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10/16/2012

Outline

• Seizure types The new landscape of • 2010 nomenclature antiepileptic drugs • AED choices based on seizure type or epilepsy syndrome

David G. Vossler, MD, FAAN • Status epilepticus – 2012 guidelines Clinical Associate Professor of Neurology • Individual AEDs University of Washington; Medical Director, Valley Neuroscience Institute • Strategies for AED resistance WSNS Annual Meeting, Oct 13, 2012

1981 Classification of Seizures* Homunculus

I. Partial (Focal, Local) Seizures A. Simple Partial Seizures (SPS) (“aura”, “focal motor”, etc.) Normal consciousness. Signs/symptoms: motor, somatosensory, special sensory, autonomic, or psychic (vary greatly between patients depending upon the brain area involved in the seizure) . B. Complex Partial Seizures (CPS) (“psychomotor”) Consciousness is impaired. May begin as SPS. Automatisms +/-. Penfield W & Jasper H. C. Partial seizures evolving to generalized seizures Epilepsy and the When SPS or CPS evolve, they usually progress to secondarily Functional Anatomy generalized tonic-clonic seizures (SGTCS). Rarely, they are hemi- of the Human Brain. clonic or incomplete GTCS. Little Brown & Co. 1954

*International League Against Epilepsy Epilepsia 1981;22:489-501

1981 Classification of Seizures* (cont.) 2010 ILAE system of terminology and concepts for organization of seizures and epilepsies*

II. Generalized Seizures (convulsive and nonconvulsive) • The 2006 classification of epilepsy syndromes was A. Absence seizures (typical and atypical) (“petit maladie”) unchanged, except the “focal” & “generalized” B. Myoclonic dichotomy is abandoned* C. Clonic • Changed many of the 1981 seizure names D. Tonic – Removes “simple and complex partial” seizures E. Generalized tonic-clonic (GTCS) (“grand maladie”) – Adds “epileptic spasms” and removes neonatal seizures F. Atonic • Clarifies generalized and focal seizure onset modes III. Unclassified seizures (incomplete data) • Etiologies are now: genetic, structural/metabolic, unknown *International League Against Epilepsy Epilepsia 1981;22:489-501 *ILAE Commission on Classification and Terminology. Epilepsia 2010;51:676-85

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Table 1* - Classification of seizures Table 2* - Descriptors of focal seizures

• Generalized Seizures – Clonic – Tonic-clonic (in any • Without impairment of consciousness or awareness combination) – Tonic – With observable motor or autonomic components – Absence – Atonic – Subjjypypyective sensory or psychic phenomena only • TilTypical • FlSiFocal Seizures • With impairment of consciousness or awareness •Atypical • Unknown: epileptic • Myoclonic absence spasms • Evolving to a bilateral, convulsive seizure (involving • Eyelid myoclonia tonic, clonic or tonic-clonic features) – Myoclonic *ILAE Commission, Epilepsia 2010;51:676-85 • Myoclonic • Myoclonic atonic *ILAE Commission, Epilepsia 2010;51:676-85 • Myoclonic tonic

Selection of AEDs by seizure type or epilepsy syndrome

Evidence–based, using head-to-head comparison trials when available

Yellowstone National Park, Wyoming

23 ezogabine Comparison trials of older AEDs ACTH gel Current U.S. AEDs 15 10

5

1900 1920 1940 1960 1980 2000 2020

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Standard and New Antiepileptic Drugs Comparison trials of older AEDs (SANAD) Studies

VA cooperative study #1 VA cooperative study #2 • Multicenter studies in UK; age > 4 years • Two head-to-head randomized, open-label trials: – CBZ, GBP, LTG, OXC, TPM for focal sz (SANAD-A) – VPA, LTG, TPM for generalized-onset sz (SANAD-B) • Primary outcome measures: 1. Retention (time to treatment failure due to inadequate seizure control or intolerable side effects) 2. Seizure control (time to 1-year seizure remission)

Marson et al. The Lancet. 2007;369(9566):1000-1015, and 1016-26.

SANAD-A: Retention SANADSANAD--A:A: Seizure Control

Probability of 12- Probability of month remission staying on-drug N = 1721

Years from randomization Years from randomization Marson et al. The Lancet. 2007;369(9566):1000-15. Marson et al. The Lancet. 2007;369(9566):1000-15.

