EPILEPSY

Sumbul Zehra, Ph.D.

 INTRODUCTION
 Epilepsy is not a single entity but an assortment
of different seizure types and syndromes
originating from several mechanisms that have
in common the sudden, excessive, an
synchronous discharge of cerebral neurons.
 This abnormal electrical activity may result in a
variety of events, including loss of consciousness,
abnormal movements, atypical or odd behavior,
and distorted perceptions that are of limited
duration but recur if untreated.
 The site of origin of the abnormal neuronal firing
determines the symptoms that are produced.
 For example, if the motor cortex is involved, the
patient may experience abnormal movements or
a generalized convulsion.
 Seizures originating in the parietal or occipital
lobe may include visual, auditory, and olfactory
hallucinations.
 ETIOLOGY
 In most cases, epilepsy has no identifiable cause.
 alteration in blood gases,
 pH, electrolytes,
 blood glucose
 environmental factors, such as sleep deprivation,
 alcohol intake,
 stress.
 The neuronal discharge in epilepsy results from the firing
of a small population of neurons in a specific area of the
brain referred to as the “primary focus.”
 ETIOLOGY
 Neuroimaging techniques, such as magnetic resonance
imaging, positron emission tomography scans, and single
photon emission coherence tomography, may identify areas
of concern.
 Epilepsy can be due to an underlying genetic, structural, or
metabolic cause or an unknown cause.
 Genetic epilepsy, Structural/metabolic epilepsy and
Unknown cause.
FOCAL GEBERALIZED UNKNOWN

Tonic-clonic
Absence
Simple Myoclonic Epileptic
Complex Clonic spasms
Tonic
Atonic
 CLASSIFICATION OF
SEIZURES
 Focal
 Focal seizures involve only a portion of the brain, typically
part of one lobe of one hemisphere.
 Focal seizures may progress to become generalized
tonic–clonic seizures.
 A) Simple partial
 FOCAL SEIZURES
SIMPLE PARTIAL COMPLEX

 These seizures are caused  These seizures exhibit

complex
by a group of hyperactive sensoryhallucinations and
neurons exhibiting mental distortion.
abnormal electrical activity  Motor dysfunction may
involve chewing movements,
and are confined to a diarrhea, and/or urination.
single locus in the brain.  Consciousness is altered.
 The electrical discharge  Simple partial seizure
activity may spread to
does not spread, and the become complex and then
patient does not lose spread to a secondarily
generalized convulsion.
consciousness or
 Complex partial seizures
awareness. may occur at any age
 The patient often exhibits abnormal activity of a single
limb or muscle group that is controlled by the region of
the brain experiencing the disturbance.
 The patient may also show sensory distortions.
 Simple partial seizures may occur at any age.
 GENERALIZED SEIZURES
 Generalized seizures may begin locally and then progress
to include abnormal electrical discharges throughout both
hemispheres of the brain.
 Primary generalized seizures may be convulsive or non-
convulsive, and the patient usually has an immediate loss
of consciousness.
 Tonic–clonic:
 These seizures result in loss of consciousness, followed by
tonic (continuous contraction) and clonic (rapid
contraction and relaxation) phases.
 The seizure may be followed by a period of confusion and
exhaustion due to the depletion of glucose and energy
stores.
 Absence:
 These seizures involve a brief, abrupt, and selflimiting loss
of consciousness.
 The onset generally occurs in patients at 3 to 5 years of age
and lasts until puberty or beyond.
 The patient stares and exhibits rapid eye-blinking, which
lasts for 3 to 5 seconds.
 An absence seizure has a very distinct three-per-second
spike and wave discharge seen on electroencephalogram.
 Myoclonic:
 These seizures consist of short episodes of muscle
contractions that may recur for several minutes. They generally
occur after wakening and exhibit as brief jerks of the limbs.
 Myoclonic seizures occur at any age but usually begin around
puberty or early adulthood.
 Clonic:
 These seizures consist of short episodes of muscle
contractions that may closely resemble myoclonic seizures.
 Consciousness is more impaired with clonic seizures as
compared to myoclonic.
 To n ic:
 These seizures involve increased tone in the
extension muscles and are generally less than 60
seconds long.
 Atonic:
 These seizures are also known as drop attacks and are
characterized by a sudden loss of muscle tone.
Mechanism of action of
antiepilepsy medications
 Drugs reduce seizures through such mechanisms as
blocking voltage-gated channels (Na+ or Ca2+), enhancing
inhibitory γ-aminobutyric acid (GABA)-ergic impulses and
interfering with excitatory glutamate transmission.
 Some antiepilepsy medications appear to have multiple
targets within the CNS, whereas the mechanism of action
for some agents is poorly defined.
 Antiepilepsy medications suppress seizures but do not
“cure” or “prevent” epilepsy.
 ANTIEPILEPSY MEDICATIONS

