Does AED Prophylaxis Work in Posttraumatic Epilepsy December 2, 2012

Transcription

1 Does AED Prophylaxis Work in Posttraumatic Epilepsy December 2, 2012 Marc A. Dichter, MD, PhD University of Pennsylvania American Epilepsy Society Annual Meeting

2 Disclosure Name of Commercial Interest None Type of Financial Relationship None I was assigned to take the affirmative side in this debate American Epilepsy Society Annual Meeting 2012

3 Learning Objectives Preventing epilepsy in those with known risks (such as TBI) is critically important TBI may produce localized changes in the brain that create brief, localized seizures, and these may be suppressible by standard AEDs Seizures under some circumstances produce damage and foster further seizures New AEDs with new mechanisms of action are available that may suppress early post-tbi seizures Animal data now exist that indicate the feasibility of this approach in TBI and other paradigms American Epilepsy Society Annual Meeting 2012

4 The Problem

5 The argument Seizures develop after TBI The latency is unknown current ideas are all based on clinical seizure observations One hypothesis is that TBI is associated first with small, localized seizures that are not visible clinically or with routine scalp EEGs and that these seizures produce increased damage and other changes associated with the development of PTE Remember the kindling paradigm It is likely that an anti-seizure drug could suppress these There are no good data to support or refute this argument More than 15 effective and relatively safe AEDs are available to test this concept In several epilepsy models (including PTE), early treatment can prevent subsequent epilepsy It is certain that doing nothing will not solve this problem

6 Rationale for using anti-seizure drugs now AEDs are available, and we have extensive experience using them AEDs are relatively safe, are known to be effective in suppressing seizures at least, and in some cases, also suppressing some epilepsy associated changes Pilot clinical trials, and even a small network of trial centers, can be started now to develop infrastructure, techniques (including long term monitoring, etc), possible biomarkers, and a better understanding of the process of epileptogenesis in man after different risks

7 Introducing the RED syndrome Risk for Epilepsy Development

8 Post-traumatic epilepsy Trauma Epilepsy Neuronal loss Activation of microglia Altered gene expression Ion channels Receptors Peptides Everything Axon sprouting Neurogenesis New circuit formation Changes in astrocytes Which of these are critical for epileptogenesis?

9 Epileptic propensity Epileptic propensity Epileptic propensity Epileptic propensity Epileptic propensity Epileptogenesis Clinical One hit Multiple hits Seizures Clinical Seizures One hit Clinical Seizures Latent period Trauma Time Two hits Clinical Seizures Time Seizures? Multiple hits Clinical Seizures Time Seizures? Time Time

10 Proofs of concept Some anti-seizure drugs can interrupt kindling (PHB, VPA, LTG, TPM, LEV, LAC, VGB, BZDs) Ethosuximide treatment prevents epilepsy in WAG rats (Blumenfeld et al, Epilepsia 2008) TTX and Gabapentin prevent hyperexcitability in undercut cortex a different model but possibly analogous to TBI (Li, Graber et al, Neurobiol of Dis 2012) mtor inhibitors block epilepsy in TS mice and may also work in status epilepticus model (Zeng LH, Xu L, Gutmann DH, Wong M, Ann Neurol 2008) (Huang et al, Neurobiol Dis 2010) Cooling cortex around TBI prevents epilepsy (D Ambrosio et al, Ann Neurol, 2012)

11 S/W seizures in WAG rats Control 2m 4m 6m Klein et al, Brain Res, 2004

12 Ethosuximide treatment prevents epilepsy Note that even after 3 months, treated rats do not catch up to untreated subjects Blumenfeld et al, Epilepsia 2008

13 Posttraumatic epilepsy induced by FPI in the rat Grade 1 seizure Stays localized Lesion Grade 2 seizure Spreads in cortex D Ambrosio et al., Brain 2005

14 Paired scalp-eeg and epidural ECoG: grade 1 seizures Note: lack of ECoG seizure o pt Limited to cortical focus ECoG 1-5 ECoG Scalp pt-o Scalp pt-o Lack of scalp seizure 1s 1s D Ambrosio et al., Brain 2005

