Epilepsy

ZAINAB SABRIE
PHARMD, MSC, PH.D.
 Epilepsy

 Epilepsyconsists of various seizure types

and syndromes caused by different
mechanisms.
 Itis characterized by sudden, excessive, and
synchronized neuronal discharges in the
brain.
 Thisabnormal electrical activity can lead to
symptoms such as loss of consciousness,
abnormal movements, unusual behavior,
and distorted perceptions, which may recur
 Epilepsy

 Thespecific symptoms depend on the

origin of the abnormal firing, such as
abnormal movements or convulsions if
the motor cortex is affected.
 Seizures
originating in the parietal or
occipital lobe may include visual,
auditory, and olfactory hallucinations.
 IDIOPATHIC AND
SYMPTOMATIC SEIZURES

 Epilepsy can be classified as

idiopathic if the cause is unknown, or
symptomatic if it results from an
identifiable condition.
 Idiopathic epilepsy

 Most cases of epilepsy are idiopathic.

 When no specific anatomical cause for
the seizures is found, the patient may be
diagnosed with idiopathic or cryptogenic
(primary) epilepsy, which may stem from
an inherited abnormality in the CNS.
 Treatmenttypically involves chronic use
of antiseizure drugs or vagal nerve
stimulation.
 Symptomatic epilepsy

 Seizures can be triggered by factors such as

illicit drug use, tumors, head injury,
hypoglycemia, meningeal infections, and
rapid alcohol withdrawal.
 When two or more seizures occur, the
patient may be diagnosed with symptomatic
(secondary) epilepsy.
Symptomatic epilepsy

 Chronic treatment options include

antiseizure medications, vagal nerve
stimulation, and surgery, which can be
used alone or in combination.
 Insome cases, if the cause of a single
seizure is identified and corrected,
therapy may not be necessary.
 CLASSIFICATION OF
SEIZURES
 Seizures have been categorized by site of
origin, etiology, electrophysiologic
correlation, and clinical presentation
 Seizures have been classified into two broad
groups:
 Partial (or focal), and
 Generalized
A diagnosis may include classifying the
seizure as partial or generalized epilepsy
depending on the onset
 Partial

 Partialseizures affect a specific brain region,

typically within one hemisphere.
 Symptoms vary based on the discharge site
and its spread.
 Consciousness is usually maintained, but the
seizure may progress to a generalized
tonic-clonic seizure.
 Simple partial

 Simplepartial seizures arise from

hyperactive neurons in a specific brain
region, without spreading or causing
loss of consciousness.
 They often involve abnormal movement
in a single limb or muscle group and
may include sensory distortions.
 These
seizures can occur at any age but
may sometimes spread.
Complex partial

 Theseseizures exhibit complex sensory

hallucinations and mental distortion
 Motor
dysfunction may involve chewing
movements, diarrhea, and/or urination
 Consciousness is altered
 Simple
partial seizure activity may spread to
become complex and then spread to a
secondary generalized convulsion
 Complex partial seizures may occur at any
 Generalized

 Generalizedseizures may begin locally and

then progress to include abnormal
electrical discharges throughout both
hemispheres of the brain
 Primarygeneralized seizures may be
convulsive or nonconvulsive, and the
patient usually has an immediate loss of
consciousness
 Generalized

 Tonic-Clonic: Characterized by loss of

consciousness, followed by tonic (continuous
contraction) and clonic (rapid contraction and
relaxation) phases.
 Post-seizure confusion and exhaustion occur due
to energy depletion.
 Absence: Brief, sudden loss of consciousness,
usually in children aged 3–5 years, persisting into
puberty or beyond.
 Symptoms include staring and rapid eye-
 Generalized

 Myoclonic:
 Brief,repetitive muscle contractions, often
occurring after waking, typically starting
around puberty or early adulthood.
 Febrile:
 Generalized tonic-clonic seizures triggered by
high fever in young children, sometimes with a
familial tendency.
 They are usually short and do not necessarily
indicate epilepsy.
 Generalized

 Status epilepticus:
 Twoor more seizures occur without
recovery of full consciousness between
them
 These
may be partial or primary
generalized, convulsive or
nonconvulsive
 Statusepilepticus is life-threatening and
requires emergency treatment
 Mechanism of action of
antiepileptic drugs
 Antiepileptic
drugs work by blocking voltage-
gated Na⁺ or Ca²⁺ channels, enhancing
inhibitory GABAergic activity, or
reducing excitatory glutamate
transmission.
 Some drugs target multiple mechanisms.
 They help control seizures but do not cure or
prevent epilepsy.
 DRUG CHOICE

 The choice of antiepileptic drugs depends on

seizure classification, patient-specific
factors (age, comorbidities, lifestyle), and
drug characteristics (cost, interactions).
 Partialand generalized seizures may require
different treatments, though some drugs
overlap.
 Drug efficacy varies, so toxicity and
patient factors guide selection.
DRUG CHOICE