Generalized-onset Epilepsy Recommended AEDs for Focal Seizures* SANAD-B: Retention • Monotherapy: – First: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate (none vastly superior) – Second: phenobarbital, primidone – Third: felbamate Probability of staying on drug • Adjunctive therapy only: N = 716 – First: ezogabine, lacosamide, levetiracetam, tiagabine, pregabalin, zonisamide – Second: vigabatrin, rufinamide?, clobazam? – Less effective: gabapentin, ,

*Based on: ILAE Treatment Guidelines Epilepsia 2006;47:1094-1120, Marson et al. The Lancet. 2007;369(9566):1016-26. FDA approval RCTs, and extensive recent literature

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Childhood SANAD B: Seizure Control Absence Study

Marson et al. The Lancet. 2007;369(9566):1016-26. NEJM 2010;362:790-9

Recommended AEDs for Generalized-onset Seizures* AEDs for Specific Syndromes • Absence: • Juvenile Myoclonic Epilepsy – First: ethosuximide, meth- or , valproate – First: clonazepam, levetiracetam*, valproate, – Second: acetazolamide, clobazam?, lamotrigine, – Second: lamotrigine?, rufinamide?, TPM?, zonisamide? levetiracetam?, rufinamide?, zonisamide? • Lennox-Gastaut Syndrome • Myoclonic: – First : cl ob azam*(d rop a ttac ks ), c lonazepam, ltii*lamotrigine*, – First: clonazepam, levetiracetam, valproate levetiracetam, rufinamide*, topiramate*, valproate – Second: AZM, clobazam?, ESM, lamotrigine, PB, PRM, – Second: felbamate* rufinamide?, zonisamide • West Syndrome (epileptic spasms) • GTCS: – ACTH*, valproate, vigabatrin* – First: LTG, LEV, topiramate, valproate *FDA approved for syndrome specifically

– Second: PB, phenytoin, PRM, zonisamide? Based on: ILAE Treatment Guidelines Epilepsia 2006;47:1094-1120, *Based on: ILAE Treatment Guidelines Epilepsia 2006;47:1094-1120, FDA approval RCTs, and extensive recent literature FDA approval RCTs, and extensive recent literature

Focal-onset epilepsy syndromes Status epilepticus

1. Temporal lobe epilepsies 1. Convulsive: GTCS lasting > 5 min, or (67%) repeated seizures without recovery of 2. Frontal lobe epilepsies consciousness between* (20%) 2. Non-convulsive 3. Occipital lobe epilepsies 1. Absence (8%) 2. Focal w/ altered awareness 4. Parietal lobe epilepsies 3. Focal motor (5%)

*Glauser and AES Guidelines Committee. JAMA 2012; in press

After Broadmann 1909, from Carpenter MB 1985

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STATUS EPILECTICUS ADMISSION ORDER SET

STATUS EPILECTICUS ADMISSION ORDER SET (CONTINUED) Allergies: Monitor Vital signs every 5-15 minutes and PRN when sedation infusions are initiated or increased

ADMIT ADMIT Admit to Attending physician: Dr. VITAL VITAL SIGNS SIGNS Continuous pulse oximetry. Record every hour and PRN.

