Epilepsy

INTRODUCTION

• Epilepsy is a disorder that afflects 2 million individuals in the

US.
• In developing countries, the incidence is higher at 100 to 190
cases per 100,000 persons per year.
• About 8% of the US population will experience a seizure
during their lifetime.
 ETIOLOGY

• In 80% is unknown and most common causes are head trauma

and stroke.
• Genetic causes in up to 25% of patients, but are often unproven.
• Brain tumors, CNS infections, and neurodegenerative diseases.
• Isolated seizures caused by stroke, CNS trauma and infections,
metabolic disturbances (hyponatremia, hypoglycemia), and
hypoxia.
• Drugs causes are tramadol, bupropion, theophylline, some
antidepressants, some antipsychotics, amphetamines, cocaine,
imipenem, lithium, excessive doses of penicillins or
cephalosporins, and sympathomimetics or stimulants.
 PATHOPHYSIOLOGY

Seizures
• All seizures involve a sudden electrical disturbance of the
cerebral cortex.
• A population of neurons fires rapidly and repetitively for
seconds to minutes.
• Cortical electrical discharges become excessively rapid,
rhythmic, and synchronous.
• An excess of excitatory neurotransmitter action
(glutamate), a failure of inhibitory neurotransmitter action
(GABA), or a combination of the two.
Neuronal Mechanisms
• Neurons firing is
excessively prolonged
and repetitive.
• Spread to adjacent
neurons or distant.
• Nearly all seizures stop
spontaneously,
because brain
inhibitory mechanisms
overcome the
abnormal excitation.
Epilepsy
• Epilepsy is the tendency to have recurrent, unprovoked
seizures or persons with a single seizure, if they have at
least a 70% chance of having another seizure.
• Epilepsy may develop days, months, or years after a brain
insult.
• May be a small group of abnormal neurons causes adjacent
or connected normal neurons.
• Occurrence of an individual seizure depends on an interplay
of environmental and internal brain factors.
• Some causes of seizures are sleep loss and fatigue, but it is
impossible to determine what triggers a specific seizure.
 SEIZURE CLASSIFICATION

• Primary Generalized Seizures

• If the entire cerebral cortex is involved in the seizure, it is
classified as primary generalized.
• This category is now referred to as “genetic generalized
seizures,” the apparent cause of most of these syndromes.
• Types of primary generalized seizures are: Tonic-clonic,
Absence, Myoclonic, and Atonic.
Partial Seizures
• When the seizure begins in a localized area of the brain, it is
defined as partial.
• There are three types of partial seizures in the current
classification system: Simple, Complex, and Secondarily
generalized.
 SEIZURE PRESENTATION

• Episodes of sudden and

brief loss of consciousness
• Episodes of uncontrolled
jerking of groups of
muscles
• Sudden unexplained falls
• Sudden and brief episodes
of confusion
 TREATMENT

