Hasan H. Sonmezturk, M.D. October 13th, 2013

Overview ó First seizure

ó Treat or not treat ó How to approach ó What medication to start with

ó Monotherapy ó Combination therapy

ó Additive benefits ó Synergism ó Side effects

ó How and when to stop AEDs

Epidemiology

Hauser et. al. Epilepsia. 1993 May-Jun;34(3):453-68.

Incidence rate Per 100,00o

Epilepsy 44

First unprovoked seizure 61

Acute symptomatic seizure 39

All seizures/epilepsy 100

Cumulative Incidence of Epilepsy 3.1%

Unprovoked Seizures ó 61 per 100,000 per year ó 16-62% will recur within 5 years (~ 40%) ó With treatment recurrence can be decreased by half (Italian

FIRST study 1993, UK MESS study 2005)

ó The ones that recurred need AED treatment regardless ó 47% will become seizure free with 1st AED ó 13% will become seizure free with 2nd AED ó 1% will become seizure free with 3rd AED

ó The recurrence may be as low as 21% in children with one

afebrile unprovoked seizure First Seizure Trial Group. Neurology 1993; 43 (3, part1): 478-483. Camfield P et al.. Neurology 1989; 39: 851-852. Kwan P, Brodie MJ N Engl J Med 2000;342:314–319

First Seizure ó Questions to be asked:

ó Seizure or not? ó If it is seizure what type?

ó Focal or generalized onset ó Presence of obvious precipitant/s?

ó Metabolic, Pro-convulsant drugs, toxic, fever, systemic infection or others

ó What studies are needed for work up? ó Should we start an AED or not?

Case #1 ó Mr. Smith is a 57-year-old Asian man who presented to

Vanderbilt ER after a small MVA resulting in minor injury to his car. When witnesses approached his car he was not responding and he kept picking on his clothing with his right hand. This lasted about a minute and a half and then he started responding but was confused for about 10 minutes. When taken out of his car it was noted that he had lost his bladder control. On exam he had severe obesity and normal vitals except irregularly irregular heart rate. He has been on warfarin for Afib.

Case #1 ó Mr. Smith is a 57-year-old Asian man who presented to

Vanderbilt ER after a small MVA resulting in minor injury to his car. When witnesses approached his car he was not responding and he kept picking on his clothing with his right hand. This lasted about a minute and a half and then he started responding but was confused for about 10 minutes. When taken out of his car it was noted that he had lost his bladder control. On exam he had severe obesity and normal vitals except irregularly irregular heart rate. He has been on warfarin for Afib.

Questions ó Is this a seizure?

ó Yes (clinical suspicion)

ó What type of seizure? ó Partial onset seizure

ó Are there any precipitants? ó None obvious (per history)

ó What studies need to be done? ó CT of Head, MRI Brain, EEG, Urine and blood toxicology

ó Should we start treatment? ó Early treatment does not protect against development of epilepsy ó 50% of untreated patients will remain seizure free ó 2-year remission rate is identical regardless..

FIRST Trial Group, Musicco et al. 1997 MESS Study Group, Marson et al. 2005

What constitutes a risk for recurrence?

ó Multiple or clustered seizures at onset ó Status epilepticus at onset ó Abnormal interictal neurological exam ó Abnormal EEG (epileptiform abnormalities) ó Abnormal imaging (MRI Brain or CT Head) ó Family history of epilepsy ó Partial seizures

W. Allen Hauser et al. Seizure recurrence after a first unprovoked seizure: An extended follow up NEUROLOGY 1990;401163-1170

TREAT or NOT TREAT ó Treat:

ó Acute or remote symptomatic seizure (cerebral insult) ó Clinically unstable patient ó Seizure related complications (fracture aspiration)

ó Recommend Treatment: ó When the risk of recurrence is high ó When a second seizure may be dangerous ó When it benefits patient’s work and function

ó No Treatment (observation) ó Low risk of seizure recurrence ó Patient’s choice with good understanding of risks

