Management of Epilepsy and new AEDs

1
Management of Epilepsy and new AEDs

• Robert L. Macdonald M.D., Ph.D.
• Department of Neurology
• Vanderbilt University Medical Center
• Nashville, TN

2
Epidemiology of Seizures and Epilepsy

• Seizures
• Incidence approximately 80/100,000 per year
• Lifetime prevalence 9 (1/3 benign febrile
  convulsions)
• Epilepsy
• Incidence approximately 45/100,000 per year
• Point prevalence 0.5-1

3
Seizure Classification

• Partial seizures (focal or local origin)
• Simple partial seizures with
• motor signs
• somatosensory or special sensory symptoms
• autonomic symptoms or signs
• psychic symptoms (disturbance of higher cerebral
  function)
• Complex partial seizures with
• Impaired consciousness
• Presence and nature of aura (simple partial
  origin)
• Automatisms and other motor activity
• Secondary generalized seizures

4
Seizure Classification

• Primary generalized seizures (bilateral origin)
• Absence
• Myoclonic
• Atonic
• Tonic
• Tonic-clonic

5
Epilepsy Syndromes

• Partial epilepsies
• Idiopathic
• Symptomatic
• Cryptogenic
• Generalized epilepsies
• Idiopathic
• Symptomatic
• Cryptogenic
• Undetermined epilepsies
• Special syndromes

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Etiologies of the epilepsies
Idiopathic/Genetic Symptomatic
Unknown 15.5
Infection 2.5
Degenerative 3.5
Probable and Known Genetic (50)
Cancer 4.1
Head Injury 5.5
Congenital 8.0
Malformations 8.0
Hauser
Stroke 10.9
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Etiology of Seizures and Epilepsy

• Infancy and childhood
• Birth injury
• Inborn error of metabolism
• Congenital malformation
• Childhood and adolescence
• Idiopathic/genetic syndrome
• CNS infection

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Etiology of Seizures and Epilepsy (cont.)

• Adolescence and young adult
• Head trauma
• Drug intoxication and withdrawal
• Older adult
• Stroke
• Brain tumor
• Acute metabolic disturbances
• causes of acute symptomatic seizures, not
  epilepsy

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Pharmacology of classical AEDs
AED INa IGABAA
ITCa Phenytoin (PHT) - - Carbamazepine
(CBZ) - - Primidone (PMD)
- - Phenobarbital (PhB)
- Valproate (VPA) ?/ ?/ Clonaze
pam (CZP) - Ethosuximide (ESX)
- -
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Spectrum of seizure efficacy for classical AEDs
AED Partial/GTC GAE GMS Phenytoin
(PHT) - - Carbamazepine (CBZ)
- - Valproate (VPA)
Primidone (PMD) -
/- Phenobarbital (PhB) -
- Clonazepam (CZP)
Methsuximide (MSX)
Ethosuximide (ESX) - -
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Pharmacology of new AEDs
AED INa IGABAA IT,NCa IGlu
IH Gabapentin (GBP) /- -/? /-
/- Lamotrigine (LTG) -
/- Topiramate (TPM) /-
/- /- - Tiagabine (TGB)
- - -
- Levetiracetam (LEV) - /- /-
- - Oxcarbazepine (OXC) -
- - - Zonisamide (ZNS)
- /?
- Felbamate (FBM) /- /- /-
/- - Vigabatrin (VGT) -
- - -
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Spectrum of seizure efficacy for new AEDs
AED Partial GAE JME LGS
PME Gabapentin (GBP) - - - - Lamotrigine
(LTG) /- - Topiramate (TPM)
/- ? Tiagabine (TGB)
- - - - Levetiracetam (LEV) /- ?
Oxcarbazepine (OXC) - - - -Zonisamide
(ZNS) /? Felbamate (FBM)
? Vigabatrin (VGT) - - ? -
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Questions Raised by a First Seizure

• Seizure or not?
• Focal or generalized onset?
• Evidence of CNS dysfunction?
• Metabolic or other precipitant?
• Seizure type? Syndrome type?
• Studies?
• Start an AED?

