Epilepsy

INTRODUCTION

• Epilepsy is a common neurologic condition in which a person is prone to

recurrent epileptic seizures.
• There are many types of epilepsies characterized by different seizure types.
• People with epilepsy face many challenges- neurodevelopmental delay,
cognitive impairment, and often suffer from comorbid depression and
anxiety.
• Clinicians treating epilepsy must try to address these common psychosocial
issues and comorbidities.
• Drug therapy should be selected to not only reduce the frequency of
seizures, but also:
✓ minimize side effects
✓ address coexisting health and social conditions
✓ enhancing quality-of-life (QOL)
 ETIOLOGY

• Thousands of medical conditions can cause epilepsy, from genetic mutations

to acquired injury.
• Childhood epilepsy is caused by genetic and/or developmental structural
abnormalities, while at older age is most often acquired structural injury
(stroke or traumatic brain injury).
• Therefore, etiologies generally classified into six categories: (1) genetic; (2)
structural; (3) infectious; (4) metabolic; (5) immune; and (6) unknown.
• Many epilepsies have etiologies that can belong to two or more categories.
• 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.
 Risk Factors and Seizure Triggers
• Risk factors include premature birth with small weight, perinatal injury
(anoxia), history of alcohol withdrawal seizures, history of febrile seizures, and
family history of seizures.
• Two of the best known seizure triggers- hyperventilation and photostimulation
(flashing lights) in certain genetic epilepsies including Juvenile Myoclonic
Epilepsy and Childhood Absence Epilepsy.
• Additional triggers- stress, sleep deprivation, sensory stimuli, and hormonal
changes around the time of menses, puberty, or pregnancy.
• Theophylline, alcohol, high-dose phenothiazines, antidepressants (especially
bupropion), associated with lowering seizure threshold.
 PATHOPHYSIOLOGY

• Alterations of K+, Na+, Ca2+, and Cl– ion channels in

neuronal membranes.
• Upregulation of synaptic vesicle protein 2A, a protein
responsible for the fusion of vesicles to the membrane.
• Alterations in neurotransmitter uptake and metabolism
(vigabatrin, inhibitor of GABA-T).
• Modifications of receptors, second messaging systems
and gene expression, and changes in extracellular ion
concentrations.
• Sprouting and reorganization of neuronal projections in
abnormal tissue or after neuronal injury (head trauma
or stroke) may also lead to increased connectivity
between neurons and a chronic susceptibility to
seizures.
• Therefore, both excitation and inhibitory connections
lie at the pathophysiologic mechanisms.
 Seizures
• A sudden electrical disturbance of the
cerebral cortex.
• Neurons fires rapidly and repetitively for
seconds to minutes.
• Excess of glutamate action and failure of
GABA action, or a combination of the
two.
 Neuronal Mechanisms
• Neurons firing is excessively
prolonged and repetitive.
• Spread to adjacent neurons or
distant.
• Stop spontaneously, because of
brain inhibitory mechanisms.
 Epilepsy
• Epilepsy is the tendency to have recurrent seizure.
• Epilepsy may develop days, months, or years.
• May be a small group of abnormal neurons causes adjacent or connected
normal neurons.
• Occurrence of seizure depends on environmental and internal brain
factors.
• Some causes are sleep loss and fatigue, but it is impossible to determine
what triggers seizure.
 SEIZURE CLASSIFICATION

Generalized Seizures
• Entire cerebral cortex is
involved.
• Referred to as genetic
generalized seizures.
• Tonic-clonic, Absence,
Myoclonic, and Atonic.
Partial Seizures
• Begins in a localized area of
the brain.
• Simple, Complex, and
Secondarily generalized.
 CLASSIFICATION OF EPILEPSIES AND EPILEPSY
SYNDROMES

• The starting point of epilepsy classification is identification of the seizure

type.
• After seizure types are determined, the epilepsy should be classified into
one of 4 categories:
• Common epilepsy syndromes include childhood absence epilepsy (CAE),
juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME).
• They are often grouped together and called the idiopathic generalized
epilepsies (IGEs) or the genetic generalized epilepsies (GGEs).
• Other well-recognized syndromes are West syndrome, Lennox–Gastaut
syndrome (LGS), and Dravet syndrome.
 SEIZURE PRESENTATION AND DIAGNOSIS

Presentation
• Sudden and brief loss of consciousness
• Uncontrolled jerking of muscles
• Sudden falls
• Sudden and brief episodes of confusion
Diagnosis
• Clinical history, including a complete description of the episodes
• Complete neurological physical examination
• Imaging of the brain: preferably a MRI, but a CT of the brain may be used in
absence of a MRI
• Laboratory tests: serum electrolytes, CBC, renal function, and liver function
• EEG recording
• Video-electroencephalogram (VEEG)
 TREATMENT

Desired Outcomes
• Elimination of seizures without adverse effects of the treatment.
• An effective treatment plan to pursue a normal lifestyle with complete
control of seizures (30% to 50% not fully achieve).
• In these cases, the goal of therapy is to provide a balance between reduced
seizure severity or frequency and medication adverse effects, enabling to
have a nearly normal lifestyle.
 General Approach to Treatment
• Selection of appropriate pharmacotherapy depends on distinguishing,
identifying, and understanding different seizure types.
 Nonpharmacologic Therapy
• The most common surgical is temporal lobectomy.
• Less likely to make a patient seizure free include corpus
callosotomy and extratemporal lesion removal.
• Vagal nerve stimulation to treat 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 (butter, heavy cream,
fatty meats) and protein with no added sugar.
 Pharmacologic Therapy

