antiepileptics in traumatic seizures

1. Prophylactic Anti Epileptics In
Post traumatic Seizures

2. Introduction
• Seizures are a longterm complication of
trauma
• Early seizures- less likely to recur
• 4% of epilepsy –are traumatic
• Major disability in trauma survivors, 15-24
years

3. Classification of post traumatic
seizures
• Immediate /concussive seizures < 24 hours
• Early 24 hrs – 7 days
• Late >7 days

5. Late post-traumatic epilepsy
• Pathogenesis of late PTE remains unknown
• Studies suggest that - Iron-induced lipid peroxidation of
neural membranes may accompany cerebral
haemorrhage
• prophylactic use of standard anticonvulsant drugs is
unsubstantiated
• K.A. Dakin, D.F. WeaverMechanisms of post-traumatic seizures: a quantum
pharmacological analysis of the molecular properties of an epileptogenic focus
following iron-induced membrane peroxidation. Seizure.Europian journal of
Epilepsy DOI: http://dx.doi.org/10.1016/S1059-1311(05)80098-6

6. Late PTE
• 86% of patients with one late posttraumatic
seizure had a second seizure within 2 years
• Haltiner AM, Temkin NR, Dikmen SS. Risk of seizure recurrence after the
first late posttraumatic seizure. Arch Phys Med Rehabil 1997;78:835–40.

7. Incidence of seizures following
trauma
Severe head injury -7.1% within 1 year and
11.5% in 5 years,
moderate injury -0.7 and 1.6%,
mild injury -0.1 and 0.6%.
 Annegers JF, Grabow JD, Groover RV, Laws ER Jr, Elveback LR,
Kurland LT. Seizures after head trauma: a population study.
Neurology. 1980 Jul;30(7 Pt 1):683-9.

8. Overall incidence
Overall incidence of PTEs, a value that ranges
from a low of ∼4% to a high of 53%

9. • Seizure activity in the early post-traumatic
period following head injury may cause
secondary brain damage as a result of
increased metabolic demands, raised
intracranial pressure and excess
neurotransmitter release.

10. NATURAL HISTORY OF
POSTTRAUMATIC EILEPSY
• The lifetime total number of seizures in patients
with PTE is not associated with any identifiable
variables such as age or severity of injury,
• 39% of patients in the Korean conflict veteran
series had a total of between one and three
seizures during a 10-year period of follow-up.
• Of the same group, however, 38% had >30
seizures
• Caveness WF, Meirowsky AM, Rish BL, et al. The nature of posttraumatic
epilepsy. J Neurosurg 1979;50:545–53.

11. • Remission rates among patients with PTE range from 25 to
40%, with higher overall remission rates reported in studies
done after the development of effective AEDs.
• One early study found that seizure remission was less likely
in patients whose seizures began later after injury,
especially if the latency to seizure onsetwas>4 years
• Jennett B. Epilepsy after non-missile head injuries. England:
William Heinemann Medical Books, 1975.

12. • However, no significant relation exists between
the latency to first seizure and seizure duration or
persistence , although patients with frequent
seizures in the first year will often continue to
have frequent seizures and have a smaller chance
of seizure remission .
• Salazar AM, Jabbari B, Vance SC, et al. Epilepsy after
penetrating head injury, I: clinical correlates: a report of
theVietnam Head Injury Study. Neurology 1985;35:1406–14.

13. • Most patients who will have a second unprovoked late
PTE do so during the first 2 years after their first late
PTE. Haltiner et al. reported that up to 86% of TBI
survivors with a first PTE will also have a second within
the following 2 years .
• A certain percentage of PTS patients remain refractory
to AED therapy. For example, in the treatment arms of
various anticonvulsant prophylactic trials, a pooled
estimate of 13.3% seized despite aggressive treatment
regimens .
• Schierhout G, Roberts I. Prophylactic antiepileptic agents after head
injury: a systematic review. JNNP 1998;64:108–12.

14. Risk factors
Chesnut RM: Secondary brain insults after head injury: clinical perspectives.
New Horiz 1995, 3:366-75.
Temkin NR: Risk factors for posttraumatic seizures in adults. Epilepsia 2003,
44(Suppl 10):18-20.

