10.

Post-Traumatic Seizure Disorder

Robert Teasell MD FRCPC, Nestor Bayona MSc, Corbin Lippert RNBScN, Shawn Marshall MSc MD FRCPC, Nora Cullen MSc MD FRCPC

Table of Contents
10.1 Classification of Post-Traumatic Seizures and Epilepsy...... 5 10.2 Incidence of Post-Traumatic Seizures.................................... 6 10.3 Risk Factors for Post-Traumatic Seizures ............................. 6
10.3.1 Identification of the High-Risk Patient ...........................................7

10.4 Natural History of Post-Traumatic Seizures .......................... 8

10.4.1 Onset ....................................................................................................8 10.4.2 Recurrence ...........................................................................................8 10.4.3 Summary of Natural History ...............................................................9

10.5 Clinical Picture of Post-Traumatic Seizures .......................... 9 10.6 Complications of Post-Traumatic Seizures ......................... 10
10.6.1 Cognitive and Behavioral Function..................................................10 10.6.2 Influence on Neurologic Recovery...................................................10 10.6.3 Functional Status...............................................................................10 10.6.4 Status Epilepticus..............................................................................11 10.6.5 Mortality..............................................................................................11

10.7 Treatment of Post-Traumatic Seizures................................. 11

10.7.1 Seizure Prevention or Prophylaxis...................................................12 10.7.1.1 Post-Traumatic Seizure Prophylaxis in Children............................21 10.7.2 Surgical Treatment of Post-Traumatic Seizures .............................23

10.8 Summary ................................................................................. 25 Reference List................................................................................. 27

Table Directory
Table 10.1 Table 10.2 Table 10.3 Table 10.4 Table 10.5 Table 10.6 Table 10.7 Table 10.8 Definitions of Post-Traumatic Seizures Studies of Risk Factors for Late Post-traumatic Seizures Studies of Post-Traumatic Seizure Recurrence Summary of Onset and Recurrence of PTS Seizure Prevention or Prophylaxis Summary of RCT Studies of Seizure Prevention or Prophylaxis Summary of non-RCT Studies of Seizure Prevention or Prophylaxis Pharmacological Seizure Prevention or Prophylaxis in Children following ABI Surgical Treatment of Post-Traumatic Seizures

Table 10.9

Key Points
Increasing age, alcohol abuse, family history, increasing injury severity, and the occurrence of early seizures immediately after the injury all increase the risk of developing late post-traumatic seizure disorder. Later onset seizures have a higher chance of recurrence. Levetiracetam is as effective as phenytoin in treating and preventing seizures in individuals in the intensive care unit post ABI. Anticonvulsants provided immediately post-ABI reduce the occurrence of seizures only within the first week. Anticonvulsants provided shortly post-ABI do not reduce long-term mortality, morbidity, or late seizures. Anticonvulsants have negative consequences on motor tasks. Early glucocorticoid exposure may increase seizures. Methylphenidate may not increase the risk of seizures. Intramuscular midazolam may be effective for acute seizure cessation. Phenytoin does not reduce early or late seizures in children post-ABI. Surgical excision can reduce seizures if the focus of the seizures can be localized.

10. Post-Traumatic Seizure Disorder

The Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation (1998) have noted that there are approximately 422,000 cases of inpatient traumatic brain injuries (TBI) in the United States every year (Kalsbeek et al., 1980). Of all TBI patients who are hospitalized, it is estimated that 5% to 7% will experience post-traumatic seizures (PTS). The number rises to 11% for patients with severe non-penetrating TBI, and up to 35% to 50% for patients with penetrating TBI (Yablon, 1993). The same group noted that the occurrence of seizures may be associated with accidental injuries, psychological effects, loss of driving privileges and reduced employability (Brain Injury SIG 1998). Moreover, there is some theoretical basis to believe that prevention of recurrent early seizures prevents the development of chronic epilepsy (Yablon 1993) which in turn has prompted the widespread use of prophylactic anticonvulsant treatment in those patients regarded at higher risk of developing PTS even though such treatment may have a negative impact in terms of cognitive side effects.

10.1 Classification of Post-Traumatic Seizures and Epilepsy

Post-traumatic seizure disorders have been defined in the Practice Parameter on the Antiepileptic Drug Treatment of Post-traumatic Seizures by the Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation (see Table below).
Table 10.1 Definitions of Post-Traumatic Seizures (1998) Seizure Discrete clinical events that reflect a temporary physiologic dysfunction of the brain characterized by excessive and hypersynchronous discharge of cortical neurons. Post-Traumatic Seizure An initial or recurrent seizure episode not attributable to another obvious cause after penetrating or nonpenetrating TBI. The term post-traumatic seizure is preferred over post-traumatic epilepsy because the former encompasses both single and recurrent events. Immediate Post-Traumatic Seizure A seizure due to TBI occurring within the first 24 hours of injury Early Post-Traumatic Seizure A seizure due to TBI occurring within the first week of injury. Late Post-Traumatic Seizure A seizure due to TBI occurring after the first week of injury. Post-Traumatic Epilepsy A disorder characterized by recurrent late seizure episodes not attributable to another obvious

cause in patients following TBI. Although the term post-traumatic epilepsy commonly has designated single or multiple seizures including early seizures, the term should be reserved for recurrent, late PTS. Nonepileptic Seizures Episodic behavioral events that superficially resemble epileptic attacks but are not associated with paroxysmal activity within the brain. Antiepileptic Drug Prophylaxis In the context of PTS, AED treatment administered to prevent seizures in patients who have not manifested seizures. Epilepsy Epilepsy is a condition characterized by recurrent unprovoked seizures. Practice Parameters Results, in the form of one or more specific recommendations, from a scientifically based analysis of a specific clinical problem.

10.2 Incidence of Post-Traumatic Seizures

Traumatic brain injuries account for 20% of symptomatic epilepsy in the general population and 5% of all epileptic cases (Yablon & Dostrow, 2001; Hauser et al., 1991). In young adults TBI is the leading cause of epilepsy (Annegers, 1996). Yablon and Dostrow (2001) have also noted that the overall incidence of late seizures following non-penetrating TBI among hospitalized patients is 4-7% (Annegers et al., 1980; Jennett, 1975). However, the incidence of PTS is much higher on rehabilitation units (as high as 17%) which is felt to reflect the increased severity of the injury and a higher number of risk factors in this population (Bontke et al., 1993; Armstrong et al., 1990; Cohen & Groswasser, 1991; Kalisky et al., 1985; Ng et al., 2004; Sazbon & Groswasser, 1990) Children with nonpenetrating TBI are less likely to suffer a late post-traumatic seizure (Annegers et al., 1980; Hahn et al., 1988; Kollevol, 1979; Asikainen et al.,1999). In contrast, patients with penetrating TBI experience much higher incidence rates (as high as 35-50%) of post-traumatic seizures (Ascroft, 1941; Caveness & LISS, 1961; Caveness et al., 1979; Salazar et al., 1985; Yablon & Dostrow, 2001).