NPO DIET DIET STAT phenytoin level & albumin 30 min after bolus completed – CALL MD WITH RESULTS Thiamine 100 mg IV over 2 minutes x 1 dose followed by Dextrose 50% 1 amp (50 ml) IV x 1 dose STAT valproic acid level 30 minutes after Valproic Acid infusion completed – CALL MD WITH RESULTS 2 mg IV every 2-4 minutes PRN seizures. Maximum dose 0.1 mg/kg (Hold for RR ≤ 12 or Sp02 < 92%) Convulsive status epilepticus* AFTER RECEIVING ONE DOSE OF LORAZEPAM THEN ADMINISTER LOADING DOSE OF: CMP now Fosphenytoin ______mg PE* IV x 1 dose now (suggested dosing 15-20 mg PE*/kg) Continuous bedside EEG monitoring (MD to contact neurologist on-call) (Recommend to infuse over 30 minutes. Rate NOT to exceed 150 mg PE*/min) *PE = phenytoin equivalent Call MD if EEG shows return of electrographic seizures or pattern other than burst suppression, with periods IF SEIZURES PERSIST AFTER FOSPHENYTOIN LOADING DOSE THEN ADMINISTER: of suppression lasting 5 – 15 seconds alternating with bursts lasting 5 – 15 seconds Valproic Acid (Depacon®) ______mg in D5W 50 ml IV x 1 dose over 60 minutes. Do not exceed 20 mg/min. & STUDIES LABS (suggested dosing 20 mg/kg OR 1000 mg) Routine bedside EEG • Step 1: Follow with Valproic Acid (Depacon®) ______mg in D5W 50 ml IV every 6 hours. Infuse over 60 minutes Other: (suggested dosing 500 mg every 6 hours) OR Weigh patient via bedscale upon admission Levetiracetam (Keppra IV®) ______mg in D5W 100 ml IV x 1 dose over 15 min (suggested dosing 1000 mg) Oxygen at 2-4 L per minute via nasal canula. Titrate to maintain Sp02 > 92%. – ABCs and obtain bloodwork OTHER OTHER Follow with Levetiracetam (Keppra IV®) ______mg in D5W 100 ml IV every 6 hours. Infuse over 15 minutes If Sp02 < 92% OR RR ≤ 12, call Anesthesia for STAT intubation. (suggested dosing 500 mg every 6 hours)

IF CLINICAL SEIZURES CONTINUE DESPITE ABOVE TREATMENT, CALL PHYSICIAN AND INITIATE FOLLOWING ORDERS: – Infuse normal saline and 100 mg thiamine

 Call anesthesia for STAT intubation

 Call for STAT beside EEG  Transfer to CCU – Then, give one ampule of D50 (adult) or 2 ml/kg of D25  Do NOT use long acting muscle relaxant (short acting muscle relaxant for intubation acceptable)

PATIENT MUST BE INTUBATED PRIOR TO INITIATION OF THE FOLLOWING ORDERS: TIONS TIONS ()g g A Midazol am –adiidminister as f fllollows: (children) if glucose < 60 mg/dl  ______mg IV bolus x 1 dose now (suggested dosing 0.2 mg/kg)  After bolus, begin continuous IV infusion at ______mg/hour (suggested dosing 0.06 mg/kg/hour) MEDIC  Titrate by _____ mg/hr IV every 10 minutes. Maximum dose 0.6 mg/kg/hour. (suggested dosing 0.06 mg/kg/hr) • Step 2:  Titrate infusion to achieve EEG indicating: Clinical cessation of seizures OR Burst suppression pattern ______

PEntobartital – administer as follows: PHYSICIAN’S SIGNATURE DATE TIME  ______mg IV bolus x 1 dose now. Rate NOT to exceed 50mg/min. (suggested dosing 15 mg/kg) – i.v. lorazepam 4 mg (2 mg for weight 13-40 kg) (not  After bolus, begin continuous IV infusion at _____ mg/hour (suggested dosing 1 mg/kg/hr)  May give ______mg IV bolus every 10 – 20 minutes if seizures continues (suggested dosing 5mg/kg)  Titrate infusion to achieve EEG indicating: Clinical cessation of seizures OR Burst suppression pattern diazepam) or i.m 10 mg (5 mg for 13-40 kg)*

PHenobarbital – administer as follows:  ______mg IV bolus x 1 dose now. Rate NOT to exceed 30mg/min. (suggested dosing 15 – 20 mg/kg)  If seizures continue, give repeated boluses of _____ mg IV every 30 minutes (suggested dosing 10 mg/kg) – be ready to place on ventilator  Repeat boluses to achieve EEG indicating: Clinical cessation of seizures OR Burst suppression pattern

Propofol – administer as follows:  ______mg IV bolus x 1 dose now (suggested dosing 1 – 2 mg/kg) – give NO muscle relaxants (except short-acting to  After bolus, begin continuous IV infusion at _____ mg/kg/hour (suggested dosing 2 – 10 mg/kg/hour)  Check Lipid panel, Amylase, Lipase, BMP daily intubate)  Titrate infusion to achieve EEG indicating: Clinical cessation of seizures OR Burst suppression pattern PRECAUTION: Use caution with doses greater than 5 mg/kg/hour or continuous infusion for greater than 5 days. -Name Label-