Special Considerations
Michaelis-Menten Metabolism
• Phenytoin metabolism is capacity limited.
• Small changes in doses result in large changes in serum concentrations.
• Too large a dose change may result in toxicity or breakthrough seizures.
• Individual differences in metabolism, result in a different relationship
between dose and serum concentrations.
 Protein Binding
• Phenytoin and valproate, are highly bound to plasma proteins.
• Certain patients have decreased protein binding, resulting in concentration
related adverse effects:
✓ Kidney failure
✓ Hypoalbuminemia
✓ Neonates
✓ Pregnant women
✓ Taking multiple highly protein-bound drugs
✓ Patients in critical care
• When valproate protein binding is altered, the risk for severe dose-related
adverse effects is less compared with phenytoin.
• Hepatic enzymes are able to efficiently metabolize the additional unbound
portion
 Autoinduction
• Carbamazepine increases the metabolism of many drugs, and its own.
• Hepatic enzymes induced over several weeks, necessitating a small initial
dose of carbamazepine (25% to 30% of the typical maintenance dose) 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
• The key to selecting effective pharmacotherapy is to base the decision on the
seizure type.
• For initial treatment of absence seizures, ethosuximide and valproate are
used.
• In absence and myoclonic seizures, carbamazepine, oxcarbazepine,
gabapentin, tiagabine, and pregabalin should be avoided due to association
with worsening of these seizure types.
• Drug therapy should be initiated carefully to minimize adverse events.
• Moderate target doses are chosen until the patient’s response can be further
evaluated.
• If seizures continue, the dose is increased gradually until seizure free or
adverse effects appear.
• In refractory seizures (unresponsive to at least two first-line AEDs) is
somewhat different.
 Complications of Pharmacotherapy
• Adverse effects of AEDs are frequently dose limiting or cause a drug to be
discontinued.
• Two types of adverse effects occur with AEDs: serum concentration-related
and idiosyncratic.
• Concentration-related adverse effects include sedation, ataxia, and diplopia
(less with lamotrigine).
• Idiosyncratic adverse effects include rash (common) and rarely severe skin,
hepatic, or hematological reactions, 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
• Because AEDs are administered for long periods of time, adverse effects due
to prolonged drug exposure are of concern.
• 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 (take Ca & vitamin D).
 Practical Issues
Comorbid Disease States
• Patients with epilepsy often have comorbid disease states.
• Care must be taken, 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 (lamotrigine, carbamazepine, oxcarbazepine) may be useful in
treating depression.
Switching Drugs
• Changing from one AED to another can be a complex process.
• New drug is started at low 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.
 Stopping Therapy
• In seizure free following surgery, medications should be slowly tapered (starting
2 years after surgery).
• Many patients will stay on at least one medication, following successful surgery.
• Discontinuation of AEDs should be done gradually, only after seizure free for 2
to 5 years and with careful consideration of factors predictive of seizure
recurrence:
✓ No seizures for 2 to 5 years
✓ Normal neurologic examination
✓ Normal intelligence quotient
✓ Single type of partial or generalized seizure
✓ Normal EEG with treatment
• Fulfill all of these criteria have a 61% chance of remaining seizure free after
AEDs are discontinued.
• Withdrawal is done slowly, 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.
• Serum concentrations may be helpful in benchmarking a specific response.
• Therapeutic ranges that are often quoted are broad guidelines for dosing,
but should never replace careful evaluation of the patient’s response.
 Drug Interactions
• Most interactions occur due to alterations in absorption, metabolism, and
protein binding.
• Tube feedings and antacids reduce the absorption of phenytoin and
carbamazepine.
• Phenytoin, carbamazepine, and phenobarbital are potent enzyme inducers.
• Valproate is enzyme inhibitor.
• Phenytoin and valproate are highly protein bound and can be displaced with
other drugs.
• When phenytoin and valproate are taken together, may be increased dose-
related adverse effects within several hours.
• This can be avoided by staggering doses or giving smaller doses more
frequently during the day.
 Special Populations
• Children and women have unique problems related to the use of AEDs.
• Control seizures as quickly as possible to avoid interference with
development of the brain and cognition in children.
• Due to rapid metabolic rates seen in children, doses of AEDs are typically
higher on a milligram per kilogram basis compared with adults.
• In women, treatment challenges include 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 if
taking valproate during pregnancy.
• 1 to 4 mg daily of folic acid reduces the risk of birth defects.
• Many AEDs induce hepatic enzymes, thus 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 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 are effective in controlling of
these age group.
 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
• Emergent drug therapy begins with IV administration of a BDZ.
• IV bolus doses of diazepam, lorazepam, and midazolam have been used
because of their rapid effects.
• Lorazepam is the preferred agent of most clinicians.
• Diazepam and lorazepam should be diluted 1:1 with normal saline to avoid
vascular irritation from the propylene glycol diluent.
 Anticonvulsants
• After the first dose of BDZ, 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 (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.