Prophylactic Anti Epileptics In Post traumatic Seizures

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

Classification of post traumatic seizures

• Immediate /concussive seizures < 24 hours• Early 24 hrs – 7 days• Late >7 days

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

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.

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.

Overall incidence

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

• 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.

NATURAL HISTORY OFPOSTTRAUMATIC 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.

• 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.

• 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.

• 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.

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.

• Prophylactic AED...

• 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.

• 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.

• 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.

Prophylactic AEDrandomised controlled trials

Cont..

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.

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.

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.

• 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.

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

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.

• 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.

• 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.

• Ideal AED.....

• 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.

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).

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

• 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 .

• 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.

• But controversies still exist....

ConclusionsLevetiracetam 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.

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

Genetic studyTo date, genetic studies have primarily focused on the molecular

events that contribute to epileptogenesis after traumatic injury. APOE 4 has been associatedaminobutyric acid receptorhaptoglobin HPh2–2 allele hypothesized that longer-term events have specific moleculartriggers, 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

Coclusions