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Seizure Precipitants

• Metabolic and Electrolyte Imbalance
• Low (occ high) blood glucose, Na, Ca, Mg
• Stimulant/other proconvulsant intoxication
• IV drug use, cocaine, ephedrine, herbal remedies
• Sedative/medication reduction
• Sleep deprivation, stress
• Hormonal variations
• Infection

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Evaluation of a First Seizure

• History, physical exam
• Blood tests CBC, electrolytes, glucose, Ca, Mg,
  hepatic and renal function
• Lumbar puncture only if meningitis or
  encephalitis suspected and potential for brain
  herniation is ruled out
• Blood or urine screen for drugs
• Electroencephalogram if indicated
• CT or MR brain scan if indicated

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Medical Treatment of First Seizure

• Whether to treat first seizure is controversial.
• 16-62 will recur within 5 years.
• Relapse rate is reduced by antiepileptic drug
  treatment.
• Abnormal imaging, abnormal EEG or family history
  increase relapse risk.
• Quality of life issues are important.
• Was the seizure precipitated?

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Choosing an Antiepileptic Drug

• Seizure type
• Epilepsy syndrome
• Pharmacokinetic profile
• Interactions/other medical conditions
• Efficacy
• Expected adverse effects
• Cost

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Choosing an Antiepileptic Drug (cont.)

• Partial onset seizures
• phenytoin gabapentin
• carbamazepine phenobarbital
• valproate primidone
• lamotrigine felbamate
• oxcarbazepine topiramate
• levetiracetam tiagabine
• zonisamide
• considered by many as drugs of choice
• associated with aplastic anemia and hepatic
  failure

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Choosing an Antiepileptic Drug (cont.)

• Generalized onset seizures
• Absence valproate ethosuximide
• Myoclonic valproate, clonazepam
• Tonic-clonic valproate phenytoin,
  carbamazepine
• Seizures in Lennox-Gastaut Syndrome
  valproate, lamotrigine, felbamate
• the risk of valproate-induced hepatic failure
  must be carefully weighed in young children
• associated with aplastic anemia and hepatic
  failure

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AEDs in generalized absence seizures

• Positive placebo-controlled or Class I trials
• Ethosuximide and valproate equally effective
• Lamotrigine (62 seizure-free 76
  seizure-reduction)
• Negative placebo-controlled or Class I trials
• Gabapentin
• Case series and anecdotal reports
• Clonazepam, zonisamide and topiramate reduced
  absence seizure frequency

Bourgeois, Epilepsia 44(suppl.2)27-32, 2003
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AEDs in JME

• No published placebo controlled Class I trials
• Nonrandomized and open studies
• Valproate open case studies (41-88 seizure free)
• Open studies favor efficacy for lamotrigine (but
  often not effective against myoclonic seizures)
• Clonazepam open case study reduced myoclonic but
  not generalized TC seizures
• Recent reports suggest that topiramate,
  levetiracetam, zonisamide may have efficacy.

Bourgeois, Epilepsia 44(suppl.2)27-32, 2003
22
AEDs in refractory primary GTC seizures

• Positive placebo-controlled trial with primary
  GTCS
• Topiramate- 56 responder rate for GTC seizures
• Negative placebo-controlled trial with primary
  GTCS
• Gabapentin
• Preliminary study with primary GTCS
• Suggests efficacy against primary GTCS for
  levetiracetam and zonisamide
• Other studies of GTCS
• Positive trials that included both generalized
  and partial epilepsy (carbamazepine, phenytoin,
  lamotrigine)
• Valproate trend over carbamazepine in GTCS
• Evidence for efficacy derived from studies of
  Lennox-Gastaut syndrome topiramate, lamotrigine

Bourgeois, Epilepsia 44(suppl.2)27-32, 2003
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Antiepileptic Drug Monotherapy

• Simplifies treatment and reduces adverse effects
• Conversion to monotherapy from polytherapy
• Eliminate sedative drugs first
• Withdraw antiepileptic drugs slowly over several
  months

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Antiepileptic Drug Interactions

• Drugs that induce metabolism of other drugs
  carbamazepine, phenytoin, phenobarbital
• Drugs that inhibit metabolism of other drugs
  valproate, felbamate
• Drugs that are highly protein bound valproate,
  phenytoin, tiagabine
• Other drugs may alter metabolism or protein
  binding of antiepileptic drugs

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AED Serum Concentrations

• In general AED serum concentrations can be used
  as a guide for evaluating the efficacy of
  medication therapy for epilepsy. Serum
  concentrations are useful when optimizing AED
  therapy, assessing compliance, or teasing out
  drug-drug interactions. They should be used to
  monitor pharmacodynamic and pharmacokinetic
  interactions.