10.3 Risk Factors for Post-Traumatic Seizures

The Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation (1998) has noted that the risk of epilepsy is highest within the first two years following brain trauma (Yablon, 1993; Dikmen et al., 1991). There are several patient and injury characteristics that increase the likelihood of developing PTS. These include a Glasgow Coma Scale score of <10, cortical contusions, depressed skull fractures, epidural hematomas, intracerebral hematomas, wounds with dural penetration, a seizure within the first week of injury, prolonged length of coma, and prolonged length of posttraumatic amnesia (Yablon 1993; Dikmen et al. 1991; Brain Injury SIG of AAPM&R 1998)

It has been noted that 20% of adults have spontaneous seizures within two years of TBI with penetrating injury of the brain, intracranial hematoma, cortical contusion, depressed skull fracture or a seizure immediately following the onset of TBI (Temkin et al., 2001). To put this is perspective, Temkin (2001) notes that this is over 200 times the rate seen in someone who has not suffered a brain injury. Although the risk of developing post-traumatic seizures is highest within months after the injury (Temkin 2001), the risk remains high for individuals with moderate-severe injuries for as long as 5 years while military personnel suffering severe penetrating missile brain injuries show elevated risks for more than 15 years after the injury (Weiss et al., 1983; Feeney & Walker, 1979; Annegers et al., 1998; Salazar et al., 1985; Caveness, 1963; Caveness et al., 1979). 10.3.1 Identification of the High-Risk Patient It is important to identify patients who are at high-risk of developing posttraumatic seizures (PTS) since these patients would benefit greatly from its prevention or from the impediment of its possible reoccurrence. Yablon and Dostrow (2001) have proposed that methods that assess the clinical characteristics of the patient, the injury, and information obtained from neuroimaging and electrophysiologic assessment techniques can be used to identify such high-risk patients. Moreover, Yablon and Dostrow (2001) have identified some key risk factors which can aid in the identification of these patients (Table 10.2).
Table 10.2 Studies of Risk Factors for Late Post-traumatic Seizures (Yablon and Dostrow 2001) Risk Factor Reference Patient Characteristics Age (Annegers et al., 1980; Asikainen et al., 1999; Hahn et al., 1988; Kollevold, 1979) Alcohol use (Evans, 1962; Heikkinen et al., 1990; Kollevold, 1978) Family history (Caveness, 1963; Evans, 1962; Heikkinen et al., 1990; Hendrick & Harris, 1968) Injury Characteristics Bone/metal fragments (Ascroft, 1941; Salazar et al., 1985; Walker & Yablon, 1959) Depresed skull fracture (Jennett, 1975; Hahn et al., 1988; Phillips, 1954; Wiederholt et al., 1989) Focal contusions/injury (da Silva et al., 1992; De Santis et al., 1992; Eide & Tysnes, 1992; Glotzner et al., 1983; Heikkinen et al., 1990) Focal neurologic deficits (da Silva et al., 1992; Jennett, 1975; Salazar et al., 1985) Lesion location (da Silva et al., 1992; Evans, 1962; Grafman et al., 1992) Dural penetration (Caveness & LISS, 1961; Evans, 1962; Salazar et al., 1985) Intracranial hemorrhage (Hahn et al., 1988; Glotzner et al., 1983) Injury severity (Evans, 1962; Jennett, 1975; Salazar et al., 1985; Walker & Yablon, 1961) Other Early post-traumatic seizures (Heikkinen et al., 1990; Jennett, 1975; Salazar et al., 1985)

Conclusions: There are several patient and injury characteristics that increase the likelihood for the development of late PTS. Some important patient characteristics include: increasing age, premorbid alcohol abuse, and family history. In terms of injury characteristics, markers of increasing injury severity such as penetrating injuries and depressed skull fracture increase the risks of late PTS. A seizure occurring immediately after the injury substantially increases the risk of late PTS. As the severity of the brain injury increases, the period of time for which a survivor is at risk of developing PTS also increases.

Increasing age, alcohol abuse, family history, increasing injury severity, and the occurrence of early seizures immediately after the injury all increase the risk of developing late post-traumatic seizure disorder.

10.4 Natural History of Post-Traumatic Seizures

10.4.1 Onset Yablon and Dostrow (2001) have noted that one-half to two-thirds of patients who suffer PTS will experience seizure onset within the first 12 months, and 75-80% will have seizures by the end of the second year following the injury (Caveness et al., 1979; da Silva et al., 1992; da Silva et al., 1990; Pohlmann-Eden & Bruckmeir, 1997; Salazar et al., 1985; Walker & Yablon, 1959; Walker & Yablon, 1961). After 5 years, adults with mild TBI no longer have a significantly increased risk relative to the general population (Annegers et al., 1998), whereas patients with moderate or severe TBI or penetrating TBI remain at increased risk for more than 5 years post-injury (Annegers et al., 1998; da Silva et al., 1992; Pagni, 1990; Salazar et al., 1985). 10.4.2 Recurrence Seizure recurrence is an important factor in the determination of disability, employment likelihood, quality of life, and increased health care costs (Baker, Nashef, & van Hout, 1997; van Hout et al., 1997; Yablon & Dostrow, 2001). Some studies have reported that following early seizures post-TBI, only one-half of the patients experienced a recurrence (De Santis et al.,1979; Kollevold, 1979) while another quarter experienced a total of only 2-3 seizures (Kollevold, 1979).
Table 10.3 Studies of Post-Traumatic Seizure Recurrence Authors Recurrence Incidence Haltiner et al., 63 adults with moderate or severe TBI and later PTS cumulative incidence of (1997) recurrent late seizures 86% over 2 yrs; 52% > 4 late seizures, 37% > 9 late seizures. Pohlmann-Eden 57 post-traumatic epilepsy patients compared to 50 age and sex-matched and Bruckmeir severe TBI controls Of PTE patients 35% became seizure-free over 3 years; (1997) 21% had > 1 seizure per week; risk factors poor seizure frequency, missile

injuries, combined seizure patterns, med noncompliance and alcohol abuse.

