Pharmacotherapy of the Epilepsies

and Anti-Epileptic Drugs

Prepared by:
Miguelita Digal Espinosa, M. D.
Epilepsy:
 is a group of neurological disorders,
characterized by unprovoked seizures that can affect
mental and physical functions.

Epileptic Seizures:
 are episodes of brief to nearly undetectable periods
to longer periods of vigorous shaking;

 due to an excessive or over synchronized discharges

of cortical neurons.

Epilepsy: is the disease.

Epileptic Seizures: are the manifestations of the disease.

Incidence of Epilepsies:
= are the most common chronic brain disorder worldwide,
affecting people of all ages.

= affect about 2.5 million people in the U.S. alone.

= Over 250,000 Australians are living with epilepsy.

= more than 40 distinct forms of epilepsy

had been identified.

= Epileptic seizures are the most devastating

manifestation of Epilepsy.

= About 30% of those taking anti-epileptic medications

to control seizures, still experience seizures.
Epilepsy is diagnosed when:

= there are 2 unprovoked seizures

occurring 24 hours apart.

= there is one unprovoked seizure and

the probability of more seizures to
happen.
Causes of Epilepsy

= The cause of most cases of Epilepsy is unknown.

= Some cases are the result of:

> Brain injury
> Stroke
> Brain tumors
> birth defects (through the process of epileptogenesis).
GABA Receptor:
 activation mediates inhibitory response for the
normal termination of a seizure.

NMDA (Glutamate) Receptor:

 mediates activation required for the propagation
of seizure activity.

NMDA Receptor Reduced GABA

activation SEIZURE Receptor Function
Epileptic Seizures Classified:

1. Partial Seizures:
A. Simple Partial Seizures:
a) Consciousness not impaired.
b) Motor signs present.
c) With special sensory or somatosensory symptoms.
d) ANS symptoms or signs present.
e) Ma have psychic symptoms.
B. Complex Partial Seizures:
a) Simple partial seizures followed by
impairment of consciousness.
b) With impairment of consciousness at onset.
C. Partial seizures evolving to secondary
generalized seizures:
a) Simple partial seizures evolving to secondary
generalized seizure.
b) Complex partial seizures evolving to secondary
generalized seizure.
c) Simple partial seizures evolving to
Complex partial seizures and further evolving
to secondary generalized seizure.
11.Generalized Seizures:
(Convulsive or Non-convulsive)
A. Absence or Atypical Absence Seizures
B. Myoclonic Seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures
Seizure:
 a transient alteration of behavior,
 due to disorders in the synchronous and rhythmic
firing of certain populations of brain neurons.

 arise from the cerebral cortex.

Epilepsy:
 a disorder of brain function,
 characterized by periodic and unpredictable seizures,
 due to disorders of neuronal excitability.
Epileptic Seizures:

= the most devastating manifestation of Epilepsy.

= often cause transient impairment of consciousness,

= leaves the patient at risk of bodily harm like:

> falls > head injuries

> asphyxia > drowning.

= usually interfers with education and employment.

Not all seizures are due to Epilepsy:
= “Non-epileptic" Seizures:
 evoked in a normal brain
 by medications such as: electroshock
or chemical convulsants.
 due to metabolic conditions; like:
a) high fever
b) abnormalities in electrolyte and
acid-base balance.

= “Epileptic" Seizures:
 can occur without evident provocation.

= Anti-seizure Drugs;
 pharmacologic agents used to inhibit seizures.
Treatment for Epilepsy:
 is basically:
1) symptomatic
2) for the prevention of seizures.

= Available drugs that inhibit seizures,

 are neither effective as:
a) Prophylaxis,
nor as
b) Definitive therapeutic agents for epilepsy.

= Compliance with medication is a problem due to the:

1) need for long-term therapy
2) unwanted effects of many drugs.
3 Major Categories of the MOA of Anti-seizure Drugs:

1. Limit the sustained, repetitive firing of neurons,

 by promoting the inactivated state of the
voltage-activated Na+ channels.

2. Enhanced γ-aminobutyric acid (GABA)–mediated

synaptic inhibition,
 mediated either by a presynaptic or
postsynaptic action.

