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Journal of Clinical Neuroscience (2004) 11(1), 1–3

0967-5868/$ - see front matter ª 2003 Published by Elsevier Ltd.

doi:10.1016/j.jocn.2003.03.002

Review

Review of the role of anticonvulsant prophylaxis followingbrain injury

Sarah Olson MBCHB (OTAGO)MBCHB (OTAGO)

Auckland Hospital, 34 Jubilee Street, Greenslopes, Qld. 4120, Australia

Summary Anticonvulsants were once routinely used as prophyllaxis for all head injuries. There has been a decline in their recent use. The

evidence for use of prophylaxis is reviewed. Questions postulated will be answered with the best available evidence.

ª 2003 Published by Elsevier Ltd.

Keywords: seizure, trauma, anticonvulsants, prophyllaxis

QUESTIONS TO BE ANSWERED

1. Which head injuries are more likely to have seizures?2. When do seizures occur and what is the incidence?3. Should paediatric head injuries be isolated?4. What does a seizure at initial injury mean?5. Do seizures do any harm to the brain?6. Do anticonvulsants prevent seizures in the short and/or long

term?7. Do anticonvulsants alter combined mortality and morbidity of

head injuries?8. Do side effects of anticonvulsants outweigh benefits?9. Which anticonvulsant should be used?0. Cost/benefit analysis.

1. Which head injuries are more likely to have seizures?

Certain risk factors have been consistently identified as placinghead injured patients at significant risk of developing post-trau-matic seizures.

• GCS <10• Cortical contusion• Depressed skull fracture• Subdural haematoma• Extradural haematoma• Intracerebral haematoma• Penetrating head wound• Seizure within 24 h of injury1

2. When do seizures occur and what is the incidence?

Seizures are defined as impact seizures (<24 h after injury), earlyseizures (<1 week after injury) or late seizures (>8 days after in-jury).6 A first seizure can occur more then 10 years after the initialevent, although 95% of head injuries will remain seizure free if theyhave had no seizures during the first three years after injury.2

In civilian head injuries the incidence of early seizures wasbetween 4% and 25% and late post-traumatic seizures (PTSs) 9–42%. One to four percent occur as impact seizures.1 In penetrating

Received 11 March 2002

Accepted 19 March 2003

Correspondence to: Dr. S. Olson, 34 Jubilee Street, Greenslopes, Qld. 4120,

Australia. Tel.: +61-7-3240-2111; Fax: +61-7-3240-5851;

E-mail: saragl_olson@hotmail.com

brain injuries the risk of post-traumatic seizures is approximately50% in patients followed for 15 years in several studies. Four to10% occur within the first week.2

In a recent Class II study of continuous EEG monitoring in94 head injured patients for 14 days the combined incidence ofnon-convulsive seizures and overt seizures was 22%. In 52% theseizures were non-convulsive.3 The actual incidence of subclinicalseizure activity was more than twice that seen overtly.

Thus the incidence of seizures appears different in non-pene-trating compared to penetrating injuries. It is higher in penetratinginjuries and these appear to occur later than in non-penetratinginjuries. The incidence of non-convulsive seizures appears under-estimated.

3. Should paediatric head injuries be isolated?

No good data here.Class II data shows that young children are more likely to have

early seizures and adults late seizures.4

Class III study that 73.3% of seizures occurred within 24 h ofinjury.2

In a Class II study of 400 paediatric patients, identified risksfor post-traumatic seizures were; <2 years of age, severe headinjury and prolonged time of unconsciousness. CT findingswere not found to be related to the incidence of post-traumaticseizures.4

There is some Class II data that there is markedly alteredprotein binding and phenytoin metabolism in children.5

Disturbing changes in intellect have been reported in childrenon longterm anticonvulsants which may or may not be reversible.7

In conclusion there is little evidence available on paediatrichead injuries and anticonvulsant management but the limited dataavailable suggests that their seizure profile and response to an-ticonvulsants is different to adults.

4. What does a seizure at initial injury mean?

Despite appearing in the guidelines for the management of severehead injury and in other Class II studies as an independent riskfactor for the development of post-traumatic epilepsy,1 Annergersand colleagues found on multivariate analysis of their Class II dataof 4541 patients that early seizures were not an independent riskfactor and may rather be a marker of injuries of sufficient severityto cause late epilepsy. In Jennets Class I data, impact seizureswere recognised not to carry an excess risk of epilepsy and ap-peared to be a feature of mild concussive injuries. McCrory and

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2 Olson

colleagues studied such immediate concussive convulsions inAustralian sportsmen and came to the same conclusion. The in-vestigators questioned whether these events are seizures or a formof acute decerebration.8

Thus this question largely remains unanswered.