10.4.3 Summary of Natural History The following table provides a summary of the natural history for the onset and recurrence of post-traumatic seizures as noted by Yablon and Dostrow (2001).
Table 10.4 Summary of Onset and Recurrence of PTS Feature Reference 20 30 % of cases of patients with early PTS (Yablon & Dostrow, 2001) experience a late seizure. Seizure onset after the first week shows a (Walker & Yablon, 1961; Haltiner et al., 1997) much higher likelihood of seizure recurrence. Seizure frequency within the first year post(Salazar et al., 1985) injury may predict future recurrence. Persistent PTS may be more common in partial seizures and less common in generalized seizures. Immediate PTS is believed to carry no increased risk of recurrence. A small number of patients experience frequent seizure recurrences, apparently refractory to conventional anti-seizure therapy. Some patients may benefit from surgical intervention. (Salazar et al., 1985) (Jennett, 1975; McCrory et al., 1997) (Haltiner et al., 1997; Ng et al., 2004; Pohlmann-Eden & Bruckmeir, 1997) (Marks et al., 1995; Diaz-Arrastia et al., 2000)

Conclusions Seizures which occur after the first week of the injury have an increased chance of seizure recurrence.

Later onset seizures have a higher chance of recurrence.

10.5 Clinical Picture of Post-Traumatic Seizures

Wiedemayer et al. (2002) retrospectively analyzed a consecutive series of 1868 adult patients with head injury. Brain injury severity was mild in 568 patients (30.4%), moderate in 681 patients (36.5%), and severe in 619 patients (33.1%). In 109 patients (5.8%), an epileptic seizure occurred in the early post-traumatic period; 39 of the 109 patients who experienced an early post-traumatic seizure, suffered from severe head injury, 58 from a moderate head injury, and 12 from a mild head injury. Sixty-six early seizures (60.5%) occurred within the first day following trauma, with a steep decline over the ensuing days. The first epileptic seizure was generalized in 69 patients (63.3%) and focal in 40 patients (36.7%).

58 patients (53.2%) experienced a second early seizure during the follow-up period.

10.6 Complications of Post-Traumatic Seizures

Seizures following TBI may themselves be a source of significant complications and morbidity and it has been noted that the recurrence of seizures is an important cause of nonelective hospitalization in patients with severe TBI (Cifu et al., 1999). Potential complications include deterioration in cognitive and behavioral functioning and overall functional status, influence on neurological recovery, status epilepticus and death. 10.6.1 Cognitive and Behavioral Function Post-traumatic seizure disorders may lead to cognitive and behavioural disorders (Yablon & Dostrow, 2001). Cognitive problems may arise during the interictal state in the absence of active seizures (Aarts et al., 1984; Aldenkamp, 1997; Binnie & Marston, 1992). Patients with PTS experience persistent behavioral abnormalities and a higher incidence of psychiatric-related hospitalizations even compared with patients with penetrating TBI who do not experience PTS (Swanson et al.,1995). 10.6.2 Influence on Neurologic Recovery Post-traumatic seizures can influence neurological recovery (Hernandez & Naritoku, 1997; Yablon & Dostrow, 2001). Yablon and Dostrow (2001) have noted that in rodent models, brief and infrequent PTS occurring early after brain damage do not appear to impact functional recovery. However, more severe and widespread seizures occurring within the first 6 days post brain injury result in permanent impairments of functional recovery; while the same seizures occurring after the 6 day mark result in no change in somatosensory recovery (Hernandez and Naritoku 1997). 10.6.3 Functional Status Recurrent PTS may exert a negative impact on functional status following TBI, an adverse effect independent of the severity of the injury (Barlow et al., 2000; Schwab et al., 1993). In the case of penetrating traumatic brain injuries, posttraumatic seizures have been reported to be an important and independent factor which affects both employment status and cognitive performance (Schwab et al. 1993). However, in the case of nonpenetrating TBI, the impact of PTS on functional prognosis and cognition is less clear (Armstrong et al., 1990; Asikainen et al., 1999). Haltiner et al. (1997) found no significant differences at one year as a consequence of later PTS in terms of neuropsychological performance and psychosocial functioning when adjusting for injury severity. Asikainen et al. (1999) found that patients with PTS did have poorer outcomes on the Glasgow Outcome Scale, although there were no significant differences in employment outcome associated with the presence of PTS.

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10.6.4 Status Epilepticus Status epilepticus can be defined as either more than 30 minutes of continuous seizure activity (Yablon & Dostrow, 2001) or two or more sequential seizures without full recovery of consciousness between seizures (Yablon, 1993). Status epilepticus is regarded as the most serious of the complications of PTS and may actually lead to additional neurological damage. Fortunately, clinically apparent status epilepticus is an infrequent complication of PTS (Kollevold, 1979). 10.6.5 Mortality Yablon and Dostrow (2001) have noted that among patients with PTS mortality remains consistently elevated (Corkin et al., 1984; Walker & Erculei, 1970; Walker & Blumer, 1989). However, the contribution of PTS to increased morality is unclear and some studies have suggested that deaths among penetrating TBI patients with PTS are due to complications of the actual injury and are not related to seizures (Rish & Caveness, 1973; Rish et al., 1983). Yablon and Dostrow (2001) have noted that the complications associated with single later post-traumatic seizures are no different than those found in any seizure and are generally associated with minimal risk. However, the risks of increased mortality and increased morbidity in the form of worsened cognitive and functional prognosis are associated with increasing frequency and severity of the seizure disorder.

10.7 Treatment of Post-Traumatic Seizures

Schierhout and Roberts (2001) have reported that a seizure which occurs soon after a head injury may cause secondary brain damage, due to the increased metabolic demands of the brain soon after the injury, increased intracranial pressure, and excessive amounts of neurotransmitter release which may lead to additional brain injury. For this reason, the primary therapeutic objective in the use of anticonvulsant drug has been the prevention of early seizures in an attempt to minimize the extent of brain damage following an injury. Some anticonvulsant drugs have been shown to have neuroprotective properties in animal studies. For example, following hypoxia, phenytoin has been linked with reduced neuronal damage in neonatal rats (Vartanian et al., 1996) and in rat hippocampal cell cultures (Tasker et al., 1992). Experimental evidence suggests that the neuroprotective effects of phenytoin are related to a blockage of voltage dependent sodium channels during hypoxia (Tasker et al. 1992; Vartanian et al. 1996) which would be expected to decrease the spread of calcium induced neurotoxicity following hypoxic brain injury. As noted by Schierhout and Roberts (2001), this suggests that anti-epileptics may have beneficial properties which may be independent of their proposed anti-seizure activity. Conversely, anti-epileptic drugs have shown toxic effects even in stable patients, with impaired mental and motor function being the most common adverse effects, although serious adverse effects including deaths as a result of

11

hematological reactions have been also reported (Reynolds et al., 1998). Schierhout and Roberts (2001) have suggested that the injured brains response to anticonvulsants may be such that toxic effects could be more pronounced and neurological recovery may be delayed.