3. Inhibition of voltage-activated Ca++ channels,

 responsible for T-type Ca++ ion currents.
Pharmacologic agents effective against the
most common forms of Epileptic seizures:

= Generalized tonic-clonic seizures,

 AED work by one of the 1st or 2nd MOA of
antiepileptic drugs.

= Absence seizure,
 AED work by the inhibition of the voltage-
activated T-type of Ca++ channels.
B. Generalized Seizures:
1) Absence Seizure:
= An abrupt onset of impaired consciousness.
= associated with staring and cessation of the
ongoing activities.
= typically lasting less than 30 seconds.

= Conventional Anti-seizure Drugs:

a) Ethosuximide c) Clonazepam
b) Valproate d) Lamotrigine
EEG hallmark of Absence Seizure:

 generalized spike-and-wave discharges

at a frequency of 3 Hz per second (3 Hz).

 recorded from electrodes in both the

Thalamus and the Neocortex,

 represent oscillations of signals between these 2 areas.

= An intrinsic property of Thalamic neurons involved
in the generation of the 3-Hz spike-and-wave discharges;

 is a particular type of Ca++ current,

 the low threshold ("T-type") of Ca++ current.

= T-type Ca++ channels;

 are activated at a much more negative membrane
potential (thus "low threshold"),
 than most other voltage-gated Ca++ channels
in the brain.

 are much larger in Thalamic neurons,

than to neurons outside the Thalamus.
= T-type currents amplify the Thalamic membrane
potential oscillations,

= with one oscillation being the 3-Hz spike-and-wave

discharge of the Absence seizure.

The principal MOA of Anti–Absence-Seizure Drugs;

( Ethosuximide, and Valproic acid)

 is by inhibition of the T-type Ca++ channels,

Epileptic Syndromes:

 refer to a cluster of symptoms, often occurring

together which focuses on the:
a) Type of seizure

b) Etiology

c) Age of onset
Epileptic Syndromes:
= More than 50 distinct Epileptic Syndromes are
identified and categorized into;
 partial versus generalized epilepsies.

= The Classification of Epileptic Syndromes;

 guides clinicians as to the:

a) Comprehensive assessment of cases.

b) Management plan.
c) Logical selection of Anti-seizure Drugs
A. Partial Epilepsy Syndromes:
= consist of any of the partial seizure types,
= account for roughly 60% of all epilepsies
= Common Etiology:
 lesion in some part of the Cortex, such as:
1) tumor
2) developmental malformation
3) damage due to trauma or stroke
4) Genetic
B. The Generalized Epilepsy Syndromes:
= characterized by one or more of the
generalized seizure types.
= account for about 40% of all epilepsies.
= etiology is usually genetic.
Juvenile Myoclonic Epilepsy.
 the most common generalized Epilepsy:

= accounts for 10% of all epileptic syndromes.

= age of onset is in the early teens,
= characterized by myoclonic, tonic-clonic,
and often absence seizures.
= a complex genetic disorder with familial
clustering of cases.
Amino Acid Neurotransmitters:
 mediate synaptic transmission in the brain:

a) γ-Aminobutyric acid (GABA)  principally inhibitory

b) Glutamate  principally excitatory

= Antagonists of the GABAA receptor, or

= Agonists of the different Glutamate-receptor Subtypes:

a) NMDA
b) AMPA, or
c) kainic acid
AMPA: (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)

is the specific agonist for the AMPA receptor.

 where it mimics the effects of the neurotransmitter

Glutamate.

AMPA Receptor:
 a non-NMDA-type of ionotropic trans-membrane
receptor for Glutamate, (iGlut receptor)

 that mediate fast synaptic transmission in the CNS

AMPA and NMDA
Receptors:
= Two types of Receptors
located at Hippocampai
synapses.

= Both receptors respond to

Glutamate.

= NMDARs are unique,

since they are fully active
only when they are gated;
 by a combination of
voltage and a ligand.
ligand.
 Receptor with a Long Memory:
  = Glutamate, is a major excitatory synaptic neurotransmitter
in all parts of the nervous system.

