1. Antiepileptic Drugs: Pitting the Old Against the New
Andrew Nguyen, MS-IV
July 12, 2016

2. Disclosures
None…
I’m not important enough to be paid the big bucks by any company.

3. 18M presents to the ED…
Was at home when girlfriend noticed he became unresponsive
“Wouldn’t answer questions and then started shaking”
What would you like to know?
Some post-episode confusion
ROS: unremarkable
PMH: DM1, migraines, childhood febrile seizure
Meds: lispro, sumatriptan
FMH: siblings had childhood febrile seizures
Social: 3 beers/day; denies tobacco, illicits
PE: tongue lacerations; otherwise unremarkable

4. 18M presents to the ED… DDx? Next steps? Workup? Epileptic seizure
Alcohol withdrawal seizure
Hypoglycemic seizure
Meningitis
Intracerebral mass lesion
Psychogenic episode
Next steps? Workup?

5. 18M presents to the ED…
Labs
Imaging
Head CT: No evidence of intracranial abnormalities.
EKG: no abnormalities
Treatment? Disposition?
4.8 13
220
138
3.8
103 24 2
1.0
146
9.2
2.0
3.1

6. Outpatient Follow-Up Follow-up EEG
Sheth RD. EEG in Common Epilepsy Syndromes. Medscape 2015.

7. Epilepsy Basic definitions Common: 50 per 100,000 people
30-40% generalized at onset
30% of cases are medically refractory
Unprovoked seizures
Simple vs. complex
Generalized vs. partial
Marson et al. Lancet 2007; 369:

8. Intro to Antiepileptic Drugs (AEDs)
Sodium channel blockers
Phenytoin (Dilantin) (1938)
Carbamazepine (Tegretol) (1965), Oxcarbazepine (Trileptal) (2000), etc.
Lacosamide (Vimpat) (2008)
GABA agonists
Benzodiazepines (1955)
Gabapentin (Neurontin) (1993), pregabalin (Lyrica) (2005)
Complicated fellows
Valproate (Depakote) (1967): sodium channels, GABA
Lamotrigine (Lamictal) (1994): sodium, calcium channels
Topiramate (Topamax) (1996): sodium, calcium, GABA, AMPA/kainate
Levetiracetam (Keppra) (1999): vesicle release
Arzimanoglou et al. Epileptic Disord 2010; 12: 3-15.

9. Important AED adverse effects
Sodium channel blockers
Phenytoin: ataxia, gingival hyperplasia
Carbamazepine, oxcarbazepine: hyponatremia, Stevens-Johnson
Lacosamide: PR prolongation
GABA agonists
Benzodiazepines: respiratory depression, sedation
Gabapentin, pregabalin: sedation
Complicated fellows
Valproate: teratogenicity, thrombocytopenia, weight gain
Lamotrigine: Stevens-Johnson
Topiramate: cognitive slowing, nephroliths, weight loss
Levetiracetam: agitation

10. Let’s go back to the patient case…
What medication(s) would you like to prescribe?

11. SANAD Study: Introduction
Unblinded randomized controlled trial performed in the United Kingdom from , follow-up through 2006
Comparison of new vs. old AEDs for generalized seizures poorly studied
Many new AEDs for partial seizures, but poorly studied
For the studies looking at AEDs for generalized seizures, they had very brief periods of follow-up and didn’t provide information on long-term seizure control; also didn’t look at QoL outcomes; other reasons for these results not being clinically useful
For the studies looking at AEDs for partial seizures, evidence for valproate as first-line monotherapy was poor (RCTs poor); support for valproate thus mainly from observational studies
Marson et al. Lancet 2007; 369:
Marson et al. Lancet 2007; 369:

12. SANAD Study: Methods 2 arms Inclusion criteria
A: Partial seizures: carbamazepine vs. gabapentin, lamotrigine, oxcarbazepine, topiramate
B: Generalized and unclassifiable seizures: valproate vs. lamotrigine, topiramate
Inclusion criteria
Primary outcomes: 1) time to treatment failure, 2) time to 1-year remission
Secondary outcomes
Intention-to-treat and per-protocol analyses both performed
Marson et al. Lancet 2007; 369:
Marson et al. Lancet 2007; 369:

13. Arm A: Partial Seizures
Oxcarbazepine added starting in 2001

14. SANAD Study: Results (Arm A)
Time to treatment failure for any reason
Lamotrigine > carbamazepine (HR 0.78 [ ])
Lamotrigine > gabapentin (HR 0.65 [ ])
Lamotrigine > topiramate (HR 1.56 [ ])
Oxcarbazepine > gabapentin (HR 0.75 [ ])
Lamotrigine ? oxcarbazepine (HR 1.15 [ ])
Marson et al. Lancet 2007; 369:

15. Marson et al. Lancet 2007; 369:

16. SANAD Study: Results (Arm A)
Time to treatment failure for inadequate seizure control
Carbamazepine > gabapentin (HR 2.45 [ ])
Carbamazepine > topiramate (HR 1.43 [ ])
Carbamazepine ? lamotrigine (HR 1.17 [ ])
Carbamazepine ? oxcarbazepine (HR 1.33 [ ])
Marson et al. Lancet 2007; 369:

17. Marson et al. Lancet 2007; 369:

18. SANAD Study: Results (Arm A)
Time to 1-year remission
Carbamazepine > gabapentin (HR 0.75 [ ])
Gabapentin > lamotrigine (HR 1.21 [ ])
Gabapentin > oxcarbazepine (HR 1.37 [ ])
Lamotrigine ? carbamazepine (HR 0.91 [ ])
Lamotrigine ? topiramate (HR 0.94 [ ])
Marson et al. Lancet 2007; 369:

19. Marson et al. Lancet 2007; 369:

20. SANAD Study: Results (Arm A)
Lamotrigine is least likely to fail for any reason
Gabapentin and topiramate are most likely to fail for any reason
Gabapentin is most likely to fail for seizure control
Carbamazepine is least likely to fail for seizure control
Carbamazepine will induce a 1-year remission the quickest
Marson et al. Lancet 2007; 369:

21. SANAD Study: Results (Arm A)
Lamotrigine had the fewest patients with adverse effects
No significant difference in QoL outcomes
Marson et al. Lancet 2007; 369:

22. SANAD Study: Discussion (Arm A)
Didn’t recruit enough subjects
Lamotrigine superior for time to treatment failure, non-inferior to carbamazepine for 1-year remission
Carbamazepine’s time to first seizure superiority: why?
Meta-analysis concordance
Due to concerns over SJS for lamotrigine, it’s more likely to be slowly titrated than carbamazepine
Marson et al. Lancet 2007; 369:

23. Arm B: Generalized and unclassifiable seizures

24. SANAD Study: Results (Arm B)
Time to treatment failure for any reason
Valproate > topiramate (HR 1.57 [ ])
Valproate ? lamotrigine (HR 1.25 [ ])
Marson et al. Lancet 2007; 369:

25. Marson et al. Lancet 2007; 369:

26. SANAD Study: Results (Arm B)
Time to treatment failure for inadequate seizure control
Valproate > lamotrigine (HR 1.95 [ ])
Valproate ? topiramate (HR 1.45 [ ])
Marson et al. Lancet 2007; 369:

27. Marson et al. Lancet 2007; 369:

28. SANAD Study: Results (Arm B)
Time to 1-year remission
Valproate > lamotrigine (HR 0.76 [ ])
Valproate ? topiramate (HR 0.93 [ ])
Marson et al. Lancet 2007; 369:

29. Marson et al. Lancet 2007; 369:

30. SANAD Study: Results (Arm B)
Valproate is least likely to fail for any reason or for seizure control
Topiramate is most likely to fail for any reason
Lamotrigine is most likely to fail for seizure control
Valproate will induce a 1-year remission the quickest
Lamotrigine -> inferior efficacy
Topiramate -> inferior tolerability
Marson et al. Lancet 2007; 369:

31. SANAD Study: Results (Arm B)
Results even more favorable for valproate for generalized-only and in per-protocol analysis
No significant difference in QoL outcomes
Marson et al. Lancet 2007; 369:

32. SANAD Study: Discussion (Arm B)
Didn’t recruit enough subjects
Thoughts on lamotrigine’s activity
Studies of AEDs distinguishing generalized from partial seizures
Majority of lamotrigine’s activity most likely due to sodium channel activity -> better for partial-onset seizures than generalized-onset
Important for studies to separate patients with generalized and partial seizures
Marson et al. Lancet 2007; 369:

33. Newer Pertinent Studies?
Problems with SANAD?
Insufficient recruitment to meet desired power
Unblinded
Levetiracetam wasn’t studied! (nor pregabalin, zonisamide)
Problems with valproate for female patients
Results from my very brief literature search on levetiracetam:
-2004 Neurology and Epilepsia articles showed levetiracetam was effective as an adjunct for refractory partial seizures but not for monotherapy for new seizures
-2011 meta-analysis w/ 10 RCTs on generalized seizures showed it was good as adjunctive therapy, no statement on monotherapy

34. Conclusion For generalized seizures, pick valproate
For partial seizures, pick lamotrigine