10.7.1 Seizure Prevention or Prophylaxis Initially, retrospective and nonrandomized clinical trials in humans showed favorable results for the efficacy of anti-epileptic drug prophylaxis (Caveness et al., 1979; Heikkinen et al., 1990; Kollevold, 1978; Murri et al., 1992; Murri et al., 1980; Price, 1980; Rish & Caveness, 1973; Servit & Musil, 1981; Wohns & Wyler, 1979; Young et al., 1979). However, prospective investigations of chronic prophylaxis for late PTS have shown less impressive results (Glotzner et al., 1983; Manaka, 1992; McQueen et al., 1983; Pechadre et al., 1991; Temkin et al., 1990; Temkin et al., 1999; Temkin et al., 1991; Young et al., 1983b; Young et al., 1983a; Formisano et al., 2007; Young et al., 1983b). Individual Studies
Table 10.5 Seizure Prevention or Prophylaxis Author/Year/ Country/Study design/ Methods Pedro & D&B Score Szaflarski et al., (2010) USA RCT PEDro=8 D&B=25 N=34 Individuals who has sustained a moderate to severe TBI and remained in hospital >24 hours, were selected for the following study and randomly assigned to either the levetiracetam (LEV) or phenytoin (PHT) group. Those in PHT group were 20mg/kg PE IV maximum of 20000 mg given over 60 minutes. The maintenance dose was 5mg/kg/day IV every 12h. Those in the LEV group were started on 20mg/kg/IV rounded to the nearest 250 mg over 60 min then started on a maintenance dose (1000 mg IV every 12 h over 15 min). Therapeutic dose was 1500 mg/12h. GCS, GOS, ICP, DRS were monitored and evaluated. N=137 Two groups were studied, one retrospectively (n=55) and the other prosepective (n=83). Patients were given anti-epileptic medications for the treatment of seizures either before or after they began.

Outcome

Duration of treatment for the PHT group was 3 to 7 days, for the LEV group was 7 days. At time of discharge and post discharge there were no differences in the GOS. There were no differences in ICP, stroke, hypotension, arrhythmia, (etc.) between the two groups. Those in the LEV group experienced a worsening of their neurological status less often than the PHT group (p=0.024). Those in the PHT group experienced anemia less often than the LEV group (p=0.076). DRS scores were lower for those in the LEV group at 3 and 6 months post discharge. Their GOSE were also higher at 6 months post intervention. In the retrospective study, the incidence of PTE was lower in the non-treated group, the time interval from TBI to seizure onset varied. In the prospective study the occurrence of late PTE was higher in patients treated with an anti-epileptic medication vs those not treated

Formisano et al., (2007) Italy/USA Pre/Post D&B=11

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Author/Year/ Country/Study design/ Pedro & D&B Score

Methods

Outcome

(p=0.004). Those who were not treated with an antiepileptic medication (n=13) did not develop a seizure disorder. Out of those treated with medication (n=69) only 30 show epileptic abnormalities on their EEGs. Evidence was not found to support the use of long-term antiepileptic medications. Dikmen et al., (1991) USA RCT PEDro = 6 D&B = 24 N=244 Patients who fulfilled at least one of the following requirements: GCS 10 within 24 hours of injury, CT evidence of cortical contusion, depressed skull fracture, subdural/epdidural/intracerebral hemorrhage, penetrating head wound, seizure within the first 24 hours after injury were randomly assigned to be treated with phenytoin or placebo for 1 year starting within 24 hours of injury. Initial dose was 20 mg/kg intravenously. Serum levels of phenytoin were maintained at 3 6 mol/l. Outcomes were assessed using a comprehensive battery of neuropsychological and psychosocial measures at 1, 12, and 24 months post-injury including: Haltead Reotan Neuropsychological Test Battery, Wechsler Memory Scale, Trails A/B and Stroop test part 1 and 2, Symptom Checklist, Katz Adjustment Scale, Sickness Impact Profile. N=279 Consecutive patients with TBI, admitted within 24 hours post-injury, at risk of post-traumatic seizures were randomized to one of three groups: 1) valproic acid (VPA) for 1 month followed by 5 months of placebo 2) Valrproic acid for 6 months or 3) phenytoin (PHT) for 1 week followed by placebo until 6 months post-injury. In the severely injured (GCS 9) phenytoin significantly impaired neuropsychological performance at 1 month as evidenced by the overall rank-sum type test (p < 0.05). No significant differences in neuropsychological performance were found between groups in either moderately injured (GCS 9) patients at 1 month or in either severity group at 1 year. Patients who stopped receiving phenytoin between 1 and 2 years improved more than corresponding placebo cases on several measures. Changes in neuropsychological measures from 12 to 24 months post-injury showed that phenytoin had negative widespread cognitive effects compared with placebo on most measures as evidenced by the overall rank-sum type test (p < 0.05).

Dikmen et al., (2000) USA RCT PEDro = 8 D&B = 25

Trend towards higher mortality rate in the valproate groups compared with phenytoin group (p=0.07). There were no significant differences at 1, 6 or 12 months on the composite measures based on all the neurospsychological measures or only on the cognitive measures. Adjustment for differential confounders did not change the lack of significance of the results. No individual measure showed a significant difference among the treatment groups at 1, 6 or 12 months post-injury.

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Author/Year/ Country/Study design/ Pedro & D&B Score Glotzner et al., (1983) Germany RCT No Score [German]

Methods

Outcome

N=139 Head injured patients over the age of 15 were randomized to treatment with carbamazepine on day 1 after accident for 1.5 2 years or placebo. Phenytoin used if carbamazepine not tolerated.

Patients on carbamazepine showed a significant decrease in posttraumatic seizures compared with placebo (p < 0.05). This difference was statically significant for early seizures (within first week) and for the follow up time in total, but not for late seizures. After a 5-year follow, there were no differences in the incidence of late seizures between severe head injury patients in the phenobarbital (16%) or the untreated (11%) group.