= Two kinds of receptors activated by Glutamate:

1) NMDA receptor:
 sensitive to the glutamate agonist 
N-methyl-D-aspartate, (NMDA)
2)  AMPA receptor: 
 sensitive to α-amino-3-hydroxy-
5-methyl-4-isoxazole-propionic acid, (AMPA).

= Both AMPA and NMDA receptors,

 work together to produce long-lasting changes
in synaptic functioning;
 an action hypothesized to encode basic units
of new memories.
MOA of the NMDA Receptors:

= Glutamate molecules;
 bind to recognition sites of both AMPA and NMDA Receptors.

= Activation of the ionotropic AMPA Receptor

 admit Na+ ions
 localized depolarization

= Rise in voltage:
 dislodges the Mg++ ions, the NMDA receptor
blocking ion.
 opens the voltage-gated Ca+ ion channels.
MOA of the NMDA Receptors:

= NMDA Receptor is unique since it is gated by;

 both ligand and voltage.

 its activation leads to Ca++ ion influx;

 resulting to up-regulation of the AMPA Receptors

to the post-synaptic membrane.

 strenghten the synapses, and respond more

rapidly to further releases of Glutamate.
Diagnosis of Epilepsies:
= There is not a single diagnostic test for Epilepsy.
= A careful history is a best tool.
 a description of the seizures from the patient
and witnesses.
= Neurologic Examination.
= Diagnostic testing:
> EEG
> MRI
= Advanced diagnostic techniques in advanced
epilepsy centers:
> Ambulatory EEG
> In patient video/EEG monitoring
Anti-seizure Drugs:

Common MOA of Anti-seizure Drugs,

 Inhibit the voltage-gated ion channels;

= With Anti–partial-seizure Drugs;

 by inhibiting voltage-activated Na+ channels

= And Anti–absence-seizure Drugs;

 by inhibiting voltage-activated Ca2+ channels,

 reduce the flow of Ca++ through

the T-type Ca++ channels.
Anti-seizure Drugs:

 prolong the inactivation

of the Na+ channels,

 reducing the ability of

neurons to fire at high
frequencies.

The inactivated channel is

blocked by the inactivation
gate _1; activation gate _ A.
GABAA Receptor:
 principal postsynaptic receptor of GABA
neurotransmitter released from the synapse.

Activation of GABAA Receptor;

 inhibits the postsynaptic cell,
 by increasing the inflow of Cl– ions into the cell,
 which tends to hyperpolarize the neuron.
Anti-seizure Drugs:

 prolong the inactivation

of the Na+ channels,

 reducing the ability of

neurons to fire at high
frequencies.

= Inactivated channel is blocked,

 by inactivation gate _1;
activation gate _ A.
 Anti-seizure Drugs:

 reduce the flow of Ca++

through the T-type Ca++
channels,

 reduce the pacemaker

current that underlies
the thalamic rhythm in
spikes and waves,

 seen in generalized
Absence Seizures
Both Benzodiazepines and Barbiturates:

 enhance GABAA Receptor–mediated inhibition.

 effective against partial and tonic- clonic seizures.

= At higher concentrations, such as in Status epilepticus,

 both drugs can also inhibit high-frequency
firing of APs.

Tiagabine MOA:
1) inhibits the GABA transporter, GAT-1,

2) reduces neuronal and glial uptake of GABA.

Hydantoins:
= Phenytoin (diphenylhydantoin; DILANTIN, others)
(Ethotoin, PEGANONE)

 effective against all types of partial and

tonic-clonic seizures.
 not effective for Absence Seizures.

MOA:
 Limits the repetitive firing of APs
 mediated by a slowing of the rate of recovery of
the voltage-activated Na+ channels from inactivation.
= Valproate compete with Phenytoin;
for protein binding sites, thus it;

a) inhibits Phenytoin metabolism,

b) results in marked and sustained increases

in free Phenytoin.

= Measurement of free rather than total Phenytoin;

 allows direct assessment of this potential
problem in patient management.
Drug interactions with Phenytoin:

= drugs metabolized by the same CYPs

 can inhibit the metabolism of Phenytoin
 and the degradation rate of other drugs,
like Warfarin.

