Anticonvulsant Therapy for Traumatic Brain Injury

Kuang-Yang Hsieh, M.D. ph.D.Kuang-Yang Hsieh, M.D. ph.D.Department of PsychiatryDepartment of Psychiatry

Chimei Medical CenterChimei Medical Center

Seizures after traumatic brain Seizures after traumatic brain injury (TBI)injury (TBI)

Early posttraumatic seizure: Early posttraumatic seizure: occurring within the occurring within the first week after injuryfirst week after injury

Late posttraumatic seizure: Late posttraumatic seizure: occurring more than a occurring more than a week (months or years) after injuryweek (months or years) after injury

Posttraumatic epilepsy: recurring late seizuresPosttraumatic epilepsy: recurring late seizures

Patients who have penetrating injury, Patients who have penetrating injury, depressed skull fracture, or depressed skull fracture, or subdural/intracerebral hematoma are more subdural/intracerebral hematoma are more susceptible.susceptible.

Nature of TBI influences the risk of epilepsy

Risk of epilepsy correlates with Risk of epilepsy correlates with severity of TBIseverity of TBI

Relative risk of developing epilepsy

General population 1

Patients with mild TBI 1.5

Patients with moderate TBI 3

Patients with severe TBI 17

Epidemiology and natural course Epidemiology and natural course of posttraumatic epilepsy (PTE)of posttraumatic epilepsy (PTE)

15-20 % of patients with severe TBI developing PTE.15-20 % of patients with severe TBI developing PTE. PTE occurs in 20-25% patients who have an early seizure, PTE occurs in 20-25% patients who have an early seizure,

in 80% of those who have a late seizure.in 80% of those who have a late seizure. 80-90% of patients with PTE have their first unprovoked 80-90% of patients with PTE have their first unprovoked

seizure within 2 years after TBI.seizure within 2 years after TBI. PatientsPatients with no seizures within 3 years after the injury with no seizures within 3 years after the injury

have only a 5% chance of developing PTE.have only a 5% chance of developing PTE. About half of PTE patients have 3 or fewer seizures and go About half of PTE patients have 3 or fewer seizures and go

into spontaneous remission.into spontaneous remission.

Pathogenesis of PTEPathogenesis of PTE

Iron hypothesis: Iron hypothesis: a cascade of events including a cascade of events including hemorrhage, hemolysis, liberation of iron or heme, hemorrhage, hemolysis, liberation of iron or heme, free radical formation, peroxidation and cell death.free radical formation, peroxidation and cell death.

Some have proposed the existence of a therapeutic Some have proposed the existence of a therapeutic window of opportunity of about 1 hour after traumatic window of opportunity of about 1 hour after traumatic brain injury. During this period, an agent may prevent brain injury. During this period, an agent may prevent or abort the epileptogenic process. Studies to explore or abort the epileptogenic process. Studies to explore such treatment are underway.such treatment are underway.

Treatment of posttraumatic Treatment of posttraumatic seizure/epilepsy (1)seizure/epilepsy (1)

Preventive anticonvulsants do not affect the overall Preventive anticonvulsants do not affect the overall prognosis of TBI, thus are not routinely given.prognosis of TBI, thus are not routinely given.

Since seizure activity is likely to further damage Since seizure activity is likely to further damage the injured brain, early seizure should be promptly the injured brain, early seizure should be promptly treated, and anticonvulsants are usually effective.treated, and anticonvulsants are usually effective.

Treatment of early seizure does not decrease the Treatment of early seizure does not decrease the risk of late seizure.risk of late seizure.

Treatment of posttraumatic Treatment of posttraumatic seizure/epilepsy (2)seizure/epilepsy (2)

For late seizure, treatment is not mandatory, as For late seizure, treatment is not mandatory, as some patients with a low frequency of seizures some patients with a low frequency of seizures may choose not to take regular medication.may choose not to take regular medication.

The efficacy of preventive anticonvulsants for The efficacy of preventive anticonvulsants for late seizure is unsatisfactory, under a 25% late seizure is unsatisfactory, under a 25% reduction in seizures.reduction in seizures.

Requirement of an ideal anticonvulsant Requirement of an ideal anticonvulsant for posttraumatic seizure/epilepsyfor posttraumatic seizure/epilepsy

No adverse effect on cognitive functionsNo adverse effect on cognitive functions No adverse drug interactionsNo adverse drug interactions Effective for emotional instabilityEffective for emotional instability Effective for depressionEffective for depression Well toleratedWell tolerated

Phenytoin, phenobarbital, diazepam, Phenytoin, phenobarbital, diazepam, clonazepam and topiramate increase the clonazepam and topiramate increase the risk of impairing cognitive function.risk of impairing cognitive function.

Phenytoin, phenobarbital and Phenytoin, phenobarbital and carbamazepine are inducers of hepatic carbamazepine are inducers of hepatic enzymes, leading to reduced serum enzymes, leading to reduced serum levels of other drugs.levels of other drugs.

Valproate, carbamazepine and lamotrigine Valproate, carbamazepine and lamotrigine are are mood stabilizersmood stabilizers, maybe helpful for , maybe helpful for emotional instability.emotional instability.

Lamotrigine is more effective for Lamotrigine is more effective for depression.depression.

Phenobarbital and topiramate may worsen Phenobarbital and topiramate may worsen depression. depression. 

Phenobarbital, diazepam and clonazepam Phenobarbital, diazepam and clonazepam are associated with sedation.are associated with sedation.

Carbamazepine and phenytoin are Carbamazepine and phenytoin are associated with hepatotoxicity. associated with hepatotoxicity.

Carbamazepine, phenytoin, phenobarbital Carbamazepine, phenytoin, phenobarbital and lamotrigine are associated with and lamotrigine are associated with Stevens-Johnson syndromeStevens-Johnson syndrome..

Neurology 2005; 64:1134-38Neurology 2005; 64:1134-38

risk per 10000 new users

Carbamazepine 1.4

Phenytoin 8.3

Phenobarbital 8.1

Lamotrigine 2.5

Valproate 0.4

Risk of Stevens–Johnson syndrome Risk of Stevens–Johnson syndrome and toxic epidermal necrolysisand toxic epidermal necrolysis

cognition drug interaction

emotion depression other side effects

phenytoin ╳ ╳ ╳carbamazepine ╳ ○ ╳valproate ○

lamotrigine ○ ○ ╳topiramate ╳ ╳phenobarbital ╳ ╳ ╳ ╳clonazepam ╳ ╳diazepam ╳ ╳

ConclusionConclusion

Among the old anticonvulsants, valproate is Among the old anticonvulsants, valproate is the best choice for treatment of the best choice for treatment of posttraumatic seizure and epilepsy.posttraumatic seizure and epilepsy.

For adjunctive therapy, newer For adjunctive therapy, newer anticonvulsants are generally well-tolerated anticonvulsants are generally well-tolerated and suitable. Among them lamotrigine is the and suitable. Among them lamotrigine is the best for mood symptoms.best for mood symptoms.

Thanks for attentionThanks for attention