1. Anticonvulsant Therapy for Traumatic Brain Injury
Kuang-Yang Hsieh, M.D. ph.D.
Department of Psychiatry
Chimei Medical Center

2. Seizures after traumatic brain injury (TBI)
Early posttraumatic seizure: occurring within the first week after injury
Late posttraumatic seizure: occurring more than a week (months or years) after injury
Posttraumatic epilepsy: recurring late seizures

3. Nature of TBI influences the risk of epilepsy
Patients who have penetrating injury, depressed skull fracture, or subdural/intracerebral hematoma are more susceptible.

4. Risk of epilepsy correlates with severity 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

5. Epidemiology and natural course of posttraumatic epilepsy (PTE)
15-20 % of patients with severe TBI developing PTE.
PTE occurs in 20-25% patients who have an early seizure, in 80% of those who have a late seizure.
80-90% of patients with PTE have their first unprovoked seizure within 2 years after TBI.
Patients with no seizures within 3 years after the injury have only a 5% chance of developing PTE.
About half of PTE patients have 3 or fewer seizures and go into spontaneous remission.

7. Pathogenesis of PTE
Iron hypothesis: a cascade of events including hemorrhage, hemolysis, liberation of iron or heme, free radical formation, peroxidation and cell death.
Some have proposed the existence of a therapeutic window of opportunity of about 1 hour after traumatic brain injury. During this period, an agent may prevent or abort the epileptogenic process. Studies to explore such treatment are underway.

8. Treatment of posttraumatic seizure/epilepsy (1)
Preventive anticonvulsants do not affect the overall prognosis of TBI, thus are not routinely given.
Since seizure activity is likely to further damage the injured brain, early seizure should be promptly treated, and anticonvulsants are usually effective.
Treatment of early seizure does not decrease the risk of late seizure.

9. Treatment of posttraumatic seizure/epilepsy (2)
For late seizure, treatment is not mandatory, as some patients with a low frequency of seizures may choose not to take regular medication.
The efficacy of preventive anticonvulsants for late seizure is unsatisfactory, under a 25% reduction in seizures.

12. Requirement of an ideal anticonvulsant for posttraumatic seizure/epilepsy
No adverse effect on cognitive functions
No adverse drug interactions
Effective for emotional instability
Effective for depression
Well tolerated

13. Phenytoin, phenobarbital, diazepam, clonazepam and topiramate increase the risk of impairing cognitive function.
Phenytoin, phenobarbital and carbamazepine are inducers of hepatic enzymes, leading to reduced serum levels of other drugs.

14. Valproate, carbamazepine and lamotrigine are mood stabilizers, maybe helpful for emotional instability.
Lamotrigine is more effective for depression.
Phenobarbital and topiramate may worsen depression. 

15. Phenobarbital, diazepam and clonazepam are associated with sedation.
Carbamazepine and phenytoin are associated with hepatotoxicity.
Carbamazepine, phenytoin, phenobarbital and lamotrigine are associated with Stevens-Johnson syndrome.

16. Risk of Stevens–Johnson syndrome and toxic epidermal necrolysis
risk per new users
Carbamazepine
1.4
Phenytoin
8.3
Phenobarbital
8.1
Lamotrigine
2.5
Valproate
0.4
Neurology 2005; 64:

17. cognition
drug interaction
emotion
depression
other side effects
phenytoin ╳
carbamazepine ○
valproate
lamotrigine
topiramate
phenobarbital
clonazepam
diazepam

18. Conclusion
Among the old anticonvulsants, valproate is the best choice for treatment of posttraumatic seizure and epilepsy.
For adjunctive therapy, newer anticonvulsants are generally well-tolerated and suitable. Among them lamotrigine is the best for mood symptoms.

19. Thanks for attention