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Rational aed


•An occasional excessive and disordered discharge of nerve tissue
•Manifestation of transient hypersynchronous abnormal neuronal behavior
– Seizure – transient manifestation of abnormal hypersynchronous discharges of cortical
– Epilepsy – disorder characterized by the occurrence of at least 2 unprovoked seizures
– Epileptic syndrome – a disorder consisting of a cluster of signs and symptoms plus its
typical EEG

Pathophysiology of Epilepsy
•Cellular level
–GABA (inhibitory)

Mechanism of Seizure Generation
Possible Causes of Seizures in Young People

Possible causes of seizures in Adults

Why Classify?
•Facilitate communication among professionals
•Facilitate communication between physician and patient •Rational prescribing of AEDs based on accurate diagnosis of seizure type •Prognosis

International League Against Epilepsy (ILAE) classification of Seizure Type
I. Partial
Simple partial seizure (consciousness not impaired) B. Complex partial seizure (with impairment of Consciousness) III. Unclassified epileptic seizures (inadequate or incomplete
The ILAE Classification of Epilepsies and Epilepsy Syndromes Shorvon, 2000
Simple and Complex Partial
Impaired Consciousness
•“The inability to respond normally to exogenous stimuli by virtue of altered awareness
and/or responsiveness”
–The ability of the patient to carry out simple commands or willed movements
–refers to the patient’s contact with events during the period in question and its recall
Abnormal flow of
electrical discharge
from a specific or
single focus

Simple Partial Seizures
•With motor symptoms
–Phonatory (vocalization or arrest of speech)
Simple Partial Seizures
• With somatosensory or special sensory symptoms
Simple Partial Seizures
•Epigastric sensation
Simple Partial Seizures
•With psychic symptoms
–Dysmnesic (déjà vu, jamais vu, memory recall, memory gaps/amnesia)
–Cognitive (dreamy states, distortions of time sense)
–Affective (fear, anger, sadness, pleasure, sexual emotion, emotional distress
–Illusions (macropsia)
–Structured hallucinations (music, scenes, visual, auditory, olfactory)
–Other (change in reality, depersonalization, feeling of a presence (“as if someone is
nearby”), forced thinking, distortion of body image)
Simple Partial Seizure
Simple Partial Seizure
•Appears to be in a dream like state.
•Unaware or unresponsive to questioning •May perform unusual actions such as picking of clothing's, grimacing, contorting to one side, chewing •Feel confused for several minutes •No recollection of the event

Complex Partial Seizure
Partial with secondary generalization
Generalized Seizures
•Begin throughout both hemispheres, more or less simultaneously
•Reflect generalized disturbance of cortical function
“Generalized Epilepsy”
Generalized Seizures
•Tonic – clonic seizures
•Myoclonic seizures

Generalized Tonic Clonic Seizures
Absence Seizure

3hz Spike Wave
Absence Seizure
Criteria for starting antiepileptic drug therapy

•Diagnosis of epilepsy must be firm
•Risk of recurrence of seizures must be sufficient •Seizures must be sufficiently troublesome –Types of seizures –Frequency of seizures –Severity of seizures –Timing of seizures –Precipitation of seizures •Good compliance must be likely •Patient has been fully counseled

Selection of An Antiepileptic Drug: Factors to Consider
•Control of Seizures

The “Older” Anticonvulsants
Why is there a need for “new” anticonvulsants?
•More effective
•Different mechanism of action: more selective
–Better tolerated: less side effect(s)
•Better for women: less teratogenicity
•Less interactions with other drugs

Newer antiepileptic drugs
Gabapentin (Neurontin)
•US FDA approval early in 1994
•Molecular structure resembles GABA but it does not bind to the GABA-Receptor
•It increases GABA levels in CNS and reduces glutamate
Gabapentin: Kinetics
•Absorption: 60% of 600 mg*
•Water soluble
•Tmax: 2 - 4 hrs
•Half life ~ 6 hrs
•Protein binding: 0%
•No hepatic metabolism, pure renal excretion
•No interactions with other drugs

Gabapentin: Current Usage
•It is a very safe and easy to use
•Rapid titration
•Most new prescriptions are for non epileptic conditions - pain, psychiatric illnesses,
sleep disorders
•Currently it is almost always used as add-on drug except in certain clinical situations -
elderly, porphyria, multidrug allergies

