“ SEIZURES “

Bernardo L. Conde, MD, FPPA, FPNA

Professor
Departement of Neurology & Psychiatry
University of Santo Tomas
Modern Neurobiological Analysis
of Epilepsy
• Began with John Hughlings Jackson’s
work in 1860s
• Jackson realized that seizures need
not involve loss of consciousness, but
could be associated with focal
symptoms, such as the jerking of the
arm
• First surgical treatment for epilepsy
– Victor Horsley in 1886
– Resected cortex adjacent to a depressed
skull fracture and cured a patient with
focal motor seizure
• The modern surgical treatment for
epilepsy dates to the work of Wilder
Penfield and Herbert Jasper in
Montreal in the early 1950s.
• Medical innovation include
– the first use of Phenobarbital by A.
Hauptmann
– development of EEG by Hans Berger
– discovery of Phenytoin by Houston Meritt
and Tracey Putnam in 1937
Schematic/Anatomic Neuron
Cell Architecture
 Cellular
Membrane
 NERNST EQUATION
The Resting Membrane Potential

N.E. Potential = -61 x log Concin/Concout

Na+ = -61 x 14/142 K+ = -61 x 140/4

= -61 x log 0.1 = -61 x log 35

= -61 x –1 = -61 x 1.54

= +62 = -94
What is Seizure and How
does it come about?
 Seizure

• An occasional
excessive and
disordered
discharge of nerve
tissue
• Manifestation of
transient
hypersynchronous
abnormal neuronal
behavior
 SEIZURES

• Paroxysmal disorder
• Altered neurological function
• Abnormal cortical electrical
discharge
• Beginning and an end
• Involuntary
 Definition
– Seizure – transient manifestation of
abnormal hypersynchronous discharges
of cortical neurons
– 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
– Sodium channels
– Calcium channels
– Potassium channels

• Synaptic level
– Glutamate
(excitatory)
– GABA (inhibitory)
 Mechanism of Seizure Generation
Seizure generation

Cellular level Synaptic level

Cations

Na+ channels Ca++ channels K+ channels Neurotransmitters

(T type channels)

Inc. influx Na Dec. intracellular K+

GABA Glutamate

Inc. intracellularly Increase influx of decrease increase

Na and water calcium concentration concentration

Neuronal swelling Cell hyperexcitability Hyperexcitable state

increase tissue excitability Firing thalamic and cortical neurons

SEIZURE
Possible Causes of Seizures in
Young People
• Infant Genetic
(0-2 years old) Hypoxia
Congenital Anomalies

• Child Head trauma

(2-12 years old) Acute Infection

• Adolescent
(12-18 years old) Head trauma
Drug and alcohol
use/withdrawal
 Possible causes of seizures in
Adults
• Young adults Head trauma
Alcoholism
Brain tumor

• Older adults Brain tumor

CVA
Metabolic disorders
Alcoholism
 Why Classify?
• Facilitate communication among
professionals
• Facilitate communication between
physician and patient
• Aid diagnosis
• Rational prescribing of AEDs based
on accurate diagnosis of seizure type
• Prognosis
 International League Against Epilepsy
(ILAE) classification of Seizure Type
I. Partial seizure
A. Simple partial seizure (consciousness not impaired)
B. Complex partial seizure (with impairment of Consciousness)
C. Partial secondarily generalized
II. Generalized seizures (bilaterally symmetrical and without local onset)
A. Absence seizures
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures (astatic)
III. Unclassified epileptic seizures (inadequate or incomplete
data)
The ILAE Classification of Epilepsies
and Epilepsy Syndromes Shorvon, 2000
Simple and Complex Partial
Seizure
Impaired Consciousness
• “The inability to respond normally to
exogenous stimuli by virtue of altered
awareness and/or responsiveness”
• Responsiveness
– The ability of the patient to carry out simple
commands or willed movements
• Awareness
– refers to the patient’s contact with events during
the period in question and its recall
 PARTIAL SEIZURE