STATUS EPILECTICUS (ADULT) ORDER SET -Name Label- *Silbergleit et al. RAMPART study. NEJM 2012;366:591-600, and (Page 2 of a continuous 2 page order set) STATUS EPILECTICUS (ADULT) ORDER SET (Page 1 of a continuous 2 page order set) Glauser and AES Guidelines Committee, JAMA 2012 (in press) BARCODE

Form Date P&T Form Date P&T

Convulsive status (cont.) Convulsive status (cont.) • Step 4 (refractory status): • Step 3: – (off label) can try i.v. valproic acid (Depacon), levetiracetam (Keppra), – give i.v. fosphenytoin (Cerebyx) 18 mg/kg P.E. load lacosamide (Vimpat) repeated (not faster than 150 mg/min) may repeat up to 30 infusions mg/kg (i.v. or i.m.) – OR midazolam or drips* or – monitor BP and heart rate ppgg,entobarbital 15 mg/kg bolus, then 1 mg/kg/hr with vasopressors – i.v. phenytoin causes bradycardia, hypotension, and – do not paralyze patient thrombophlebitis. NEVER give phenytoin i.m., in – continuous video-EEG monitoring anything other than saline, or >50 mg/min! *Vossler, Novotny, Naritoku, Faught et al. Epilepsy Currents 2013 (in preparation)

AED Choice by Seizure Type Older Antiepileptic Drugs (AEDs)

Focal-onset Generalized-onset Simple 1857 salts Complex 1912 phenobarbital Secondarily TonicTonic-- Epileptic Tonic Myoclonic Atonic Absence generalized clonic Spasms 1938 phenytoin phenytoin, 1954 primidone carbamazepine, phenobarbital, ACTH 1960 ethosuximide gabapentin, topiramate? tiagabine, valproate? 1968 diazepam oxcarbazepine vigabatrin pregabalin, 1974 carbamazepine lacosamide, ethosuximide vigabatrin 1975 clonazepam 1978 valproic acid valproate, lamotrigine, topiramate, zonisamide, levetiracetam, rufinamide, clobazam, felbamate

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Newer AEDs 1993 felbamate ACTH 1994 gabapentin 1995 lamotrigine • Injectable adrenocorticotropic hormone (H.P. Acthar® gel) 80 U/ml, a porcine extract 1996 fosphenytoin • Indication: FDA approved 12/2010 for treating 1997 topiramate, tiagabine, vagus nerve stimulator epileptic spasms in children under age 2. 1999 levetiracetam Effective in unknown and symptomatic cases. 2000 oxcarbazepine, zonisamide • One 1996 study showed 13/15 infants responded 2005 pregabalin to ACTH and 4/14 responded to prednisone. 2009 lacosamide, rufinamide, vigabatrin • Side effects: Cushingoid appearance, infection, 2010-12 ACTH gel, ezogabine, clobazam hypertension, irritability, acne. Less with 75 U/m2 2 2013+, brivaraceteam, , BID than 150 U/m daily eslicarbazepine,

Carbamazepine Carbamazepine (cont.)

• Indication: focal-onset seizures. Can reduce •MOA:enhance rapid Na+ channel inactivation, some genetic GTCS, but can worsen absence modulate L-type Ca2+ channels and myoclonic seizures •Dose: 300-2400 mg/day (given tid-qid; bid for • : extended release forms) – hepatic enzyme inducer – Undergoes autoinduction over 2-3 months -> need • Range: 4 - 12 g/ml; check CBC monthly at first low starting doses (2-3 mg/kg/d) and build up • Adverse Effects: diplopia, ataxia, nausea, rash, gradually over 3 months Stevens Johnson Syndrome, aplastic anemia – 75% bound to serum proteins (<1/65,000), SIADH –T1/2 14 hrs • Names: Tegretol ™, Tegretol XR ™, Carbatrol ™

