minnesota, U.S.A., (Hauser et al., 1993). Epilepsia ILAE

3 6 D. H. Lowenstein Figure 2. Relative risks for developing epilepsy (adapted from Herman, 2002). Epilepsia ILAE comparing head injuries that occur in civilian populations versus those sustained by combatants in war. The relative risks (RRs) for developing epilepsy after various brain insults have been nicely summarized in an article published by Susan Herman in Neurology in This provides an excellent overview of the place of TBI as a risk factor relative to other acquired factors (Herman, 2002). As shown in Fig. 2, 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. In general, risk factors are thought to be a likely cause for a condition if the RR is greater than 10, whereas the association is considered probable when the RR is between 4 and 10. Numerous studies have looked at the incidence of early and late posttraumatic seizures in the civilian population. The main results from a selection of these studies are shown in Table 1. The studies are heterogeneous in design, including different ages of patients (children vs. adults), different settings (population-based vs. admissions to emergency departments or rehabilitation centers), and different entry criteria (e.g., all forms of TBI vs. only patients with certain Glasgow coma scale ratings and imaging findings). Nonetheless, these investigations provide a general estimate of the incidence of late seizures (i.e., development of epilepsy) in the setting of TBI. In population-based studies, the incidence is approximately 2%, whereas in studies of patients admitted to the hospital, the incidence is approximately 10 13%. In addition, these studies have all helped confirm the observation that the main, critical determinant of the development of posttraumatic epilepsy is the severity of the head injury. Key risk factors included skull fracture, intracranial hematoma, and a depressed level of consciousness at the time of admission to the emergency department. In addition, the occurrence of seizures within the first week after TBI (i.e., early seizures) also appears to be a risk factor for the later development of epilepsy. A closer look at two of the more recent studies investigating the incidence of posttraumatic epilepsy and risk factors is instructive. One of the most carefully done population-based clinical studies is that of Annegers et al., who looked at cases of TBI occurring between 1935 and 1984 and found through the Rochester Epidemiology Project at the Mayo Clinic (Annegers et al., 1998). The authors Table 1. Incidence of early and late posttraumatic seizures in civilian populations (adapted from Garga & Lowenstein, 2006) Study Feature N Early Sz Late Sz Risk factors Jennett & Lewin, 1960 Admitted % 10.2% Early seizure, PTA >24 h, depressed skull fracture, intracranial hematoma Annegers et al., 1980 Population % 1.9% Severe injury, early seizure Desai et al., 1983 Admitted, pediatric % N/A N/A Annegers et al., 1998 Population % 2.1% Severe injury, brain contusion, subdural hematoma, LOC/PTA >24 h Hahn et al., 1988 Admitted, pediatric % N/A N/A Angeleri et al., 1999 Admitted 137 8% 13.1% GCS 3 8, early seizures, single brain CT lesions, EEG focus Asikainen et al., 1999 TBI Rehab Center % 25.3% Early seizures, depressed skull fracture Englander et al., 2003 Admitted with CT findings or GCS % 10.2% Multiple or bilateral cortical contusions, dural penetration, multiple intracranial operations, midline shift >5 mm, evacuated SDH CT, computed tomography; GCS, Glasgow coma scale; LOC, loss of consciousness; N/A, not applicable; PTA, posttraumatic amnesia; SDH, subdural hematoma.