Abnormal flow of
electrical discharge
from a specific or
single focus
 Simple Partial Seizures
• With motor symptoms
– Focal motor without march
– Focal motor with march (Jacksonian)
– Versive
– Postural
– Phonatory (vocalization or arrest of
speech)
 Simple Partial Seizures
• With somatosensory or special
sensory symptoms
– Somatosensory
– Visual
– Auditory
– Olfactory
– Gustatory
– Vertiginous
 Simple Partial Seizures
With autonomic symptoms
• Epigastric sensation • Erythema
• Pallor • Genital
• Sweating sensations/orgasm
• Flushing • Hyperventilation
• Piloerection • Lacrimation
• Pupillary dilatation • Miosis/mydriasis
• Apnea • Palpitations
• Arrhythmias/bradyarr • Pilomotor excitation
hythmia • Tachycardia
• Chest pain • Urinary
• Cyanosis urgency/incontinence
• Vomiting
 Simple Partial Seizures

• With psychic symptoms

– Dysphasic
– 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)
 Partial Seizures
SEIZURE SPREAD
• The spread of seizure activity
– Involves normal cortical circuitry
– Follows the same pathways as does
normal cortical activity
– Thalamocortical, subcortical and
transcallosal pathways become involved
in seizure process
Partial seizure
Seizur Seizur
e e
focus focus

Spread Secondary
generalization
Primary generalized seizure
 What Terminates a Seizure
• During the initial 30 seconds, typical of
secondarily generalized tonic-clonic seizure,
neurons in the involved areas
– undergo prolonged depolarization
– continuously fire action potentials
• This is associated with the loss of after-
hyperpolarization that follows PDS.
 What Terminates a Seizure

• As the seizure evolves, the neurons

begin to repolarize and the after-
hyperpolarization reappears.
SIMPLE PARTIAL EPILEPSY
Simple Partial Seizure
Simple Partial Seizure
COMPLEX PARTIAL EPILEPSY

• 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 SEIZURES
Complex Partial Seizure
COMPLEX PARTIAL EPILEPSY
PARTIAL EPILEPSY with secondary GENERALIZATION

• Starts off as simple

seizure which later
evolves into
generalized seizure
Partial with secondary
generalization
Partial with secondary generalization
 Generalized Seizures
• Begin throughout
both hemispheres,
more or less
simultaneously
• Do not have
localized onset
• Reflect generalized
disturbance of
cortical function
 “Generalized Epilepsy”

• May cry out or gasp, fall

down, become rigid
• Muscle may jerk,
breathing becomes
shallow
• May lose bladder and
bowel control
• May drool, bite the
tongue or lips and may
turn blue
• Post ictal -maybe
confused, drowsy, sleep
for a while or have
headache
 Generalized Seizures
• Tonic – clonic seizures
• Clonic seizures
• Tonic seizures
• Atonic seizures (astatic)
• Absence seizure
• Myoclonic seizures
Generalized Tonic Clonic Seizures
Absence Seizure
Absence Seizure
3hz Spike Wave
Absence Seizure
Myoclonic
Atonic Seizure
FEATURES HELPFUL IN DIFFERENTIATING BETWEEN
PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC
SEIZURES
FEATURE EPILEPTIC
PSYCHOGENIC
SEIZURES
“SEIZURES”

Sex Male or Female Mostly

Female
Age Any age
Adolescence or
early
adult

Precipitating Variable; lack of

Emotional
FEATURES HELPFUL IN DIFFERENTIATING
BETWEEN PSCHOGENIC “SEIZURES”and TRUE
EPILEPTIC SEIZURES
FEATURE EPILEPTIC SEIZURES
PSYCHOGENIC “SEIZURES”

Precipitant Usually none Often and

emotional
Precipitant

Occurrence and
Circumstances
in sleep when alone Common Rare
Common Less common

Onset Usually abrupt Maybe gradual

may have short with increasing
aura emotional
symptoms
FEATURES HELPFUL IN DIFFERENTIATING BETWEEN
PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC
SEIZURES
FEATURE EPILEPTIC PSYCHOGENIC
SEIZURES “SEIZURES”
Vocalization During automatism Common during a
“seizure”
Manifestation Stereotyped Variable
Phenomenon Usually both tonic Often tonic clonic
and clonic phase or only
clonic
Amplitude and

frequency during
the attack
Pelvic thrusting
Pseudoclonic
movements
Injury Common Rare
FEATURES HELPFUL IN DIFFERENTIATING
BETWEEN PSCHOGENIC “SEIZURES”and TRUE
EPILEPTIC SEIZURES
FEATURE EPILEPTIC PSYCHOGENIC
SEIZURES “SEIZURES”
Inconsistence Common Rare
Tongue Biting Common Rare
Consciousness Usually totally lost Maybe
unresponsive
often possible
to
communicate
during an attack
Duration of Usually short Maybe
prolonged
Seizure (but with auto- Maybe gradual,
often
matism sometimes) with emotional
display
Confusion Common Unusual
Drowsiness/sleep Common Unusual
COMMON PRECIPATATING FACTORS
FOR SEIZURES IN YOUNG PATIENTS
• Fever
• Stress
• Fatigue
• Sleep
• Deprivation
• Drug abuse
• Menstrual cycle
• Photic stimulation
• Alcohol
 FACTORS LOWERING
SEIZURE THRESHOLD