Manaka (1992) Japan RCT PEDro = 3 D&B = 10

N=126 Severe head injury patients (788 years of age) who showed either a disturbance of consciousness, bloody cerebrospinal fluid, focal neurological sign, depressed fractures or basal fracture, abnormal CT, dural tears, early convulsion, and/or linear fracture were randomized to receive phenobarbital (10 25 g/ml) or no treatment started 4 weeks after head injury and continuing for 2 years. Patients were gradually tapered off the medication during the third year. Follow up continued for 5 years. N=164 Head injured patients (5-65 years of age) admitted within < 8 to > 30 days post-ABI whose head injury was complicated by at least one of the following: dural penetration, intracranial hameatoma, depressed skull fracture, persistent neurological deficit or PTA > 24 hours were randomized to receive either phenytoin for 1 year or placebo. Patients with early seizures were excluded. N=86 head injured patients (3-60 years of age) were randomly assigned to treatment with phenytoin (for 3 months or one year) or placebo. Phenytoin treatment started within the first 24 hours following brain injury. Follow-up continued for 2 years. N=82 ABI patients who had previously been treated with phenytoin (n = 40) or carbamazepine (n = 42) after their head injury and who had been continuously maintained on their anticonvulsant drug for at least 6 months prior to this study were

McQueen et al., (1983) RCT PEDro = 7 D&B = 20

No apparent differences between groups in the incidence of posttraumatic seizures for up to 24 months post-injury; 6 patients in the phenytoin group and 5 patients in the placebo group developed posttraumatic epilepsy within one year. A further 4 patient developed seizures between 1 and 2 years after injury. After a 2-year follow-up, there was a significant difference (p< 0.001) in the incidence of late PTS between groups, with the treated patients showing an incidence rate of only 6% compared to an incidence rate of 42% in the untreated group. No significant differences were found between patients in the medication and placebo groups for either drug (phenytoin or carbamazepine) on any of the outcome measures at the end of the placebo phase. Patients in both drug groups (phenytoin and

Pechadre et al., (1991) RCT PEDro = 3 D&B = 14 [French]

Smith, Jr. et al., (1994) RCT PEDro = 6 D&B = 22

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Author/Year/ Country/Study design/ Pedro & D&B Score

Methods

Outcome

randomly assigned to continue their anticonvulsant therapy or switch to a placebo for a period of 4 weeks. A battery of neuropsychological tests was administered during a 4-week baseline period (treatment with stable doses of the patients anticonvulsant continued), at the end of a 4 to 5 week period of continued drug treatment or placebo, and after 4 weeks of not receiving medication. Temkin et al., (1990) USA RCT PEDro = 6 D&B = 24 N=404 Severe ABI patients meeting at least one of the following criteria: cortical contusion visible on a CT scan, subdural, epidural or intracerebral hematoma, a depressed skull fracture, a penetrating head wound, a seizures within 24 hours of injury, or a GCS 10 were randomly assigned to treatment with phenytoin (n=208) or placebo (n=196) Treatment was started within 24 hours of brain injury and continued for 1 year with a 2-year follow-up. Initial dose was 20 mg/kg intravenously within 24 hours of injury. Serum levels of phenytoin were maintained at 36 mol/l. The incidence of early (within 1 week) or late (> 8 days after initial drug loading) seizures was compared between groups. N=379 Patients were initially randomly assigned to one of three groups: phenytoin for 1 week followed by placebo until 6 months post-injury, Valproate for 1 month followed by placebo for 5 months, or valproate for 6 months. 283 patients were followed up through 2 years. Occurrence of late seizures (> 7 days after injury) and mortality rates followed up for 2 years.

carbamazepine) showed significant improvements (p < 0.01) on several measures of motor and speeded performance following cessation of anticonvulsant drug treatment.

During the first week of treatment, there was a significant reduction in the number of seizures in the phenytoin group compared with the placebo group (3.6% vs. 14.2%, p < 0.001). Between day 8 and the end of year 1 and at the 2 year follow up, there were no significant differences in the occurrence of seizures between groups (p > 0.2 for each comparison). This lack of late effect could not be attributed to differential mortality, low phenytoin levels, or treatments of some early seizure in patients assigned go the placebo group.

Temkin et al., (1999) USA RCT PEDro = 7 D&B = 23

The rates of early seizures were low and not significantly different when using either valproate or phenytoin (1.5% in the phenytoin group and 4.5% in the combined valproate groups, p = 0.14). The rates of late seizures did not significantly differ between groups (15% in the 1-week phenytoin group, 16% in the 1-month valproate group, and 24% in the 6month valproate group, p = 0.19). Mortality rates were not significantly different between groups, but there was a trend toward higher mortality rates in the valproate groups (7.2% in the phenytoin groups and 13.4% in the combined valproate groups, p = 0.07).

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Author/Year/ Country/Study design/ Pedro & D&B Score Young et al., (1983a) USA RCT PEDro = 6 D&B = 23

Methods

Outcome

N=244 Individuals with severe brain injury patients with either a penetrating missile wound or a blunt head injury were randomly assigned to receive either Phenytoin or placebo within first 24 hours post-injury. The incidence of early seizures (within one week of injury) between groups was assessed.

There were no significant differences between groups in the percentage of early (within 7 days post-injury) seizures. There was no significant difference in the interval from injury to first seizure between the treated and placebo groups

Young et al., (1983b) USA RCT PEDro = 6 D&B = 23

N=179 Same method of randomization There were no significant differences as that employed in Young et al. between groups in the percentage of [1983a]. Initially 214 patients were late (> 7 days post-injury) seizures. randomized, but only 179 patients completed the intervention. The incidence of late seizures between groups was compared. The incidence of late seizures was 25% in the control group (most occurring during the first year after injury) and 2.1% in the prophylactically treated group following the discontinuance of drug therapy (p<0.001).

Servit and Musil N=167 Moderate to severe (duration of loss of conciousness > 1 hour) brain (1981) Czechoslovakia injury patients were divided into two Non-RCT similar groups in terms of severity and D&B = 8 localization of brain injury. The control group (n=24) was treated by conventional methods whereas the other group (n=143) was prophylactically treated with phenytoin (160-240 mg/day) and phenobarbital (30-50 mg/day) orally for at least 2 years for the prevention of seizures. The incidence of late seizures was compared between groups. Watson et al., (2004) USA Cohort D&B = 18 N=404 Individuals with severe TBI (GCS 10) who were exposed to glucocorticoid medications (n = 125) within 1 week of TBI were compared with those without any exposure (n = 279) to glucocorticoids. Any type, dose or route of administration of glucacorticoids was considered significant. Patients were followed up for 2 years to compare seizure development and mortality rates.

