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Intractable epilepsy and craniocerebral trauma: Analysis of 163 patients with blunt and penetrating head injuries sustained in war
Injury, Int. J. Care Injured 43 (2012) 2132–2135
Contents lists available at SciVerse ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Intractable epilepsy and craniocerebral trauma: Analysis of 163 patients with blunt and penetrating head injuries sustained in war Hadi Kazemi a,b, Sohrab Hashemi-Fesharaki a, Soodeh Razaghi a, Masomeh Najafi a, Peir Hossein Kolivand a, Stjepana Kovac c, Ali Gorji a,d,* a
Shefa Neuroscience Research Center, Tehran, Iran Pediatric Department, Shahed University, Tehran, Iran Klinik und Poliklinik fu¨r Neurologie, Universita¨tsklinikum Mu¨nster, Mu¨nster, Germany d Institut fu¨r Physiologie I, Westfalische Wilhelms-Universita¨t Mu¨nster, Mu¨nster, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 12 June 2012
Post-traumatic epileptic seizure is a common complication of brain trauma including military injuries. We present clinical characteristics and correlates of post-traumatic epilepsy in 163 head-injured veterans suffering from intractable epilepsy due to blunt or penetrating head injuries sustained during the Iraq–Iran war. The medical records of 163 war veterans who were admitted by the Epilepsy Department of the Shefa Neuroscience Center between 2005 and 2009 were retrospectively reviewed. The mean follow-up period after developing epilepsy was 17.2 years. The time interval between the trauma and the first seizure was shorter and the seizure frequency was higher in epileptic patients suffering from penetrating head trauma. There was no difference in seizure type between epileptic patients traumatised by blunt or penetrating injury. Patients with seizure frequency of more than 30 per month mostly had simple partial seizure. Frontal and parietal semiologies were observed more frequently in patients with penetrating trauma, whereas patients with blunt trauma showed a higher temporal semiology. The most common brain lesion observed by CT scan was encephalomalacia followed by porencephaly and focal atrophy. There was no association between intracerebral retained fragments and different characteristic features of epilepsy. Patients with military brain injury carry a high risk of intractable post-traumatic epilepsy decades after their injury, and thus require a long-term medical follow-up. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: Gunshot injury Seizure Metal fragments Refractory epilepsy
Introduction The relation of epilepsy and head trauma has been recognised for several centuries.1 Post-traumatic epilepsy refers to a recurrent seizure disorder, the cause of which is believed to be a traumatic brain injury. Studies have found that the incidence of posttraumatic epilepsy ranges between 1.9 to more than 30%, varying by severity of injury and by the amount of time the studies followed patients’ trauma.2 Seizures may develop immediately after a brain injury or may occur months or years after the initial trauma. Overall, 5% of all cases of epilepsy are attributable to head injury.3 Post-traumatic epilepsy is most likely to occur after a penetrating injury, though on occasion, it can follow a blunt head injury. Within the first year after head trauma the incidence of
* Corresponding author at: Institut fu¨r Physiologie I, Universita¨t Mu¨nster, RobertKoch-Strasse 27a, D-48149 Mu¨nster, Germany. Tel.: +49 251 8355564; fax: +49 251 8355551. E-mail address: [email protected] (A. Gorji). 0020–1383/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.injury.2012.06.007
seizures exceeds 12 times the population risk.4 Predictive factors associated with epilepsy risk are missile wound with dural penetration, parietal lobe trauma, single temporal or frontal lesions revealed in brain CT, occurrence of early seizure, and presence of an intracerebral haematoma. Other risk factors associated with epilepsy include prolonged post-traumatic amnesia, brain tissue loss, and retained metal fragments.4,5 The heterogeneity of injuries in brain trauma sustained during war has made it difficult to interpret results of clinical studies with respect to intervention and prevention of epilepsy. Epilepsy due to military brain injury tends to become less frequent in Western countries in the last 20–30 years. However, the number of epileptic patients with military brain injuries increased in the Middle East due to several wars in the last two decades. There are several hundred patients who survived head injuries during the Iraq–Iran war (1980–1988) and on whom detailed medical and follow-up data are available. In spite of treatment with modern antiepileptic drugs, some of these patients developed intractable epilepsy. This population offers unique opportunities for the study of long-term effects of different prognostic factors that might have influenced
H. Kazemi et al. / Injury, Int. J. Care Injured 43 (2012) 2132–2135
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Table 1 General characteristics of the 163 patients suffering from penetrating or blunt post-traumatic medically intractable epilepsy. Variables
Blunt trauma (n = 97)
Penetrating trauma (n = 66)
P value