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AED Serum Concentrations

• Serum concentrations are also useful when
  documenting positive or negative outcomes
  associated with AED therapy. Most often
  individual patients define their own therapeutic
  range for AEDs. The new AEDs have potential
  serum ranges where patients in clinical trials
  had optimal seizure control and minimal
  side-effects from the medication. For the new
  AEDs there is no clearly defined therapeutic
  range.

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Dose Initiation and Monitoring

• Discuss likely and unlikely but important adverse
  effects
• Discuss likelihood of success
• Discuss recording/reporting seizures (seizure
  calendar), adverse effects, potential precipitants

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Evaluation After Seizure Recurrence

• Progressive pathology?
• Avoidable precipitant?
• If on AED
• Problem with compliance or pharmacokinetic
  factor?
• Increase dose?
• Change medication?
• If not on AED
• Start therapy?

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Discontinuing AEDs

• Seizure free ?2 years implies overall gt60 chance
  of successful withdrawal in some epilepsy
  syndromes
• Favorable factors
• Control achieved easily on one drug at low dose
• No previous unsuccessful attempts at withdrawal
• Normal neurologic status and EEG?
• Primarily generalized seizures except JME
• Benign syndrome
• Consider relative risks/benefits (driving,
  pregnancy)

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Non-Drug Treatment/Lifestyle Modifications

• Adequate sleep
• Avoidance of alcohol, stimulants, etc.
• Avoidance of non-precipitants
• Stress reduction specific techniques
• Adequate diet
• Exercise

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AED Alternatives Ketogenic Diet

• Anti-seizure effect of ketosis, acidosis
• Low carbohydrate, low protein, high fat after
  fasting to initiate ketosis
• Main experience with children, especially with
  multiple seizure types
• Long-term effects unknown

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AED Alternatives Vagal Nerve Stimulator

• Intermittent programmed electrical stim of L
  vagus
• Option of patient-triggered stimulation (auras)
• Adverse effects related to local stimulus
  (hoarseness, throat discomfort, dyspnea)
• Mechanism unknown
• Clinical trials show 26 effective
• FDA says useful for partial onset seizures

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AED Alternatives Surgery

• Epilepsy syndrome not responsive to medical
  management
• Unacceptable seizure control despite maximum
  tolerated doses of 2-3 appropriate drugs as
  monotherapy
• Epilepsy syndrome amenable to surgical treatment

34
Evaluation for Surgery

• History and Exam consistency, localization of
  seizure onset and progression
• MRI 1.5 mm coronal cuts with sequences sensitive
  to gray-white differentiation and to gliosis
• Other neuroimaging options PET, ictal SPEC
• EEG ictal and interictal, special electrodes
• Neuropsychological battery and WADA test
• Psychosocial evaluation

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Surgical Treatment

• Potentially curative
• Resection of epileptogenic region (focus)
  without causing significant new neurologic
  deficit
• Palliative
• Partial resection of epileptogenic region
• Disconnection procedure to prevent seizure spread
  corpus callosotomy
• Vagal nerve stimulation

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Epilepsy Surgery Outcomes

• Temporal Extra
  Lesional HemisphX Callosotomy
  Temporal
• Seizure Free 68 45 66 45 8
• Improved 23 35 22 35 61
• Not improved 9 20 12 20 31
• Total 100 100 100 100 100

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Old AEDs

• Phenytoin
• 5-7 mg/kg, BID
• Carbamazepine
• 10-20 mg/kg, TID
• Valproate
• 20-60 mg/kg, TID
• Ethosuximide
• 20-60 mg/kg, TID
• Phenobarbital
• 2-3 mg/kg, QD

39
New AEDs Levetiracetam (KeppraTM

• Indications
• Adjunctive therapy for partial seizures in adults
• Suggestive evidence in the literature of efficacy
  in primary generalized seizures
• Mechanisms of Action
• Unknown

40
New AEDs Levetiracetam (KeppraTM)

• Absorption
• Rapid nearly complete. Oral tablet
  bioavailability 100
• Time to peak serum concentration
• Within 1 hr. Linear dose plasma relationship
• Plasma ½ life
• 7-8 hrs
• Metabolism
• Not extensively metabolized. Hydrolysis to
  inactive carboxylate is independent of cytochrome
  P450 system
• Excretion
• Primarily renal as unchanged drug (66 of dose)