COMMON OCCASIONAL
• Sleep deprivation • Barbiturate withdrawal
• Alcohol withdrawal • Hyperventilation
• Dehydration • Flashing lights
• Drugs and drug • Diet and missed meals
interactions • Specific “reflex” triggers
• Systemic infection
• Trauma
• Malnutrition
CEREBRAL ENERGY METABOLISM

IN A SINGLE SEIZURE
• There is rapid and abrupt depletion in the
high energy phosphates, ATP and PCR, the
ultimate sources of energy used by virtually
all metabolic processes in the brain;
• There are corresponding rises in the
breakdown products; ADP, AMP and
creatine along with marked elevations in
lactate and the lactate/pyruvate ratio.
 PROGNOSIS OF EPILEPSY

• THE LONGER THE FOLLOW-UP,

THE LOWER THE FINAL REMISSION
RATE
• THE LONGER SEIZURES REMAIN
UNCONTROLLED, THE LESS
LIKELY CHANCE FOR REMISSION
RISK OF SEIZURE RECURRENCES

• HIGHER RECURRENCE IF WITH

STRUCTURAL DISORDERS
• WITH APPROPRIATE TREATMENT
COMPLETE SEIZURE CONTROL IS
ACHIEVED IN 50-90% OF CASES
RISK OF PERSISTENT SEIZURES
• PROGRESSIVE NEUROLOGIC
DAMAGE

• WORSENING SEIZURES

• ADVERSE COGNITIVE AND

PSYCHOSOCIAL EFFECTS

• CUMULATIVE DRUG TOXICITY

PRINCIPLES OF TREATMENT
SEIZURES
• Establish the diagnosis and the rule
out underlying cerebral pathology;

• Classify seizure type, using EEG and

clinical criteria;

• Select AED of first choice for seizure

type
PRINCIPLES OF TREATMENT
• Increase dose slowly until end-point is
reached:
– Complete seizure control
– Optimum plasma drug level
– Toxic side effects appear
• If poor seizure control gradually withdraw
first drug while replacing with second drug
of choice for seizure type.
• Monotherapy is preferable to polypharmacy
PRINCIPLES OF TREATMENT
• If improvement is only partial, other
drugs may be necessary;
• Adjust gradually (if possible, using
plasma levels as a guide) keeping in
mind
– Pharmacokinetics of each drug
– Potential drug interactions
PRINCIPLES OF TREATMENT
• Continue treatment to achieve
minimum seizure free period of 3 to 5
years;
• If best medical therapy is
unsuccessful, refer to a neurologist.
 SEIZURES

• Paroxysmal disorder
• Altered neurological function
• Abnormal cortical electrical
discharge
• Beginning and an end
• Involuntary
STATUS EPILEPTICUS
• SINGLE PROLONGED SEIZURE
LASTING MORE THAN 30 MINUTES

• FREQUENT SEIZURES; NO
RECOVERY OF CONSCIOUSNESS
BETWEEN ATTACKS
STATUS EPILEPTICUS
• CONVULSIVE STATUS
– Generalized Tonic-clonic Seizures
– Partial Motor Seizures
• NON-CONVULSIVE STATUS
– Absence Status
– Complex Partial Status
– Partial Sensory Status
 CAUSES OF STATUS
EPILEPTICUS

• Sudden Withdrawal Of Anti- Epileptic

Medication
• CNS Infections
• Others
ANTIEPILEPTIC DRUGS-
STATUS EPILEPTICUS

1. Diazepam - 0.3-0.5 mg/kg/slow IV

or
lorazepam - 0.5-0.1 mg/kg/slow IV
2. Phenytoin
(Dilantin) - 18-20 mg/kg/slow IV
3. Phenobarbital - 20-25 mg/kg/slow IV
4. Penthotal - 5mg/kg/slow IV
0.2% in D5W IV
drip
 ASSOCIATIONS WITH
INTRACTABLE EPILEPSY
• STRUCTURAL BRAIN DISEASE
– Focal Vs. Diffuse
– Static Vs. Progressive
• INEFFECTIVE TREATMENT
– Inappropriate AED choice or
– Inadequate dose
– Drug interactions
– Non-compliance
 “ Rationalizing
Pharmacotherapy in
Epilepsy “