Clobazam Clonazepam

• Names: Onfi® • Indication: myoclonic, typical absence, atypical • U.S. FDA approval: 10/2011 for Lennox-Gastaut Syndrome (LGS) age ≥2 years absence (Lennox-Gastaut Syndrome) seizures - • Effective on drop attacks in 2 studies on LGS* at 1.0 •MOA:binds GABA-Aγ receptors → enhances Cl mg/kg/day (max 40 mg/day) • Pharmacokinetics: hepatic metabolism. 80% •MOA:GABA receptor agonist – 1,5 protein bound. T1/2 is 24 hrs. • Dose: 10-40 mg daily (given BID) •Dose: 0.5-6 mg/day (divided tid) • Used in >100 countries also for focal-onset seizures • Range: 0.04-0.07 g/ml • AEs: sedation, fever, URI, drooling, constipation, cough, UTI, insomnia, aggression, fatigue, irritability, depression, • Adverse Effects: somnolence, dizziness, vomiting, trouble swallowing, dyscoordination, bronchitis, depression, fatigue, dependence and pneumonia •Name: Klonopin ™ *Ng et al. Neurology 2011;771473-81

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Diazepam & Lorazepam Diazepam and Lorazepam (cont.)

• Class: 1,4 •MOA:binds GABA-Aγ receptors → enhances Cl- • Indication: frequent focal sz or GTCS (acute • Pharmacokinetics: hepatic metabolism. therapy only); can cause absence status. Tolerance and dependence develop • Lorazepam is preferred for ivi.v. use in status • Dose equiv.: 5 mg diazepam = 2 mg lorazepam epilepticus because, unlike diazepam, there is no = 5 mg midazolam = 1 mg clonazepam redistribution back out of the brain 30 - 60 minutes • Rectal diazepam gel for cluster seizures later. Lorazepam has a shorter half-life in serum • Adverse Effects: somnolence, dizziness, than diazepam due to less uptake into peripheral depression, fatigue, tolerance, dependence fatty tissue. Can be given with any iv fluids. • Names: Valium ™, rectal Diastat ™; Ativan ™

Ethosuximide Ezogabine

• Indication: adjunctive for partial seizures in adults • Indication: absence (? myoclonic) seizures •MOA: Potassium , increasing M-current, which •MOA:modulates slow T-type Ca channels in turn stabilizes the resting and sub-threshold membrane potential (K ) • Pharmacokinetics: hepatic metabolism. 0% bound to v7.2-5 • Pharmacokinetics: glucuronidation → renal serum protiteins. T i40his 40 hrs 1/2 •Dose: 600-1200 total daily, given TID •Dose: 250-1500 mg/day (given bid-tid) • Range: ? g/ml • Range: 40 - 100 g/ml • Adverse Effects: urinary retention (3%), dizziness, blurred vision, neuropsychiatric effects, 7 msec QT prolongation, • Adverse Effects: nausea, abdomen pain, sedation, increased digoxin & levels ataxia, leukopenia, pancytopenia, Stevens-Johnson • Names: Potiga®, ( outside U.S.) •Name: Zarontin ™ • FDA approval 10/11, final 3/2012

Felbamate Gabapentin • Indication: partial seizures; Lennox-Gastaut Syndrome • Indication: adjunctive - partial seizures, > age 12 •MOA:enhance rapid Na channel inactivation, ↓ Ca2+ channels •MOA:modulates Ca channel at α2-δ subunit • Pharmacokinetics: hepatic metabolism; enzyme • Pharmacokinetics: renal excretion. 0% bound to inhibitor. T is 15-20 hrs serum proteins. T1/2 = 6 hrs. Bioavailability = 60% at 1/2 lower doses but falls to 30% at higher doses •Dose: 1200-3600 mg/day (given TID) •Dose: 900-1800 mg/day (bid-tid) (occ. more) • Range: 60-100 g/ml; check CBC, LFTs monthly • Range: 4-8.5 g/ml • Adverse Effects: Fatal aplastic anemia (31/10,000), fatal hepatic failure (16/10,000), insomnia, headache, • Adverse Effects: drowsiness, ataxia, dizziness; no anorexia/weight loss serious organ toxicity •Name: Felbatol ™ •Name: Neurontin ™

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Physiology of Voltage-Gated Lacosamide Sodium Channels

Carbamazepine, lamotrigine, • Indication: adjunctive, adult, focal-onset seizures oxcarbazepine, phenytoin, rufinamide

•MOA:enhances sodium-channel slow inactivation, Repolarization • Pharmacokinetics: linear; partially renally-excreted Inactivated statefast Local anesthetics (within ms)

and partially metabolized by CYP 2C19. No known rane l b drug in terac tions. 15% pro te in boun d Resting Depolarization Open • AEs: diplopia, HA, nausea, dizziness, ataxia, syncope, state state potentia longer PR and QTc Inactivated stateslow •Dose: 200-400 mg/day (given BID), Also available I.V. mem Resting (within sec and beyond) • Name: Vimpat® Regulation of • I have a genetic GTCS study open (SP982) Lacosamide long-term availability

Epilepsia 2007;48:1308-17 and 2009;50:443-453 Beyreuther BK, et al. CNS Drug Rev. 2007;13:21-42.