Patients dosed with glucocorticoids within 1 day of TBI were more likely to develop first late seizures than were those without the medication (p = 0.04). This early glucocorticoid exposure was associated with an increase of 74% in the risk of a first seizure. Receiving glucocorticoids 2 days after TBI was not associated with first late seizure development (p = 0.66). Receiving glucocorticoids within 1 day (p = 0.28), or 2 days (p = 0.54) after TBI was not associated with the development of a second late seizure. No difference was noted in cumulative mortality between groups (p = 0.57). There was no statistically significant difference in seizure occurrence

Wroblewski et al., (1992)

N=30 Severe (PTA > 24 hours) brain injury patients with documented late

16

Author/Year/ Country/Study design/ Pedro & D&B Score USA Case Series D&B = 13

Methods

Outcome

post-traumatic seizures (> 7 days after injury) who were being treated with methylphenidate for a variety of cognitive and behavioral problems participated in this retrospective chart review. All but 2 of the 30 patients were receiving concurrent anticonvulsant drug therapy (carbamazepine n = 26, valproic acid n = 2). Any seizure occurrence, anticonvulsant use and other comedication use was recorded for (1) 3 months prior to methylphenidate use (baseline); (2) the duration of methylphenidate treatment and (3) 3 months proceeding methylphenidate use (follow-up). N=10 Patients who had suffered a TBI resulting from a motor vehicle accident, fall or anoxic encephalopathy received intramuscular midazolam after other benzodiazepine drugs proved not useful for acute seizure cessation. Seizure occurrence and behavioural changes were assessed.

while patients were received methylphenidate compared with the period when patients were off the drug on measures of seizure occurrence, however there was a trend toward a lesser incidence of seizures in patients during methylphenidate treatment (p = 0.063).

All patients experienced seizure cessation within minutes of midazolam administration. Slight to moderate sedation were the only reported side effects. In those individual treated for behavioural problems, midzolan alleviated agitation and violence with no obvious effects on cognition. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). D&B = Downs and Black (1998) quality assessment scale score

Wroblewski & Joseph (1992) USA Case Study No Score

Table 10.6 Summary of RCT Studies of Seizure Prevention or Prophylaxis Authors/Year Methods Results Szaflarski et al., N = 34 Patients admitted to ICU -Levetiracetam was showen to be as 2010 post ABI. Phenytoin and safe as phenytoin in reducing seizures levetiracetam were given to patients post ABI. Levetiracetam was found to within 24 hours of admission have fewer side effects and better GOSE outcomes 3 months post discharge. Dikmen et al., N = 244 high risk patients. - for neuropsychological performance at (1991) Phenytoin vs. placebo for 1 year 1-month in severely injured (GCS 9) starting within 24 hours of injury. ND for neuropsychological performance in moderately injured (GCS > 9) at 1month or either severity group at 1 year. Dikmen et al., N = 279 of high risk patients. Trend towards higher mortality in (2000) Valproate x 1 mos + placebo x 5 valproate vs. phenytoin. mos; valproate x 6 mos; phenytoin x 1 wk; + placebo x 6 mos. Otherwise ND on any measure. Glotzner et al., N = 139 Carbamazepine at day 1 x + for early seizures (1983) 1.5-2 years or placebo ND for later seizures Manaka N = 126 Phenobarbital x 2 years vs. ND for late seizures

17

(1992) McQueen et al., (1983) Pechadre et al., (1991) Smith, Jr. et al., (1994) Temkin et al., (1990) Temkin et al., (1999)

no treatment at all with 5 year follow-up. N =164 Phenytoin x 1 year. Excluded early seizures. N = 91 Phenytoin x 3 mos vs. 1 year with 2 year follow-up. N = 82 patients previously treated with phenytoin or carbamazepine randomly assigned to continue on anticonvulsant or switch to placebo N = 404 Phenytoin x 1 year vs. placebo with 2 year follow-up. N = 379 high-risk patients. Phenytoin x 1 week; valrproate x 1 mos; valproate x 6 mos. Follow up for up to 2 years

ND for post-traumatic epilepsy up to 24 months post-injury. + for late seizures + for performance on several measures of motor and speeded performance following cessation of anticonvulsant drug treatment. + for reduction in seizures in 1st week ND in seizure occurrence after 1st week. ND between drugs, both Phenytoin and valproate + for early seizures. ND between drugs, both negative for late seizures. Trend toward higher mortality in valproate vs. phenytoin. ND for incidence of early seizures (within 7 days post-injury)

Young et al., (1983a)

N = 244 Severe brain injury patients. Phenytoin vs. placebo within 24 hours post-injury. Young et al., N = 214 Phenytoin or placebo ND for incidence of late seizures (> 7 (1983b) within first 24 hours post-injury. days post-injury). ND = No difference between groups; + = Improvement compared with control; - = Impairments compared with control

Table 10.7 Summary of non-RCT Studies of Seizure Prevention or Prophylaxis Authors/Year Methods Results Formisano et al., N=137 Two groups of patients were In both groups PTE was found to be (2007) evaluated (one retrospectively and lower in the non-treatment group. In the prospectively) after sustaining a prospective study the occurrence of late severe. Seizure activity was PTE was higher in patients treated with monitored in all patients even if an an antiepileptic medication than those anti-epileptic medication was not not treated. prescribed Watson et al., N=404 Comparison of TBI patients ND in mortality or late seizures. (2004) exposed or not exposed to Early (< 2 days after TBI) exposure to glucacorticoids within 1 week of glucocorticoids is associated with higher injury. Follow up for 2 years. risks of seizures. Wroblewski et al., N=27 Patients with late occurrence ND in seizure occurrence between pre(1989) seizures or at high risk for PTS. and pos carbamazepine periods. Taken off phenytoin, phenobarbital or primidone and treated with carbamazepine instead. Wroblewski et al., N=30 ABI patients at risk of Trend towards lower frequency of (1992) developing seizures who were seizures while on methylphenidate. receiving anticonvulsant drug therapy and concurrently receiving methylphenidate for a variety of cognitive and behavioural problems. Wroblewski and N=10 TBI patients. + for seizure cessation within minutes of Joseph (1992) Treated with intramuscular midazolan administration midazolan (0.5 20 mg) for acute seizure cessation. ND = No difference between groups; + = Improvement compared with control