5. Do seizures do any harm to the brain?

It has been postulated that seizures may precipitate adverse effectsin the injured brain due to elevation in ICP, blood pressurechanges, changes in oxygen delivery, and excessive neurotrans-mitter release. The occurrence of seizures may also be associatedwith accidental injury, psychological effects, and loss of drivingprivileges. There has also been a belief that prevention of earlyseizures may prevent the development of chronic epilepsy. Ex-perimental studies have supported the idea that initial seizuresmay initiate kindling, that may then generate a permanent seizurefocus.1

Vespa in his Class II cohort of 94 patients found that the in-cidence of ICP> 20 was similar in the seizure and non-seizuregroups (42% and 38%, respectively). The mean overall ICP washigher in the non-seizure group, all of which was non-significant.The mean CPP was statistically higher on days of seizures (86.6)than on non-seizure days. (84.3).3

Haltiner and colleagues in a Class I trial, found more deathsamong patients who had early seizures. This observation wasexplained by the fact that these had more severe head injuries.They concluded that phenytoin was effective in preventing someearly seizures and that patients with early seizures had a higherdeath rate. The reduction of early seizures itself had no detectableimpact on mortality.9

There is thus no clear evidence that seizures are detrimental tobrain recovery.

6. Do anticonvulsants prevent seizures in the shortand/or long term?

Young et al. conducted a prospective randomised double blindstudy of 244 head injured patients and reported that phenytoin wasnot effective in preventing early or late seizures. However, manyof their patients did not have therapeutic levels.

McQueen et al. conducted a prospective randomised doubleblind study of 164 patients receiving Dilantin or placebo for theprevention of late PTS. No significant reduction in late PTS wasfound in the treatment group.

Glotzer et al. evaluated the effect of Carbamezapine in pre-vention of early and late PTS in a prospective randomised doubleblind study of 1139 patients. There was a significant reduction inthe number of early PTS in the treated group and no significantreduction in late PTS with treatment.

Pechedre et al. conducted a prospective randomised study ofphenytoin in 86 patients for early and late PTS, which was neitherblinded, or placebo controlled. There was a significant reductionin early PTS and also significant reduction in late PTS in theactive treatment group. The incidence of late PTS was higher thanin any of the similar trials, but the number of patients studied wassmall.

Temkin et al. reported the results of the largest prospectiverandomised double-blind placebo controlled trial to date. Thisrandomised 404 patients to evaluate the effect of phenytoin onearly and late PTS. There was a significant reduction in the in-cident of early PTS in the treated group. There was no significantreduction in the incidence of late PTS in the treated group. Thesurvival curves for the placebo and active treatment groupsshowed no significant difference.

Journal of Clinical Neuroscience (2004) 11(1), 1–3

Manake et al. conducted a prospective randomised doubleblind study of 126 patients receiving placebo or Phenobarbital forthe prevention of late PTS. There was no significant reduction inthe active treatment group.1;9

Class I studies do thus not support the routine use of anti-convulsants for the prevention of post-traumatic epilepsy. Routineseizure prophylaxis beyond one week is thus not recommended.

To prevent early seizures therapeutic levels must be obtained.

7. Do anticonvulsants alter combined mortality andmorbidity of head injuries?

In a study in 1973, 60% of clinicians in the USA used prophylacticanticonvulsants following head injury. A recent survey of 127neurosurgical departments has shown that 36% do not prophy-lactically treat head injured patents, 12% prescribe prophylacticanticonvulsant in all head trauma and the remaining 52% make adecision base on risk factors.6

In a Cochrane review of 10 RCT, there was found to be noevidence that treatment with prophylactic anticonvulsants reducedthe occurrence of late seizures or has any effect on death andneurological disability. Insufficient evidence was available toestablish the net benefit of prophylactic treatment at any time afterinjury.9

A recent Lancet review concluded there is reasonable evidencethat antiepileptic drugs started as soon as possible reduce thefrequency of early seizures. Phenytoin has the best evidence tosupport its use for this indication and, if treatment is given foronly one week, the risk of acute idiosyncratic reactions will besmall. There is no evidence that the prevention of early seizuresaffects mortality, morbidity or the development of late post-traumatic epilepsy.8

There is no evidence that prevention of early seizures affectsmortality or morbidity following head injury.