Gabapentin: Side Effects
•Most people tolerate the drug very well, most common side effects are drowsiness and
•About 20% of patients gain weight
•About 10% of patients become “aggressive” or have behavioral issues
•Rash is almost unheard of

Lamotrigine (Lamictal)
•US FDA approval 1994
•Phenyltriazine derivative
•Inhibits voltage gated Na+ channels

Lamotrigine (Lamictal)
•Half life: 24 hours
•Broad spectrum of activity
•May be used as monotherapy
•Rapidly and completely absorbed
•Protein binding is 55%

•Hepatic conjugation and LTG does not change the clearance of other drugs
•Inducers: Carbamazepine, phenobarbital, and phenytoin increase LTG clearance
•Valproic acid significantly reduces the LTG clearance

Lamotrigine: Current Usage
•Used as anticonvulsant and in bipolar disorder
•Effective against multiple seizure types, including absence and in Lennox-Gastaut
•As monotherapy:
–Very well tolerated
–Not associated with an increased incidence of teratogenicity

Lamotrigine: Current Usage
•Initial adult dose is 25 to 50 mg/day with gradual titration upwards to 200 mg-600
•If the patient is taking valproic acid, initial adult dose is 25 mg QOD with slow titration
up to 200 to 300 mg/day

Lamotrigine: Toxicity
•Diplopia, dizziness (common)
•Less sedating than many AEDs and is not associated with weight gain or cognitive
•Organ toxicity is very rare
•Incidence of rash is elevated if patient is given high initial doses/rapid titration; with
slow titration, the rash rate is lower than either phenytoin or carbamazepine
Lamotrigine discontinuation over one year
Topiramate (Topamax)
•Fructopyranose sulfamate derivative
•Inhibits voltage gated Na+ channels, enhances GABA activity, and blocks AMPA
receptor at higher levels

Topiramate: Kinetics
•Well absorbed
•Tmax: 1-4 hrs
•Not significantly metabolized, excreted unchanged in urine in monotherapy
•Half life ~20 hrs
•Protein binding ~15%

Topiramate (Topamax)
•Broad spectrum anticonvulsant effective in:
–Partial/focal epilepsy
–Generalized epilepsy including myoclonic seizures
–Lennox-Gastaut syndrome

Topiramate: Drug Interactions
•TPM has no significant effect on CBZ or VPA blood levels
•TPM decreases PHT clearance by <20% in some patients
•TPM decreases ethinyl estradiol level (BCP) 33%
•PHT, CBZ, PB decrease TPM level up to 50%
•VPA has no significant effect on TPM level

Topiramate: Side Effects
•Dizziness, ataxia, somnolence, and fatigue are the most common AEs
•Weight loss in 25%
•Paresthesias in 10%
•Nephrolithiasis in 1.5%
•Metabolic acidosis
•Cognitive symptoms, which may develop insidiously, seen in 10 to 30%, less likely with
slow titration

Topiramate: Current Usage
•In addition to epilepsy, used for migraine prophylaxis and weight loss
•Under evaluation for psychiatric conditions, pain, and neuroprotection
•Used as monotherapy and add-on for multiple seizure types

Topiramate discontinuation over one year
Levetiracetam (Keppra)
•Related to piracetam (used in Europe)
•The mechanism(s) of action largely unknown
•In animals: prevents kindling
•Inactive in maximal electroshock and pentylenetetrazol seizure models in mice and rats
•Inactive in convulsions induced by GABAergic chemoconvulsants in mice

Levetiracetam (Keppra)
•US FDA approval 2000
•It is approved for add-on treatment of:
•Partial seizures
•It does appear to have a broad spectrum of activity against multiple seizure types
including myoclonic seizures and generalized epilepsies
•Successfully used as monotherapy
•May be rapidly titrated and clinical onset of action is very rapid

Levetiracetam: Kinetics
•Rapid and complete absorption
•Low protein binding
•Clearance is renal not hepatic
•Half life is approximately 8 hour
•No drug interactions

(Pooled data from 3 efficacy studies
, n=904)
Levetiracetam: Toxicity
•Most common side effects are fatigue, drowsiness, ataxia
•Weight neutral
•No rash
•No organ toxicity
•About 15% of patients have behavioral changes:
–Mentally retarded
Levetiracetam: Most common side effects
Levetiracetam: Reason for discontinuation
15% of patients taking levetiracetam
11% of patients taking Placebo
Oxcarbazepine: Metabolism
Oxcarbazepine (Trileptal)
•Plasma half-life of MHD 9.3 ± 1.8 hours
•Anticonvulsant activity similar to CBZ
•Approved for monotherapy
•Some patients who “fail” CBZ may do well on OxCBZ
•30% of patients with CBZ rash will have rash with OxCBZ

