EPILEPSY

 Epilepsy is a disorder that is best viewed as a symptom of disturbed electrical activity in the
brain, which may be caused by a wide variety of etiologies
 Seizures that are prolonged or repetitive can be life-threatening
 Patients with epilepsy also may display neurodevelopmental delay, memory problems, and/or
cognitive impairment.
 Epilepsy is a chronic disorder characterized by recurrent unprovoked seizures
EPIDEMIOLOGY

 Each year, 120 per 100,000 people in the United States come to medical attention because of
a newly recognized seizure.
 At least 8% of the general population will have at least one seizure in a lifetime. However, it
is common to have a seizure and not have epilepsy
 The rate of recurrence of a first unprovoked seizure within 5 years ranges between 23% and
80%
ETIOLOGY

 Seizures occur because a group of cortical neurons discharge abnormally in synchrony.

Anything that disrupts the normal homeostasis of neurons and their stability can trigger
hyperexcitability and seizures.
 Patients with mental retardation, cerebral palsy, head injury, or strokes are at an increased risk
for seizures and epilepsy.
 Idiopathic etiology is the term used for suspected primary generalized seizures, whereas
cryptogenic etiology is used if no obvious cause is found for partial-onset seizures.
 The incidence of idiopathic epilepsy is higher in children
 Hyperventilation can precipitate absence seizures.
 Sleep, sleep deprivation, sensory stimuli, and emotional stress increase the frequency of
seizures.
 Hormonal changes occurring around the time of menses, puberty, or pregnancy have also
been associated with the onset of or an increased frequency of seizure
PATHOPHYSIOLOGY

 Firing is reflected on EEG as a sharp wave or spike.

 Initially, a small number of neurons fire abnormally. Normal membrane conductances and
inhibitory synaptic currents break down, and excess excitability spreads, either locally to
produce a focal seizure or more widely to produce a generalized seizure
 There are multiple mechanisms that might contribute to synchronous hyperexcitability
including:
 alterations in the distribution, number, type and biophysical properties of ion channels in the
neuronal membranes;
 biochemical modifications of receptors;
 modulation of second messaging systems and gene expression; (4) changes in extracellular
ion concentrations;
 alterations in neurotransmitter uptake and metabolism in glial cells; and (6) modifications in
the ratio and function of inhibitory circuits.
 In addition local neurotransmitter imbalances could be a potential mechanism for focal
epileptogenesis
  transitory imbalances between the main neurotransmitters, glutamate (excitatory) and γ-
aminobutyric-acid (GABA) (inhibitory), and neuromodulators (e.g., acetylcholine,
norepinephrine, and serotonin) might play a role in precipitating seizures in susceptible
patient
 classification
I. Partial seizures (seizures begin locally)
A. Simple (without impairment of consciousness)
1. With motor symptoms
2. With special sensory or somatosensory symptoms
3. With psychic symptoms
B. Complex (with impairment of consciousness)
1. Simple partial onset followed by impairment of consciousness—with or without
automatisms
2. Impaired consciousness at onset—with or without automatisms
C. Secondarily generalized (partial onset evolving to generalized tonic-clonic seizures)
II. Generalized seizures (bilaterally symmetrical and without local onset)
A. Absence
B. Myoclonic
C. Clonic
D. Tonic
E. Tonic-clonic
F. Atonic
G. Infantile spasms
III. Unclassified seizures
IV. Status epilepticus
CLINICAL PRESENTATION