Age (years) Time since injury (years) Duration between trauma and refractory epilepsy (years) Duration of suffering refractory epilepsy (years) Seizure frequency (per month) Loss of consciousness (days)
42.3 19.1 2.3 16.8 8.3 20.2
42.0 20.0 1.5 18.5 13.7 41.0
0.90 0.84 0.59 0.29 0.02 0.001
the occurrence and persistence of the post-traumatic epilepsy after penetrating or blunt head injuries sustained during war. Materials and methods Medical records of 163 war veterans with post-traumatic intractable epilepsy (blunt or penetrating trauma) who were admitted by the Epilepsy Department of the Shefa Neuroscience Center in Khatam Hospital (a veteran hospital) during 2005–2009 were retrospectively reviewed. This centre is the only institute for the management of intractable epilepsy patients with head injuries sustained during war. Closed head injuries are injuries in which nothing penetrates the skull. An open head injury is one where the skull is penetrated by an object, as occurs in a gunshot or shrapnel wound. Patients with any risk factor such as a first-degree family history of epilepsy, a history of epilepsy prior to injury, or a history of being exposed to potential confounding factors (i.e. brain tumours or chemical warfare agents) apart from trauma for epilepsy were excluded from the study. A clinical profile was established for each patient that included gender, age at trauma, type of trauma, duration of unconsciousness after trauma, the localisation of shrapnel fragments in the brain (if present), history of cranial surgery, neuropsychological parameters, type of epilepsy, characteristics of the seizures (such as the time interval between trauma and the first unprovoked seizure attack, seizure type, frequency, aura, seizure-related injuries, trigger factors, and anti-epileptic drugs), duration of epilepsy, epilepsy semiology, length of follow-up, and the results of EEG, CT scan, and X-ray. All patients had epileptiform EEG. Patients with psychogenic seizures were excluded. All X-ray and CT scans were initially described by a neuro-radiologist. EEGs were reviewed by a neurologist for the purpose of the present study. All patients received 2–6 different antiepileptic drugs and serum levels for these drugs were measured. Penetrating brain injuries were localised by cerebral topography. Intractable epilepsy was defined as failure to control epilepsy by at least two first-line antiepileptic drugs, with a seizure frequency of at least one per month for 18 months. The Mann–Whitney rank-sum test was used to compare continuous variables. Chi-square test was used to compare proportions and correction for continuity was performed (Yates’ correction). Patient data are presented as mean standard deviation (SD). The results were considered statistically significant at a probability level <0.05. All statistical analyses were performed using the statistical software SPSS for windows, version 14.0 (SPSS Inc., Chicago, IL, USA). The study was approved by the Ethics Committee of Shefa Neuroscience Center, Tehran, Iran (S-1023–11) and informed consent was obtained from all patients.
(SD (SD (SD (SD (SD (SD
7.2) 4.6) 1.6) 6.2) 4.4) 10.2)
epilepsy. The extent of neurological deficits due to refractory epilepsies induced by penetrating (n = 53) or blunt (n = 37) injuries are presented in Table 2. Among neurological outcomes, hemiparesis (P = 0.04) was correlated with seizure in patients with penetrating trauma. Psychological disorders (including depression, anxiety, etc.) were observed in 12 epileptic patients with penetrating trauma and in 10 patients with blunt trauma. Entrance region of penetrating trauma was parietal (n = 32), temporal (n = 18), frontal (n = 9), and occipital (n = 7). The region of the blunt trauma was frontal (n = 38), parietal (n = 29), temporal (n = 19), or occipital (n = 11). First unprovoked seizure occurred earlier in patients with penetrating trauma. Seventy-eight and twenty-two percent of patients with penetrating trauma experienced their first seizure during the first year and one year after the trauma, respectively. Only 38% of patient with blunt trauma and epilepsy, however, reported their first seizure during the first year of the trauma. The seizure frequency was significantly higher in epileptic patients with penetrating trauma (P = 0.02). In addition, the duration of unconsciousness was significantly longer in patients with penetrating head trauma (P = 0.01). There was also a significant correlation between seizure type and seizure frequency (P = 0.046). Simple partial seizures and complex partial seizures were accompanied with higher seizure frequencies (more than 30 attacks per month). Tonic–clonic seizures were more often observed in patients with lower seizure frequencies (Fig. 1). There was no difference in seizure type between epileptic patients traumatised by blunt or penetrating injury. Thirty percent of patients with epilepsy were suffering from tonic–clonic seizure activity. About 27% of patients had simple or partial seizures and 43% of patients had simple or partial seizures with secondary generalisation. Patients with seizure frequency of more than 30 per month more frequently had simple partial seizures (P = 0.03). In addition, simple partial seizures were often associated with frontal semiology, while complex partial seizures were associated with temporal semiology. Ictal semiologies of both blunt and penetrating trauma groups are presented in Table 3. There was a trend towards different ictal semiologies depending on the type of trauma, i.e. blunt or penetrating (P = 0.08). Parietal semiology was observed more frequently in patients with penetrating trauma, whereas patients with blunt trauma showed higher temporal and frontal semiologies. Interestingly, there was no significant
