Hanan Fathy

• Depolarising Na+ and Ca++ ionic current

shifts are activated by glutamate receptors.

• Repolarising K+ currents are mediated by

GABA receptors.

• Hyperpolarisation is mediated by GABAa

receptors creating an influx of Cl- => inhibition
of impulse generation.
• A transient occurrence
of signs and/or
symptoms due to
abnormal excessive or
synchronous neuronal
activity in the brain.
• Commonly generated
in cortex and
hippocampus, may
also be subcortical
Na

Ca
• Abnormal electrical discharge in the brain.

• Coordinated activity among neurons depends on a controlled

balance between excitation and inhibition.

• Any local imbalance will lead to a seizure.

• Imbalances occur between glutamate-mediated excitatory

neurotransmission and gamma-aminobutyric acid (GABA)
mediated inhibitory neurotransmission.

• Generalised epilepsy is characterised by disruption of large

scale neuro-networks in the higher centres.
What causes the seizure?

• Hyperexcitability in a critical mass of neurons

• Hypersynchony
• Propagation
– Normal pathways
– Pathologic pathways
What causes neuronal hyperexcitability?

• Changes in ion channels

• Changes in receptors
Resting membrane potential

-70
2
mV
Action Potential
Na Channels

• Essential for depolarization during action

potential
• Blocking fast channel inactivation leads to
increased excitability
– Induces paroxysmal depolarization shifts
– Increasing synchrony
K Channels

• Important for post-excitatory membrane re-

polarization
• M current controls sub-threshold membrane
excitability
• K Channel blockade produces epileptiform
discharges in vitro
• M current defect identified in benign neonatal
familial convulsions
Ca Channels

• Different types of channels (T, N, L, P, Q)

• Ca currents contribute to the paroxysmal
depolarization shift
• May be responsible for long-term structural changes
affecting excitability and synaptic efficacy
• Participate in cytotoxicity
• Activation of T-type channels is thought to underlie
the abnormal thalamocortical rhythmicity associated
with 3-Hz spike-and-wave in absence
What causes neuronal hyperexcitability?

• Changes in ion channels

• Changes in receptors
– Excitatory amino acid receptors
– GABA-A receptor
Excitatory amino acid (EAA) receptors

• EAA:
glutamate and
aspartate
• Two main
receptor
types:
AMPA/kainate
and NMDA
NMDA receptor

• Sustains long-lasting
depolarization events
• NMDA agonists
induce epilepsies in
animals
• Structural changes
have been seen in
surgical specimens
• Involved in long term
potentiation
GABA receptors

• Activation leads
to membrane
hyperpolarization
via inflow of Cl
and outflow K
• Decreased
neuronal firing
Cellular and Synaptic Mechanisms of Epileptic
Seizures

(From Brody et al., 1996)

Other possible causes

• Inherited mutations of proteins involved in the

ion channels

• Reduction in the activity of homeostatic

ATPase pumps within neuron cell membranes
• Lifestyle
• pharmacotherapy
• surgery; ablative
• surgery: deep brain stimulation
• vagal nerve stimulation
• ketogenic diet
Basis of Pharmacological Rx

Most anti-epileptic agents act either by

blockade of depolarisation channels (Na+ and
Ca++)

OR

Enhancing the activity of GABA

(neurotransmission inhibition)
SEIZURE INHIBITING DRUGS
• Seizures can arise from removal of GABA induced inhibition when
GABA levels drop.

• Most GABA is eventually converted to succinate by GABA

aminotransferase

• A GABA aminotransferase inhibitor, Na dipropylacetate, is widely used

as anti convulsant.

• GABA is most commonly found in local circuit interneurons

• Drugs that acts as agonists or modulators for postsynaptic GABA

reseptors, such as BARBITURATES, are also used to treat eplipsy.
Treatment of Epilepsies
Goals:
• Block repetitive neuronal firing.
• Block synchronization of neuronal
discharges.
• Block propagation of seizure.

Minimize side effects with the simplest drug

regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
Treatment of Epilepsies

Strategies:
• Modification of ion conductances.

• Increase inhibitory (GABAergic)

transmission.

• Decrease excitatory (glutamatergic)

activity.
Targets
• Excitation (aim to reduce)
– Ionic-inward Na+, Ca++ currents
– Neurotransmitter: glutamate

• Inhibition (aim to increase)

– Ionic-inward CI-, outward K+ currents
– Neurotransmitter: GABA

• Remove by surgery, if focus is well-defined and

if drugs do not work well.
• A drug which decreases the frequency
and/or severity of seizures in people with
epilepsy
• Treats the symptom of seizures, not the
underlying epileptic condition
• Goal—maximize quality of life by
minimizing seizures and adverse drug
effects
STAGED APPROACH TO EPILEPSY MANAGEMENT

• Tolerability and long-term safety are the most

important factors in choosing the first drug.

