Treatment of Post-Traumatic Seizures

Schierhout and Roberts (2001) reported that a seizure occurring soon after head injury may cause secondary brain damage by increasing metabolic demands of the brain, increasing intracranial pressure, and leading to excessive amounts of neurotransmitter release. For this reason, the primary therapeutic objective in the use of anticonvulsant drugs has been the prevention of early seizures in an attempt to minimize the extent of secondary brain damage following TBI. 

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 in stable patients, with impaired mental and motor function being the most common adverse effects; serious adverse effects, including deaths as a result of hematological reactions, have been also reported (Reynolds et al. 1998). Schierhout and Roberts (2001) have suggested that the injured brain’s response to anticonvulsants may be such that toxic effects could be more pronounced and neurological recovery may be delayed.  

Seizure Prevention or Prophylaxis

Initially, retrospective and nonrandomized clinical trials in humans showed favourable results for the efficacy of anti-epileptic drug prophylaxis; however, prospective investigations of chronic prophylaxis for LPTS have been less impressive. This section summarizes literature exploring the use of various drugs for seizure prevention. 

Table: Seizure Prevention or Prophylaxis

Table: Summary of RCTs Studying Prophylaxis for Early and Late Seizures

Authors/Year N Methods Results
Early Seizures Late Seizures
Szaflarski et al. (2010) 52 Phenytoin versus Levetiracetam  ND NA
Temkin et al. (1990) 379 Phenytoin (1wk) versus Valproate (1mo) versus Valproate (6mo)   ND ND
Manaka (1992) 191 Phenytoin vs. Placebo  NA ND
Temkin et al. (1990) 123 Phenytoin vs. Placebo + ND
Young et al. (1983)a 244 Phenytoin vs. Levetiracetam  ND NA
Young et al.  (1983)b 179 Phenytoin (1wk) vs. Valproate (1mo) vs. Valproate (6mo)  NA ND
McQueen et al. (1983) 164 Phenobarbital vs. No treatment NA ND

ND=No difference between groups; + = Improvement compared with control; - = Impairments compared with control; NA=Not applicable.

Table: Summary of non-RCT Studies Studying Prophylaxis of Early and Late Seizures

Authors/Year N Methods Results
Early Seizures Late Seizures
Radic et al. (2014) 288

Phenytoin versus Levetiracetam

ND NA
Gabriel et al. (2014) 19

Phenytoin versus Levetiracetam
*groups were not similar at baseline

ND ND
Bhullar et al. (2014) 93 Phenytoin versus No prophylaxis ND NA
Inaba et al. (2013) 813 Phenytoin versus Levetiracetam ND NA
Kruer et al. (2013) 109 Phenytoin versus Levetiracetam ND NA
Jones et al. (2008) 27 Phenytoin versus Levetiracetam ND NA
Formisano et al. (2007) 137 Anti-epileptic medication versus no medication NA -
Watson et al. (2004) 404 Glucocorticoids (within 1d) versus no glucocorticoids NA -

ND=No difference between groups; + = Improvement compared with control; - = Impairments compared with control; NA=Not applicable.

Discussion

When it comes to seizure prophylaxis, phenytoin is the most commonly studied medication. When the administration of phenytoin is compared to a placebo, its effect on the occurrence of early seizures is inconclusive; Bhullar et al. (2014); Temkin et al. (1990), found it to be effective but Young et al. (1983) did not. A systematic review by Thompson et al. (2015) found that the traditional antiepileptic drugs, phenytoin or carbamazepine, decreased the risk of early seizures compared to controls (RR 0.42; 95% CI, 0.23 to 0.73, p=0.003); however, the evidence was low quality. Moreover, phenytoin was found to be no more effective than placebo in preventing late seizures (McQueen et al. 1983; Temkin et al. 1990; Young et al. 1983). In fact, Formisano et al. (2007) found that the occurrence of late seizures was significantly higher in patients treated with anti-epileptic medications than those who were not. It should be noted that phenytoin has been shown to have a negative impact on recovery. Dikmen et al. (1991) found that severely injured individuals receiving phenytoin performed more poorly on neuropsychological measures than controls at 1 month but no significant differences were found at 1 year. The following year (12 to 24 months), phenytoin was shown to have a small but negative effect on cognition (Dikmen et al. 1991). Further, those taking phenytoin had longer hospital stays and worse functional outcomes at discharge than individuals receiving no treatment (Bhullar et al. 2014). Overall, the evidence for the use of phenytoin for prevention of seizures is not favourable. There was no significant difference in mortality between those treated with antiepileptic drugs (phenytoin and carmazepam) and control subjects (RR 1.08; 95% CI, 0.79 to 1.46, p=0.64)(Thompson et al. 2015).  