More Info/History on Mr. Smith ó CT Head ànormal ó MRI brain à hyperintensity over his right hippocampus ó Wife reported several previous staring events with lip

smacking ó EEG à normal ó No family history of seizures ó Never had a head injury ó Was a healthy full term baby born with natural delivery ó As per his mother he had had a prolonged febrile seizure at

age 6 months. ó Works in aviation industry as an engineer ó Has Type-A personality and anxiety

More Info/History on Mr. Smith ó CT Head ànormal ó MRI brain à hyperintensity over his right hippocampus ó Wife reported several previous staring events with lip

smacking ó EEG à normal ó No family history of seizures ó Never had a head injury ó Was a healthy full term baby born with natural delivery ó As per his mother he had had a prolonged febrile seizure at

age 6 months. ó Works in aviation industry as an engineer ó Has Type-A personality and anxiety

Should we treat this patient? ó YES!

ó Then what medication should we start with?

ó Multiple factors contributes to that decision:

ó Seizure type/classification ó Epilepsy Syndrome ó Patient’s age and gender ó Drug efficacy and tolerability ó Patient’s comorbidities ó Drug-drug interactions ó Drug formulations ó Ease of administration ó Side effect profile ó Cost

Why the confusion? ó So many available AEDs

ó Partly due to the heterogeneity of their efficacy and tolerability among patients

ó In other medical conditions there is some degree of predictability of response to treatment ó However in epilepsy it is impossible to predict whether

a given AED will prove to be effective in a particular patient. ó Efficacy comparisons of AEDs showed no clear

advantage for one therapy over another Cockerell OC et al. Remission of epilepsy: results from the

National General Practice. Study of Epilepsy. Lancet. 1995;346(8968):140-144

Brief Overview of Current AEDs

Adapted from Brodie MJ. Seizure 19 (2010) 650–655

Choosing the First AED ó Majority of patients who become seizure-free on a

single AED will do so at a modest or moderate dosage. ó The emphasis should be on: ó Tolerability ó Safety

ó Choose a drug with a spectrum of activity, side-effect and interaction profiles that has the potential to produce seizure-freedom without long-term sequelae.

Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia . 2001; 42: 1255–1260

Choosing Anti-epileptic Drugs

Broad-Spectrum Agents Narrow-Spectrum Agents (For Partial onset seizures)

ó Valproate ó Felbamate ó Phenobarbital# ó Lamotrigine ó Topiramate ó Zonisamide ó Levetiracetam ó Benzodiazepines ó Primidone

ó Phenytoin* ó Ezogabine* ó Perampanel* ó Carbamazepine~ ó Gabapentin~ ó Pregabalin~ ó Tiagabine~ ó Lacosamide* ó Oxcarbazepine~ ó Vigabatrin@ ó Rufinamide

ó Ethosuximide

Important to Note! ó The newer AEDs have shown no better efficacy than

the classic AEDs, but: ó They are easier to use ó They have much better pharmacokinetic profiles ó Fewer drug interactions ó Less teratogenicity ó Less hypersensitivity reactions ó They have minimal or no long term side effects ó They also have fewer immediate side effects (?) ó No CBC, CMP or level monitoring ó Newer AEDs tend to have broad-spectrum anti-epileptic

activity

Epilepsia, **(*):1–13, 2013 doi: 10.1111/epi.12074

We should not forget! ó Drug trials aim to achieve the end points that are

valued by the FDA and has not much clinical use ó Proving superiority over placebo ó Proving less deterioration rather than improvement

(conversion to monotherapy studies) ó Dosing in trials are much higher than the dosing in real life

What about the Mechanism of Action (MOA)

ó Existing data do not seem to support consideration of

MOA as a criterion for choosing an AED whether with monotherapy or as add on. ó Adverse effects may be more ó An additive effect may exist?? ó Many AEDs have multiple MOA and some have

unknown MOA

Dodrill CB at al. Epilepsy Res. 2000;42(2-3):123-132. Deckers CL et al. Epilepsia 2000 Nov;41(11):1364-74. Biton V. et al. Epilepsia. 1998;39(suppl 6):125