 Monotherapy is preferred for newly

diagnosed patients, adjusting as
needed for seizure control or toxicity.
 There will be patients who require a
combination of medications to control
their seizures
 PRIMARY ANTIEPILEPTIC
DRUGS
 The
list of drugs FDA approved since
1990 includes
 Felbamate, gabapentin
 Lacosamide, lamotrigine
 Levetiracetam, oxcarbazepine
 Pregabalin, rufinamide
 Tiagabine, topiramate
 Vigabatrin, zonisamide
 These are labeled as second generation
 Older antiepileptics

 Carbamazepine, divalproex
 Ethosuximide, phenobarbital
 Phenytoin
 Valproic acid
 Several studies have failed to provide
sufficient evidence that the second-
generation drugs are significantly better
than the older agents in terms of efficacy
and lack of adverse effects
Benzodiazepines

 Benzodiazepinesbind to GABA inhibitory

receptors to reduce firing rate
 Diazepam and lorazepam are most often
used as an adjunctive therapy for
myoclonic as well as for partial and
generalized tonic-clonic seizures
 Carbamazepine

 Carbamazepine reduces the propagation of

abnormal impulses in the brain by blocking
sodium channels, thereby inhibiting the
generation of repetitive action potentials
in the epileptic focus and preventing their
spread
 Effective
for treatment of partial seizures
and, secondarily, generalized tonic-clonic
seizures
 Also used to treat trigeminal neuralgia and
 Carbamazepine

 Carbamazepine induces CYP1A2, CYP2C,

CYP3A, and UGT enzymes.
 It is less tolerated in the elderly, with
risks of hyponatremia requiring therapy
adjustment.
A rash may occur early but doesn’t always
necessitate discontinuation.
 Itis contraindicated in absence seizures
as it may worsen them.
 Ethosuximide

 Ethosuximide reduces propagation of

abnormal electrical activity in the brain,
most likely by inhibiting T-type calcium
channels
 Effective
in treating only primary
generalized absence seizures
 Useof ethosuximide is limited because of this
very narrow spectrum of activity
 Felbamate

 Thisdrug acts by blocking voltage-

dependent Na⁺ and Ca²⁺ channels,
inhibiting NMDA glutamate receptors,
and enhancing GABA activity.
 It
inhibits CYP2C19 while inducing
CYP3A4.
 Due to the risk of aplastic anemia and
hepatic failure, it is reserved for refractory
epilepsy, particularly Lennox-Gastaut
syndrome.
 Gabapentin

 Gabapentin is a GABA analog but does

not act on GABA receptors, enhance
GABA activity, or convert to GABA.
 Its exact mechanism is unknown.
 It
is approved as adjunct therapy for
partial seizures and postherpetic
neuralgia.
 Due to its mild side effects, it is well
tolerated in elderly patients with partial
seizures.
 Lacosamide

 Lacosamide stabilizes hyperexcitable

neuronal membranes by affecting voltage-
gated Na⁺ channels and binds to CRMP-2,
though its role in seizure control is unclear.
 Approvedas adjunct therapy for partial
seizures, it can cause euphoria similar to
alprazolam and is classified as a Schedule V
controlled substance.
 Aninjectable form is available, with
dizziness, headache, and fatigue as
 Lamotrigine

 Lamotrigine blocks Na⁺ channels and high-

voltage-dependent Ca²⁺ channels.
 It is effective for partial, generalized, and
typical absence seizures, as well as Lennox-
Gastaut syndrome.
 Lamotrigine is also approved for bipolar
disorder.
 Rapid dose escalation can cause rash, which
may progress to a severe, life-threatening
reaction.
 Levetiracetam

 Levetiracetam is approved for adjunct

therapy in partial onset, myoclonic, and
primary generalized tonic-clonic seizures
in both adults and children.
 Its
exact anticonvulsant mechanism is
unknown, but it binds to the synaptic
vesicle protein SV2A.
 Common side effects include dizziness, sleep
disturbances, headache, and weakness.
 Oxcarbazepine

 Oxcarbazepineis a prodrug converted to

the 10-monohydroxy (MHD) metabolite,
which blocks Na⁺ channels and may
modulate Ca²⁺ channels to prevent
abnormal discharge spread.
 Approved for partial onset seizures in
adults and children, it is a less potent
inducer of CYP3A4 and UGT than
carbamazepine.
 Common side effects include nausea,
Phenobarbital

 Its
primary mechanism of action is
enhancing the inhibitory effects of
GABA-mediated neurons
 Phenobarbital in epilepsy should be
used primarily in the treatment of
status epilepticus
 Phenytoin and
fosphenytoin