When phenytoin was compared to levetiracetam, the two drugs were comparable in terms of seizure rates (Inaba et al. 2013; Jones et al. 2008; Kruer et al. 2013; Radic et al. 2014), complications, adverse drug reactions, mortality rates (Inaba et al. 2013) and length of hospital stay (Kruer et al. 2013). A randomized controlled trial (RCT) by Szaflarski et al. (2010) found similar results in terms of there being no difference for early seizure rates, death or adverse events between the two drugs; however, the authors found that those on levetiracetam performed significantly better on the Disability Rating Scale at 3 and 6 months (p=0.042), and the Glasgow Outcome Scale at 6 months (p=0.039) post intervention compared to the phenytoin group. Furthermore, upon differentiation Radic et al. (2014) found that individuals with a midline shift greater than 0 millimeters were at a higher risk for electrographic seizures and a lower risk for adverse drug reactions on levetiracetam compared to phenytoin. Overall, a meta-analysis by Zafar et al. (2012) concluded that there was no superiority of either drug at preventing early seizures.

In terms of other medications studied, phenobarbital alone has been shown to have no prophylactic effect on PTE (Manaka 1992). Glucocorticoids given within one day post injury may put patients at an increased risk of developing late seizures (Watson et al. 2004); however, there is no association between late seizures and glucocorticoids if given after the first day post injury (Watson et al. 2004).

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 et al. (1992) reported on a collection of ten case studies of patients with TBI 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 was the only reported side effect.

Conclusions

There is Level 1b evidence to suggest that levetiracetam is as safe and effective as phenytoin in the treatment and prevention of early seizures in individuals in the intensive care unit post ABI.

There is Level 1b 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 1a evidence that anticonvulsants given shortly after the onset of injury do not reduce mortality, persistent vegetative state, or the occurrence of late seizures (>1 week post injury).

There is Level 1a evidence that seizure prophylactic treatment with either phenytoin or valproate results in similar incidences of early or late seizures and similar mortality rates. 

There is Level 2 evidence that glucocorticoid exposure after brain injury is not associated with a decrease in late seizures, and early exposure (within 1 day post 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 post-traumatic seizures as it is not associated with an increase in seizure frequency.

There is Level 4 evidence that acute intramuscular Midazolam can be used for acute seizure cessation.

There is Level 2 evidence indicating that phenobarbital given post ABI does not reduce the risk of late seizures.

 

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 only reduce the occurrence of seizures within the first week.

Anticonvulsants provided shortly post ABI do not reduce late seizures.

Anticonvulsants have negative consequences on motor tasks.

Intramuscular midazolam may be effective for acute seizure cessation.

Phenobarbital has not been shown to be effective in reducing the risk of late seizure development post ABI.

Glucocorticoid administration increases the risk of developing first late seizures when administered within one day post injury; however, it does not impact late seizures when administered outside that time frame.

 

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. 

Surgical Excision of the Post-Traumatic Seizure Focus

Some studies have reported a decrease in seizures following surgical resection among a selected group of PTE patients (Diaz-Arrastia et al. 2000; Doyle et al. 1996). The major challenge in this treatment approach is the accurate localization of the exact region responsible for the development of seizures. This is particularly true for patients with severe ABI who frequently show multiple and bilateral sites of brain injury (Diaz-Arrastia et al. 2000). 

Table: Surgical Treatment of Post-Traumatic Seizures 

Discussion

Marks et al. (1995) reported that, in a cohort of 25 patients with PTS, it was possible to successfully localize the seizure focus in less than half of the sample. Subsequent surgical excision of the area presumed to be the seizure focus resulted in seizure reduction in all treated patients. In those patients who showed a favourable result, the brain injury lesion was specifically limited to the hippocampus or neocortex (Marks et al. 1995); thus, making the identification and surgical resection more accurate. This study supports that surgical excision of the seizure focus may only be a viable treatment option for a subgroup of ABI patients in whom the site of brain injury can be accurately identified. Therefore patients suffering severe ABI with multiple and bilateral localizations would not be suitable.

In a more recent study, Hakimian et al. (2012) retrospectively examined patients with TBI who had an extratemporal resection for PTE. The resection resulted in 28% of patients being seizure free, 50% had a reduction in seizure frequency, and 19% did not benefit from treatment. Overall, good to excellent outcomes were achieved and the risk of complications was found to be minimal. Zheng et al. (2013) found that for 63.9% of patients with supratentorial meningioma and preoperative seizures, were seizure free post-surgery.  

Conclusions

There is Level 4 evidence that a subgroup of ABI patients (those where the seizure focus can be accurately localized) would benefit from surgical resection for post-traumatic seizures.

There is Level 4 evidence that extratemporal resection is effective in controlling post-traumatic epilepsy.

 

 

Surgical resection can reduce seizures if the focus of the seizures can be localized.