Michael Privitera, MD Am J Manag Care. 2011;17:S195-S203

Mechanism Of Action (Cont) ó Limited data to support:

ó Na-channel blockers + GABAergic ó GABA mimetic + GABA mimetic ó AMPA antagonist + NMDA antagonist

ó But tolerability may be reduced with these combinations

ó Combining two Na-channel blockers seems less promising

Michael Privitera, MD Am J Manag Care. 2011;17:S195-S203

Some Facts! ó In year 2000, an analysis of 1617 patients remaining seizure-free

for at least 1 year was undertaken. Of these, 332 (20.5%) were controlled on more than one AED.

ó In the intervening decade, a further six AEDs had been licensed for the adjunctive treatment of epilepsy. Five of these have different mechanisms of action. This time 10 years later seizure freedom with combined therapy was 20.4%.

ó In the two data sets, the percentage of patients seizure free on 4 AEDs was virtually identical at 0.9% (n = 3) in 2000 and 1.2% (n = 6) in 2010.

(Stephen and Brodie, 2002).

Antiepileptic drug combinations—–Have newer agents altered clinical outcomes? Linda J. Stephen, Murray Forsyth, Kevin Kelly, Martin J. Brodie∗ Epilepsy Research (2012) 98, 194—198

Choose one AED for Mr. Smith a) Lamotrigine b) Valproate c) Topamax d) Levetiracetam e) Carbamazepine f) Oxcarbazepine g) Phenytoin h) Phenobarbital i) Felbamate

Case #1 ó Mr. Smith is a 57-year-old Asian man who presented to

Vanderbilt ER after a small MVA resulting in minor injury to his car. When witnesses approached his car he was not responding and he kept picking on his clothing with his right hand. This lasted about a minute and a half and then he started responding but was confused for about 10 minutes. When taken out of his car it was noted that he had lost his bladder control. On exam he had severe obesity and normal vitals except irregularly irregular heart rate. He has been on warfarin for Afib.

More Info/History on Mr. Smith ó CT Head ànormal ó MRI brain à hyperintensity over his right hippocampus ó Wife reported several previous staring events with lip

smacking ó EEG à normal ó No family history of seizures ó Never had a head injury ó Was a healthy full term baby born with natural delivery ó As per his mother he had had a prolonged febrile seizure at

age 6 months. ó Works in aviation industry as an engineer ó Has Type-A personality and anxiety

Choose one AED for Mr. Smith a) Lamotrigine b) Valproate c) Topamax d) Levetiracetam e) Carbamazepine f) Oxcarbazepine g) Phenytoin h) Phenobarbital i) Felbamate

What about the cause of Epilepsy? ó In one study 57% of all patients had been seizure free at their last

clinic visit for at least a year ó Patients with mesial temporal sclerosis (MTS 42% seizure free)

were less likely to be controlled (p < 0.01) than were those with ó AVMs 78% ó Cerebral infarction 67% ó Primary tumour 63% ó Cortical gliosis 57% ó Cerebral atrophy 55% ó Cortical dysplasia 54%

ó Among the seizure free patients, those with MTS were more

likely to require more than one AED compared with those with other etiologies (48 vs. 35%; p < 0.05).

ó MTS-related seizures had the worst prognosis

Stephen at al Epilepsia, 42(3):357–362, 2001 Does the Cause of Localisation-Related Epilepsy Influence the Response to Antiepileptic Drug Treatment?

How do AEDs affect each other?

Dieter Schmidt Epilepsy & Behavior 15 (2009) 56– 65

Dieter Schmidt Epilepsy & Behavior 15 (2009) 56–65

Case #2 ó Ms. Jones is a 21-year-old woman who was witnessed to

have a GTC seizure while studying in the library. She was brought to ER and by the time she was examined she was back to her baseline. Her PE was normal, MRI brain was normal, EEG was also normal. She had no symptoms or signs to suggest CNS infection. Patient has no family history of epilepsy or any other risk factors for seizures. She is on BCPs.

