Learning objectives

1. Management of Seizure DisordersMark Kotlarewsky, MD FACPDepartment of MedicineMedstar Washington Hospital Center

2. Learning objectives • Understand the definition of seizure, epilepsy • Understand the types of treatment, both medical and surgical • Understand notable side effects of common antiepileptic drugs • Understand treatment and management of epilepsy-related comorbidities • Management of antiepileptic drugs in women • Management of status epilepticus

3. Conflicts of interest • None

4. Definitions • seizure: abnormal, excessive, or synchronous neuronal activity in the cerebral cortex • 1-2 min, altered consciousness is common, confusion/fatigue after an episode, increased HR, tonic-clonic movement, paresthesias, aphasia • epilepsy: two or more unprovoked seizures

5. Seizure types • Partial • simple - does not impair awareness (eg. epileptic auras, jacksonian march) • complex - impairs awareness by typically spreading to one or both temporal lobes • secondarily generalized - when simple type spreads to involve both hemispheres diffusely • Generalized • primary - tonic-clonic • absence - impairment of consciousness • myoclonic - muscle contractions in rapid succession without consciousness impairment

6. Epilepsy types • partial • temporal lobe - mesial temporal sclerosis • generalized • juvenile myoclonic - morning myoclonus, absence

7. Mesial temporal sclerosis

8. Epilepsy-related comorbidities • psychiatric disorders - depression, suicide, anxiety • cognitive problems - visual/verbal memory, attention • osteoporosis, heart disease, hypertension, stroke, obesity, obstructive sleep apnea • sudden death

9. Choosing an antiepileptic drug (AED) • effectiveness for seizure type • side effects • drug-drug interactions • comorbid conditions • age • gender • lifestyle, patient preferences • cost

10. Choosing an AED by epilepsy type • partial - nearly all, particularly lamotrigine, carbamazepine, oxcarbazepine, levetiracetam • generalized - lamotrigine, levetiracetam, topiramate, zonisamide, NOT carbamazepine, gabapentin, pregabalin as they can sometimes exacerbate this type • absence - ethosuximide, valproate • atypical absence, myoclonic, atonic - valproate, lamotrigine, levetiracetam

11. Initiating/adding treatment • usually one drug, rather than two or more • 2nd drug should have different mechanism, different side effect profile • published therapeutic serum ranges should not be used if patient is doing well clinically (?) • unclear whether generic substitutions lead to poorer control

12. Mechanisms • inhibitory transmission (benzodiazepines, clobazam, phenobarbital, tiagabine, vigabatrin) • sodium channels (carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenytoin, rufinamide) • calcium channels (ethosuximide) • potassium channels (ezogabine) • excitatory transmission (perampanel) • multiple mechanisms (felbamate, valproate, gabapentin, levetiracetam, topiramate)

13. AED side effects • sedation, ataxia • folate deficiency • renal metabolism - gabapentin, levetiracetam, pregabalin, topiramate, zonisamide • hepatic metabolism - carbamazepine, phenytoin, valproate • elderly: • YES - gabapentin, lamotrigine, levetiracetam • NO - oxcarbazepine, phenytoin, carbamazepine

14. AED side effects • suicide - levetiracetam, topiramate, vigabatrin • Stevens Johnson Synrome, toxic epidermal necrolysis, drug rash - phenytoin, carbamazepine (allele screening hlab1502 in asians), oxacarbazepine, primidone, phenobarbital, zonisamide, lamotrigine • osteoporosis - especially with: phenytoin, carbamazepine, phenobarbital, primidone and valproate; consider checking bone mineral density after five years • use with caution in patients with cardiac conduction pathology: lacosamide, phenytoin, ezogabine

15. AED side effects • weight loss - zonisamide, felbamate, topiramate • weight gain - pregabalin, gabapentin, valproate • insomnia - felbamate, lamotrigine • nephrolithiasis - topiramate, zonisamide • valproic acid - exacerbates sx of polcystic ovarian disease • carbamazepine - induces own metabolism