Table 2 Neurological deficits of the 163 patients suffering from penetrating or blunt posttraumatic refractory epilepsy. Neurological deficits
Blunt trauma Number of patients (percentage of total 97 patients)
Penetrating trauma Number of patients (percentage of total 66 patients)
P value
Hemiplegia Hemiparesis Aphasia Hemianopsia Facial paresis Paraplegia
8 4 12 5 10 0
28 11 16 7 10 4
0.08 0.04 0.70 0.68 1 –
Results Demographic and clinical data for the 163 patients suffering from intractable epilepsy due to blunt (n = 97) or penetrating (n = 66) head injuries sustained during the Iraq–Iran war (1980– 88) are presented in Table 1. All patients were male veterans. The mean follow-up period was 17.2 years (range: 5–24) after onset of
(SD 6.9) (SD 5.4) (SD 1.2) (SD7.9) (SD 9.9) (SD 29.0)
(8.2%) (4.1%) (12.4%) (5.2%) (10.3%)
(42.4%) (16.7%) (24.2%) (10.6%) (15.2%) (6.1%)
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Fig. 1. Metal fragments from shrapnel within brain tissue obtained from three different patients with intractable epilepsy. A: Multiple shrapnel fragments were observed in lateral skull X-ray in the brain. B: CT scan showing left-sided porencephaly after penetrating head trauma. C: CT scan shows left-sided encephalomalacia after penetrating head trauma.
correlation observed between ictal semiology and the site of retained shrapnel fragments (P = 0.70). There were no significant differences in seizure frequency between patients that were not operated vs. patients who underwent an operation from both groups (P = 0.35). However, there was a significant difference in duration of unconsciousness in these two groups of patients. Patients with cranial operation suffered a longer loss of consciousness [35.6 (SD 20.6) days vs. 16.5 (SD 10.5) days, P = 0.003]. Longer loss of consciousness association with surgery may be confounded by severity of injury and complications after craniotomy, such as haematoma and brain oedema. Different brain lesions were observed by CT scans. The most common brain lesions observed by CT scan was encephalomalacia, porencephaly, and focal atrophy. Encephalomalacia refers to the formation of cystic cavities of various sizes in the cerebral cortex due to head trauma.6 Encephalomalacia and porencephaly were observed more frequently in patient with penetrating trauma. Sixty-one percent of patients with penetrating trauma (40 patients from 66 patients) and 23% of patients with blunt trauma (22 patients from 97 patients) had imaging evidence of encephalomalacia and porencephaly. These lesions did not have any significant correlation with seizure frequency (P = 0.62). However, there was a significant relationship between encephalomalacia and porencephaly with the duration of loss of consciousness (P = 0.04) and ictal semiology (P = 0.02).
Discussion Posttraumatic epilepsy, the most common cause of new-onset epilepsy in young people, is often refractory to medical therapy.7 Head trauma is the cause of epilepsy in approximately 5% of patients referred to specialised epilepsy centres.8 About 75% of patients with cranial trauma during Iraq–Iran war suffered from persistent seizure.9 This rate seems to be higher than figures reported for previous wars (World War I, 38%; World War II, 34%;
Table 3 Ictal semiology of the 163 patients suffering from penetrating or blunt posttraumatic refractory epilepsy. Ictal semiology
Blunt trauma Number of patients (percentage of total 97 patients)
Penetrating trauma Number of patients (percentage of total 66 patients)
Frontal Parietal Temporal Occipital Generalised/non-localising
29 13 26 2 27
15 25 10 4 12
(29.9%) (13.4%) (26.8%) (2.1%) (27.8%)
(22.7%) (37.9%) (15.1%) (6.1%) (18.2%)
Korea, 36.5%; Vietnam, 53%).10 A possible explanation of this discrepancy may include the longer follow-up and inclusion of patients with injuries so severe that they would not have survived in previous wars. Another possible cause may be the involvement of more complex weapons in this war. In the present study, patients with penetrating trauma experienced their first seizure attacks earlier and with a higher rate of porencephaly and encephalomalacia compared to patients suffering from blunt trauma. The most reliable predictors of seizure risk include the time elapsed after a head injury and the severity of the injury, as manifested by estimated lesion size and neurological findings.10,11 Our findings confirm the validity of this, since patients with penetrating trauma suffered from a higher frequency of seizure attacks. The type of seizure has been reported as an important predictor of response to the treatment of post-traumatic epilepsy. Our data show partial simple and partial complex seizures in about 70% of the patients with refractory epilepsy induced by head trauma. In addition, patients with more than 30 seizure