Goals of Therapy
• Elimination of all seizures without adverse effects of the
treatment.
• An effective treatment plan allows the patient to pursue a
normal lifestyle with complete control of seizures.
• 30% to 50% of patients are not able to fully achieve these
outcomes.
• In these cases, the goal of therapy is to provide a tolerable
balance between reduced seizure severity and/or frequency
and medication adverse effects, enabling the individual to
have a lifestyle as nearly normal as possible.
NonpharmacologicTherapy
• The most common surgical approach for epilepsy is temporal
lobectomy.
• Less likely to make a patient seizure free include corpus
callosotomy and extratemporal lesion removal.
• Vagal nerve stimulation to treate all types of seizures (an unit
that generates an intermittent electrical current is placed
under the skin in the chest).
• Ketogenic diet produces a keto-acidotic state through the
elimination of nearly all carbohydrates.
• The diet consists of dietary fats (eg, butter, heavy cream, fatty
meats) and protein with no added sugar.
• Daily urinalysis for ketones is performed to ensure the patient
remains in ketosis.
Pharmacologic Therapy
Special Considerations
• Phenytoin metabolism is capacity limited.
• The clinical significance is that small changes in doses result in
large changes in serum concentrations.
• Too large a dose change may result in concentration-related
toxicity or breakthrough seizures.
• Individual differences in metabolism, result in a different
relationship between dose and serum concentrations.
• Some AEDs, especially phenytoin and valproate, are highly
bound to plasma proteins.
• Normally, 88% to 92% of phenytoin is bound to plasma
protein, leaving 8% to 12% as unbound.
• Certain patient groups have decreased protein binding,
resulting in increased concentration related adverse effects:
• Kidney failure
• Hypoalbuminemia
• Neonates
• Pregnant women
• Taking multiple highly protein-bound drugs
• Patients in critical care
• Carbamazepine is a potent inducer of hepatic microsomal
enzymes and increases the rate of metabolism for many other
drugs, and the rate of its own metabolism.
• Hepatic enzymes become maximally induced over several
weeks, necessitating a small initial dose of carbamazepine
(25% to 30% ) that is increased over time to compensate for
the enzyme induction.
• The dosage is increased weekly until the target maintenance
dose is achieved within 3 to 4 weeks.
Drug Selection and Seizure Type
• Antiepileptic drug therapy should usually be initiated
carefully to minimize adverse events.
• Moderate target doses are chosen until the patient’s
response can be further evaluated in the clinic.
• If seizures continue, the dose is increased gradually until the
patient becomes seizure free or adverse effects appear.
• Treatment of refractory seizures (ie, unresponsive to at least
two first-line AEDs) is somewhat different.
Complications of Pharmacotherapy
• Common concentration-related adverse effects include
sedation, ataxia, and diplopia (less with lamotrigine).
• Idiosyncratic adverse effects are not dose or concentration
related.
• Rash is the most common and also severe skin, hepatic, or
hematological reactions occur rarely, but are potentially life-
threatening (discontinue).
• Carbamazepine, phenytoin, phenobarbital, valproate,
lamotrigine, oxcarbazepine, and felbamate are most likely to
cause reactions.
• Possibility of cross reactivity for carbamazepine, phenytoin,
phenobarbital, and oxcarbazepine.
Chronic Adverse Effects
• Some chronic adverse effects with AEDs include peripheral
neuropathy and cerebellar atrophy.
• Extensions of acute adverse effects, for example, weight gain.
• Osteoporosis is a major chronic adverse effect of several
drugs.
• Carbamazepine, phenytoin, phenobarbital, oxcarbazepine,
and valproate decrease bone mineral density, after 6 months
of treatment (take supplemental calcium and vitamin D).
Practical Issues
• Care must be taken when treating comorbid conditions, as
numerous drugs can interact with AED.
• Depression is common in patients with epilepsy.
• Most AEDs can exacerbate depression, and patients should be
warned to watch for mood changes.
• Some AEDs (eg, lamotrigine, carbamazepine, oxcarbazepine)
may be useful in treating depression.
• Chose an agent that is unlikely to increase seizures and does
not interact with AEDs.
• Changing from one AED to another can be a complex
process.
• The new drug is started at a low initial dose and gradually
increased over several weeks.
• Once the new drug is at a minimally effective dose, the drug
to be discontinued is gradually tapered while the dose of the
new drug continues to be increased to the target dose.
• Some patients who are seizure free may desire to
discontinue their medications.
• Patients who become seizure free following surgery for
epilepsy may have medications slowly tapered starting 2
years after surgery.
• Many patients will choose to stay on at least one
medication, following successful surgery, to ensure they
remain seizure free.
• Discontinuation of AEDs should be done gradually, only after
the patient has been seizure free for 2 to 5 years:
• No seizures for 2 to 5 years, Normal neurologic examination,
Normal intelligence quotient, Single type of partial or
generalized seizure and Normal EEG with treatment
• Individuals who fulfill all of these criteria have a 61% chance
of remaining seizure free after AEDs are discontinued.
• Additionally, there is a direct relationship between the
duration of seizure freedom with medications and the
chance of remaining seizure free after medications are
withdrawn.
• Withdrawal of AEDs is done slowly, usually with a tapering
dose over at least 1 to 3 months.
Dosing
• Dosing of AEDs is determined by general guidelines and
response of the patient.
• Therapeutic ranges that are often quoted are broad
guidelines for dosing, but should never replace careful
evaluation of the patient’s response.
Drug Interactions
• Tube feedings and antacids are known to reduce the
absorption of phenytoin and carbamazepine.
• Phenytoin, carbamazepine, and phenobarbital are potent
inducers of CYP450 but alproate is a CYP450 and UDP-
glucuronosyltransferase (UGT) inhibitor.
• Phenytoin and valproate are highly protein bound and can be
displaced when taken together or with other highly
proteinbound drugs.
• For example, when phenytoin and valproate are taken
together, there may be increased dose-related adverse effects
within several hours of dosing.
• This can be avoided by staggering doses or giving smaller
doses more frequently during the day.
Special Populations
• In children, developmental changes occur rapidly, and
metabolic rates are greater than those seen in adults.
• Control seizures as quickly as possible to avoid interference
with development of the brain and cognition.
• Due to rapid metabolic rates seen in children, doses of AEDs
are typically higher on a milligram per.
• For women, the treatment of epilepsy poses challenges,
including teratogenicity, breastfeeding, interactions between
AEDs and hormonal contraceptives, and reduced fertility.
• Neural tube defects (spina bifida, microcephaly, anencephaly)
are associated most commonly with valproate and possibly
carbamazepine.
• Valproate is associated with impaired cognitive development
in children born to women taking valproate during pregnancy.
• All women of childbearing potential who take AEDs should
take 1 to 4 mg daily of supplemental folic acid to reduce the
risk of birth defects.
• Many AEDs induce hepatic enzyme systems and reduce the
effectiveness of hormonal contraceptives (use other forms of
birth control).
• Serum concentrations of many AEDs, drop during pregnancy,
and dose increases based on frequent serum concentration
monitoring is necessary.
• Valproate has been associated with a drug-induced polycystic
ovarian syndrome.
• The highest incidence of seizures and epilepsy is in individuals
older than 65 years.
• Cerebrovascular disease, tumors, trauma, and
neurodegenerative diseases are the primary causes of
epilepsy in this age group.
• Carbamazepine, lamotrigine, and gabapentin have been
studied in older adults, and all are effective in controlling.
 Status Epilepticus