17. • Prophylactic AED...

18. • The idea behind the use of AEDs in the
immediate post-injury period is based on the
desire to prevent the development of late PTE
as a long-term, and at times debilitating,
comorbidity, ie, finding a time window for an
intervention that will stop the process of
epileptogenesis.

19. • As per guidelines from multiple organizations,
including the Brain Trauma Foundation and the
American Academy of Neurology, the most
commonly used prophylactic agent is PHT, which
is typically administered for the first 7 days after
TBI.
• Chang BS, Lowenstein DH; Quality Standards Subcommittee of the American Academy of
Neurology. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain
injury: report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology. 2003;60(1):10–16.
• Rowe AS, Goodwin H, Brophy GM, et al; Neurocritical Care Society Pharmacy Section. Seizure
prophylaxis in neurocritical care: a review of evidence-based support. Pharmacotherapy.
2014;34(4):396–409.

20. • But, while prophylaxis with PHT decreases the
incidence of early posttraumatic seizures from
14.2% to 3.6% when compared with placebo,
this treatment has not been shown to
decrease the risk of late posttraumatic
seizures and epilepsy
• Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin
for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497–502.

21. Prophylactic AED
randomised controlled trials

22. Cont..

23. Cochrane review...
• six randomised controlled trials, including 1405 participants
• the pooled relative risk (RR) for early seizure prevention was 0.34 (95%CI
0.21, 0.54); based on this estimate, for every 100 patients treated, 10 would
be kept seizure free in the first week.
• Seizure control in the acute phase was not accompanied by a reduction in
mortality (RR = 1.15; 95%CI 0.89, 1.51), a reduction in death and
neurological disability (RR = 1.49; 95%CI 1.06, 2.08 for carbamazepine
and RR = 0.96; 95%CI 0.72, 1.26 for phenytoin) or a reduction in late
seizures (pooled RR = 1.28; 95%CI 0.90, 1.81). The pooled relative risk for
skin rashes was 1.57 (95%CI 0.57, 39.88).
• Schierhout G1, Roberts I, Antiepileptic drugs for preventing seizures following
acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Jun
13;6:CD000173. doi: 10.1002/14651858.CD000173.

24. author concluded
• that Prophylactic AED -reduces early seizures,
no evidences for late seizures.
• Pitfall - Insufficient evidence is available to
establish the net benefit of prophylactic
treatment at any time after injury.

25. Conclusions—Seizures occur in more than one in
five patients during the 1st week after moderate-to-
severe brain injury and may play a role in the
pathobiological conditions associated with brain
injury.

26. • Whether the usual 7- day course of antiepileptic
prophylaxis established by Temkins et al., and
now widely used within the neurosurgical
community for the TBI population, could be
applied to specific subset of patients????
• The role of antiseizure prophylaxis following
head injury. Brain Trauma Foundation:
Antiseizure prophylaxis. J Neurotrauma.
2007;24:S83–6.

27. • There are ample number of evidences
regarding prophylactic AED for early PTE but
evidences are lacking for late PTE

28. PTE in paediatric population
• Prophylactic AED is recommended in children
with diffuse cerebral edema, acute subdural
hematoma, open, depressed skull fracture with
parenchymal damage, or severe head injury
• 35% of severely head-injured children compared
to 5.1% with minor head injury .
• Hahn YS1, Fuchs S, Flannery AM, Barthel MJ, McLone DG. Factors
influencing posttraumatic seizures in children. Neurosurgery. 1988
May;22(5):864-7.

29. • BTF recommended prophylaxis therapy to
prevent early post-traumatic seizure in TBI
patients who are at high risk for seizures
• The risk factors include: GCS score < 10, cortical
contusion, depressed skull fracture, subdural
hematoma, epidural hematoma, intracerebral
hematoma, penetrating TBI, and seizures within
24 hours of injury
• Chesnut RM: Secondary brain insults after head injury:
clinical perspectives. New Horiz 1995, 3:366-75.
• Temkin NR: Risk factors for posttraumatic seizures in adults.
Epilepsia 2003, 44(Suppl 10):18-20.