attacks per month also suffered from different types of partial seizures. Persistent seizures were also more common in patients with partial simple and partial complex seizures due to military head injuries during the Vietnam War. These patients also had significantly higher seizure frequencies.10 Retained metal fragments have been reported to have a significant correlation with seizure in 421 veterans who had penetrating brain wounds.10 In contradiction to this finding, other groups did not find any association between intracerebral-retained fragments and enhancement of immediate or late complications, including epilepsy.12,13 The suggested therapy for foreign bodies in missile head-wounded patients ranged from no surgical intervention to craniotomy and aggressive debridement of all necrotic brain tissue, haematoma, and in-driven bone and metal fragments.14,15 Aggressive intracranial debridements are, however, associated with a higher degree of neurological deficit, including the possibility of converting a transient deficit to a permanent one.16 It has been reported that no surgical treatment or simple repair of the scalp wounds, leaving behind some or all the in-driven bone and shell fragments, did not increase the risk for epilepsy.12,17 Our data also support these results as there was no association between location of the fragments and ictal semiology of the patients. In addition, we did not find any differences in seizure frequency between patients that were not operated vs. patients who underwent an operation. In the present study, a common imaging finding was porencephaly. Total brain volume loss on CT had a significant correlation with seizure in other investigations.10 The most common imaging abnormality in these patients was encephalomalacia. Encephalomalacia resulting from destructive brain injury
H. Kazemi et al. / Injury, Int. J. Care Injured 43 (2012) 2132–2135
is a lesion known for its potential epileptogenicity and for its association with intractable epilepsy.18 Diffuse encephalomalacia and widespread change in the white matter due to traumatic injuries were identified as indicators of significant rotational stresses on cerebral matter that might impact the function of the brain. It was suggested that subtle changes remote from the site of predominant injury must remain to be considered a probable epileptogenic focus.19 Traumatic brain injuries elicit complex neuropathology, involving both inflammatory cascades and diffuse neuronal degeneration. Localising neutrophils along blood vessels in the traumatic area may lead to a blood–brain barrier breakdown and further neuronal damage.20 Indeed, resection of encephalomalacia is reported as a very effective treatment of intractable epilepsy.21,22 The difficulty of accurately localising post-traumatic epileptogenic foci was demonstrated.23 Using MR is contraindicated in the case of intracranial metallic bodies, because of the potential risk for migration and further injuries. However, using other techniques such as SPECT and PET could help to localise the epileptic foci for further resection with minimal brain loss in these patients. In spite of substantial progress over the past few decades in the diagnosis and treatment of the epilepsies, posttraumatic intractable epilepsy is a major health problem in patients with military head injury. Patients traumatised by blunt or penetrating military brain injury carry a high risk of intractable post-traumatic epilepsy decades after their injury, and thus require a long-term medical follow-up. Further studies are needed to develop new strategies for treatment of these patients in both acute and chronic stages after the head injury.
Conflict of interest There is no conflict of interest. References 1. Gorji A, Khaleghi Ghadiri M. History of epilepsy in medieval Iranian medicine. Neuroscience and Biobehavioral Reviews 2001;25:455–61. 2. D’Ambrosio R, Perucca E. Epilepsy after head injury. Current Opinion in Neurology 2004;17:731–5. 3. Langendorf F, Pedley TA. Post-traumatic seizures. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven Publishers; 1997. p. 2469–74. 4. Willmore LJ. Posttraumatic epilepsy. Neurologic Clinics 1992;10:869–78.
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5. Angeleri F, Majkowski J, Cacchio` G, Sobieszek A, D’Acunto S, Gesuita R, et al. Posttraumatic epilepsy risk factors: one-year prospective study after head injury. Epilepsia 1999;40:1222–30. 6. Weidenheim KM, Bodhireddy SR, Nuovo GJ, Nelson SJ, Dickson DW. Multicystic encephalopathy: review of eight cases with etiologic considerations. Journal of Neuropathology and Experimental Neurology 1995;54:268–75. 7. Annegers JF. The epidemiology of epilepsy. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore, MD: Williams & Wilkins; 1996. p. 165–72. 8. Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51:1256–62. 9. Eftekhar B, Sahraian MA, Nouralishahi B, Khaji A, Vahabi Z, Ghodsi M. Prognostic factors in the persistence of posttraumatic epilepsy after penetrating head injuries sustained in war. Journal of Neurosurgery 2009;110:319–26. 10. Salazar AM, Jabbari B, Vance SC, Grafman J, Amin D, Dillon JD. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology 1985;35:1406–14. 