18

Discussion Szaflarski et al. (2010), looked at the effects of levetiracetam (LEV) or phenytoin (PHT) on individuals (n=34) who has sustained a moderate to severe TBI. All subjects were randomly assigned to one of two groups the LEV or PHT. Subjects in the PHT group were administered 20mg/kg PE IV up to a maximum of 20000 mg given over 60 minutes. The PHTs maintenance dose was 5mg/kg/day IV every 12h and was administered to patients for the next 3-7 days. The LEV group was started on 20mg/kg/IV which was rounded to the nearest 250 mg over the first 60 minutes. The group was then started on a maintenance dose (1000 mg IV every 12 h over 15 min) and remained on this for 1-7 days (Szaflarski et al., 2010). The Glasgow Coma Scale (GCS), the Glasgow Outcome Scale (GOS), Intracranial Pressure (ICP) and the Disability Rating Scale were all used to evaluate the groups pre- and post treatment. Results indicate that those on LEV performed significantly better on the DRS at 3 months (p=0.042) and the GOS at 6 months (p=0.039) post intervention compared to the PHT group. There were no differences in the number of seizures experienced by study participants regardless of the group they were assigned to (Szaflarski et al., 2010). Overall, most published randomized control trials have failed to find any favorable evidence for prophylaxis of late PTS (Young et al., 1983a; Glotzner et al., 1983; McQueen et al., 1983; Temkin et al., 1990). In some of these reports, the occurrence of PTS was actually higher in patients treated with anticonvulsant medications (Young et al.1983b; McQueen et al.1983; Temkin et al.1990; Formisano et al. 2007). In contrast to late PTS, Yablon and Dostrow (2001) have reported that anticonvulsant drug prophylaxis consistently reduces the incidence of early PTS (Glotzner et al. 1991; Temkin et al. 1990; Temkin et al. 1999; Young et al.1983a). Similar to most of the studies on late PTS, there is no evidence that anticonvulsant drug prohylaxis of early seizures reduces the occurrence of late PTS or has any effect on mortality or neurologic disability (Schierhout and Roberts 1998). As mentioned earlier, patients who suffer severe penetrating brain injuries experience higher risks of PTS. However, due to the small number of patients with penetrating TBI in most reports, it is not clear if anticonvulsant drug prophylaxis has any effects, either positive or negative, on the occurrence of PTS is this subgroup of brain injury patients. Schierhout and Roberts (2001) conducted a Cochrane review of anti-epileptic drugs for preventing seizures following acute traumatic brain injury. This review of six trials including 1218 randomized patients. The authors noted that all of the included trials were restricted to patients considered to be at high risk for PTS. Most of the trials excluded patients who already had one seizure with the intervention started within 24 hours of admission in four trials; the remaining two trials initiated the intervention between 4 and 8 weeks post head injury. Four trials used phenytoin, one trial phenobarbital and one trial carbamazepine. Drug was provided between 1-2 years in all the trials duration of follow-up was two

19

years in most cases. Loss to follow-up ranged from 5-72%. Four trials reported early and late seizure; two trials reported late seizures only (Schierhout and Roberts 2001). The number of patients with early seizures (within the first week after injury) was available from 4 trials representing 890 randomized subjects. The pooled relative risk for early seizure prevention was 0.34 (95% CI 0.21, 0.54) with the number needed to treat to keep one patient seizure-free in the acute phase was 10. However, there was no evidence that this resulted in a reduction in mortality or a reduction in death or persistent vegetative state. The occurrence of late seizure was not reduced by anti-epileptic prophylaxis at any time. There was insufficient data to examine non-fatal adverse effect, with the exception of a trend towards an increased risk of skin rashes. The authors Schierhout and Roberts (2001) note that, There is no evidence that prophylactic anti-epileptics used at any time after head injury, reduce death and disability. There is evidence that prophylactic anti-epileptics reduce early seizures, but this is not supported by a reduction in late seizures. Insufficient evidence is available to establish the net benefit of treatment at any time after head injury. (pg 1) There appears to be very little research to evaluate the efficacy of anticonvulsants given to treat seizures after they have occurred. We identified only one such study in this review. Wroblewski and Joseph (1992) reported on a collection of ten case studies of TBI patients treated with intramuscular midazolam for acute seizure cessation after other benzodiazepine drugs had failed. The authors reported that in all patients, seizures ceased within minutes of midazolam administration. Midazolam also prevented the onset of prolonged seizures or status epilepticus. Slight to moderate sedation were the only reported side effects. Conclusions: There is Level 1 evidence to suggest levetiracetam is as safe and effective as phenytoin in treatment and prevention of seizures in individuals in the intensive care unit post ABI. Based on meta-analysis and the findings of this review there is Level 1 evidence that anticonvulsants given during the first 24 hours post-ABI reduce the occurrence of early seizures (within the first week post-injury). There is Level 1 evidence that anticonvulsants given shortly after the onset of injury, do not reduce mortality or persistent vegetative state or the occurrence of late seizures (> one week post-injury).

20

There is Level 1 evidence that seizure prophylactic treatment with either phenytoin or valproic acid results in similar incidences of early or late seizures and similar mortality rates. There is Level 1 evidence that both phenytoin and carbamazepine have negative effects on cognitive performance, particularly on tasks with motor and speed components, which theoretically may have a negative impact upon learning during rehabilitation. There is Level 2 evidence that glucocorticoid exposure after brain injury is not associated with a decrease in late seizures, and early exposure (< 2 days after injury) is associated with increased seizure activity. There is Level 4 evidence that methylphenidate for the treatment of cognitive and behavioral problems can be safely used in brain injured patients at risk for posttraumatic seizures as it is not associated with an increase in seizure frequency. There is Level 5 evidence that acute intramuscular Midazolam can be used for acute seizure cessation.

Levetiracetam is as effective as phenytoin in treating and preventing seizures in individuals in the intensive care unit post ABI. Anticonvulsants provided immediately post-ABI reduce the occurrence of seizures only within the first week. Anticonvulsants provided shortly post-ABI do not reduce long-term mortality, morbidity, or late seizures. Anticonvulsants have negative consequences on motor tasks. Early glucocorticoid exposure may increase seizures. Methylphenidate may not increase the risk of seizures. Intramuscular midazolam may be effective for acute seizure cessation. 10.7.1.1 Post-Traumatic Seizure Prophylaxis in Children Head injury is reported as the one of the leading causes of morbidity and mortality in children (Young et al., 2004; Kraus et al., 1990). PTS contributes to secondary injury following head injury and has been commonly observed in children with moderate to severe brain injury (Annegers et al., 1980). Children are different from adults in terms of mechanism of injury and likely the pathophysiology leading to the development of PTS. Children have been

21

reported to react differently to a brain injury than adults, particularly with an increased amount of significant edema (Aldrich et al., 1992). This may affect the development of PTS as intracerebral heme deposition has been postulated to be an important mediator in the pathogenesis of both early and late PTS (Willmore, 1990). As mentioned earlier, prophylactic anticonvulsants have proved effective in reducing early PTS in adults and thus it is important to investigate their efficacy in the pediatric population. Individual Studies
Table 10.8 Pharmacological Seizure Prevention or Prophylaxis in Children following ABI Author/Year/ Country/ Methods Outcome Study design/ PEDro and D&B Score Young et al., (1983) USA RCT PEDro = 6 D&B = 23 Young et al., (2004) RCT USA PEDro= 6 D&B = 19 N=41 Pediatric subjects with either a penetrating missile wound or a blunt head injury who were admitted within 24 hours following a severe head injury participated in this study. Same method of randomization as that employed in Young et al. 1983 [1983a]. There was no significant difference between groups regarding the percentage of children having late seizures (> 7 days post-injury).