What to do next? ó Give the relevant info/data to the patient ó Allow her to make an informed decision ó It is OK to treat ó It is also OK not to treat ó The risk of having another seizure within the next 5 years is

~ 40% ó If another seizure occurs the patient will have longer

periods of restrictions for driving, swimming, climbing, and many other activities which is crucial for a young person ó On the other hand being on no meds may help with

finding a job.

Ms. Jones ó Lets assume we will treat

ó It is easy to start an AED but it is difficult to stop/switch an AED ó Patient may not want to risk another seizure ó Clinician may be reluctant to make a change especially if the patient

resumed driving and other activities. ó Clinician will also be afraid of destabilizing the patient. 20% will

not be controlled even if the initial AED is resumed. ó Consider long term side effects ó Consider all other factors:

ó Drug interactions (OCPs) ó Possible pregnancy (teratogenicity) ó Cost/Insurance coverage ó Seizure classification

Chaves J. et al. Epilepsia 2005;46(suppl 9): 133-139.

ó Patients who had an epileptic event requiring

acute care were about 80% more likely than matched controls without an acute event to have recently had an antiepileptic drug substitution.

Rascati et al Pharmacotherapy 2009;29(7):769–774

First AED ó First AED is very important

ó Only 11-13% additional will be seizure free after the

first AED fails

Brodie MJ, Kwan P. The star systems: overview and use in determining antiepileptic drug choice. CNS Drugs . 2001; 15: 1–12.

Why choose a broad spectrum agent? ó We do not know the seizure classification or epilepsy

syndrome ó Carbamazepine

ó One of the most widely used AED for partial seizures ó May increase the risk of absence, atonic, and myoclonic

seizures in patients with generalized epilepsy

ó Phenytoin, oxcarbazepine, gabapentin, pregabalin, tiagabine and vigabatrin

ó These agents may increase generalized seizures too.

Snead OC et al. N Eng J Med. 1985;313:916-921. Johnsen SD et al. Ann Neurol. 1984;16:392-393. Shields WD et al. Neurology. 1983;33:1487-1489.

Choose one AED for Ms. Jones a) Lamotrigine b) Valproate c) Topamax d) Levetiracetam e) Carbamazepine f) Oxcarbazepine g) Phenytoin h) Phenobarbital i) Felbamate

Ms. Jones (modified history) óWhat if Ms Jones reported:

ó Twitches in her hands especially in the mornings that may result in dropping things. ó Extremely bothered with exposure to flashing

sunlight while driving ó And her EEG showed brief bursts of generalized 4-

6 Hz sharp-and-slow-wave complexes. óMost likely syndromic diagnosis?

ó JME

Choose one AED for Ms. Jones (modified)

a) Lamotrigine b) Valproate c) Topamax d) Levetiracetam e) Carbamazepine f) Oxcarbazepine g) Phenytoin h) Phenobarbital i) Felbamate

Epilepsia, **(*):1–13, 2013 doi: 10.1111/epi.12074

Idiopathic Generalized Epilepsy FDA Indications

ó Older AEDs

ó Ethosuximide (absence) ó Valproate and Clonazepam ó Methsuximide (only as second line for absences)

ó New AEDs ó Topiramate ó Lamotrigine ó Levetiracetam

Karceski S, Morrell M, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005 Epilepsy & Behavior 7 (2005) S1–S64

Karceski S, Morrell M, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005 Epilepsy & Behavior 7 (2005) S1–S64

Expert Consensus ó Initial monotherapy

ó IGE (GTC, Absence Myoclonic) ó valproate

ó IGE – GTC seizures

ó lamotrigine and topiramate usually appropriate

ó IGE – Absence ó Ethosuximide ó lamtorigine usually appropriate

Expert Consensus ó Initial Monotherapy:

ó SLRE – SPS and SLRE – SGTC ó carbamazepine and oxcarbazepine ó Lamotrigine and levetiracetam usually appropriate

ó SLRE – CPS ó carbamazepine, lamotrigine and oxcarbazepine ó Levetiracetam was usually appropriate

ó Women who are pregnant or trying to conceive ó Lamotrigine

ó In the elderly

ó lamotrigine ó Levetiracetam and gabapentin were usually appropriate

The Expert Consensus Guidelines

ó Idiopathic generalized epilepsy ó Symptomatic localization-related epilepsy ó Symptomatic generalized epilepsy.