 Benzodiazepines
 Most benzodiazepines are reserved for emergency or acute
seizure treatment due to tolerance.
 Diazepam is also available for rectal administration to
avoid prolonged generalized tonic–clonic seizures when
oral administration is not possible.
 CARBAMAZEPINE
 Carbamazepine blocks sodium channels, thereby
inhibiting the generation of repetitive action potentials in
the epileptic focus and preventing their spread.
 Carbamazepine is effective for treatment of focal seizures
and, additionally generalized tonic–clonic seizures,
trigeminal neuralgia, and bipolar disorder.
 Carbamazepine is an inducer of the CYP1A2, CYP2C, and
CYP3A and UDP glucuronosyltransferase (UGT)
enzymes, which increases the clearance of other drugs.
 Hyponatremia may be noted in some patients, especially
the elderly, and may necessitate a change in medication.
 Carbamazepine should not be prescribed for patients with
absence seizures because it may cause an increase in
seizures.
 Eslicarbazepine

 Eslicarbazepine acetate is a prodrug that is converted to

the active metabolite eslicarbazepine by hydrolysis. S-
licarbazepine is the active metabolite of oxcarbazepine
 It is a voltage-gated sodium channel blocker and is
approved for partial-onset seizures in adults.
 The side effect profile includes dizziness, somnolence,
diplopia, and headache.
 Serious adverse reactions such as rash, psychiatric side
effects, and hyponatremia occur rarely.
Ethosuximide
 Inhibiting T-type calcium channels.
 It is only effective in treating absence seizures.
Ezogabine
 Ezogabine is thought to open voltage-gated M-type potassium
channels leading to stabilization of the resting membrane
potential.
 Possible unique side effects are urinary retention, QT interval
prolongation, blue skin discoloration, and retinal abnormalities.
Felbamate
 Felbamate
 Multiple proposed mechanisms including the blocking of
voltage-dependent sodium channels,
 competing with the glycine agonist binding site on the N-
methyl-d-aspartate (NMDA) glutamate receptor, blocking of
calcium channels, and potentiating GABA action.
 It is reserved for use in refractory epilepsies (particularly
Lennox-Gastaut syndrome) because of the risk of aplastic
anemia (about 1:4000) and hepatic failure.
Gabapentin
 Gabapentin is an analog of GABA. However, it does not act at
GABA receptors, enhance GABA actions or convert to GABA.
 Its precise mechanism of action is not known.
 It is approved as adjunct therapy for focal seizures and
treatment of postherpetic neuralgia.
 Reduced dosing is required in renal disease. Gabapentin is well
tolerated by the elderly population with partial seizures due to
its relatively mild adverse effects.
 It may also be a good choice for the older patient because there
are few drug interactions.
Laco samid e
 Lacosamide affects voltage-gated sodium channels,
resulting in stabilization of hyperexcitable neuronal
membranes and inhibition of repetitive neuronal firing.
 Lacosamide is approved for adjunctive treatment of
focal seizures.
 It is available in an injectable formulation. The most
common adverse events that limit treatment include
dizziness, headache, and fatigue.
 Lamotrigine
 blocks sodium channels, as well as high voltage-
dependent calcium channels.
 Lamotrigine is effective in a wide variety of seizure
types, including focal, generalized, absence seizures,
and Lennox- Gastaut syndrome.
 It is also used to treat bipolar disorder.
 Slow titration is necessary with lamotrigine (particularly
when adding lamotrigine to a regimen that includes
valproate) due to risk of rash, which may progress to a
serious, life-threatening reaction.
 Levetiracetam
 Levetiracetam is approved for adjunct therapy of
focal onset, myoclonic, and primary generalized
tonic–clonic seizures in adults and children. The
exact mechanism of anticonvulsant action is
unknown.
 Oxcarbazepine
 Oxcarbazepine is a prodrug that is rapidly reduced to the 10-
monohydroxy (MHD) metabolite responsible for its
anticonvulsant activity.
 MHD blocks sodium channels, preventing the spread of the
abnormal discharge. It is also thought to modulate calcium
channels.
 It is approved for use in adults and children with partial-
onset seizures.
 The adverse effect of hyponatremia limits its use in the
elderly.
 Perampanel
 Perampanel is a selective α-amino-3-hydroxy-5- methyl-4-
isoxazolepropionic acid antagonist resulting in reduced
excitatory activity.
