1. Management of Seizure Disorders Mark Kotlarewsky, MD FACP Department of Medicine Medstar 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 2 nd 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? 1. switch to lamotrigine 2. add lamotrigine 3. switch to ethosuximide 4. switch back to levetiracetam 5. 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? 1. switch to valproic acid 2. switch to gabapentin 3. continue primidone, low INR is due to warfarin noncompliance 4. switch to lacosamide 5. 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? 1. folic acid and carbamazepine 2. folic acid and lamotrigine 3. phenytoin 4. folic acid and topiramate 5. 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? 1. IV valproic acid, 30mg/kg at 3mg/kg/min 2. fosphenytoin 18 PE/kg at150PE/min 3. phenytoin 18mg/kg at 50mg/min 4. lorazepam 2mg 5. propofol 2-5 mg/kg bolus

31. Thank you!