= Like Phenytoin,
 Carbamazepine, Oxcarbazepine,
Phenobarbital, and Primidone;

 can induce CYP3A4 and might increase

degradation of oral Contraceptives

= has potential teratogenic effects.

Fosphenytoin, (CEREBYX, others):
= a water-soluble prodrug.
= which is converted into Phenytoin,
 by phosphatases in the liver and red blood cells.

= t1/2 of 8-15 minutes.

= extensively bound (95-99%) to plasma albumin.
= This binding is saturable
= Fosphenytoin
 displaces Phenytoin from protein-binding sites.

= Fosphenytoin is useful for adults with partial or

generalized seizures when IV or IM administration
is indicated.
= Fosphenytoin:
 is administered IV at an excessive rate,
in an emergency setting,

 for the treatment of Status Epilepticus.

Most notable Toxic signs:

 Cardiac arrhythmias with or without hypotension,
and/or CNS depression.
 occurs more frequently in older patients and in
those with known cardiac diseases.
Acute oral over dosage of Phenytoin:
 dose-related cerebellar and vestibular effects
at high doses.

 marked cerebellar atrophy.

Phenytoin Toxicity:

a) CNS toxic effects associated with chronic treatment:

a) Behavioral changes.
b) Increased frequency of seizures.
c) GI symptoms.
d) Gingival hyperplasia.
b) Other Phenytoin Toxic effects:

1) Osteomalacia with Hypocalcemia:

 elevated alkaline phosphatase activity due to:
a) altered metabolism of vitamin D
b) inhibition of intestinal absorption of Ca++ ion.

2) Increases the metabolism of Vitamin K

 reduces the concentration of
vitamin K–dependent proteins
 important for normal Ca++ ion metabolism in bone.

= This explains why the Osteomalacia is not always

ameliorated by the administration of Vitamin D.
Hypersensitivity Reactions to Phenytoin:

= morbilliform rash in 2-5% of patients

= Stevens-Johnson Syndrome, (SJS)

= Toxic epidermal necrolysis, (TEN)

= Systemic lupus erythematosus, (SLE)

= Lymphadenopathy, resembling Hodgkin's disease

and Malignant lymphoma,
 associated with reduced immunoglobulin A (IgA)
production.
Anti-Seizure Barbiturates:

Phenobarbital (LUMINAL, others)

= the first effective organic anti-seizure agent.
= has relatively low toxicity,
= is inexpensive,

= is still one of the more effective and widely

used drugs for seizures.
MOA of Phenobarbital:
= potentiation of synaptic inhibition through
the GABAA Receptor.

= increases GABAA Receptor–mediated current,

 by increasing the duration of bursts of GABAA
receptor–mediated currents.

= limits sustained repetitive firing at levels exceeding

therapeutic concentrations,
 achieved during therapy of Status Epilepticus.
Toxicity of Phenobarbital:

= Sedation,
 the most frequent undesirable effect of phenobarbital,

= Tolerance develops during chronic medication.

= Nystagmus and Ataxia occur at excessive dosage.

= Irritability and Hyperactivity in children,

Agitation and Confusion in the elderly.
Toxicity of Phenobarbital:
1) Scarlatiniform or morbilliform rash,
 as drug allergy in 1-2% of patients.

2) Hypoprothrombinemia with hemorrhage;

 in newborns of mothers who received
Phenobarbital during pregnancy;
 Vitamin K is effective for treatment or prophylaxis.

3) Megaloblastic anemia;
 that responds to folate.

4) Osteomalacia;
 that responds to high doses of vitamin D.
Therapeutic Uses of Phenobarbital:
= Effective agent for generalized tonic-clonic
and partial seizures.

= Efficacy, low toxicity, and low cost.

= Its sedative effects and its tendency to disturb

behavior in children,
 have reduced its use as a primary agent.

= Not effective for Absence Seizures.

Iminostilbenes:
Carbamazepine (TEGRETOL, CARBATROL, others)
= Used for the treatment of Trigeminal neuralgia.

= A primary drug for the treatment of,

 Partial and Tonic-clonic Seizures.