Bernardo L. Conde, MD, FPPA, FPNA

Professor
Departement of Neurology & Psychiatry
University of Santo Tomas
FEATURES HELPFUL IN DIFFERENTIATING
BETWEEN
PSCHOGENIC
FEATURE
“SEIZURES”and
EPILEPTIC
TRUE
EPILEPTIC
PSYCHOGENICSEIZURES
SEIZURES
“SEIZURES”

Sex Male or Female Mostly

Female
Age Any age
Adolescence or
early
adult

Precipitating Variable; lack of

Emotional
FEATURES HELPFUL IN DIFFERENTIATING
BETWEEN PSCHOGENIC “SEIZURES”and
TRUE EPILEPTIC SEIZURES
FEATURE EPILEPTIC SEIZURES
PSYCHOGENIC “SEIZURES”

Precipitant Usually none Often and

emotional
Precipitant

Occurrence and
Circumstances
in sleep when alone Common Rare
Common Less
common

Onset Usually abrupt Maybe

gradual
FEATURES HELPFUL IN DIFFERENTIATING
BETWEEN PSCHOGENIC “SEIZURES”and
TRUE EPILEPTIC SEIZURES
FEATURE EPILEPTIC PSYCHOGENIC
SEIZURES “SEIZURES”
Vocalization During automatism
Common during a
“seizure”
Manifestation Stereotyped
Variable
Phenomenon Usually both tonic Often tonic
clonic
and clonic phase or only
clonic
Amplitude
and
frequency during
COMMON PRECIPATATING
FACTORS FOR SEIZURES IN
YOUNG PATIENTS
• Fever
• Stress
• Fatigue
• Sleep
• Deprivation
• Drug abuse
• Menstrual cycle
• Photic stimulation
• Alcohol
 RISK OF SEIZURE
RECURRENCES

• HIGHER RECURRENCE IF WITH

STRUCTURAL DISORDERS
• WITH APPROPRIATE TREATMENT
COMPLETE SEIZURE CONTROL IS
ACHIEVED IN 50-90% OF CASES
 RISK OF PERSISTENT
SEIZURES
• PROGRESSIVE NEUROLOGIC
DAMAGE

• WORSENING SEIZURES

• ADVERSE COGNITIVE AND

PSYCHOSOCIAL EFFECTS

• CUMULATIVE DRUG TOXICITY

 PRINCIPLES OF
TREATMENT
• EstablishSEIZURES
the diagnosis and the rule
out underlying cerebral pathology;

• Classify seizure type, using EEG and

clinical criteria;

• Select AED of first choice for seizure

type
 PRINCIPLES OF
TREATMENT
• Increase dose slowly until end-point is
reached:
– Complete seizure control
– Optimum plasma drug level
– Toxic side effects appear
• If poor seizure control gradually withdraw
first drug while replacing with second drug
of choice for seizure type.
• Monotherapy is preferable to polypharmacy
 PRINCIPLES OF
TREATMENT
• If improvement is only partial, other
drugs may be necessary;
• Adjust gradually (if possible, using
plasma levels as a guide) keeping in
mind
– Pharmacokinetics of each drug
– Potential drug interactions
 PRINCIPLES OF
TREATMENT
• Continue treatment to achieve
minimum seizure free period of 3 to 5
years;
• If best medical therapy is
unsuccessful, refer to a neurologist.
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
• Tolerability
• Pharmacokinetic properties
• Patient Characteristics
• Drug interactions
• Cost
Cellular basis of epileptogenesis
Astrocyte

GABAergic
interneuron
Glutamine synthase

Glutamate Transporter
GABA-T

Ca++ channel

Na+ channel

NMDA
receptor GABA
Glutamate receptor

Non-NMDA
receptor

Presynapse Postsynapse
The “Older” Anticonvulsants

Phenobarbital 1912
Phenytoin Dilantin TM 1938
Primidone Mysoline TM 1954
Ethosuximide ZarontinTM 1960
Carbamazepine TegretolTM 1974
Valproate DepakoteTM 1978
“Old” Drugs that decrease excitation
Astrocyte