ó The strategies for treating these 3 syndromes were largely identical: ó Initiating patients on AED monotherapy ó If that failed, a second monotherapy was tried ó If a second monotherapy also failed then the expert

consensus was divided between trying a third monotherapy (70%) or attempting combination therapy with 2 drugs (30%)

ó Failure at that stage was widely agreed to require dual therapy

ó If that failed, the consensus was widely diverged.

ó It is very important to note that these guidelines were based on

expert opinion, and the experts were not asked to rank the level of evidence supporting their opinions.

Back to Mr. Smith ó Lamotrigine was started and titrated up to 100mg po

bid ó Patient comes back to ER with a similar seizure which

started with staring followed by lip smacking and right hand automatisms for 2 minutes and then that was followed by a GTC seizure. ó What to do next??? ó Maximize Lamotrigine ó Increase by 100mg per 2 weeks

Mr. Smith (Cont) ó Lamotrigine dose reached 400mg po bid ó Seizures are getting more frequent (1/wk) ó What to do next? ó Switch to another monotherapy? ó Add a second agent?

ó Oxcarbazepine

ó (HLA-b 1502 allele??)

Mr. Smith (Cont) ó Oxcarbazepine started and titrated up to 600mg po

bid. Six month later seizures (CPSz) decreased but still occurring at a rate of one every 1-2 months. ó What to do next? ó Oxcarbazepine increased to 900mg po bid ó Six months later continued to have CPSzs at a rate of

one per 1-2 months ó What to do next? Add another agent or switch to third

monotherapy? ó Add another agent

What about Ms. Jones? ó She returns to your clinic 3 months later. She is on

levetiracetam 500mg po bid. Her twitches decreased by 50% but she still has them. She had no more GTC seizures. ó What to do next?

a) Increase LVT to seizure freedom/toxicity b) Switch to another monotherapy c) Add a second agent to LVT d) Stop LVT and watch the patient off medication e) Do not make any changes

Wiebe S, Blume WT, Girvin JP, Elasziw M, for the Effectiveness and Efficacy of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal lobe epilepsy. N Engl J Med . 2001; 345: 311–318.

Ms. Jones (Cont) ó She returns to clinic after 6 months. She is on LVT

1500mg po bid. Continues to have twitches at a rate similar to her last visit. On one occasion her twitches occurred progressively more frequently and she had a GTC seizure. She reports anger issues and excessive sleepiness affecting her daily life dramatically. ó What to do next?

Ms. Jones (Cont) a) Add a second agent and decrease LVT b) Switch LVT to another agent c) Increase LVT further d) Decrease LVT to the previous dose e) Do nothing

Wiebe S, Blume WT, Girvin JP, Elasziw M, for the Effectiveness and Efficacy of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal lobe epilepsy. N Engl J Med . 2001; 345: 311–318.

Ms. Jones (Cont) óWhich agent would be best as an add

on to levetiracetam? a) Oxcarbazepine b) Topiramate c) Lamotrigine d) Phenytoin e) Carbamazepine

Drug Resistant Epilepsy! ó 525 patients were prospectively studied:

ó 63% became seizure free with AED treatment ó Symptomatic or Cryptogenic epilepsy with higher rate of drug

resistance than idiopathic epilepsies ó 40% vs 26% p=0.004

ó Also drug resistance was higher in patients who had > 20 seizures prior to starting treatment than the ones who had fewer seizures ó 51% vs 29% p<0.001

ó When initial monotherapy failed: ó Another monotherapy

ó Add-on combination therapy

ó 26% became seizure free with add-on combination therapy ó 17% became seizure free with another monotherapy

Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-319.