Oxcarbazepine: Kinetics
•Complete absorption
•Protein binding 40% (CBZ = 70%)
•Hepatic glucuronidation, not oxidation
•No active epoxide
•No auto-induction
•Fewer drug interactions than CBZ
•Induce CYP 3A4:
– Other drugs metabolized by CYP3A4 (eg BCPs) may have lower blood levels

Oxcarbazepine: Mechanisms of action
•Probably similar to carbamazepine
•Block voltage-sensitive Na+ channels
•Modulation of voltage-activated Ca++ currents
•No significant interactions with brain neurotransmitters or modulation of receptor sites
•Increases K+ conductance

Oxcarbazepine: Side Effects
•Dizziness and diplopia are fairly common especially if an individual dose is large and
taken on an empty stomach
•Slow titration reduces side effects
•Hyponatremia less common than with CBZ but may occur, especially in the elderly

General Guidelines in AED Management
•Start with single (preferably old) drug appropriate for seizure types and patient; give QD
or BID if possible
•Educate the patient about the drug, its side effects and interactions, and that it helps to
control but not “cure” seizures
•Start slow and low: Begin with low dose and slowly increase

Blood Levels in AED Management
•“Therapeutic level” is a misnomer!
•A “good” level is one in which the patient has no seizures and no side effects
•The quoted ranges for PB (20-40 mcg/ml), phenytoin (10-20 mcg/ml), carbamazepine
(6-12 mcg/ml), and valproic acid (50-100 mcg/ml) are rough guides at best

When to Get AED Levels?
•After initiation of treatment
•After dose changes (up or down) of phenytoin
•When there are questions of compliance, toxicity, or drug interactions
•When there are breakthrough seizures
•Routine every 6 - 24 months
•I do it when filling out driver’s forms for BMV

Do we have the ideal anticonvulsant?
•Do we have effective AEDs?
•Do we have more selective AEDs?
•Do we have non teratogenic AED?
•Do we have AEDs that do not interact with other medications?
•What next???

•New AEDs may represent advances over the old in terms of pharmacokinetics, side
•Efficacy differences have not been established
•Each new AED will be the “magic bullet” for some patients

Report of the Therapeutics and Technology Assessment Subcommittee and Quality
Standards Subcommittee of the American Academy of Neurology and the American
Epilepsy Society
Background and Justification

•Age-adjusted epilepsy prevalence of 6.8/1,000 population
•Cumulative incidence through age 74 was 3.1%

In the last 10 years, the following drugs were approved by the US FDA

Prior to 1990s, six major AEDs were available for the treatment of epilepsy
•Valproic acid

•The older drugs, while effective in patients with newly-diagnosed epilepsy share some
–Phenytoin, carbamazepine, phenobarbital, and primidone are hepatic enzyme inducers

Advantages of older AEDs

•Broad familiarity
•Lower cost
•Known efficacy
•Wide availability
•Long term experience

The Analytical Process
•Literature search (MEDLINE, CURRENT CONCEPTS) for relevant articles published
between Jan ’87 – Sept 2001
•Manual search by panel members covering Sept 2001 – May 2002
•A manual search for Class I articles are updated to include those published through
March 2003
•Cochrane library search for randomized controlled trials in epilepsy in Sept 2002

Criteria for Selection of Articles
•Relevance to the clinical questions of efficacy, safety, tolerability or mode of use
•Human subjects only
•Type of studies: randomized controlled trials, cohort, case control, observational or case
•All languages for randomized controlled trials not available in English
•Relevant to patients with newly-diagnosed epilepsy
Exclusion Criteria
•Articles classified as reviews, meta-analyses and articles related to non-epilepsy uses of
AEDs unless adverse reactions are disclosed based on AED mechanism of action

•Total # of articles – 1464
–Gabapentin – 240
–Lamotrigine – 433
–Topiradeate – 244
–Tiogabine – 177
–Zonisamide – 146

•Question 1
–How does the efficacy and tolerability of the new AEDs compare with that of older
AEDs in patients with newly diagnosed epilepsy?