= is chemically related to the Tricyclic Anti-depressants.

= A derivative of Iminostilbene with a Carbamyl group

at 5 position,
 essential for potent anti-seizure activity.
Pharmacological Effects of Carbamazepine:
= Therapeutic responses in manic-depressive patients,
even those where Lithium carbonate is not effective.

= Has anti-diuretic effects associated with

 increased concentrations of ADH in plasma.

MOA:
= Like Phenytoin, it limits the repetitive firing of Aps,
 mediated by a slowing of the rate of recovery of
voltage-activated Na+ channels from inactivation.
= Its metabolite, 10,11-epoxycarbamazepine, still
limits sustained repetitive firing at therapeutic levels.
= 10,11-epoxide.
Metabolite is as active as the parent compound,
its concentrations in plasma and brain may reach 50% of
the Carbamazepine dose, especially if co- administered
with Phenytoin or Phenobarbital.

= The 10,11-epoxide is metabolized further to inactive

compounds, excreted in the urine as glucuronides.

= is inactivated by conjugation and hydroxylation.

Hepatic CYP3A4 is responsible for biotransformation.

= It induces CYP2C, CYP3A, and UGT, enzyme metabolism.

oral contraceptives are also metabolized by CYP3A4.
Toxicity of Carbamazepine:

= Acute intoxication can result in :

a) Hyperirritability
b) Convulsions
c) Stupor or coma
d) Respiratory depression
Drug Interactions of Carbamazepine:
= Phenobarbital, Phenytoin, and Valproate;
 may increase the metabolism of carbamazepine
by inducing CYP3A4;
= Carbamazepine
 enhance the biotransformation of Phenytoin.

= Concurrent administration of Carbamazepine

 lower concentrations of Valproate, Lamotrigine,
Tiagabine, and Topiramate.
= Reduces both the plasma concentration and therapeutic
effect of Haloperidol.

= Metabolism of Carbamazepine;
 inhibited by Propoxyphene, Erythromycin,
Cimetidine, Fluoxetine, and Isoniazid.
= Carbamazepine
 the primary agent for the treatment of:

1) Trigeminal neuralgia.
2) Glossopharyngeal neuralgias (70% relief).
3) Lightning-type ("tabetic") pain associated
with bodily wasting.
4) Also for the treatment of Bipolar affective disorders.
Succinimides:
Ethosuximide (ZARONTIN, others):
a primary agent, selective for the treatment of
Absence Seizures.

 has alkyl substituents,

 the most active of the Succinimides against seizures

induced by pentylenetetrazol.
 MOA of Ethosuximide:
 Reduces low threshold Ca++ currents (T-type currents)
in Thalamic neurons.

 the mechanism by which it inhibits Absence seizures.

= Thalamus plays an important role in generation of,

 3-Hz spike-and-wave rhythms,
 typical of absence seizures.

= Normally neurons in thalamus exhibit

 large-amplitude T-type currents.
.
MOA of Ethosuximide:

= inhibits the T-type of Ca++ ion current.

= does not inhibit sustained repetitive firing

or enhance GABA responses at clinically
relevant concentrations.

= By contrast, Succinimide derivatives with

anti-convulsant properties do not inhibit this current.
Plasma Concentrations of Ethosuximide:
during long-term therapy;
 averages ~2 g/mL per daily dose of 1 mg/kg.

A plasma concentration of 40-100 g/mL

 for satisfactory control of Absence seizures.

Therapeutic Uses of Ethosuximide:

 is effective against Absence seizures,
but not for tonic-clonic seizures.
Benzodiazepines:
 are used primarily as sedative-anti-anxiety drugs.

= Most Benzodiazepines have broad anti-seizure properties,

= Only Clonazepam (KLONOPIN, others)

and Clorazepate (TRANXENE, others)
 are approved in the U.S. for the long-term treatment,
of certain types of seizures.

= Diazepam (VALIUM, DIASTAT; others)

and Lorazepam (ATIVAN, others)
 have well-defined roles in the management
of status epilepticus
MOA of Benzodiazepines:
= At therapeutic concentrations, Benzodiazepines
 act at subsets of GABAA receptors, and
 increase the frequency, but not duration,
of openings at GABA-activated Cl– channels.

 to enhance GABA-mediated synaptic inhibition.