4 Epilepsy after Head Injury 7 identified 4,541 children and adults, and used definitions of TBI and early versus late seizures as summarized earlier. They found that the cumulative probability of unprovoked seizures 5 years after TBI was 0.7% in patients with mild TBI, 1.2% in patients with moderate TBI, and 10.0% in patients with severe TBI. For the cohort with 30 years of follow-up, the cumulative incidence was 2.1% for mild TBI, 4.2% for moderate TBI, and 16.7% for severe TBI. When taking into account the expected incidence of epilepsy in the general population of Rochester, Minnesota, U.S.A., the overall standardized incidence ratio for seizures in the study population was 3.1 [95% confidence interval (CI), ]. However, the ratio was 17.0 (95% CI, ) for severe TBI, and in those patients who developed epilepsy within the first year after injury, the ratio was 95.0 (95% CI, ). Another important finding from this study was that the highest rate ratios for seizures after TBI were associated with the presence of brain contusion or subdural hematoma (with rate ratios ranging from approximately depending on the multivariate model used), compared to rate ratios of 2.2 and lower for other factors such as linear skull fracture, loss of consciousness, posttraumatic amnesia for greater than 24 h, or older age. A second interesting study was published by Englander et al., 2003, in which they prospectively followed 647 patients (age 16 years) admitted to any of four trauma centers within 24 h of injury (Englander et al., 2003). All the patients had significant injury, since the enrollment criteria required computed tomographic (CT) evidence of midline shift, brain compression, focal lesions, or cerebral contusions, or a Glasgow coma scale score of 10. After follow-up of up to 2 years, 66 patients (11%) developed a late, unprovoked seizure. The highest cumulative probability for late seizures included biparietal contusions (66%), dural penetration with bone and metal fragments (63%), multiple intracranial operations (37%), multiple subcortical contusions (33%), subdural hematoma (28%), midline shift >5 mm (26%), and multiple or bilateral contusions (25%). In addition, the authors identified a doseresponse for the number of cerebral contusions and the development of late seizures the cumulative probability of unprovoked seizures by 2 years was approximately 25% for patients with multiple contusions, compared to 8% for a single contusion and 6% for no contusions. Clinical Seizure Types A number of clinical studies have provided observations on the type of late seizures developing after TBI, but the data are variable and no consistent patterns are clear (Haltiner et al., 1997; Diaz-Arrastia et al., 2000; Englander et al., 2003). 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 (although most experienced epileptologists have seen apparent cases) and may have a predilection for children, perhaps related to the increased vulnerability of the hippocampus to TBI in younger patients (Mathern et al., 1994). Biomarkers The identification of reliable biomarkers (i.e., biologic characteristics that can be used to measure the progress of disease or the effects of treatment) for the development of epilepsy after TBI remains one of the holy grails of epilepsy research. This is in large part because patients experiencing moderate or severe TBI are among the very best groups with which to attempt to study antiepileptogenesis therapies, given that the likelihood of developing late seizures is as high as 40 50%, and there is typically a significant delay between the initial head injury and the development of epilepsy. The identification of biomarkers for posttraumatic epilepsy would have a profound effect on the ability to do studies faster and with fewer patients. Unfortunately, progress in this area has been extremely limited. Electroencephalography has, not surprisingly, been shown to be useful for the localization of a seizure focus in patients who develop posttraumatic epilepsy, but it has not proved to be helpful in predicting the development of epilepsy after TBI (Jennett & Van De Sande, 1975). Imaging appears to do somewhat better. CT evidence of acute focal hemorrhagic changes in the brain, which has been considered a criterion for severity of injury in many clinical studies of TBI, is a strong predictor of the development of late seizures (D Alessandro et al., 1982). In addition, the presence of hemosiderin deposits and gliotic scarring, which can be identified by T 2 -weighted magnetic resonance imaging (MRI), may be a predictor of epilepsy as well (Kumar et al., 2003). Special Considerations Related to War Although it is difficult to document fully the evolution of thinking about posttraumatic epilepsy in the 20th century, it appears that the recognition of brain injury as a clear and important cause of epilepsy came from studies of soldiers injured in battle. As shown in Table 2, studies of the consequences of missile injuries to the head from World War I up through conflicts in the Middle East during the 1980s have shown a remarkably consistent pattern in terms of the development of epilepsy after this severe form of TBI (Salazar et al., 1999). Within 5 years after the injury, the incidence of epilepsy ranges from 22 43% (median 34%). In the four studies that have looked at