Lamotrigine Levetiracetam

• Indication: focal seizures, primary GTCS, and Lennox- • Indication: adults & kids: adjunctive for partial seizures, Gastaut Syndrome ≥ age 2 myoclonic seizures in JME, and genetic GTCS •MOA:enhances rapid inactivation of Na+ channel • MOA: unknown • Pharmacokinetics: hepatic metabolism. 0% bound to serum • Pharmacokinetics: renal excreted, liver hydrolyzed; <10% proteins. T1/2 = 25 hrs alone; 13 hrs with enzyme inducing bound to serum proteins. T 7hrs7 hrs AEDs (PB, PHT, CBZ, PRM) oral contraceptives or 1/2 rifampin; 70 hrs with inhibitor (valproate). Serum levels fall •Dose: 1000-3000 mg/day (bid) by 67% in third trimester of pregnancy • Range: 20-40 g/ml •Dose: 100-500 mg/day (bid); up to 1000 mg/day • Available: oral or i.v. forms • Range: 4-20 g/ml • Adverse Effects: somnolence, fatigue, asthenia, dizziness, • Adverse Effects: dizziness, blurred vision, vomiting, <0.1% infection, irritability, depression Stevens-Johnson or TENS, rare multi-organ failure •Name: Keppra ™ •Name: Lamictal ™

Oxcarbazepine Phenobarbital and Primidone • Indication: partial seizures over age 3 • Indication: partial and generalized seizures. PRM helps •MOA:enhance rapid Na+ channel inactivation, modulate myoclonic seizures N- and P-type Ca2+ channels •MOA:binds GABA-A receptors nonspecifically → enhances • Pharmacokinetics: hepatic reduction to MHD then renal Cl- conductance excretion. No autoinduction. 40% bound to serum • Pharmacokinetics: hepatic enzyme inducers. PB is 50%, PRM proteins. T is 9 hrs; shorter w/ EIAEDs. OC estrogen 1/2 is <5%, bound to serum proteins. T1/2 is 96 hrs for PB, 12 hrs falls at 1200 mg/d for PRM. PRM -> PB. •Dose: 1200-2400 mg/day (bid-tid); up to 3 g/d •Dose: 60-180 mg/day for PB, 250-2000 mg/day for PRM • Range: 12-35 g/ml (MHD - watch lab error) • Range is 15-45 (PB), 6-12 (PRM) g/ml • Adverse Effects: dizziness, nausea, ataxia, hyponatremia • Adverse Effects: sedation, cognitive slowing, depression, (2.5%) rash, Stevens-Johnson, nausea, tolerance, dependence •Name: Trileptal ™ • Names: phenobarbital; Mysoline ™

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Phenytoin & fosphenytoin Pregabalin

• Indication: partial and generalized tonic-clonic seizures • Indication: adjunctive - partial szs in adults + 2+ •MOA:enhance rapid Na channel inactivation • Mechanisms: binds α2-δ unit of Ca channel, • Pharmacokinetics: hepatic enzyme inducer. 90-95% bound to modulates Ca2+ current, glutamate, noradrenaline, serum proteins. T1/2 is 22 hrs in adults - longer at higher and substance P doses due to zero-order kinetics , longer in elderly/neonates • Pharmacoki ne tics: 100% rena l excre tion; T½ = 6h6 hr, •Dose: 200-600 mg/day (q day-tid) p.o.; fosphenytoin i.m./i.v. Cmax = 1 hr; 90% bioavailability 200-600 mg/day P.E. (given q8h). • Therapeutic range is 10-20+ g/ml •Dose: 150-600 mg/d (given tid). Category V. • Adverse Effects: nystagmus, ataxia, dysarthria, cognitive • Adverse effects: dizziness, dry mouth, somnolence, slowing, gingival hyperplasia, hypertrichosis, rash, Stevens- decreased attention/concentration, edema, blurred Johnson, lymphadenopathy, pseudolymphoma, osteomalacia vision, weight gain • Names: Dilantin ™; for i.m./i.v.= Cerebyx ™ •Name: Lyrica™