30. • Vivek Ramakrishnan et al. Anti-epileptic prophylaxis in traumatic brain injury:
A retrospective analysis of patients undergoing craniotomy versus
decompressive craniectomy, Surg Neurol Int. 2015; 6: 8. Published online 2015
Jan 20. doi: 10.4103/2152-7806.149613 PMCID: PMC4310133
• Study shows a trend toward increased seizure incidence in
craniectomy group, which does not reach significance, but
suggests they are at higher risk. Whether this higher risk
translates into a benefit on being on AEDs for a longer
duration than the current standard of 7 days cannot be
concluded as there is no significant difference or trend on
the onset date for seizures in either group. Moreover, a
prospective study will be necessary to more profoundly
evaluate the duration of AED prophylaxis for each one of
the stated groups.

31. • Ideal AED.....

32. • None of the drugs studied (phenytoin,
phenobarbital, their combination,
carbamazepine, valproate, or magnesium)
have shown reliable evidence that they
prevent, or even suppress,
epileptic seizures after TBI
• Epilepsia. 2009 Feb;50 Suppl 2:10-3. doi: 10.1111/j.1528-1167.2008.02005.x.
• Preventing and treating posttraumatic seizures: the human experience.
• Temkin NR1.

33. Leviteracetam vs phenytoin
• Past attempts at preventing posttraumatic
epilepsy (PTE) using antiepileptic drugs (AEDs)
have been unsuccessful, probably because
those older AEDs either had no
antiepileptogenic effect in animal models
(phenytoin sodium and carbamazepine) or
had effects in doses too high and toxic for
human use (phenobarbital sodium, valproate
sodium, and clonazepam).

34. Incidence of PTE less with
levetiracetam- Pavel kleim et al 2012

35. • Löscher and Brandt review:
• Relevant levetiracetam levels in blood retards
kindling with a true antiepileptogenic (vs
anticonvulsant
• prevents epilepsy in a genetic model of epilepsy,
the “spontaneously epileptic rat.”
• levetiracetam attenuates the development of
spontaneous seizures after self-sustaining status
epilepticus .

36. • block increases in neuronal excitability and
synchronization, 2 key processes of
epileptogenesis. Other AEDs (such as
phenobarbital, valproate sodium, lamotrigine,
or clonazepam) lack these effects.

37. • But controversies still exist....

38. Conclusions
Levetiracetam treatment resulted in a similar incidenceof EEG-proven PTS when
compared to phenytoin with similar ICU, hospital, and study drug cost.
Phenytoin prophylaxis was associated with a higher total AED cost than
levetiracetam.

39. Other drugs
• Prophylactic efficacy of other drugs, like lipid
peroxidation inhibitors, neuroprotectors
(especially antioxidants), glutamic receptor
blockers, NMDA receptor blockers, and drugs
that modulate apoptosis via caspasas
inhibition--- to be well established
• Rev Neurol. 2002 Mar 1-15;34(5):448-59.
• [Preventive prophylactic treatment in posttraumatic epilepsy].
• Oliveros-Juste A1, Bertol V, Oliveros-Cid A

40. Genetic study
To date, genetic studies have primarily focused on the molecular
events that contribute to epileptogenesis after traumatic injury.
APOE 4 has been associated
aminobutyric acid receptor
haptoglobin HPh2–2 allele
hypothesized that longer-term events have specific molecular
triggers, which in turn could be linked to specific genotypes.
warrant further study for targetted medications.
Gurnett CA, Hedera P. New ideas in epilepsy genetics: novel epilepsy genes, copy number alterations, and gene regulation. Arch
Neurol 2007;64:324 –328.
Benarroch EE. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology 2007;68:612– 614.
Bazan NG, Serou MJ. Second messengers, long-term potentiation, gene expression and epileptogenesis. Adv Neurol 1999;79:659–
664.
Prince DA. Epileptogenic neurons and circuits. Adv Neurol 1999;79:665– 684

41. Coclusions