41
New AEDs Levetiracetam (KeppraTM)

• Drug-Drug (AED) Interactions
• Minimal. Does not affect and is not affected by
  phenytoin, carbamazepine, valproic acid,
  phenobarbital, lamotrigine, gabapentin, or
  primidone
• Major Side Effects
• Pregnancy category C
• Fatigue, somnolence, dizziness, asthenia, and
  infection
• Minor but statistically significant decreases in
  total mean erythrocyte count, mean hemoglobin
  level, mean hematocrit compared with placebo

42
New AEDs Levetiracetam (KeppraTM)

• Dosing
• Available as 250, 500 or 750-mg tablets
• Start at 1000 mg/day given as 500 mg twice daily
• Increase by 1000 mg/day (approximately every 2
  weeks based on clinical response)
• Can be taken with or without food

43
New AEDs Oxcarbazepine (TrileptalTM)

• Indications
• Monotherapy in adults and adjunctive therapy for
  adults and children 4 to 16 years of age for
  partial seizures
• Mechanisms of Action
• Blocks voltage-sensitive sodium channels in
  rapidly firing neurons

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New AEDs Oxcarbazepine (TrileptalTM)

• Absorption
• Complete
• Time to peak serum Concentration
• 4.5 hrs (range from 3 to 13 hours)
• Plasma ½ life
• 9 hrs (MHD)
• Metabolism
• Extensively metabolized to its active monohydroxy
  derivative, with further glucuronidation. No
  autoinduction
• Excretion
• Predominately from the kidneys as metabolites

45
New AEDs Oxcarbazepine (TrileptalTM)

• Drug-Drug (AED) Interactions
• No inhibition of most CYP enzymes except CYP2C19
  and CYP3A4/5, which lowers plasma concentrations
  of dihydropyridine calcium antagonists and oral
  contraceptives
• Oxcarbazepine increases plasma levels of
  phenytoin (40) and phenobarbital (14)
• Carbamazepine, phenytoin, and phenobarbital
  decrease MHD plasma levels by 29 to 40

46
New AEDs Oxcarbazepine (TrileptalTM)

• Major Side Effects
• Pregnancy category C
• Fatigue, diplopia, nausea, vomiting, ataxia,
  abnormal vision, abdominal pain, tremor,
  dyspepsia, abnormal gait, somnolence, and
  dizziness
• Rash more common in those sensitive to
  carbamazepine
• No blood tests necessary as per package insert,
  but may need to monitor sodium levels

47
New AEDs Oxcarbazepine (TrileptalTM)

• Dosing 1
• Available as 150, 300, and 600-mg scored tablets
  or 300 mg/5 mL oral suspension
• Adjunctive therapy Start with 600 mg/day bid
  (in children 8-10 mg/kg/day). Increase by 600
  mg/day at weekly intervals, if needed
• Recommended daily dose is 1200 mg/day

48
New AEDs Oxcarbazepine (TrileptalTM)

• Dosing 2
• Conversion to monotherapy Start with 600 mg/day
  bid and reduce other AEDs over 3-6 weeks.
  Achieve maximal oxcarbazepine dose by 2-4 weeks.
  Increase by 600 mg/day at weekly intervals
• Recommended daily dose is 2400 mg/day
• Initiation of monotherapy Start with 600 mg/day
  bid increase by 300 mg/day every 3rd day to 1200
  mg/day final dose

49
New AEDs Tiagabine (GabitrilTM)

• Indications
• Adjunctive therapy in adults and children 12
  years and older for partial seizures
• Mechanisms of Action
• Enhances GABA activity ( in vitro) by inhibiting
  GABA reuptake into presynaptic neurons

50
New AEDs Tiagabine (GabitrilTM)

• Absorption
• Rapid nearly complete (gt95). Oral
  bioavailability 90
• Time to peak serum concentration
• About 45 min in a fasting state
• Plasma ½ life
• 7-9 hrs
• Metabolism
• Not fully known. Likely to be metabolized by
  CYP3A
• Excretion
• 25 excreted into the urine, 63 excreted into
  feces, primarily as metabolites

51
New AEDs Tiagabine (GabitrilTM)

• Drug-Drug (AED) Interactions
• Tiagabine causes a 10 decrease in valproic
  acid concentration, and no effect on phenytoin or
  carbamazepine concentration.
• Tiagabine clearance is 60 greater in patients
  taking carbamazepine, phenobarbital, or
  phenytoin, irrespective of other enzyme-inducing
  AEDs.
• It is not affected by valproate, but valproate
  increases in vitro concentration of free
  tiagabine.
• The clinical relevance of these findings is not
  known