• If the first AED is poorly tolerated at low dosage an

alternative should be chosen.

• If the first AED does not completely abolish seizures –

combination therapy may be tried.

• Work-up for epilepsy surgery should be considered

after failure of two well-tolerated AED’s.

• If needed, subsequent combinations of two or at most

three AED’s may be effective
Treatment of Epilepsies
• AEDs: 1st generation
• Benzodiazepines and barbiturates
• Carbamazepine and phenytoin
• Ethosuximide
• Valproic acid

• AEDs: 2nd generation

• Felbamate
• Gabapentin
• Lamotrigine
• Levetiracetam
• Oxcarbazepine
• Pregabalin
• Tiagabine
• Topiramate
• Zonisamide
• All share a common problem: “Start low, go slow”
Standard pharmacological targets

• Sodium channels
• Calcium channels
• GABA receptors: chloride channels
• Glutamate receptors: NMDA,
AMPA/KAINATE
 Classification of Anticonvulsants

Action on Ion Enhance GABA Inhibit EAA

Channels Transmission Transmission
Na+: Benzodiazepines Felbamate
Phenytoin, (diazepam, clonazepam) Topiramate
Carbamazepine, Barbiturates (phenobarbital)
Lamotrigine Valproic acid
Topiramate Gabapentin
Valproic acid Vigabatrin
Ca++: Topiramate
Ethosuximide Felbamate
Valproic acid
Na+: Most effective in myoclonic
For general tonic-clonic but also in tonic-clonic and
and partial seizures partial
Ca++: Clonazepam: for Absence
For Absence seizures
 Phenytoin

Na1+ Na1+

I I
GABA reuptake

GAT-1 transports GABA into neurons and GAT-2,3 into glia, to help clear the
synaptic cleft. Driving force is from ion gradients across membrane.
Tiagabine (gabatril) blocks reuptake and increases extracellular GABA levels.
Cl- Cl-
Cl-
Barbiturate
GABA
Cl- Cl-

GABA
Benzodiazepines and Barbiturates

• Enhance inhibitory neurotransmission by

modulating the GABA-A receptor complex
• Barbiturates increase the duration that the
channel is open
• BZDs increase the opening frequency
Carbamazepine and Phenytoin

• Block post-tetanic potentiation

• Limit sustained repetitive firing in neurons in
culture
• Inhibit voltage-gated Na channels
• Oxcarbazepine is similar
Ethosuximide

• Reduces low-threshold T-type calcium

currents in thalamic neurons thought to
underlie the abnormal thalamocortical
rhythmicity associated with 3-Hz spike-and-
wave in absence
• May also have Na effects
Valproic Acid

• Extremely broad spectrum likely related to

multiple mechanisms of action.
• Block sustained repetitive firing of mouse
neurons in culture
• Effects on voltage-gated Na channels
• Reduces T-type Ca currents
• Elevates whole brain GABA levels
• Potentiates GABA responses
Felbamate

• Broad spectrum
• Multiple mechanisms:
– Na channels
– Enhance GABA-mediated Cl currents
– Blocks NMDA evoked currents, may have
neuroprotective qualities
– Use limited by hematologic and hepatic toxicities
Gabapentin

• Designed to mimic the steric conformation of

GABA, but does not seem to function this way
• Interacts with Na and Ca channels
• May increase GABA in certain brain regions
• Pregabalin probably similar mechanism
Lamotrigine

• Broad spectrum
• Acts at voltage dependent Na channel
• Inhibits sustained repetitive firing in cultured
neurons
• Interacts with N and P type voltage gated
calcium channels
Levetiracetam

• Mechanism unclear
• May modulate high-voltage Ca currents
• May prolong hyperpolarization associated
with GABA-mediated neurotransmission
Topiramate

• Broad spectrum
• Has effects against Na and Ca currents
• Antagonistic to AMPA/kainate receptor
• Also may enhance GABA-evoked Cl currents
• Carbonic anhydrase inhibition altering
bicarbonate homeostasis
Zonisamide

• Broad spectrum
• Na
• T-type Ca
• GABA-A
Oxcarbazepine
– Blocks voltage-dependent sodium channels at high
firing frequencies
– Exerts effect on K+ channels

Pregabalin
– Increases neuronal GABA
– Increase in glutamic acid decarboxylase
– Decrease in neuronal calcium currents by binding of
alpha 2 delta subunit of the voltage gated calcium
channel
The Future – Other Treatments

• Brain stimulation
• Deep Brain Stimulation
• Focus Stimulation
• Vagal stimulation already useful
• Seizure prediction to guide when to
medicate/stimulate
• More precise brain surgery
• Stem cells: release adenosine, GABA, NPY
• Gene therapy: GABA release, more (effective)
receptors
Treatment of first seizure

• Patient should know following statistics:

– 4% of population to age 74 will have an unprovoked
seizure of some sort
• With normal EEG, risk of 2nd seizure in 2 years is 24%
• With abnormal EEG, risk of 2nd seizure in 2 years is 50%
(generally 1.5-3 fold increased risk)
• Symptomatic seizures with abnormal EEG carry a 65%
risk of 2nd seizure
• Risk of seizure after 2nd seizure is 70-80%
Current Treatment Options

Partial Generalized

Simple
Complex Tonic- Tonic Myoclonic Atonic Infantile Absence
Secondarily generalized clonic spasms

CBZ, PHT, PB, ACTH, ESX

GBP, VGB VGB

VPA, LTG, TOP

(FBM), LEV
Partial Onset Seizures

• With secondary generalization

– First-line drugs are carbamazepine and phenytoin
(equally effective)
– Valproate, phenobarbital, and primidone are also
usually effective
• Without generalization
– Phenytoin and carbamazepine may be slightly
more effective
• Phenytoin and carbamazepine can be used
together (but both are enzyme inducers)
Partial Onset Seizures—New
Drugs

• Adjunctive (add-on) therapy where

monotherapy does not completely stop
seizures—newer drugs felbamate, gabapentin,
lamotrigine, levetiracetam, oxcarbazepine, tiagabine,
topiramate, and zonisamide

• Lamotrigine, oxcarbazepine, felbamate approved for

monotherapy where phenytoin and carbamazepine have
failed.

• Topirimate can effective against refractory partial

seizures.
Generalized Onset Seizures

• Tonic-clonic, myoclonic, and absence seizures—

first line drug is usually valproate

• Phenytoin and carbamazepine are effective on tonic-

clonic seizures but not other types of generalized
seizures

• Valproate and ethoxysuximide are equally effective in

children with absence seizures, but only valproate
protects against the tonic-clonic seizures that sometimes
develop. Rare risk of hepatoxicity with valproate—should
not be used in children under 2.
 Generalized Onset Seizures
• Clonazepam, phenobarbital, or primidone can be useful
against generalized seizures, but may have greater
sedative effects than other AEDs

• Tolerance develops to clonazepam, so that it may lose

its effectiveness after ~6 months

• Carbamazepine may exacerbate absence and

myoclonic, underscoring the importance of appropriate
seizure classification

• Lamotrigine, topiramate, and zonisamide are effective

against tonic-clonic, absence, and tonic seizures
Infantile spasms
Infantile spasms are an epileptic syndrome and not a seizure type.

The attacks although sometimes fragmentary are most often bilateral

and are included, for pragmatic purposes with the generalized
seizures

Characterized by recurrent myoclonic jerks with sudden flexion or

extension of the body and limbs; the form of infantile spasms are,
however, quite heterogeneous. 90% have their first attack before
the age of 1 year. Most patients are mentally retarded,
presumably from the same cause of the spasms.

The cause is unknown. Infections, kernicterus, tuberous sclerosis

and hypoglycemia have all been implicated.
INFANTILE SPASMS

Drugs of choice: Corticotropin or

Corticosteroids
Zonisamide

Alternatives: Clonazepam
Vigabatrin
Phenobarbital
Classifying Side Effects of AEDs
• Adverse
– Dose-related (usually neurotoxicity)
• Acute (titration-related;
transient vs persistent)
• Chronic
– Idiosyncratic
• Allergic (mild; severe, possibly
life-threatening)
• Non-allergic
– Chronic
• Effects on organs or tissues
• Neurotoxicity (including
cognitive)
– Teratogenicity
• “Beneficial”
Some Less Common Side Effects of Newer
AEDs

• Clobazam • Lamotrigine
– Weight gain – Insomnia
– Impotence • Topiramate
• Vigabatrin
– Kidney stones (< 1.5%)
– Hair loss
– Especially with family
– visual field
constriction history, males,
dehydration
• Gabapentin
– Myoclonus
– Choreoathetosis
Serious Side Effects
of New Antiepileptic Drugs

• Vigabatrin
– Psychosis: 2 - 4%
– Peripheral retinal degeneration: ? 1/3
(rarely symptomatic)
• Lamotrigine
– Severe skin reactions (e.g. Stevens-Johnson)
• 1/100 children
• 1/300 - 1/1,000 adults
• Felbamate
– Aplastic anemia: 1/2,000 - 1/5,000
– Hepatic failure: 1/5,000 - 1/10,000
GENERAL ASPECTS OF PROGNOSIS

FOUR GROUPS
• Benign epilepsies – (20-30%) in which remission occurs after a
few years and treatment can often be avoided
(e.g. BECTS, Benign Occipital)
• Pharmacosensitive – seizure control is easy and spontaneous
remission occurs after a few years
(e.g. childhood absence)
• Pharmacodependent – drug treatment will control seizures but
no spontaneous remission occurs
(e.g. JME)
4. Pharmacoresistant (refractory) – poor prognosis
ANTI EPILEPTIC DRUGS - THERAPY