Kwan P, Arzimanoglou A, et al. Definition of drug resistant epilepsy: Epilepsia. 2010;51(6):1069-1077.

ó 2010 consensus document by ILAE ó Drug resistant epilepsy is defined as:

ó Failure of adequate trials of 2 tolerated and appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom.

Polytherapy ó Wide range of combinations of two or perhaps three

AEDs can be effective in some patients ó 20 individual anti-epileptic agents

ó200 possible duotherapies

óMore than 1000 triple therapy regimens

ó Recent literature suggested that approximately 5% more patients per year will be seizure free with polytherapy.

Stephen LJ, Brodie MJ. Seizure-freedom with more than one antiepileptic drug. Seizure. 2002 Sep;11(6):349-51. Callaghan et al. Ann Neurol 2007 Oct;62(4):382-9.

Successful Combinations ó The majority (81.3%) of seizure free patients on

polytherapy were: ó On two AEDs ó With 64 effective duotherapy regimens ó The most common being lamotrigine + sodium valproate

(24.3%) ó 17.5% of seizure free patients were controlled on 3

AEDs ó There were 57 effective regimens ó The most successful regimens comprised

ó lamotrigine + topiramate + sodium valproate ó levetiracetam + lamotrigine + sodium valproate

Antiepileptic drug combinations—Have newer agents altered clinical outcomes? Linda J. Stephen, Martin J. Brodie Epilepsy Research (2012) 98, 194—198

Rational Polytherapy ó First consider AED to AED interactions

ó Phenobarbital and Valproate ó Sedation and Weight gain can be difficult to combat

ó Phenytoin and Carbamazepine ó Dizziness and diplopia are common, difficult to maintain

therapeutic levels due to bidirectional induction of metabolism

ó Valproate and lamotrigine ó Lamotrigine level may triple and adjustment needed. However

a synergism of this combination has been reported.

ó Topiramate, Lamotrigine or Zonisamide with enzyme inducers (carbamazepine, phenytoin)

ó Doses need to be higher due to increased clearance as a result of enzyme inducers

Brodie MJ et al. Lamotrigine substitution study: Evidence for synergism with Sodium Valproate Epilepsy Res 1997;26(3):423-432.

Rational Polytherapy (Cont) ó Try to avoid the combination of AEDs with similar side

effects such as dizziness, imbalance diplopia. 1. Carbamazepine and Lamotrigine

2. Carbamazepine and Lacosamide

3. Oxcarbazepine and Lacosamide

4. Lamotrigine and Lacosamide

Ø You will often need to reduce the original dose of one of the AEDs for better tolerance of the combination.

Rational Polytherapy (Cont) ó When epilepsy proves refractory in some cases

polypharmacy is inevitable. ó Eliminate the drugs which are deemed ineffective, this will

allow: ó Increased doses of newer drugs

ó Avoidance of complex drug-drug interactions

ó Reduction of overall drug burden on a patientís body

ó Withdrawal should always be slow (over many weeks) ó Even ineffective drug withdrawals can trigger seizures or SE

ï Uptitrate the new drug as much as the patient can tolerate

ï Then taper the old drug over many weeks

Rational Polytherapy (Cont) ó Consider specific situations

ó Lamotrigine is not a good choice if hx of rash or hypersensitivity is present

ó Cross-sensitivity exist between phenytoin, phenobarbital and carbamazepine

ó Levetiracetal, gabapentin, pregabalin and valproate have low risk of hypersensitivity

ó Valproate, gabapentin, pregabalin, carbamazepine, ezogabine known to cause weight gain

ó Topiramate and Zonisamide may cauuse weight loss ó Levetiracetam, gabapentin and pregabalin are exclusively renally

cleared. ó Avoid enzyme inducers in patients with other med problems

ó 2/3 of all drugs will undergo increased clearance with inducers

Case-3 ó Mr. Gilbert is a 78-year-old man has drug resistant

focal epilepsy for the last 3o years. He is s/p two epilepsy surgeries (Rt temporal lobectomy and then extension). He is currently on phenytoin, carbamazepine, lamotrigine, levetiracetam, topiramate. Has had bone fractures due to osteoporosis, is sedated and depressed, has CRI, DM-II, on warfarin for a DVT. Drug levels of carbamazepine and topiramate were high therapeutic the rest of the AEDs were subtherapeutic.