 divided into two main pathophysiologic groups—partial seizures and generalized seizure
 Partial seizures with an alteration of consciousness are described as complex partial (CP)
 A partial seizure that becomes generalized is referred to as a secondarily generalized seizure.
 Generalized absence seizures are manifested by a sudden onset, interruption of ongoing
activities, a blank stare, and possibly a brief upward rotation of the eyes.
 Brief shock-like muscular contractions of the face, trunk, and extremities are known as
myoclonic jerks.
 A sudden loss of muscle tone is known as an atonic seizure.
DIAGNOSIS
Laboratory Tests
 There are currently no diagnostic laboratory tests for epilepsy.
 In some cases, particularly following GTC (or perhaps CP) seizures, serum prolactin levels
can be transiently elevated.
 Other Diagnostic Tests
■ EEG is very useful in the diagnosis of various seizure disorders.
■ An epileptiform EEG is found in only approximately 50% of the patients who have
epilepsy. ■ A prolactin serum level obtained within 10 to 20 minutes of a tonic-clonic seizure
can be useful in differentiating seizure activity from pseudoseizure activity but not from
syncope.
■ Although magnetic resonance imaging (MRI) is very useful (especially imaging of the
temporal lobes), a computed tomography (CT) scan typically is not helpful except in the
initial evaluation for a brain tumor or cerebral bleeding.
PHARMACOTHERAPY
NONPHARMACOLOGIC THERAPY
 Nonpharmacologic therapy for epilepsy includes diet, surgery, and vagus nerve stimulation
(VNS).
 A vagal nerve stimulator is an implanted medical device that is FDA approved for use as an
adjunctive therapy in reducing the frequency of seizures in adults and adolescents older than
12 years of age with partial-onset seizures that are refractory to AEDs.
 It is also used off-label in the treatment of generalized epilepsy.
 VNS changes the cerebrospinal fluid (CSF) concentration of inhibitory and stimulatory
neurotransmitters and activates specific areas of the brain that generate or regulate cortical
seizure activity through increased blood flow
 The VNS device is relatively safe.
 The most common side effect associated with stimulation is hoarseness, voice alteration,
increased cough, pharyngitis, dyspnea, dyspepsia, and nausea. Serious adverse effects
reported include infection, nerve paralysis, hypoesthesia, facial paresis, left vocal cord
paralysis, left facial paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-
grade fever
 Surgery is the treatment of choice in selected patients with refractory focal epilepsy
 The ketogenic diet was devised. It is high in fat and low in carbohydrates and protein and thus
leads to acidosis and ketosis
 Most of the calories are provided in the form of heavy cream and butter, and no sugar is
allowed
PHARMACOLOGICAL TREATMENT