8. Do side effects of anticonvulsants outweigh benefits?

Animal models have shown that phenytoin reduces neuronaldamage in hypoxia, and that Carbamazepine and Valproate arealso thought to have neuroprotective effects. For this reason itwas believed that Phenytoin might have additional effects ratherthan seizure prophyllaxis only. However, antiepileptics unusuallyhave narrow therapeutic margins and well-documented toxicity,even in neurologically stable patients. The most common ad-verse effects are impaired mental and motor functions and cu-taneous and haematological reactions as severe as StevensJohnson syndrome. The injured brains response to this may bemore be more pronounced and neurological recovery could beimpaired.

In the Cochrane review, two RCTs documented skin rashes.On the pooled relative risk for every 100 patients treated, 4 woulddevelop skin rashes.

However, as the period of antiepileptic prophyllaxis extendedbeyond one week, the incidence of skin reactions increased andthus this may be an overestimate for treatment of only one weeksduration.9

Dikmen et al. found that Phenytoin significantly impairedperformance on neuropsychological tests at one month after injuryin severely head injured patients; however, the difference was notapparent at one year.10

Temkin documented adverse neuro-behavioural effects. Thistrial showed cognitive impairments in patients receiving antiepi-leptics. The authors did not report an overall effect measure. Thereis some preliminary evidence to suggest that anticonvulsants mayinhibit learning and brain plasticity in children.11

ª 2003 Published by Elsevier Ltd.

Review of the role of anticonvulsant 3

There is experimental evidence from animal research to sug-gest that patients treated with diazepam do not recover somato-sensory evoked potentials and dilantin may increase hemiplegia inhead injuries.3

There has also been some Class II data to suggest that bothPhenytoin and Carbamazepine have negative effects on cognition,particularly tasks with significant motor and speed components.These improved when patients stopped taking the drugs.13

There is thus no evidence for added benefits of using anti-convulsants other than that of preventing early seizures. The sideeffects become more prominent if treatment with anticonvulsantsis extended beyond one week. There is some disturbing evidence tosuggest cognitive impairment of patients on long term anticon-vulsants.

9. Which anticonvulsant should be used?

Phenytoin and Carbamazepine have been shown to prevent theoccurrence of early seizures in high-risk patients following headinjury.1

Valproate was recently studied in a RCT as it was believed thatthe more benign side effect profile of Valproate might make itmore attractive in prophyllaxis. However, in a RCT of 132 pa-tients, no benefit was found over short-term Phenytoin for pre-vention of early seizures and neither treatment prevents lateseizures. There was a trend towards high mortality rate amongValproate treated patients. The lack of additional benefits, and thepotentially high mortality rate seen in the Valproate treated groupsuggest that Valproate should not be used for prevention of post-traumatic seizures.12

New compounds such as free radical scavengers and antiper-oxidents show encouraging results, but their use is still experi-mental and their clinical use is limited.6

Thus it appears that any of the anticonvulsants reduce earlypost-traumatic seizures but that Phenytoin and Carbamazepinehave been best studied.

10. Cost–benefit analysis

Two million head injuries are seen in the ED in the USA per yearof which 500,000 are admitted. Survival rates are increasing as isthe cost of treatment. There has been found to be no difference inthe length of stay of in-patients who have seizures compared tothose who don’t.2

If preventing early seizures is the primary objective, then inmonetary terms the cost is small. In New Zealand the cost ofDilantin 300 mg for one week would be approximately $1.50 witha nine dollar dispensing fee. Tegretol at 200 mg bd would besimilarly costed and Valproate approximately double to quadruplethe cost of Phenytoin and Carbamazepine.17

In a prospective study of 210 patients no significant differencein neuropsychological outcomes at one year was found betweenthose head injured patients who had post-traumatic seizurescompared to those who did not.14

At 5 years post-injury, recurrent seizures play a large role inthe causes for readmission along with psychiatric difficulties andgeneral health maintenance.15

In a prospective study of 490 patients having seizures, estab-lished epilepsy appeared to reduce functional and social outcomebut had no effect on rehab goals and re-employment.16

Thus it appears that prophylaxis with anticonvulsants has nonet benefit in terms of cost of treatment in either the short or longterm except in those patients with established post-traumatic ep-ilepsy. If preventing early seizures per se is the primary objectivethen the monetary cost of prophylaxis is relatively small.