52
New AEDs Tiagabine (GabitrilTM)

• Major Side Effects
• Pregnancy category C
• Dizziness/lightheadness, asthenia/lack of energy,
  somnolence, nausea, nervousness/irritability,
  tremor, abdominal pain, thinking
  abnormal/difficulty concentrating
• Dosing
• Available as 2, 4, 12, 16, 20-mg tablets
• Start at 4 mg qd increase total daily dose by 4
  to 8 mg at weekly intervals until clinical
  response or up to 56 mg/day
• Give total daily dose in 2 to 4 doses
• Titration schedule slower for patients taking
  enzyme-inducing AEDs

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New AEDs Topiramate (TopamaxTM)

• Indications
• Adjunctive therapy for partial seizures in adults
  and pediatric patients (2-16 years), or primary
  generalized tonic-clonic seizures, and in
  patients 2 years and older with seizures
  associated with Lennox-Gastaut syndrome
• Mechanisms of Action
• State-dependent blocking of sodium channels
• Increases the frequency at which GABA activates
  GABAA receptors and potentiates GABA inhibitory
  activity
• Inhibits activation of kainate/AMPA receptors by
  kainate with no apparent effect on NMDA receptors

54
New AEDs Topiramate (TopamaxTM)

• Absorption
• Rapid. Oral bioavailability 80 with tablets
• Time to peak serum concentration
• About 2 hrs
• Plasma ½ life
• 21 hrs
• Metabolism
• Not extensively metabolized
• Excretion
• Eliminated unchanged in urine ( 70 of dose)

55
New AEDs Topiramate (TopamaxTM)

• Drug-Drug (AED) Interactions
• Decrease in topiramate concentration of 48, 40
  and 14 in the presence of phenytoin,
  carbamazepine, and valproic acid, respectively
• Increases the effects of alcohol and CNS
  depressants use extreme caution
• Increases the risk of renal stone formation with
  carbonic anhydrase inhibitors
• Decreases estrogenic components of oral
  contraceptives by 18 to 30 at 200 - 800 mg/day
  doses, respectively
• Decreases serum digoxin AUC by 12 but clinical
  relevance has not been established

56
New AEDs Topiramate (TopamaxTM)

• Major Side Effects
• Pregnancy category C
• For 400 mg/day, nervousness, concentration
  difficulty, confusion, language problems, weight
  loss
• Dosing
• Available as 25, 100, 200-mg tabs 15, 25-mg caps
• Recommended daily dose is 400 mg/day in divided
  doses
• Dosesgt400 mg/day do not improve responses for
  partial onset seizures in studies
• Start at 25-50 mg/day and titrate to an effective
  dose by increasing the dose by 25-50 mg weekly

57
New AEDs Zonisamide (ZonegranTM)

• Indications
• Adjunctive therapy for partial seizures in
  adults.
• Suggestive evidence for efficacy for other
  seizure types, generalized tonic-clonic seizures,
  myoclonic seizures and infantile spasms.
• Mechanisms of Action
• Blocks voltage-dependent sodium T-calcium
  channels
• Modulates dopaminergic activity
• Inhibits carbonic anhydrase

58
New AEDs Zonisamide (ZonegranTM)

• Absorption
• Rapidly and nearly completely
• Time to peak serum concentration
• 2 to 6 hrs
• Plasma ½ life
• 63 hrs
• Metabolism
• Undergoes glucuronidation, acetylation and
  hydroxylation, then cleavage mediated by CYP3A
• Excretion
• 62 excreted from the kidneys

59
New AEDs Zonisamide (ZonegranTM)

• Drug-Drug (AED) Interactions
• Phenytoin, carbamazepine, and phenobarbital can
  decrease by the half-life of zonisamide by almost
  50
• Drugs that induce or inhibit liver enzymes are
  expected to increase metabolism and clearance of
  zonisamide and decrease its half-life
• Drugs that induce or inhibit CYP3A4 are expected
  to alter serum concentrations of zonisamide.
• Not expected to interfere with drugs metabolized
  by CYP450 enzymes

60
New AEDs Zonisamide (ZonegranTM)

• Major Side Effects
• Pregnancy category C
• Somnolence, anorexia, headache, nausea,
  agitation/irritability, dizziness
• Dosing
• Available as 100 mg two-piece hard gelatin
  capsule
• Start at 100 mg daily, increasing by 100 mg after
  2 weeks and maintained on the new doses at least
  2 weeks. Increase up to 600 mg/day