11. Wiedemayer H, Triesch K, Scha¨fer H, Stolke D. Early seizures following nonpenetrating traumatic brain injury in adults: risk factors and clinical significance. Brain Injury 2002;16:323–30. 12. Chaudhri KA, Choudhury AR, al Moutaery KR, Cybulski GR. Penetrating craniocerebral shrapnel injuries during ‘‘Operation Desert Storm’’: early results of a conservative surgical treatment. Acta Neurochirurgica 1994;126:120–3. 13. Levi L, Borovich B, Guilburd JN, Grushkiewicz I, Lemberger A, Linn S, et al. Wartime neurosurgical experience in Lebanon, 1982–85. I. Penetrating craniocerebral injuries. Israel Journal of Medical Sciences 1990;26:548–54. 14. Ascorf PB. Treatment of head wounds due to missiles. Analysis of 500 cases. Lancet 1943;2:211–8. 15. Splavski B, Vrankovic D, Saric G, Saftic´ R, Maksimovic´ Z, Bajek G, et al. Early surgery and other indicators influencing the outcome of war missile skull base injuries. Surgical Neurology 1998;50:194–9. 16. Brandvold B, Levi L, Feinsod M, George ED. Penetrating craniocerebral injuries in the Israeli involvement in the Lebanese conflict, 1982–1985. Analysis of a less aggressive surgical approach. Journal of Neurosurgery 1990;72:15–21. 17. Amirjamshidi A, Abbassioun K, Rahmat H. Minimal debridement or simple wound closure as the only surgical treatment in war victims with low-velocity penetrating head injuries. Indications and management protocol based upon more than 8 years follow-up of 99 cases from Iran–Iraq conflict. Surgical Neurology 2003;60:105–10. 18. Foerster O, Penfield W. The structural basis of traumatic epilepsy and results of radical operation. Brain 1930;53:99–119. 19. Hartzfeld P, Elisevich K, Pace M, Smith B, Gutierrez JA. Characteristics and surgical outcomes for medial temporal post-traumatic epilepsy. British Journal of Neurosurgery 2008;22:224–30. 20. Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. Journal of Neuroscience 1995;15:8223–33. 21. Cukiert A, Olivier A, Andermann F. Posttraumatic frontal lobe epilepsy with structural changes: excellent results after cortical resection. Canadian Journal of Neurological Sciences 1996;23:114–7. 22. Kazemi NJ, So EL, Mosewich RK, O’Brien TJ, Cascino GD, Trenerry MR, et al. Resection of frontal encephalomalacias for intractable epilepsy: outcome and prognostic factors. Epilepsia 1997;38:670–7. 23. Marks DA, Kim J, Spencer DD, Spencer SS. Seizure localization and pathology following head injury in patients with uncontrolled epilepsy. Neurology 1995;45:2051–7.
Contents lists available at SciVerse ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Intractable epilepsy and craniocerebral trauma: Analysis of 163 patients with blunt and penetrating head injuries sustained in war Hadi Kazemi a,b, Sohrab Hashemi-Fesharaki a, Soodeh Razaghi a, Masomeh Najafi a, Peir Hossein Kolivand a, Stjepana Kovac c, Ali Gorji a,d,* a
Shefa Neuroscience Research Center, Tehran, Iran Pediatric Department, Shahed University, Tehran, Iran Klinik und Poliklinik fu¨r Neurologie, Universita¨tsklinikum Mu¨nster, Mu¨nster, Germany d Institut fu¨r Physiologie I, Westfalische Wilhelms-Universita¨t Mu¨nster, Mu¨nster, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 12 June 2012
Post-traumatic epileptic seizure is a common complication of brain trauma including military injuries. We present clinical characteristics and correlates of post-traumatic epilepsy in 163 head-injured veterans suffering from intractable epilepsy due to blunt or penetrating head injuries sustained during the Iraq–Iran war. The medical records of 163 war veterans who were admitted by the Epilepsy Department of the Shefa Neuroscience Center between 2005 and 2009 were retrospectively reviewed. The mean follow-up period after developing epilepsy was 17.2 years. The time interval between the trauma and the first seizure was shorter and the seizure frequency was higher in epileptic patients suffering from penetrating head trauma. There was no difference in seizure type between epileptic patients traumatised by blunt or penetrating injury. Patients with seizure frequency of more than 30 per month mostly had simple partial seizure. Frontal and parietal semiologies were observed more frequently in patients with penetrating trauma, whereas patients with blunt trauma showed a higher temporal semiology. The most common brain lesion observed by CT scan was encephalomalacia followed by porencephaly and focal atrophy. There was no association between intracerebral retained fragments and different characteristic features of epilepsy. Patients with military brain injury carry a high risk of intractable post-traumatic epilepsy decades after their injury, and thus require a long-term medical follow-up. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: Gunshot injury Seizure Metal fragments Refractory epilepsy
Introduction The relation of epilepsy and head trauma has been recognised for several centuries.1 Post-traumatic epilepsy refers to a recurrent seizure disorder, the cause of which is believed to be a traumatic brain injury. Studies have found that the incidence of posttraumatic epilepsy ranges between 1.9 to more than 30%, varying by severity of injury and by the amount of time the studies followed patients’ trauma.2 Seizures may develop immediately after a brain injury or may occur months or years after the initial trauma. Overall, 5% of all cases of epilepsy are attributable to head injury.3 Post-traumatic epilepsy is most likely to occur after a penetrating injury, though on occasion, it can follow a blunt head injury. Within the first year after head trauma the incidence of