Rufinamide Tiagabine

• Rufinamide (Banzel®) • Indication: adjunctive - partial seizures age 12+ – Indication: seizures in Lennox-Gastaut Syndrome, age 4+ •MOA: selective GABA reuptake inhibitor (SGRI) –MOA:enhances rapid inactivation of Na+ channel • Pharmacokinetics: hepatic metabolism. 0% – Pharmacokinetics: bound to serum proteins; displaced by VPA. T1/2 • Absorption is slow and nonlinear: extent of absorption decreases with is 40 hrs; shorter with EIAEDs higher doses, but is enhanced by food • Metabolized by hydrolysis, not CYP 450 •Dose: 32-56mg/day (bid-qid) • T ½ = 6-10 hours • Range: 5-70 g/ml – AEs: sedation, fatigue, dizziness, ataxia, dizziness, nausea, • Adverse Effects: sedation, cognitive slowing, shorter QTc interval dizziness, tremor, anxiety, nausea –Dose: 400-3200 mg/day (divided BID) •Name: Gabitril ™

Neurology 2008;70:1950-58, Epilepsia Aug 2009

Topiramate Valproate

• Indication: monotherapy for partial seizures, GTCS, and • Indication: partial; absence, myoclonic and GTCS Lennox-Gastaut Syndrome •MOA:↑ rapid Na+ channel inactivation, ↑ GABA-A, modulate •MOA:↑ rapid Na+ channel inactivation, ↑ GABA-A, modulate L- L-type Ca2+ channels type Ca2+ channels, ↓ glutamate, inhibit carbonic anhydrase • Pharmacokinetics: hepatic enzyme inhibitor. 80-90% bound to

• Pharmacokinetics: 70% renal excretion. 15% bound to serum serum proteins – displaced by ASA. T 1/2 is 15-20 hrs in adults proteins. T1/2 is 21 hrs (15 hr with EIAEDs); induces phenytoin •Dose: 500-6000 mg/day (divided bid-tid) 25% and oral contraceptives at 200 mg/d •Dose: 200-400 mg/day (given bid-tid) • Range: 50-150 g/ml • Range: 15-25 g/ml • Adverse Effects: nausea, vomiting, abdominal pain, • Adverse Effects: renal stones (1.5%), glaucoma, tingling, word- hyperinsulinemia -> obesity, weight loss, tremor, alopecia, finding difficulties, cognitive slowing, metabolic acidosis hyperammonemia, hepatic failure, sedation •Name: Topamax ™ • Names: Depakene, Depakote ™; i.v. = Depacon ™

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Vigabatrin Zonisamide • Indication: partial seizures age 16 and above • Indication: infants ages 1 mo – 2 years with infantile • MOA: enhance rapid Na+ inactivation, ↓ T-type Ca2+ spasms, and for adults with refractory complex partial current, ↓ GABA, inhibit carbonic anhydrase seizures •MOA:GABA transaminase inhibitor - irreversible • Pharmacokinetics: hepatic metabolism. T 1/2 = 69 hr monoRx; 27-38 hr w/ EIAEDs, 46 hr w/ VPA • Pharmacokinetics: Renal excretion. • Dose: 3000-6000 mg/day, given BID •Dose: 400-600 mg/day (given daily or bid) • AEs: sedation, weight gain, anemia, peripheral neuropathy • Range: 20-30 g/ml • Serious AE: visual field constriction due to irreversible • Adverse effects: sulfa: Stevens-Johnson or blood retinal cell damage in 30% of patients; infants may get MRI dyscrasia; somnolence, dizziness, nausea, rhinitis, ataxia, T2 white matter changes HA, weight loss (10%), renal stones (<4%) • Name: Sābril® •Name: Zonegran ™ • FDA approved 8/21/09 Vossler et al. Clin Med Therapeutics 2010 2:1-9