16. Oral contraceptives • carbamazepine, phenytoin, phenobarbital, primidone tend to decrease contraceptive serum levels (also felbamate, topiramate, oxcarbazepine, rufinamide, clobazam, perampanel) • no interaction with levetiracetam, valproate • reduced lamotrigine concentrations, which then go up during the week of inactive tablets

17. Pregnancy • 4-6% rate of teratogenicity, 2-3x general population • seizure control more important than teratogenicity • aim: monotherapy at lowest dose for control • avoid older AED’s: phenytoin, phenobarbital, valproate; latter two associated with oral cleft, cardiac, urinary tract, and neural tube defects, lower IQ • topiramate: oral cleft, hypospadias • better: lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, gabapentin, but monitor levels closely

18. Pregnancy • induces AED metabolism, esp. lamotrigine • phenytoin, carbamazepine, primidone, phenobarbital: hemorrhage in newborn due to vitamin K deficiency • folate: give 4mg starting 1-3 months prior to conception if on carbamazepine, valproic acid; standard dose for others

19. Drug-drug interactions • phenytoin, carbamazepine, primidone, phenobarb, (oxcarbazepine, topiramate) • warfarin, OCP’s, anti-infectives, anti-cancer • between AED’s (eg. carbamazepine reduces lamotrigine levels, valproate increases them) • alcohol: 1-2 drinks in well-controlled patient OK, highest risk of seizure 7-48hrs after cessation of alcohol

20. Alternative tx • vagal nerve stimulation, deep brain stimulation of anterior nucleus of thalamus, responsive neurostimulator • epilepsy surgery - high rate of cure in patients with known lesions (eg. tumor, vascular malformation, mesial temporal sclerosis) • ketogenic/modified Atkins diet (hi fat, low carb)

21. STATUS! • convulsive • continued seizure activity >30 min; practically, initiate treatment within 5 min • lorazepam • fosphenytoin • intubate, sedate, additional AED

22. STATUS! • nonconvulsive • 20% treated for convulsive status epilepticus, develop EEG seizure • start management if altered mental status more than 20min post cessation of convulsive episode • sensitivity of EEG increases longer it is done (95% at 48 hrs) • paradoxical improvement with low dose benzodiazepines

23. Case #1 • 35 yom w h/o simple partial seizure, failed levetiracetam due to side effects, recently switched to carbamazepine, presents c/o recurrent seizure

24. What to do? • switch to lamotrigine • add lamotrigine • switch to ethosuximide • switch back to levetiracetam • check carbamazepine level

25. Case #2 • 70yof w h/o osteoarthritis,1st degree AV block, hepatic disease, deep venous thrombosis on warfarin was diagnosed with partial seizure disorder and started on primidone; patient was lost to follow up but showed up in the ED with another DVT and a subtherapeutic INR

26. What to do? • switch to valproic acid • switch to gabapentin • continue primidone, low INR is due to warfarin noncompliance • switch to lacosamide • switch to carbamazepine

27. Case #3 • 31yof w h/o nephrolithiasis, renal insufficiency, and partial seizure disorder taking valproic acid and OCP is interested in having a child; aside from stopping her OCP...

28. What do you recommend? • folic acid and carbamazepine • folic acid and lamotrigine • phenytoin • folic acid and topiramate • folic acid and valproic acid

29. Case #4 • 21yom w h/o juvenile myoclonic epilepsy presents to the ED with uncontrolled seizure; after 15minutes of observed tonic-clonic seizure, and 6mg of IV lorazepam, the patient’s clinical status does not improve

30. What to do next? • IV valproic acid, 30mg/kg at 3mg/kg/min • fosphenytoin 18 PE/kg at150PE/min • phenytoin 18mg/kg at 50mg/min • lorazepam 2mg • propofol 2-5 mg/kg bolus

31. Thank you!