* Corresponding author at: Institut fu¨r Physiologie I, Universita¨t Mu¨nster, RobertKoch-Strasse 27a, D-48149 Mu¨nster, Germany. Tel.: +49 251 8355564; fax: +49 251 8355551. E-mail address: [email protected] (A. Gorji). 0020–1383/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.injury.2012.06.007
seizures exceeds 12 times the population risk.4 Predictive factors associated with epilepsy risk are missile wound with dural penetration, parietal lobe trauma, single temporal or frontal lesions revealed in brain CT, occurrence of early seizure, and presence of an intracerebral haematoma. Other risk factors associated with epilepsy include prolonged post-traumatic amnesia, brain tissue loss, and retained metal fragments.4,5 The heterogeneity of injuries in brain trauma sustained during war has made it difficult to interpret results of clinical studies with respect to intervention and prevention of epilepsy. Epilepsy due to military brain injury tends to become less frequent in Western countries in the last 20–30 years. However, the number of epileptic patients with military brain injuries increased in the Middle East due to several wars in the last two decades. There are several hundred patients who survived head injuries during the Iraq–Iran war (1980–1988) and on whom detailed medical and follow-up data are available. In spite of treatment with modern antiepileptic drugs, some of these patients developed intractable epilepsy. This population offers unique opportunities for the study of long-term effects of different prognostic factors that might have influenced
H. Kazemi et al. / Injury, Int. J. Care Injured 43 (2012) 2132–2135
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Table 1 General characteristics of the 163 patients suffering from penetrating or blunt post-traumatic medically intractable epilepsy. Variables
Blunt trauma (n = 97)
Penetrating trauma (n = 66)
P value
Age (years) Time since injury (years) Duration between trauma and refractory epilepsy (years) Duration of suffering refractory epilepsy (years) Seizure frequency (per month) Loss of consciousness (days)
42.3 19.1 2.3 16.8 8.3 20.2
42.0 20.0 1.5 18.5 13.7 41.0
0.90 0.84 0.59 0.29 0.02 0.001
the occurrence and persistence of the post-traumatic epilepsy after penetrating or blunt head injuries sustained during war. Materials and methods Medical records of 163 war veterans with post-traumatic intractable epilepsy (blunt or penetrating trauma) who were admitted by the Epilepsy Department of the Shefa Neuroscience Center in Khatam Hospital (a veteran hospital) during 2005–2009 were retrospectively reviewed. This centre is the only institute for the management of intractable epilepsy patients with head injuries sustained during war. Closed head injuries are injuries in which nothing penetrates the skull. An open head injury is one where the skull is penetrated by an object, as occurs in a gunshot or shrapnel wound. Patients with any risk factor such as a first-degree family history of epilepsy, a history of epilepsy prior to injury, or a history of being exposed to potential confounding factors (i.e. brain tumours or chemical warfare agents) apart from trauma for epilepsy were excluded from the study. A clinical profile was established for each patient that included gender, age at trauma, type of trauma, duration of unconsciousness after trauma, the localisation of shrapnel fragments in the brain (if present), history of cranial surgery, neuropsychological parameters, type of epilepsy, characteristics of the seizures (such as the time interval between trauma and the first unprovoked seizure attack, seizure type, frequency, aura, seizure-related injuries, trigger factors, and anti-epileptic drugs), duration of epilepsy, epilepsy semiology, length of follow-up, and the results of EEG, CT scan, and X-ray. All patients had epileptiform EEG. Patients with psychogenic seizures were excluded. All X-ray and CT scans were initially described by a neuro-radiologist. EEGs were reviewed by a neurologist for the purpose of the present study. All patients received 2–6 different antiepileptic drugs and serum levels for these drugs were measured. Penetrating brain injuries were localised by cerebral topography. Intractable epilepsy was defined as failure to control epilepsy by at least two first-line antiepileptic drugs, with a seizure frequency of at least one per month for 18 months. The Mann–Whitney rank-sum test was used to compare continuous variables. Chi-square test was used to compare proportions and correction for continuity was performed (Yates’ correction). Patient data are presented as mean standard deviation (SD). The results were considered statistically significant at a probability level <0.05. All statistical analyses were performed using the statistical software SPSS for windows, version 14.0 (SPSS Inc., Chicago, IL, USA). The study was approved by the Ethics Committee of Shefa Neuroscience Center, Tehran, Iran (S-1023–11) and informed consent was obtained from all patients.