• Among 470 epileptic patients about 47% responded to

their first AED
• 13% responded to a second AED
• 4% responded to a third monotherapy
• Only 35 were controlled with 2 AED’s

• About 30% are “pharmacoresistant”

= refractory epilepsy

Brodie, Neurology 2002

Refractory Epilepsy

30% of epilepsy patients are resistant to treatment

with multiple AEDs
- Occurs even though AEDs used on the same
person have different mechanisms

P-glycoprotein involvement is an attractive hypothesis

– Is there an association with polymorphism and
drug resistance in epilepsy?
Hypothesis

• An insufficient amount of drug is crossing the

BBB for therapeutic levels to be reached

• Polymorphisms of pharmacokinetic and

pharmacodynamic processes (especially
transporters) is a popular explanation
P-glycoprotein

• Pgp and multidrug-resistance-

associated proteins (MRPs) -
- found in apical membrane of
BBB capillary endothelial cells
- Defense mechanism to protect
the brain from xenobiotics
• Expression of P-glycoprotein is
increased in seizure foci of
experimental animals
- Association of transport protein
overexpression with acute seizure
activity
• Some AEDs considered to be
substrates of Pgp and MRPs
Multidrug transporter hypothesis

• Refractory epilepsy result from localized

transporter overexpression at BBB
• Resistance can occur even if mechanism of
drugs are different
What can be done?

Surgery
• Identify epileptogenic zone using structural magnetic
resonance imaging in lesional epilepsy
• Intraaxial structural abnormality may indicate site of seizure
onset
• Resection identified area

Limitations
• Invasive
• In some patients, cannot identify epileptic brain tissue
accurately (nonlesional partial epilepsy)
• Risk of damaging healthy brain
What can be done?

Ketogenic diet
• Effective against different types of seizures
• It is a high-fat diet (4:1 lipid:nonlipid ratio) which induces
ketosis
• Used to treat intractable pediatric epilepsy
• Mechanism not known
Ketosis
• Excessive amount of ketone bodies found in normal blood
and interstitial fluids
• Ketone bodies replace glucose as substrate of
metabolism
Ketogenic Diet

• An alternative for intractable epilepsy not amenable to

surgery since 1920’s

• Fasting for seizure control has been suggested since

biblical times
Ketogenic Diet – Possible Mechanisms

• Acidosis

• Water balance and dehydration

• Direct action of acetoacetate or hydroxybutyrate

• Changing energy sources of the brain from glucose to

ketones
Energy Metabolism

• BBB function
disrupted during
seizures
• Suggested
decreased transport
of glucose by GLUT1
• Decreased uptake of
glucose in epileptic
foci (hypometabolic)
• Ionic homeostasis
harder to maintain
• KD increases energy
reserve
• Better maintenance
of ionic homeostasis
Ketogenic diet-clinical use

• Absence

• Symptomatic myoclonic

• Lennox-Gaustaut Sy

At Johns Hopkins: “The Ketogenic diet is considered

for all children who have intractable seizures of any
type and from any cause who have not responded to
a variety of regimens”.
Ketogenic Diet

• Classic: Ratio of Ketogenic to antiketogenic

is 4 : 1
fat (protein + carbohydrates)
- The diet allows 1 gr of protein/kg body weight daily
- Restriction of fluids
- Vitamins supplement
 Ketogenic Diet - efficacy

• 1/3 – complete seizure control

• 1/3 – greater than 50% seizure improvement

• 1/3 – no improvement

• 2/3 – one drug reduced

• 10% - all drugs discontinued

 Ketogenic Diet –Side effects

• Renal stones

• Hyperuricemia

• Acidosis

• Hypocalcemia

• Eating problems

• Secondary carnitine deficiency

 ANTIEPILEPTIC DRUG INTERACTIONS

With other antiepileptic Drugs:

- Carbamazepine with
phenytoin Increased metabolism of carbamazepine
phenobarbital Increased metabolism of epoxide.

- Phenytoin with
primidone Increased conversion to phenobarbital.

- Valproic acid with

clonazepam May precipitate nonconvulsive status
epilepticus
phenobarbital Decrease metabolism, increase toxicity.
phenytoin Displacement from binding, increase
toxicity.
 ANTIEPILEPTIC DRUG INTERACTIONS

With other drugs:

antibiotics  phenytoin, phenobarb, carb.
anticoagulants phenytoin and phenobarb
met.
cimetidine displaces pheny, v.a. and BDZs
isoniazid  toxicity of phenytoin
oral contraceptives antiepileptics  metabolism.
salicylates displaces phenytoin and v.a.
theophyline carb and phenytoin may
effect.