 Phenytoin blocks voltage-gated Na⁺

channels and, at high concentrations, also
affects voltage-dependent Ca²⁺ channels.
 Itis effective for partial seizures,
generalized tonic-clonic seizures, and
status epilepticus.
 Phenytoin induces CYP2C, CYP3A
 Smalldose increases can lead to significant
plasma concentration changes and
 Phenytoin and
fosphenytoin
 Gingival hyperplasia,
peripheral neuropathies, and
osteoporosis are potential
side effects of long-term
phenytoin use.
 Fosphenytoin, a prodrug of
phenytoin, can be given
intramuscularly (IM) and
intravenously (IV), whereas
phenytoin sodium should not
be administered IM due to the
risk of tissue damage and
 Pregabalin

 Pregabalin binds to the α2-δ site, an auxiliary

subunit of voltage-gated Ca²⁺ channels in the
CNS, inhibiting excitatory neurotransmitter
release.
 Its exact role in treatment is unclear.
 Itis effective for partial onset seizures,
neuropathic pain (diabetic peripheral
neuropathy, postherpetic neuralgia), and
fibromyalgia.
 Common side effects include drowsiness,
 Rufinamide

 Rufinamide acts on sodium channels and

is approved as an adjunctive treatment
for seizures in Lennox-Gastaut syndrome.
 It is a weak CYP2E1 inhibitor and CYP3A4
inducer, potentially reducing birth control
effectiveness.
 Adverse effects include shortened QT
intervals, making it contraindicated in
familial short QT syndrome.
 Tiagabine

 Tiagabine blocks GABA uptake into

presynaptic neurons, increasing
available GABA for receptor binding
and enhancing inhibitory activity.
 Itis effective in reducing seizures in
patients with partial onset epilepsy.
 Common side effects include fatigue,
dizziness, and gastrointestinal upset.
 Tiagabine is not approved for and
should not be used for any other
 Topiramate

 Topiramate blocks voltage-dependent

sodium channels, enhances GABAA
receptor activity, reduces L-type
calcium currents, and inhibits
carbonic anhydrase.
 It may also affect NMDA receptors.
 Approved for partial and generalized
epilepsy and migraine treatment, it
inhibits CYP2C19 and is induced by
phenytoin and carbamazepine.
 Topiramate

 Coadministrationof topiramate reduces

ethinyl estradiol, so women taking the drug
should be advised to use additional birth
control methods.
 Common adverse effects include
somnolence, weight loss, and
paresthesias.
 Renalstones are more common in topiramate
users compared to the general population,
and glaucoma, oligohidrosis, and
 Valproic acid and
divalproex
 Valproicacid is available as a free acid, while
divalproex sodium is a combination of
sodium valproate and valproic acid, which
is converted to valproate in the
gastrointestinal tract.
 Divalproexwas developed to enhance the
gastrointestinal tolerance of valproic acid.
 Itsmechanisms of action include sodium
channel blockade, inhibition of GABA
transaminase, and action at T-type calcium
Valproic acid and
divalproex
 Effective
for the treatment of partial and
primary generalized epilepsies
 Valproate
inhibits metabolism of the
CYP2C9, UGT, and epoxide hydrolase
systems
 Rare
hepatic toxicity may cause a rise in
hepatic enzymes in plasma, which should
be monitored frequently
 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
 Vigabatrinis associated with adverse
effects resulting in visual field loss
ranging from mild to severe
 Zonisamide

 Zonisamide is a sulfonamide derivative that

blocks both voltage-gated sodium channels
and T-type calcium currents.
 Ithas limited carbonic anhydrase activity
and should be used cautiously in patients with
sulfonamide allergies.
 Zonisamide is approved for partial epilepsy
treatment.
Zonisamide

 Common CNS side effects occur, and it

may also cause kidney stones.
 Oligohidrosis has been reported, so
patients should be monitored for
increased body temperature and
decreased sweating.
 VAGAL NERVE
STIMULATION

 Vagal nerve stimulation (VNS) involves the

surgical implantation of a small pulse
generator with a battery and lead wires
wrapped around the vagal nerve.
 Approved in 1997, it is also used to
treat depression.
 The mechanism of action remains
unknown, but it is thought to influence
seizure control through diffuse
neuronal circuits.
 VAGAL NERVE
STIMULATION

 VNS is effective in treating partial onset

seizures and can reduce drug therapy in
some cases.
 Itserves as an alternative for patients
with drug-resistant conditions, those
sensitive to adverse drug effects, or
those struggling with medication
adherence.
 However,it is a costly and invasive
procedure.
 DEEP BRAIN STIMULATION

 Deepbrain stimulation (DBS) therapy uses a

pacemaker-like device to deliver targeted
electrical stimulation to the anterior
nucleus of the thalamus
 The therapy is FDA approved with conditions
for adjunctive treatment for partial-onset
seizures in adults with medically refractory
epilepsy
 DBSis also FDA approved for treatment of
advanced Parkinson disease and