N=102 Children under the age of 16 who The occurrence of post-traumatic experienced an acute blunt head injury with a seizures within 48 hours marked alterations in consciousness defined between groups was compared. as GCS score 10 for patients 4 yrs of age No significant differences in the or Childrens Coma Scale (CCS) score 9 incidence of early post-traumatic for patients younger than 4 yrs of age, and seizures within the 48 hours pulse rate > 60 beats/min were randomized observation period between to phenytoin or placebo within 60 minutes of groups (phenytoin = 7% vs. presentation to a pediatric trauma centre. placebo = 5%). Phenytoin group received initial intravenous loading dose of 18 mg/kg of body weight, infused over 20 minutes. Maintenance doses of 2 mg/kg of body weight of phenytoin were administered every 8 hours for 48 hours for a total of 5 additional doses. Placebo group received an equivalent volume of the placebo solution. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al. 2002). D&B = Downs and Black (1998) quality assessment scale score.

Discussion We identified two RCTs investigating the incidence of PTS in pediatric ABI patients who were prophylactically treated with phenytoin. In the first study, Young et al. (1983c) investigated the incidence of late PTS in 46 children who were prophylactically treated with phenytoin or placebo within 24 hours of injury onset. The authors reported that phenytoin was ineffective in reducing the incidence of late seizures compared with placebo. In the more recent study

22

conducted by a different group of investigators, Young and colleagues evaluated the efficacy of phenytoin in reducing the incidence of early seizures in 102 children (Young et al., 2004). Similar to the findings for late seizures, these authors reported that phenytoin did not reduce the rate of early seizures. Conclusions There is Level 1 evidence that phenytoin does not reduce the occurrence of early seizures in children. Moreover, there is also Level 1 evidence from another study that phenytoin is ineffective in reducing late seizures in children.

Phenytoin does not reduce early or late seizures in children post-ABI.

10.7.2 Surgical Treatment of Post-Traumatic Seizures Yablon and Dostrow (2001) noted the recent interest in a subgroup of ABI patients who experience continued PTS despite treatment with multiple antiepileptic drugs. For this special group of patients, surgical treatment may be a viable option. Individual Studies
Table 10.9 Surgical Treatment of Post-Traumatic Seizures Author/Year/ Country/ Study design/ D&B Score Marks et al., (1995) USA D&B = 12 Case Series

Methodology

Outcome

N=25 (17 males: 8 females) head Seizures were successfully localized injuryed patients (mild to severe injuries) in 9 patients. All nine underwent who sustained a head injury that surgical excision and were seizure preceded the onset of seizures and that free 1-year post surgery. The was of sufficient magnitude to cause remaining 16 patients did not have a either loss of consciousness or PTA. focal MRI lesion and their seizures Patients underwent surgical resection were not adequately localized. when there was sufficient concordance of In those patients who showed a presurgical data (MRI, ictal and favorable reduction in seizures intericatal audiovisual and EEG following surgical excision, brain monitoring, intracarotid amobarbital and injury lesions were specifically limited intracranial EEG monitoring) to identify to the hippocampus or neocortex. the seizure focus. D&B = Downs and Black (1998) quality assessment scale score.

Surgical Excision of the Post-Traumatic Seizure Focus Some studies have reported a decrease in seizures following resective surgery among a selected group of PTE patients (Diaz-Arrastia et al., 2000; Doyle et al., 1996). The major challenge encountered by this treatment approach is the

23

accurate localization of the exact region responsible for the development of seizures, particularly in patients with severe ABI who frequently show multiple and bilateral sites of brain injury (Diaz-Arrastia et al., 2000). Marks et al. (1995) reported that in a cohort of 25 patients with PTS, surgical excision of the presumed area responsible for PTS resulted in favorable seizure reduction in less than half of these patients. In those patients who showed a favorable reduction in seizures following surgical excision, brain injury lesions were specifically limited to the hippocampus or neocortex (Marks et al., 1995) thus, making the identification and excision more accurate. Thus, surgical excision of the post-traumatic seizure focus may only be a viable treatment option for a subgroup of ABI patients in whom the site of the brain injury lesion can be accurately identified, thus excluding patients suffering severe ABI with multiple and bilateral localization of brain injury. Conclusions There is Level 4 evidenced that a subgroup of ABI patients where the seizure focus can be accurately localized would benefit from surgical excision. Surgical excision can reduce seizures if the focus of the seizures can be localized.

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10.8 Summary
1. There are several patient and injury characteristics that increase the likelihood for the development of late PTS. Some important patient characteristics include: increasing age, premorbid alcohol abuse, and family history. In terms of injury characteristics, markers of increasing injury severity such as penetrating injuries and depressed skull fracture increase the risks of late PTS. A seizure occurring immediately after the injury substantially increases the risk of late PTS. As the severity of the brain injury increases, the period of time for which a survivor is at risk of developing PTS also increases. Seizures which occur after the first week of the injury have an increased chance of seizure recurrence. There is Level 1 evidence to suggest levetiracetam is as safe and effective as phenytoin in treatment and prevention of seizures in the intensive care unit in individuals post ABI. Based on meta-analysis and the findings of this review there is Level 1 evidence that anticonvulsants given during the first 24 hours postABI reduce the occurrence of early seizures (within the first week post-injury). There is Level 1 evidence that anticonvulsants given shortly after the onset of injury, do not reduce mortality or persistent vegetative state or the occurrence of late seizures (> one week post-injury). There is Level 1 evidence that seizure prophylactic treatment with either phenytoin or valproic acid results in similar incidences of early or late seizures and similar mortality rates. There is Level 1 evidence that both phenytoin and carbamazepine have negative effects on cognitive performance, particularly on tasks with motor and speed components, which theoretically may have a negative impact upon learning during rehabilitation. There is Level 2 evidence that glucocorticoid exposure after brain injury is not associated with a decrease in late seizures, and early exposure (< 2 days after injury) is associated with increased seizure activity. There is Level 4 evidence that methylphenidate for the treatment of cognitive and behavioral problems can be safely used in brain injured patients at risk for posttraumatic seizures as it is not associated with an increase in seizure frequency.

2.

3.

4.

5.

6.

7.

8.

9.

25

10.

There is Level 5 evidence that acute intramuscular midazolam can be for acute seizure cessation. There is Level 1 evidence from one study that phenytoin does not reduce the occurrence of early seizures in children. Moreover, there is also Level 1 evidence from another that phenytoin is ineffective in reducing late seizures in children. There is Level 4 evidenced that a subgroup of ABI patients where the seizure focus can be accurately localized would benefit from surgical excision.

11.

12.

26

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