Ethosuximide

Phenytoin
Carbamazepine
Ca++ channel

Na+ channel

NMDA
receptor
Ketamine
Glutamate

Non-NMDA
receptor

Presynapse Postsynapse
“Old” Drugs that enhance inhibition

GABAergic
interneuron

GABA-T

GABA
Phenobarbital receptor
Benzodiazepines
 Why is there a need for “new”
anticonvulsants?
• More effective
• Different mechanism of action: more
selective
– Better tolerated: less side effect(s)
– Safer
• Better for women: less teratogenicity
• Less interactions with other drugs
 Newer antiepileptic drugs
Felbamate FelbatolTM Wallace
Gabapentin NeurontinTM Pfizer
Lamotrigine LamictalTM GSK
Topiramate TopamaxTM Ortho-McNeil
Tiagabine GabitrilTM Cephalon
Levetiracetam KeppraTM UCB Pharma
Oxcarbazepine TrileptalTM Novartis
Zonisamide ZonegranTM Elan Pharma
 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 ataxia
• 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%
 Lamotrigine
• Hepatic conjugation of 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
syndrome
• 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
mg/day

• 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
dysfunction
• 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
 Mechanisms of Action
of Topiramate
H2CO3 ↔ H2O + CO2
Inhibition of
carbonic anhydrase

Potentiation of GABA TOPIRAMATE Antagonism of glutamate

Glutamate

Na+ and Ca++ channel blockade X

GABA Cl-
Na+
Ca++

Excitation
X X inhibited
Cl-
Inhibition
flux X Excitation inhibited

Shank RP et al. Epilepsia. 2000;41(suppl 1):S3.

 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
 Levetiracetam
(Pooled data from 3 efficacy studies, n=904)

45 % of patients responding

40

35
p < 0.001 ***
30
p < 0.01 ** 41 ***
25

20 32 ***
15 28 *** ***
22
10
1 7 ***
12 **
5 3
8 ***
3 4 ** 2 NS
0 1
Placebo LEV 1000 mg LEV 2000 mg LEV 3000 mg

Seizure free 75% responder rate 50% responder rate

 Levetiracetam: Toxicity

• Most common side effects are fatigue,

drowsiness, ataxia
• Weight neutral
• No rash
• No organ toxicity
• About 15% of patients have behavioral
changes:
– Elderly
– Mentally retarded
 Levetiracetam: Most common side
effects

LEV Placebo
(n=769) (n=439)

Somnolenc 14.8% 8.4%

e
14.7% 9.1%
Asthenia
13.7% 13.4%
Headache
13.4% 7.5%
Infection
8.8% 4.1%
Dizziness
Levetiracetam: Reason for discontinuation
15% of patients taking levetiracetam
11% of patients taking Placebo
 Oxcarbazepine: Metabolism

O OH Gluc O
No
autoinduction

N N N
Reduction Conjugation
O NH2
O NH2 O NH2

Oxcarbazepine MHD

O
OH OH Autoinduction

N
N
N
O NH2 Oxidation Hydrolysis
O NH2 O NH2
Carbamazepine 10, 11-epoxide
Schachter S. Exp Opin Invest Drugs.
1999;8(7):1-10.
 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???
 Conclusion

• New AEDs may represent advances over

the old in terms of pharmacokinetics, side
effects
• Efficacy differences have not been
established
• Each new AED will be the “magic bullet” for
some patients
 SEIZURES
B. L. CONDE, MD, FPNA, FPPA
2001 June*AUT
Efficacy and tolerability of the
new antiepileptic drugs:

Treatment of new onset epilepsy

Bernardo L. Conde, MD, FPPA, FPNA

Professor
Departement of Neurology & Psychiatry
University of Santo Tomas
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
• Felbamate
• Gabapentin
• Lamotrigine
• Topiramate
• Tiagabine
• Oxcarbazepine
• Levetiracetam
• Zonisanide
 Prior to 1990s, six major AEDs were
available for the treatment of epilepsy