Case 3 (Cont) ó Mr. Gilbert had 3-4 GTC szs per month and 2-3 CPSzs

per month. ó What would you do with this gentleman’s AEDs.

ó First goal is better seizure control or seizure freedom ó Second goal is decrease AED burden and side effects

ó His neurologist attempted to decrease his phenytoin from 300mg qhs to 200mg qhs thinking this was the one driving lamotrigine level down. ó Patient had a cluster of GTC seizures and is in ER ó What would you do next???

Case 3 (Cont) ó Epilepsy monitoring unit ó Decrease phenytoin with

ó simultaneous increases in lamotrigine and levetiracetam

ó While in EMU Phenytoin and Topiramate were successfully tapered off ó Three months later he reported feeling much better

with more energy and joy. His seizure frequency decreased by half. However he noted nose bleeds and also gum bleeding during brushing. ó What’s next???

Case 3 (Cont) ó INR returned 4 ó Warfarin dose was reduced (INR normalized) ó What else could we do to help this patient? ó Try to get rid of carbamazepine? ó Further maximize LVT and LTG? ó Or add another agent?

ó Lacosamide? ó Valproate? ó Ezogabine? ó Don’t do anything just check INR frequently?

SURPRISING? ó Adverse effects:

ó Did not differ between monotherapy and polytherapy patients ó Did not correlate with AED load ó This was thought to be a result of physicians’ intervention in

individualizing treatment regimens.

ó Adverse effects are determined more by individual susceptibility, type of AEDs used, and physicians’ skills, than number of coprescribed AEDs and AED load.

Canevini et al. Epilepsia, 51(5):797–804, 2010

Stopping AEDs ó Treatment with AEDs alone:

ó About 70-80% eventual seizure freedom ó Illusion of cure with AEDs? Not sure if it exists ó Relapse after stopping treatment is 11-41%

ó Children relapse rate after stopping AEDs is about 20% and adults is about 40%

CHADWICK, D. (1984) The discontinuation of antiepileptic therapy. In: Recent Advances in Epilepsy, vol.2, pp.111-125. CHADWICK, D. and REYNOLDS, E.H. (1985) When do epileptic patients need treatment? Starting and stopping medication. Br. Med. J. 290, 1885-1888.

MRC Antiepileptic Drug Withdrawal Group (1991) Randomized study of antiepileptic drug withdrawal in patients in remission. Lancet 337, 1175-1180.

ó In the large study above:

ó Patients in long-term remission were randomized either to: ó Withdraw treatment

ó Continue treatment

ó The risk of relapse in the first two years after randomization ó 41% in patients coming off treatment

ó 22% in patients continuing on medication

ó Most relapses occurred within the first year of treatment reduction or withdrawal

ó The more severe and long lasting a patientís active epilepsy before remission the greater the risk of relapse

ó JME or the presence of a structural lesion underlying the epilepsy also enhanced the risk of relapse

Patient specific approach ó Young women with 2-3 year seizure freedom could

prefer drug withdrawal during pregnancy. ó Patient’s with intolerable side effects ó Patient’s having difficulty finding a job while on AEDs

General Rules? ó 2-5 year seizure freedom

ó Depends on the type of epilepsy ó Relapse rate is 2% in rolandic epilepsy ó Relapse rate is 85% in JME with GTC seizures

ó Average relapse 20-25% in children ó Average relapse 35-40% in adults

ó In Idiopathic Generalized Epilepsy discontinuation should be attempted if any at all prior to age 18 ó Prefer to have a normalized EEG ó After age 18 (driver's license, finding a job, need for mobility) ó If already driving recommend to avoid driving for 3 months

ó Discontinuation should last 6-12 months

óQUESTIONS