Summary of Findings
•Efficacy in newly diagnosed patients
–GBP is effective in the treatment of newly diagnosed patient epilepsy
–LTG, TPM, & OXC are effective in mixed population of newly diagnosed and
generalized tonic-clonic seizures

–At present there is insufficient evidence to determine effectiveness in newly diagnosed
patients for TGB, ZNS, & LEV

•Newly diagnosed epileptic patients maybe initiated in standard AEDs (CBZ, PHY; VPA,
PB) or new AEDs (LTG, GBP, OXC, TPM)
•Choice of AED will depend on individual patient characteristics (Level A)


•All of the drugs have proved efficacies as add-on therapy in patient with refractory
partial epilepsy.
Partial Seizure in Adults
•GBP (600-1800mg/day);
•LTG (300-500mg/day);
•LEV (1000-3000mg/day);
•OXC (600-2400mg/day;
•TGB (16-50mg/day);
•TPM (300-1000mg/day)
•are effective in reducing frequency as adjunctive therapy in refractory partial seizures.

•GBP, LTG, TGB, TPM, OXC AND ZON are more effective at higher doses
•and ZON (100-400mg/day)
•LEV evidence for a dose response is less clear but more patient responded at
•Side effects and drop-outs increase in a dose dependent manner for all drugs
•Slower titration reduces side effects for GBP and TPM

•It is appropriate to use GBP, LTG, TGB, TPM, OXC, ZON, LEV as add-on therapy in
patients with refractory epilepsy

Summary of Evidence
(Monotherapy for refractory partial epilepsy)
LTG 500mg/day is superior to 100mg/day of VPA (acting as pseudoplacebo)
OXC 2400mg/day is superior to 300mg/day
TPM 1000mg/day is superior to 100mg/day

There is insufficient evidence at present to determine the efficacy of LEV, TGB or
In one trial, GBP 1200mg and 2400mg were not more effective than a
pseudoplacebo dose of 600mg in this population
•OXC and TPM can be used as monotherapy in patients with refractory partial epilepsy
•LTG can be used (Level B downgraded due to drop-outs)
•There is insufficient evidence to recommend use of GBP,LEV, TGB or ZON in
monotherapy of refractory partial epilepsy (Level U)


What is the evidence that the new AEDs are effective for the seizures seen in
patients at the refractory idiopathic generalized epilepsy?
•Trials for refractory generalized epilepsy has been criticized due to the fact that not all
patients were required to have an EEG demonstrating a generalized pattern.

(Refractory primary generalized epilepsy)
•TPM 6mg/kg/day is effective for the treatment of refractory generalized tonic clonic
convulsions +/- other seizure types
•GBP 1200mg is not effective in refractory GTCS in patients with primary or secondary
generalized epilepsy
•TPM may be used in the treatment of refractory GTCS in children and adults (Level A)
•There is insufficient evidence to recommend GBP, LTG, OXC, TGB, LEV or ZON for
the treatment of refractory generalized tonic-clonic seizures in adults and children (Level

What is The Evidence That The New AEDs are effective as monotherapy in children
with refractory partial seizures?

*no monotherapy trials have been performed in this population
•An NIH consensus conference… partial seizures in children are similar in
pathophysiology to those in adults.

•An AED with demonstrable efficacy in adults will demonstrate the same efficacy or
adjunctive therapy in children >2 years of age.
Summary of Evidence

•GBP; LTG; TPM; OXC are effective in reducing seizure frequency as adjunctive
therapy in children with refractory partial seizures
What is the Evidence that the new AEDs are effective in children and/or adults with
Lennox-Gestaut Syndrome?
•Patients with Lennox-Gestaut syndrome are difficult to treat and are most susceptible to
exacerbation by AEDs.
•TPM and LTG appear to be effective in this population and should be considered for use.
•LTG at doses adjusted for weight and VPA use reduces seizure associated with Lennox-
Gestaut syndrome.
•TPM 6mg/kg/day is effective in reducing drop attacks (tonic-clonic seizures) in patients
with Lennox-Gestaut syndrome.

•To date, there is no Class I or II evidence that GBP, TGB, OXC, LEV or ZON are
•In case reports, LTG and GBP worsened myoclonic seizures in some patients.
What Is the Risk of Teratogenicity with new AEDs compared to the old AEDs?
•Category D - drugs (AEDs) with known teratogenicity in both animal and human
e.g. Phenytoin, Carbamazepine, Valproic Acid
•Category C – drugs (AEDs) with demonstrable teratogenicity in animals but not in
e.g. newer AEDs


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