(SD (SD (SD (SD (SD (SD
7.2) 4.6) 1.6) 6.2) 4.4) 10.2)
epilepsy. The extent of neurological deficits due to refractory epilepsies induced by penetrating (n = 53) or blunt (n = 37) injuries are presented in Table 2. Among neurological outcomes, hemiparesis (P = 0.04) was correlated with seizure in patients with penetrating trauma. Psychological disorders (including depression, anxiety, etc.) were observed in 12 epileptic patients with penetrating trauma and in 10 patients with blunt trauma. Entrance region of penetrating trauma was parietal (n = 32), temporal (n = 18), frontal (n = 9), and occipital (n = 7). The region of the blunt trauma was frontal (n = 38), parietal (n = 29), temporal (n = 19), or occipital (n = 11). First unprovoked seizure occurred earlier in patients with penetrating trauma. Seventy-eight and twenty-two percent of patients with penetrating trauma experienced their first seizure during the first year and one year after the trauma, respectively. Only 38% of patient with blunt trauma and epilepsy, however, reported their first seizure during the first year of the trauma. The seizure frequency was significantly higher in epileptic patients with penetrating trauma (P = 0.02). In addition, the duration of unconsciousness was significantly longer in patients with penetrating head trauma (P = 0.01). There was also a significant correlation between seizure type and seizure frequency (P = 0.046). Simple partial seizures and complex partial seizures were accompanied with higher seizure frequencies (more than 30 attacks per month). Tonic–clonic seizures were more often observed in patients with lower seizure frequencies (Fig. 1). There was no difference in seizure type between epileptic patients traumatised by blunt or penetrating injury. Thirty percent of patients with epilepsy were suffering from tonic–clonic seizure activity. About 27% of patients had simple or partial seizures and 43% of patients had simple or partial seizures with secondary generalisation. Patients with seizure frequency of more than 30 per month more frequently had simple partial seizures (P = 0.03). In addition, simple partial seizures were often associated with frontal semiology, while complex partial seizures were associated with temporal semiology. Ictal semiologies of both blunt and penetrating trauma groups are presented in Table 3. There was a trend towards different ictal semiologies depending on the type of trauma, i.e. blunt or penetrating (P = 0.08). Parietal semiology was observed more frequently in patients with penetrating trauma, whereas patients with blunt trauma showed higher temporal and frontal semiologies. Interestingly, there was no significant
Table 2 Neurological deficits of the 163 patients suffering from penetrating or blunt posttraumatic refractory epilepsy. Neurological deficits
Blunt trauma Number of patients (percentage of total 97 patients)
Penetrating trauma Number of patients (percentage of total 66 patients)
P value
Hemiplegia Hemiparesis Aphasia Hemianopsia Facial paresis Paraplegia
8 4 12 5 10 0
28 11 16 7 10 4
0.08 0.04 0.70 0.68 1 –
Results Demographic and clinical data for the 163 patients suffering from intractable epilepsy due to blunt (n = 97) or penetrating (n = 66) head injuries sustained during the Iraq–Iran war (1980– 88) are presented in Table 1. All patients were male veterans. The mean follow-up period was 17.2 years (range: 5–24) after onset of
(SD 6.9) (SD 5.4) (SD 1.2) (SD7.9) (SD 9.9) (SD 29.0)
(8.2%) (4.1%) (12.4%) (5.2%) (10.3%)
(42.4%) (16.7%) (24.2%) (10.6%) (15.2%) (6.1%)
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Fig. 1. Metal fragments from shrapnel within brain tissue obtained from three different patients with intractable epilepsy. A: Multiple shrapnel fragments were observed in lateral skull X-ray in the brain. B: CT scan showing left-sided porencephaly after penetrating head trauma. C: CT scan shows left-sided encephalomalacia after penetrating head trauma.
correlation observed between ictal semiology and the site of retained shrapnel fragments (P = 0.70). There were no significant differences in seizure frequency between patients that were not operated vs. patients who underwent an operation from both groups (P = 0.35). However, there was a significant difference in duration of unconsciousness in these two groups of patients. Patients with cranial operation suffered a longer loss of consciousness [35.6 (SD 20.6) days vs. 16.5 (SD 10.5) days, P = 0.003]. Longer loss of consciousness association with surgery may be confounded by severity of injury and complications after craniotomy, such as haematoma and brain oedema. Different brain lesions were observed by CT scans. The most common brain lesions observed by CT scan was encephalomalacia, porencephaly, and focal atrophy. Encephalomalacia refers to the formation of cystic cavities of various sizes in the cerebral cortex due to head trauma.6 Encephalomalacia and porencephaly were observed more frequently in patient with penetrating trauma. Sixty-one percent of patients with penetrating trauma (40 patients from 66 patients) and 23% of patients with blunt trauma (22 patients from 97 patients) had imaging evidence of encephalomalacia and porencephaly. These lesions did not have any significant correlation with seizure frequency (P = 0.62). However, there was a significant relationship between encephalomalacia and porencephaly with the duration of loss of consciousness (P = 0.04) and ictal semiology (P = 0.02).