= the Benzodiazepine receptor,

 is an integral part of the GABAA receptor.
MOA of Benzodiazepines:
= At higher concentrations, Diazepam and other
Benzodiazepines
 can reduce sustained high-frequency firing of neurons,
similar to effects of Phenytoin, Carbamazepine,
and Valproate.

= The same concentration of Diazepam,

 for the treatment of status epilepticus
PK/ PD of Benzodiazepines:
= are well absorbed orally,

= maximum plasma concentrations within 1-4 hours.

= After IV administration, they are rapidly redistributed

being a highly lipid-soluble agents.

= Diazepam is redistributed rapidly,

 with a t1/2 of redistribution of ~1 hour.

= extent of binding of Benzodiazepines to plasma proteins,

correlates with lipid solubility,
> ~99% for Diazepam
> ~85% for Clonazepam
PK/ PD of Benzodiazepines:
= The t1/2 of Diazepam is between 12 and 24 hours,
 while that of N-desmethyl-diazepam is ~60 hours.

Clonazepam:
= The t1/2 in plasma is ~23 hours.

Lorazepam:
= is metabolized chiefly by conjugation with glucuronic acid;
 its t1/2 in plasma is ~14 hours.
Toxicity of Benzodiazepines:

The principal side effects of long-term

oral therapy with Clonazepam are:

a) Drowsiness and lethargy in ~50% of patients,

but tolerance often develops with prolong use.
b) Muscular incoordination and ataxia.
c) Hypotonia, dysarthria, and dizziness.
d) Behavioral disturbances, especially in children.
aggression, hyperactivity, irritability, and
difficulty in concentration anorexia and hyperphagia.
Toxicity of Benzodiazepines:
e) Increased salivary and bronchial secretions.

f) Seizures may be exacerbated.

Status epilepticus may precipitate,
if the drug is discontinued abruptly.

g) Cardiovascular and respiratory depression may occur,

after IV Diazepam, Clonazepam or Lorazepam,
 particularly if other anti-seizure agents or central
depressants have been administered previously.
Other Anti-Seizure Drugs:
Gabapentin (NEURONTIN) and Pregabalin (LYRICA)
 consist of a GABA molecule covalently bound to a
lipophilic cyclohexane ring or isobutane, respectively.

Gabapentin:
 designed as a centrally active GABA agonist,
 its high lipid solubility facilitate transfer across BBB.

= Both bind with high affinity to a protein in the

cortical membranes with an amino acid sequence
identical to that of the Ca++ channel.
= Topiramate (TOPAMAX, others)
 a sulfamate-substituted monosaccharide.

 for Lennox-Gastaut syndrome in patients

2 years of age and older,
 for migraine headache prophylaxis in adults.

 FDA-approved as initial monotherapy

(in patients at least 10 years old)

 as adjunctive therapy for partial-onset,

or, primary generalized tonic-clonic seizures,
(for patients as young as 2 years of age)
MOA of Topiramate:
 reduces voltage-gated Na+ currents in
cerebellar granule cells.
 act on the inactivated state of ion channel
similar to Phenytoin.
 activates a hyperpolarizing K+ current,
 enhances postsynaptic GABAA-receptor currents,
 limits activation of the AMPA-kainate-subtype(s)
of glutamate receptor.

Topiramate is a weak carbonic anhydrase inhibitor.

Febrile Convulsions:

= 2 to 4% of children experience convulsions

associated with a febrile illness.

= 25-33% of these children will have another

febrile convulsion.

= Only 2-3% become Epileptic in later years,

 a 6-fold increase in risk compared with
the general population.
Associated Risk Factors to developing Epilepsy:

1) preexisting neurological disorder, or developmental delay.

2) a family history of Epilepsy.

3) a complicated febrile seizure;

 febrile seizure lasted > 15 minutes, and one-sided,

 or was followed by a 2nd seizure on the same day.