15 Paired scalp-eeg and epidural ECoG: seizures ECoG 1-5 Contralateral Ipsilateral Scalp 1s pt-o ECoG Scalp From Ray D Ambrosio

16 Progression of posttraumatic epilepsy E C o G - e v e n t p r o p o r t i o n * * * *** Grade1 Grade2 Grade3 * * * * * * Bilateral at onset Spreads from focus Weeks Post Injury From, Ray D Ambrosio

17 Frequency frequency (seizures/hr) 2 o C cooling prevents epileptic seizures after TBI (blind and randomized studies) A Cooling B Cont Cool, p< Slide Wk1 Wk2 Wk6 Unavailable Wk cool rpfpi ECoG 0.75 Randomization to treatment Time Post-FPI (weeks) D Ambrosio et al., Ann Neurol 2012

18 Time Time seizing Seizing (sec/hr) (s/hr) Frequenc y (Seizures/hr) frequency (seizures/hr) 2 o C cooling prevents epileptic seizures after TBI (blind and randomized studies) C Cool 8-10 wks, p<0.05 Slide 45 Unavailable cool Cooling blocks Cont Cool, n.s. Cool, p< Time Post-FPI (weeks) Time post-fpi (weeks) D Cont wks Cont 8-10 wks Cool wks, p<0.05 >1 s >3 s >5 s >15 s Seizure durations (sec) Seizure Definition Criterion seizures of all durations D Ambrosio et al., Ann Neurol 2012

19 All AEDs are not alike in their possible actions Current AEDs have multiple mechanisms of action Some work well for neuropathic pain Some are sedating; other s are not Some suppress abnormal network activity in AD models; others are ineffective Need to examine multiple AEDs to assess effectiveness in TBI models

20 Conclusion Epilepsy after TBI is an important problem that needs to be solved More basic research is needed, including testing newer AEDs in TBI models More clinical research is also needed to determine the phenomena and mechanisms associated with the epileptogenic process in man AEDs may prove useful in suppressing epileptogenesis if used early and appropriately Other strategies involving drugs that do not directly suppress seizures, or devices, are likely to be useful as well

21 Current prevention strategy after TBI This is unacceptable!

22 Impact on Clinical Care and Practice Individuals with moderate to severe TBI need to be monitored for epilepsy development Acute continuous scalp, subgaleal, and intracranial EEG monitoring may reveal subclinical seizures that are amenable to treatment early Early treatment with AEDs may reduce the incidence of PTE More basic and clinical research is needed in this area Doing nothing will definitely not solve this problem

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24 Yes we can! Yes we can! Yes we can!

25 AED Prophylaxis Does NOT Work in Posttraumatic Epilepsy December 2, 2012 Patrick Kwan, MD, PhD University of Melbourne, Melbourne, Australia Chinese University of Hong Kong, Hong Kong American Epilepsy Society Annual Meeting 25

26 Disclosure Eisai GSK Pfizer UCB Pharma Consultancy, research contract Consultancy, research contract Research contract Speaker, research contract American Epilepsy Society Annual Meeting

27 Learning Objectives Systematic reviews of clinical trials of AED prophylaxis for early and late posttraumatic seizures Highlights from individual studies American Epilepsy Society Annual Meeting

28 Classification of TBI-related Seizures Seizures 7 day = acute symptomatic (provoked) seizures <24 hours = immediate seizures 24 hrs to 7 days = early seizures Seizures >7 days = late (unprovoked) seizures = post-traumatic epilepsy Beghi E. Epilepsia 2003;44(Suppl. 10):21 6; Beghi E et al, Epilepsia 2010;51:

29 Observational Studies % with seizures Study AED(s) No. Follow-up (mo) Treated Untreated Servit 1981 PB, PHT Wohns 1979 PHT Young 1979 PHT Murri 1980 PB Murri 1992 PB Price 1980 VPA Beghi E. Epilepsia 2003;44(Suppl. 10):

30 RCT: Phenytoin to Prevent PTE Patients with severe TBI (predicted seizure risk 20%) Double-blind randomization to receive within 24 hrs of injury Placebo, or Phenytoin (i.v. then oral) for 12 months TDM to maintain therapeutic serum concentration Maintained in >70% patients Within therapeutic range in 75% of patients who had late seizures Temkin NR et al, N Engl J Med 1990;323:

31 Early Seizures P<0.001 Temkin NR et al, N Engl J Med 1990;323:

32 Late Seizures (PTE) P>0.02 Temkin NR et al, N Engl J Med 1990;323:

33 Prospective Controlled Studies of AED Prophylaxis for PTE after Severe TBI: Systematic Reviews Treatment groups Cochrane Beghi AAN Study Random AED (n) Control (n) McQueen 83 Y PHT (84) Placebo (80) Young 83 Y PHT (119) Placebo (95) Glötzner 83 Quasi CBZ (75) Placebo (76) Temkin 90 Y PHT (208) Placebo (196) Temkin 99 Y VPA (247) PHT 1 wk (132) Manaka 92 Y PB (50) None (76) Pechadre 91 Quasi PHT (34) None (52) Servit 81 N PHT+PB (143) None (24) CBZ. Carbamazepine; LEV, levetiracetam; PB, phenobarbital; PHT, phenytoin Schierhout and Roberts, Cochrane Library 2002; Beghi E, Epilepsia 2003; Chang and Lowestein, Neurology

34 Early Post-traumatic Seizures Chang and Lowenstein, Neurology 2003;60:

35 Late Post-traumatic Seizures Chang and Lowenstein, Neurology 2003;60:

36 AED to Prevent PTE: The Hopefuls Previously tested AEDs have many adverse effects Newer AEDs have not been adequately tested The antiepileptogenic argument Should test AEDs shown to have antiepileptogenic effects in animal models 36

37 Prospective Controlled Studies of AED for Prophylaxis of Seizures after Severe Head Trauma Treatment groups Study Random AED (n) Control (n) McQueen 83 Y PHT (84) Placebo (80) Young 83 Y PHT (119) Placebo (95) Glötzner 83 Quasi CBZ (75) Placebo (76) Temkin 90 Y PHT (208) Placebo (196) Temkin 99 Y VPA (247) PHT 1 wk (132) Manaka 92 Y PB (50) None (76) Pechadre 91 Quasi PHT (34) None (52) Servit 81 N PHT+PB (143) None (24) Jones 2008 N LEV (32) Historical PHT (41) Klein 2012 N LEV (66) None (60) CBZ. Carbamazepine; LEV, levetiracetam; PB, phenobarbital; PHT, phenytoin Schierhout and Roberts, Cochrane Library 2002; Beghi E, Epilepsia 2003; Chang and Lowestein, Neurology

38 Cumulative incidence of PTE Phase 2 Nonrandomized LEV Study for PTE Untreated LEV Klein P et al, Arch Neurol 2012;69:

39 Phase 2 Nonrandomized LEV Study for PTE Primarily to evaluate safety and feasibility 6-87 years old with severe TBI. All given PHT for 1 week Treatment groups: Presented 8 hours LEV 55mg/kg/d for 30 days (n=66) Presented 8-24 hours No treatment (n=60) Followed up to 24 months 12% stopped LEV early Mortality: 10.9% treated adults vs. 7.5% untreated adults Klein P et al, Arch Neurol 2012;69:

40 RCT VPA to Prevent PTE 1 week PHT vs. 1 month VPA or 6 months VPA Temkin NR et al, J Neurosurg 1999;91:

41 RCT VPA to Prevent PTE: No Good Seizures VPA 6 mo (n=120) VPA 1 mo (n=127) P=0.19 PHT 1 wk (n=132) Temkin NR et al, J Neurosurg 1999;91:

42 RCT VPA to Prevent PTE: More Harm? 1 week PHT vs. 1 month VPA or 6 months VPA Mortality VPA 6 mo (n=120) VPA 1 mo (n=127) P=0.07 PHT 1 wk (n=132) Temkin NR et al, J Neurosurg 1999;91:

43 Conclusion Prophylactic AEDs reduced acute symptomatic seizures after severe TBI but not posttraumatic epilepsy Antiepileptogenic effects in animal models have not been translated to human evidence Potential harm with AEDs outweighs benefits Intrinsic adverse effects Deleterious effects on brain recovery AED prophylaxis does NOT work in posttraumatic epilepsy 43

44 Rebuttal Slide 44

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