• Status epilepticus (SE) is a neurologic emergency that can

lead to permanent brain damage or death.
• SE is defined as continuous seizure activity lasting more than
5 minutes or two or more seizures without complete recovery
of consciousness.
• Refractory status epilepticus (RSE) is unresponsive to
emergent (first-line) or urgent (second-line) therapy.
• Decreased GABAA-receptor response and increasing
neuronal injury with prolongation of seizure activity
necessitates rapid control of SE.
 TREATMENT

Benzodiazepines
• Initial or emergent drug therapy begins with IV
administration of a benzodiazepine.
• Intravenous bolus doses of diazepam, lorazepam, and
midazolam have been used in SE because of their rapid
effects on GABA receptors.
• Lorazepam is the preferred agent of most clinicians.
• Diazepam and lorazepam should be diluted 1:1 with normal
saline before parenteral administration via peripheral veins
to avoid vascular irritation from the propylene glycol diluent.
Anticonvulsants
• After administering the first dose of benzodiazepine, an AED
such as phenytoin, valproate sodium, or phenobarbital
should be started to prevent further seizures (urgent
therapy).
• AEDs must not be given as first-line therapy since they are
infused relatively slowly to avoid adverse effects, delaying
their onset of action.
• If the underlying cause of the seizures has been corrected
(eg, hypoglycemia) and seizure activity has ceased, an AED
may be unnecessary.
• After the AED LD is administered, maintenance doses should
be initiated to ensure that therapeutic levels are sustained.