= If all of these risk factors are present,

 the risk of developing epilepsy is ~10%.
= For children at high risk of developing;
Recurrent febrile seizures and Epilepsy,

 Diazepam rectally at the time of fever

may prevent recurrent seizures.

 and avoid the side effects of chronic therapy.

Seizures in Infants and Young Children:

= Infantile spasms with hypsarrhythmia (abnormal

inter-ictal high amplitude slow waves and multifocal
asynchronous spikes on EEG),

 are refractory to the usual anti-seizure agents.

= Repository Corticotropin (H.P. ACTHAR GEL)

 Corticotropin or the Glucocorticoids commonly used,
 designated as an orphan drug for this purpose.
Lennox-Gastaut Syndrome:

= a severe form of Epilepsy usually in childhood,

 characterized by cognitive impairments and
multiple types of seizures,
 tonic-clonic, tonic, atonic, myoclonic,
and atypical absence seizures.

= Lamotrigine is an effective and well-tolerated

drug for this treatment-resistant form of epilepsy.

= Topiramate, also effective for Lennox-Gastaut syndrome .

Status Epilepticus:
= is a neurological emergency.

= Mortality for adults is about 20%.

= The goal of treatment;

 is rapid termination of behavioral
and electrical seizure activity;

= The longer an episode of Status Epilepticus

is left untreated,
 the more difficult it is to control,
 the greater the risk of permanent brain damage.
Critical to the management of Status Epilepticus:

a) A clear treatment plan.

b) Prompt treatment with effective drugs

in adequate doses.

c) Attention to hypoventilation and hypotension,

 may be necessary to assist respiration temporarily.

d) Drugs should be administered by IV route only.

Anti-epileptic Drugs Used:
A. Diazepam primarily by IV,
B. followed by Phenytoin, Lorazepam, Phenobarbital.
and Phenytoin alone.

= Success rates with these treatments ranges

 from 44-65%.

= Lorazepam alone was significantly better than

Phenytoin alone.
Teratogenicity of Anti-seizure Drugs:
= Evidences showed that anti-seizure drugs
 have teratogenic effects.
= The teratogenic effects,
 come on top of oral contraceptive failure.
= Infants of epileptic mothers,
 are at a 2-fold greater risk of major congenital
malformations than offspring of non-epileptic mothers
(4-8% compared to 2-4%).
= Malformations include: congenital heart defects,
neural tube defects, cleft lip, cleft palate, and others.
Teratogenicity of Anti-seizure Drugs:

= Phenytoin, Carbamazepine, Valproate,

Lamotrigine, and Phenobarbital,
 are all associated with teratogenic effects.

= Polytherapy with toxic levels should be avoided.

= Folate supplementation (0.4 mg/day)

 recommended by the U.S. Public Health Service
for all women of childbearing age,

 to reduce the likelihood of neural tube defects,

 and for epileptic women.

Teratogenicity of Anti-seizure Drugs:

= Anti-seizure drugs that induce CYPs,

 associated with Vitamin K deficiency in the newborn,

 can cause coagulopathy and intracerebral hemorrhage.

= Treatment with Vitamin K1, (10 mg/day);

 is recommended as prophylaxis during the last
month of gestation.
THANK YOU
 Assignments
Device a treatment plan for the following
pathologic conditions:

Case No. 1:
C. T. a 67 –year old male, former teacher in grade school, who
developed a single generalized tonic-clonic seizures for the first
time, two months after he was discharged from the hospital for
stroke. Patient is hypertensive with maintenance medications:
1) Telmisartan 40 mgs/Amlodipine 5mgs daily.
2) Rosuvastatin 20 mgs daily
3) Multivitamins and Minerals one tablet daily
He has good compliance in his medications as well as his
follow-up visits to his attending physicians.
Case No 2.
C.S. a 26- year old single house helper, often had her attention
called by her employer for her low output in whatever job
she is assigned to. Suddenly she started having nausea and
occasional vomiting. Her self administered pregnancy test
turned positive.
While she was in the doctor’s clinic for prenatal check up
she was noticed to have a brief period of unconscious
and blank stare.
Diagnosis: Pregnancy 16 weeks, with
Absence Epileptic episode.