(1) Carbamazepine
 Mechanism of Action The exact mechanism by which carbamazepine suppresses
seizure spread is obscure, although it is believed to act primarily through inhibition of
voltage gated sodium channels
 400 mg/day Because of the auto- and heteroinduction of carbamazepine metabolism,
it is necessary to administer the drug two to four times per day
 Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia,
unsteadiness, dizziness, and headache)
 Leukopenia is the most common hematologic side effect
 Carbamazepine should be considered a firstline therapy for patients with newly
diagnosed partial seizures and for patients with primary generalized convulsive
seizures
(2) Ethosuximide
 Mechanism of Action The exact mechanism of action of ethosuximide remains
elusive, however, it is believed to exert its main action through inhibition of T-type
calcium channels
  500 mg/day, Ethosuximide is still a first-line treatment for absence seizures.
 The most frequently reported side effects are nausea and vomiting
(3) Felbamate
 Mechanism of Action At therapeutic doses felbamate appears to act by blocking N-
methyl-D-aspartate (NMDA) synaptic responses and by modulating GABAA
receptors. At higher doses it may modulate sodium channels and inhibit high-voltage
activated calcium channels
 1,200 mg/day, reserved for patients not responding to other AEDs.
 approved for treating atonic seizures in patients with the Lennox Gastaut syndrome
and is effective in treating patients with partial seizures.
 side effects with felbamate prior to marketing were anorexia, weight loss, insomnia,
nausea, and headache, aplastic anemia and acute liver failure
(4) Gabapentin
 Mechanism of Action Gabapentin was designed to be a GABA agonist but does not
react at the GABA receptor, alter GABA uptake, or interfere with GABA
transaminase. Gabapentin appears to bind to an amino acid carrier protein and
appears to act at a unique receptor. Gabapentin inhibits high-voltage activated
calcium channels
 900 mg/day, second-line agent for patients with partial seizures who have failed
initial treatment.
 Fatigue, somnolence, dizziness, and ataxia are the most frequently reported side
effects. Aggressive behavior has been reported in children
(5) Lamotrigine
 Mechanism of Action A primary mechanism of action for lamotrigine appears to be
inhibition of voltage dependent sodium channels, calcium channels
 25 mg every other day if on VPA; 25–50 mg/day if not on VPA. Valproic acid
substantially inhibits the metabolism of lamotrigine
 Lamotrigine is useful as both adjunctive treatment in patients with partial seizures
and as monotherapy.
 The most frequently reported side effects of lamotrigine include diplopia, drowsiness,
ataxia, and headache.75 Adverse effects are more common when lamotrigine is given
in combination with other AEDs (e.g., diplopia when given concomitantly with
carbamazepine or tremor with valproic acid)
(6) Levetiracetam
 Mechanism of Action : S-enantiomer pyrrolidone derivative, reduction in high-
voltage activated calcium ion (Ca2+) currents and delayed-rectifier potassium ion
(K+) currents
 500–1,000 mg/day, levetiracetam is indicated for patients with partial seizures who
have failed initial therapy.
 Adverse effects appear to be modest, with sedation, fatigue, and coordination
difficulties being the most common CNS effects.
(7) Oxcarbazepine
 Mechanism of Action Oxcarbazepine, which is structurally related to carbamazepine,
is a prodrug that is rapidly converted to a 10-monohydrate derivative (MHD)
 300–600 mg/day, Oxcarbazepine is indicated for use as monotherapy or adjunctive
therapy in the treatment of partial seizures in adults and as monotherapy and
adjunctive therapy in the treatment of partial seizures in patients as young as 4 years
of age with epilepsy. It is also a potential first-line drug for patients with primary
generalized convulsive seizures
  adverse events were dizziness, nausea, headache, diarrhea, vomiting, upper
respiratory tract infections, constipation, dyspepsia, ataxia, and nervousness. In
comparative trials, oxcarbazepine generally caused fewer side effects than phenytoin,
valproic acid, or carbamazepine. Dizziness may be more common in elderly patients
than in young adults
(8) Phenobarbital
 Mechanism of Action Phenobarbital may elevate seizure threshold by interacting with
GABA receptors to facilitate intrinsic chloride channel function, was well as by
blocking high voltage-activated calcium channels
 1–3 mg/kg/day (10–20 mg/kg LD), Phenobarbital is the drug of choice for neonatal
seizure
 CNS side effects are the primary factors limiting the use of phenobarbital. Tolerance
usually develops to initial complaints of fatigue, drowsiness, sedation, and depression
(9) Phenytoin
 Mechanism of Action The primary mechanism of action of phenytoin is believed to
be caused by its ability to inhibit voltage-dependent sodium channels
 PO: 3–5 mg/kg (200–400 mg) (15–20 mg/kg LD), Phenytoin has long been a first-
line AED for primary generalized convulsive and partial seizures
 CNS depressant effects can result in lethargy, fatigue, incoordination, blurred vision,
higher cortical dysfunction, and drowsiness
(10) Pregabalin
 Mechanism of Action Pregabalin’s mechanism of action is unknown, however, it is
proposed that the binding of the drug to the subunit of the voltage-gated calcium
channel may be responsible for a large part of its activity. This binding results in a
decrease in the release of several excitatory neurotransmitters including glutamate,
noradrenaline, substance P, and calcitonin gene-related peptide
 150 mg/day, Pregabalin is a second-line agent for patients with partial seizures who
have failed initial treatment. Pregabalin is also useful in the treatment of chronic
neuropathic pain and generalized anxiety disorder
 Dizziness, somnolence, ataxia, blurred vision, and weight gain are the most
frequently reported side effects
(11) Tiagabine
 Mechanism of Action Tiagabine is a potent and specific inhibitor of GABA uptake
into glial and other neuronal elements. Thus, tiagabine enhances the action of GABA
by decreasing its removal from the synaptic space
 4–8 mg/day,Tiagabine is considered a second-line therapy for patients with partial
seizures who have failed initial therapy
 The most frequently reported adverse effects of tiagabine are dizziness, asthenia,
nervousness, tremor, diarrhea, and depression.
(12) Topiramate
 Mechanism of Action Topiramate is a sulfamate-substituted monosaccharide that has
multiple modes of action involving voltage-dependent sodium channels, GABA
receptor subunits, high voltage calcium channels, and kainate/AMPA subunits.The
drug also inhibits the enzyme carbonic anhydrase
 25–50 mg/day,Topiramate is a first-line AED for patients with partial seizures. The
drug is also approved for the treatment of tonic-clonic seizures in primary
generalized epilepsy
 The main adverse events of topiramate are ataxia, impaired concentration, memory
difficulties, attentional deficits, confusion, dizziness, fatigue, paresthesia,
somnolence, and “thinking abnormally,” which rarely has included psychosis
(13) Valproic Acid/Divalproex Sodium
 Pharmacology and Mechanism of Action Initially it was believed that valproic acid
increased GABA by inhibiting its degradation or by activating its synthesis.
 15 mg/kg (500–1,000 mg),Valproic acid is first-line therapy for primary generalized
seizures such as myoclonic, atonic, and absence seizures. It can be used as both
monotherapy and adjunctive therapy for partial seizures, and it can be very useful in
patients with mixed seizure disorders
 The most frequently reported side effects are gastrointestinal complaints including
nausea, vomiting, and anorexia, as well as weight gain. Pancreatitis is rare
(14) Zonisamide
 Pharmacology and Mechanism of Action Zonisamide, a synthetic 1,2-
benzisoxazole derivative classified as a sulfonamide, inhibition of slow sodium
channels, by blockade of T-type Ca2+ channels, and possibly by inhibition of
glutamate release
 100–200 mg/day,Zonisamide is currently approved for the adjunctive treatment
of partial seizures.
 The most common adverse effects of zonisamide include somnolence, dizziness,
anorexia, headache, nausea, agitation, word-finding difficulties, and irritability.
Adverse effects may be more common during rapid dose escalation.