Treatment – new definitions* Surgical Treatment

• Anterior (medial) temporal lobectomy • “Treatment failure” = sz recurrence after • Lesionectomy adequate Rx • Focal Cortical Resection • “Drug resistance” = failure of 2+ AEDs to achieve se izure free dom • Multiple Subpial Transections • “Seizure free” = freedom of all sz for either 3X • Corpus Callosotomy longest pre-Rx sz-free interval or 12 months • Hemispherectomy (whichever is longer) • Vagus Nerve Stimulation • Research only: Responsive and Deep Brain *Kwan & Brodie. Lancet Neurology 2009;9:27-9. Stimulation, stereotactic radiosurgery

Comparative Efficacies TLE surgery - results Treatment Age Indication Efficacy Adverse Effects Antiepileptic Children Specific AEDs for specific 64% sz freedom Vary by AED, Drugs Adults seizure types with first 3 AED- often CNS-related therapy trials1

• ERSET study seizure- Ketogenic Children All seizure types Rarely sz-free; Lipid disorders, # Diet 54% pts >50% sz ketoacidosis freedom: reduction at 2 – 0% medical group vs. 3 months Cognitive effects , SilSurgical Children Pharmacores ist ant 85% sz freedom3, surgery-related risks – 85% surgical group Resection Adults partial epilepsy improved quality (O.R. = ∞) (TLE) of life Voice alteration, 12 and Pharmacoresistant Rarely sz-free5; cough, dyspnea, VNS older partial epilepsy 43% of pts >50% infection, high cost for sz reduction at 3 rare sz freedom years4 # Engel J et al. (Vossler DG). 1Brodie MJ, Kwan P. Neurology 2002;58(suppl 5):S2-S8. JAMA 2012;307:922-30 2Vining EP, et al. Arch Neurol 1998;55:1433-1437. 3Engel et al. JAMA 2012;307;922-30. 4Morris GL III, Mueller WM. Neurology 1999;53:1731-1735. 5Renfroe JB, Wheless JW. Neurology 2002;59(suppl60 4):S26-S30.

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VNI Epilepsy Center Future AEDs

• David Vossler MD FAAN, neurology & neurophysiology • Seeking US FDA approval: • Baburaj Thankappan MD, neurology & neurophysiology – Brivaraceteam • Kevin Joseph DO, pediatric neurology & sleep medicine – Eslicarbazepine • Erica-Brandling-Bennett PhD, neuropsychology – Perampanel • Peter Balousek MD, neurosurgery • Still in research • Carole Burton RN, clinical research – Carabersat, remacemide • Tony Bell, Zoë Goldeshtein, Amarjit Kaur, R EEG/EP T • Vicki Murphy MSW, social work • Rejected by FDA: • Heather Shimamoto PharmD, pharmacy – • (Halford JJ, Ben-Menachem E, Kwan P et al. Neurology 2011;52:816- 25) 425-656-4004 or 888-686-4964 (4WNI) www.valleymed.org/neuro

Eslicarbazepine

• BIA 2-093, Zebenix®, a dibenzapine like CBZ, OXC • Brivaraceteam • Indication: adjunctive for partial-onset seizures – Effective in partial-onset seizures* •MOA:enhance rapid Na+ channel inactivation, modulate N- – 2-pyrrolidinone derivative and P-type Ca2+ channels – Analogs of levetiracetam (Keppra), seletracetam and • Pharmacokinetics: not metab. by inducible CYP 450 pp(piracetam (Nootropil®) •Dose: 800 – 1200 mg qDay – Like LEV, it binds synaptic vesicle protein 2A (SV2A) • Range: ? g/ml – It also inhibits voltage-dependent Na+ currents#, and it • Adverse Effects: headache, dizziness, diplopia, reverses the inhibition of GABA- and glycine-induced nasopharyngitis* currents • We are conducting adjunctive (BIA 304) and monotherapy – UCB Pharma trials (BIA 045) – excludes HLA-B 1502 *French et al. Neurology 2010;75:519-25 #Zona et al. Epilepsy Research 2010;88:46-56 * Halasz et al. Epilepsia 2010;51:1963-9

Perampanel

• Perampanel (E2007) – Doses of 8 & 12 mg effective in 2 RCTs (Eisai 304, 305) – Glutamate (()gAMPA) antagonist

Big Sky Mountain, Montana

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