Discussion Posttraumatic epilepsy, the most common cause of new-onset epilepsy in young people, is often refractory to medical therapy.7 Head trauma is the cause of epilepsy in approximately 5% of patients referred to specialised epilepsy centres.8 About 75% of patients with cranial trauma during Iraq–Iran war suffered from persistent seizure.9 This rate seems to be higher than figures reported for previous wars (World War I, 38%; World War II, 34%;
Table 3 Ictal semiology of the 163 patients suffering from penetrating or blunt posttraumatic refractory epilepsy. Ictal semiology
Blunt trauma Number of patients (percentage of total 97 patients)
Penetrating trauma Number of patients (percentage of total 66 patients)
Frontal Parietal Temporal Occipital Generalised/non-localising
29 13 26 2 27
15 25 10 4 12
(29.9%) (13.4%) (26.8%) (2.1%) (27.8%)
(22.7%) (37.9%) (15.1%) (6.1%) (18.2%)
Korea, 36.5%; Vietnam, 53%).10 A possible explanation of this discrepancy may include the longer follow-up and inclusion of patients with injuries so severe that they would not have survived in previous wars. Another possible cause may be the involvement of more complex weapons in this war. In the present study, patients with penetrating trauma experienced their first seizure attacks earlier and with a higher rate of porencephaly and encephalomalacia compared to patients suffering from blunt trauma. The most reliable predictors of seizure risk include the time elapsed after a head injury and the severity of the injury, as manifested by estimated lesion size and neurological findings.10,11 Our findings confirm the validity of this, since patients with penetrating trauma suffered from a higher frequency of seizure attacks. The type of seizure has been reported as an important predictor of response to the treatment of post-traumatic epilepsy. Our data show partial simple and partial complex seizures in about 70% of the patients with refractory epilepsy induced by head trauma. In addition, patients with more than 30 seizure attacks per month also suffered from different types of partial seizures. Persistent seizures were also more common in patients with partial simple and partial complex seizures due to military head injuries during the Vietnam War. These patients also had significantly higher seizure frequencies.10 Retained metal fragments have been reported to have a significant correlation with seizure in 421 veterans who had penetrating brain wounds.10 In contradiction to this finding, other groups did not find any association between intracerebral-retained fragments and enhancement of immediate or late complications, including epilepsy.12,13 The suggested therapy for foreign bodies in missile head-wounded patients ranged from no surgical intervention to craniotomy and aggressive debridement of all necrotic brain tissue, haematoma, and in-driven bone and metal fragments.14,15 Aggressive intracranial debridements are, however, associated with a higher degree of neurological deficit, including the possibility of converting a transient deficit to a permanent one.16 It has been reported that no surgical treatment or simple repair of the scalp wounds, leaving behind some or all the in-driven bone and shell fragments, did not increase the risk for epilepsy.12,17 Our data also support these results as there was no association between location of the fragments and ictal semiology of the patients. In addition, we did not find any differences in seizure frequency between patients that were not operated vs. patients who underwent an operation. In the present study, a common imaging finding was porencephaly. Total brain volume loss on CT had a significant correlation with seizure in other investigations.10 The most common imaging abnormality in these patients was encephalomalacia. Encephalomalacia resulting from destructive brain injury
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is a lesion known for its potential epileptogenicity and for its association with intractable epilepsy.18 Diffuse encephalomalacia and widespread change in the white matter due to traumatic injuries were identified as indicators of significant rotational stresses on cerebral matter that might impact the function of the brain. It was suggested that subtle changes remote from the site of predominant injury must remain to be considered a probable epileptogenic focus.19 Traumatic brain injuries elicit complex neuropathology, involving both inflammatory cascades and diffuse neuronal degeneration. Localising neutrophils along blood vessels in the traumatic area may lead to a blood–brain barrier breakdown and further neuronal damage.20 Indeed, resection of encephalomalacia is reported as a very effective treatment of intractable epilepsy.21,22 The difficulty of accurately localising post-traumatic epileptogenic foci was demonstrated.23 Using MR is contraindicated in the case of intracranial metallic bodies, because of the potential risk for migration and further injuries. However, using other techniques such as SPECT and PET could help to localise the epileptic foci for further resection with minimal brain loss in these patients. In spite of substantial progress over the past few decades in the diagnosis and treatment of the epilepsies, posttraumatic intractable epilepsy is a major health problem in patients with military head injury. Patients traumatised by blunt or penetrating military brain injury carry a high risk of intractable post-traumatic epilepsy decades after their injury, and thus require a long-term medical follow-up. Further studies are needed to develop new strategies for treatment of these patients in both acute and chronic stages after the head injury.
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