5 8 D. H. Lowenstein Conflict Table 2. Posttraumatic epilepsy following craniocerebral missile wounds in armed conflicts during the 20th century (adapted from (Salazar et al., 1999) Author(s), year No. of patients Posttraumatic epilepsy (%) 5 years years WW I Credner, WW I Ascroft, WW I Caviness, WW II Russell & Whitty, WW II Walker & Erculei, Korean War Caveness et al., Korean War Taylor & Kretschmann, Vietnam War Caveness et al., Vietnam War Salazar et al., 1985, Iran Iraq Aarabi, Lebanon Brandvold et al., the development of epilepsy by 10 years or more after the injury (with combined observations on 3,066 soldiers), the incidence is almost exactly 50% in all the studies. This pattern of increased incidence over time is wellrecognized and consistent with observations in civilian populations as well. Most studies show that the majority of patients who go on to develop epilepsy after TBI will do so within 1 year of the injury, although, as indicated by the data in Table 2, there are a significant number of patients who manifest their first seizure more than 5 and sometimes more than 10 years after the injury. To put these data into further perspective, the study by Salazar and colleagues of the development of epilepsy in 520 Vietnam War veterans found that the RR compared to the normal population was 520 (coincidentally, the same number as the number of patients) in the first year after injury, 90 at 2 5 years, 36 at 5 10 years, and 25 at years (Salazar et al., 1987). These observations raise great concern about the longterm neurologic consequences of the current conflicts in Iraq and Afghanistan. The primary mechanism of trauma in the Iraq war, to both combatants and civilians, is blast injury due to weapons such as improvised explosive devices, grenades, mortars, and land mines. Because of the use of body armor, which protects the thorax and abdomen of the soldiers, injuries of the head, neck, and extremity are the main reasons for evacuation, disability, and death, and TBI is considered the signature injury of the current conflict. In fact, head and neck injuries, including severe TBI, have been reported in approximately 25% of U.S. soldiers who have served in Iraq and Afghanistan (Okie, 2005; Xydakis et al., 2005). The exact number of individuals with severe brain injury is unknown, but is likely to be in the many thousands for the following reasons. First, the number of soldiers who survive injury is higher than in any previous war. In World War II the survival death ratio was 1.6; in Vietnam it was 2.8; and in the current war it is 7.0 (Stiglitz & Bilmes, 2008). Therefore, in addition to the almost 4,000 American troops who have died, at least 67,000 have been injured, of which 45,000 have injuries directly attributable to the conflict. Second, more than 263,000 veterans have already been treated at veterans medical facilities to date, and many of these veterans are seeking help for neurologic and psychiatric conditions (Stiglitz & Bilmes, 2008). Finally, a recent study found that, of 2,525 infantry soldiers who had been in active combat in Iraq, approximately 15% reported injuries with loss of consciousness or altered mental status (Hoge et al., 2008). Given that hundreds of thousands of soldiers have been exposed to combat conditions in Iraq and Afghanistan, all of these observations suggest that the number of soldiers surviving with severe TBI must be substantial. And the extent of TBI among Iraqi and Afghani civilians, many of whom have been exposed to similar forms of blast injury, is, at the moment, incalculable. Conclusions TBI is a common and well-recognized cause of epilepsy. Civilian patients who experience severe TBI have up to a 30-fold increased incidence of epilepsy compared to the general population, and the risks are even higher among soldiers exposed to missile and blast injuries. There is often a delay in the emergence of chronic seizures after the initial injury, which creates an exceptional opportunity for intervention with antiepileptogenesis therapies once they have been developed. To this end, there is a great need for the identification of biomarkers that provide quantitative measures of the process of posttraumatic epileptogenesis and predict which TBI patients are likely to develop epilepsy. Finally, TBI is the signature injury of the current conflicts in the Middle East, and it seems likely that many cases of epilepsy will arise in soldiers and civilians as a result of these wars. Acknowledgment Disclosure: The author declares no conflicts of interest. References Aarabi B. 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