• Carbamazepine
• Phenobarbital
• Phenytoin
• Primidone
• Valproic acid
• Ethosuximide
• The older drugs, while effective in
patients with newly-diagnosed
epilepsy share some characteristics:
– 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
1. Literature search (MEDLINE, CURRENT
CONCEPTS) for relevant articles
published between Jan ’87 – Sept 2001
2. Manual search by panel members
covering Sept 2001 – May 2002
3. A manual search for Class I articles are
updated to include those published
through March 2003
4. Cochrane library search for randomized
controlled trials in epilepsy in Sept 2002
Criteria for Selection of Articles
1. Relevance to the clinical questions of
efficacy, safety, tolerability or mode of use
2. Human subjects only
3. Type of studies: randomized controlled
trials, cohort, case control, observational
or case series
4. All languages for randomized controlled
trials not available in English
5. 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
 Recommendation
1. Newly diagnosed epileptic patients
maybe initiated in standard AEDs
(CBZ, PHY; VPA, PB) or new AEDs
(LTG, GBP, OXC, TPM)
2. Choice of AED will depend on
individual patient characteristics
(Level A)
 What is the Evidence that the
New AEDs are effective in
Refractory Partial Epilepsy as
Adjunctive therapy?

Refractory Epilepsy
• failed 3 or more AEDs
• average 3 to 4 seizures a month

Bernardo L. Conde, MD, FPPA, FPNA

Professor
Departement of Neurology & Psychiatry
University of Santo Tomas
 CONCLUSION

• 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
3000mg/day
• Side effects and drop-outs increase in a
dose dependent manner for all drugs
• Slower titration reduces side effects for GBP
and TPM
 Recommendation
• It is appropriate to use GBP, LTG,
TGB, TPM, OXC, ZON, LEV as add-
on therapy in patients with refractory
epilepsy
What is the evidence that the new
AEDs are effective as monotherapy
in patients with refractory partial
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 ZON

• In one trial, GBP 1200mg and 2400mg were not more

effective than a pseudoplacebo dose of 600mg in this
population
 Recommendation
• 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)
IDIOPATHIC EPILEPSY IN
ADULTS
What is the evidence that the
new AEDs are effective for
the seizures seen in patients
at the refractory idiopathic
generalized epilepsy?
 CONCLUSION
• 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.
SUMMARY OF EVIDENCE
(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
RECOMMENDATIONS
• 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
U)
 TREATMENT OF
REFRACTORY EPILEPSY
IN CHILDREN

What is the evidence that the new AEDs

are effective in refractory partial epilepsy as
adjunctive therapy in children?
Bernardo L. Conde, MD, FPPA, FPNA
Professor
Departement of Neurology & Psychiatry
University of Santo Tomas
AED Study Level of Dosing Result Discontinuat AEs
Profile Evidence Seizure-Free ion Rate
Reduction
GBP 247 patient Class 1 23-35 35% EPS↓ GBP – 5% Viral infection
3-12 year mg/kg/day 28% 2ºGTCS↓ PBO – 2% Fever
DB, PBO – PBO Hostility
12 wks 12%- EPS ↓ Fatigue
13%- GTCS↑ Weight gain

LTG 199 children Class 1 1-3mg/kg Responder Rate LTG – 5% Ataxia

2-16 year (VPA) 45% - LTG PBO – 6% Dizziness
PBO – 1-5mg/kg 25% - PBO Tremor
controlled (PHY; Nausea
CBZ; PHB) Asthenia
5-15 mg/kg S-J syndrome
(enzyme-
inducing
AED)
AED Study Level of Dosing Result Discontinuati AEs
Profile Evidence Seizure-Free on Rate
Reduction
TPM 86 children Class 1 125-400 Responder Rate None–TPM Emotional
2-16 year mg/day (50% reduction) 2 - PBO lability
PBO – 39% - TPM Difficulty
controlled Starting concentrating
20% - PBO
16 wks. dose = Fatigue
25mg/day Memory deficits
Median reduction
Weight loss
33% - TPM
10.5% - PBO

OXC 267 children Class 1 30-46 Responder Rate OXC – 10% Headache
3-17 year mg/kg/day 41% - OXC PBO – 3% Somnolence
DB; PBO 22% - PBO Vomiting
Nausea
Median reduction Rash (4%)
35% - OXC
8.9% - PBO
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
 CONCLUSION

• 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?
 CONCLUSION
• 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.
SUMMARY OF EVIDENCE
• 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 effective.

• 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
pregnancies
e.g. Phenytoin, Carbamazepine, Valproic Acid

• Category C – drugs (AEDs) with

demonstrable teratogenicity in animals but
not in humans
e.g. newer AEDs
 “ Rationalizing
Pharmacotherapy in
Epilepsy “

Bernardo L. Conde, MD, FPPA, FPNA

Professor
Departement of Neurology & Psychiatry
University of Santo Tomas