 Perampanel has a long half-life enabling once-daily dosing.
 It is approved for adjunctive treatment of partial-onset
seizures in patients 12 years or older.
 Perampanel is a newer antiepileptic agent, and limited data
are available in patients.
 Phenobarbital and primidone
 The primary mechanism of action of
phenobarbital is enhancement of the inhibitory
effects of GABA-mediated neurons.
 Primidone is metabolized to phenobarbital (major)
and phenylethylmalonamide, both with
anticonvulsant activity.
 Phenobarbital is used primarily in the treatment
of status epilepticus when other agents fail.
 Phenytoin
 Phenytoin blocks voltage-gated sodium channels
by selectively binding to the channel in the
inactive state and slowing its rate of recovery.
 It is effective for treatment of focal and
generalized tonic–clonic seizures and in the
treatment of status epilepticus.
 nystagmus and ataxia
 Peripheral neuropathies and osteoporosis
 Fosphenytoin
 Fosphenytoin is a prodrug that is rapidly
converted to phenytoin in the blood within
minutes.
 Whereas fosphenytoin may be administered
intramuscularly (IM), phenytoin sodium should
never be given IM, as it causes tissue damage and
necrosis.
 Fosphenytoin is the drug of choice and standard of
care for IV and IM administration of phenytoin.
 Because of sound-alike and look-alike trade
names, there is a risk for prescribing errors.
 Preg abalin
 Pregabalin binds to voltage-gated calcium channels in the
CNS, inhibiting excitatory neurotransmitter release.
 The exact role this plays in treatment is not known, but the
drug has proven effects on focal-onset seizures, diabetic
peripheral neuropathy, postherpetic neuralgia, and
fibromyalgia.
 Rufinamide
 Rufinamide acts at sodium channels.
 It is approved for the adjunctive treatment of seizures
associated with Lennox- Gastaut syndrome in children over
age 4 years and in adults.
 Tiagabine
 blocks GABA uptake into presynaptic neurons
permitting more GABA to be available for receptor
binding, and therefore, it enhances inhibitory activity.
 Tiagabine is effective as adjunctive treatment in partial
-onset seizures.
 Topiramate
 has multiple mechanisms of action.
 It blocks voltage-dependent sodium channels, reduces high
-voltage calcium currents (L type), is a carbonic anhydrase
inhibitor, and may act at glutamate (NMDA) sites.
 Topiramate is effective for use in partial and primary
generalized epilepsy.
 It is also approved for prevention of migraine.
 Valproic acid
 Possible mechanisms of action include sodium channel
blockade, blockade of GABA transaminase, and action at
the T-type calcium channels.
 These varied mechanisms provide a broad spectrum of
activity against seizures.
 It is effective for the treatment of focal and primary
generalized epilepsies.
 Divalproex sodium (sodium valproate and valproic acid)
 It was developed to improve gastrointestinal tolerance of
valproic acid.
 Teratogenicity is also of great concern.
 Vigabatrin
 Vigabatrin acts as an irreversible inhibitor of γ-
aminobutyric acid transaminase (GABA-T). GABA-T is
the enzyme responsible for metabolism of GABA.
 Vigabatrin is associated with visual field loss ranging from
mild to severe in 30% or more of patients.
 Vigabatrin is only available through physicians and
pharmacies that participate in the restricted distribution
SHARE program.
 Zonisamide
 Zonisamide is a sulfonamide derivative that has a broad
spectrum of action.
 The compound has multiple effects, including blockade of
both voltage-gated sodium channels and T-type calcium
currents.
 Zonisamide is approved for use in patients with focal
epilepsy.
 STATUS EPILEPTICUS
 In status epilepticus, two or more seizures occur without
recovery of full consciousness in between episodes.
 These may be focal or primary generalized, convulsive or
nonconvulsive.
 Status epilepticus is life threatening and requires
emergency treatment usually consisting of administration
of a fast-acting medication such as a benzodiazepine,
followed by a slower-acting medication such as phenytoin.
 WOMEN HEALTH AND EPILEPSY
 Women of childbearing potential with epilepsy require
assessment of their antiepilepsy medications in regard to
contraception and pregnancy planning.
 Several antiepilepsy medications increase the metabolism
of hormonal contraceptives, potentially rendering them
ineffective.
 These include phenytoin, phenobarbital, carbamazepine,
topiramate, oxcarbazepine, rufinamide, and clobazam.