ª 2003 Published by Elsevier Ltd.

CONCLUSIONS

The theory behind prophylactic anticonvulsants was based onretrospective trials before the 1980s. The impression was that theoccurrence of seizures may cause adverse events in the injuredbrain and that seizures may also be associated with accidentalinjury, psychological effects and loss of driving privileges. It waspostulated that early seizures may predispose to chronic epilepsybecause of the kindling effect. For this reason early prophylacticanticonvulsants were advocated.

There is reasonable evidence that antiepileptic drugs started assoon as possible reduce the frequency of early seizures. There isno evidence that early seizures do any harm in terms of braininjury or in terms of monetary cost. There is no evidence that theroutine use of prophylactic anticonvulsants prevents late seizuresor has any impact on morbidity or mortality. The relevance ofimpact seizures remains uncertain.

Therefore, there seems no justification for the routine use ofantiepileptic drugs in patient with severe head injuries.

If preventing early seizures is the aim of the clinician thenPhenytoin has the best evidence supporting its use for this indi-cation. If treatment is given for only one week, the risk of acuteidiosyncratic reactions and the monetary cost will be small. Thisshould ideally be confined to those patients at most risk of sei-zures as outlined in the above article.

The role for seizure prophylaxis appears in economic terms toprevent rehospitalisations and enables relatively normal social andeconomic function in those patients with established epilepsy.

REFERENCES

1. Guidelines for the management of severe Head Injury. 1995 Brain TraumaFoundation. The Role of Antiseizure Prophylaxis following Head Injury.

2. Antiseizure prophylaxis for Penetrating Brain Injury. J Trauma 2001;51: S41–S43.

3. Vespa PM et al. Increased incidence and impact of nonconvulsive andconvulsive seizures after traumatic brain injury as detected by continuouselectroencephalographic monitoring. J Neurosurg 1999;91: 750–760.

4. Ratan SK, Kulshrestha R, Pandey R. Predictors of posttraumatic convulsions inhead injured children. Pediatr Neurosurg 1999; 30: 127–131.

5. Stowe CD et al. Altered phenytoin pharmokinetics in children with severe acutetraumatic brain injury. J Clin Pharmacol 2000; 4: 1452–1461.

6. Iudice A, Murril. Pharmacological prophylaxis of posttraumatic epilepsy. Drugs2000; 59: 1091–1099.

7. Camfield PR. Recurrent seizures in the developing brain are not harmful.Epilepsia 1997; 38(6): 735–737.

8. Chadwick D. Seizures and epilepsy after traumatic brain injury. Lancet 2000;355: 334–335.

9. Schierhout G, Roberts I. Antiepileptic drugs for preventing seizures followingacute traumatic brain injury. (Cochrane Review). In: the Cochrane Library,Issue 3, 2001. Oxford: Update software.

10. Dikmen SS, Temkin NR et al. A randomised double blind study of phenytoinfor the prevention of posttraumatic seizures. N Eng J Med 1990;323: 497–502.

11. Temkin NR, Dikman SS, Winn HR. Posttraumatic seizures. Neurosurg ClinNorth Am 1991; 2: 425–435.

12. Temkin NR, Dikmen SS et al. Valproate therapy for prevention ofposttraumatic seizure a randomised trial. J Neurosurg 1999; 91: 593–600.

13. Haltiner AM, Temkin NR et al. The impact of posttraumatic seizures one yearneuropsychological and psychological outcome after head injury. J IntoNeurosis Soc 1996; 2(6): 494–504.

14. Marwitz JH, Cifu DX et al. A multicenter analysis of rehospitalisations fiveyears after brain injury. J Head Trauma Rehab 2001;16(4): 307–317.

15. Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures intraumatic brain injury rehabilitation patients: brain injury factors causing lateseizures and influence of seizures on long-term outcome. Epilepsia1999; 40(5): 584–589.

16. Smith KR et al. Neurobehavioural effects of phenytoin and carbamazepine inpatients recovering from brain trauma: a comparative study. Arch Neurol 1994;51(7): 653–660.

17. Drug information. Auckland Public Hospital. 2001. Tess Camfield.

Journal of Clinical Neuroscience (2004) 11(1), 1–3