Seizure Disorders Patty Ghazvini, PharmD., CGP Associate
Professor of Pharmacy Practice Florida A&M University
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Case Presentation My son had his first seizure at 21 years old.
His seizures are horrible; they last around 15 minutes, and he has
a postictal period anywhere from 1-10 or so hours. During these
postictal periods, he arches his back and moans or cries or
sometimes screams. He also tends to hurt himself. He had 40
stitches in both his hands after a seizure this last summer. He is
having seizures, what seems to us, in a pattern. He will have them
almost to the day every other month. The doctors say he isn't a
"text book" epileptic. They don't know how to medicate him. He has
been on Keppra for almost three years. They just decided to finally
try another med last week and he will be starting Dilantin. He had
a terrible allergic reaction to Depakote. We are really hoping that
the Dilantin will give him a break for at least longer than a
month.
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Definitions Seizure an uncontrolled paroxysmal discharge of the
CNS that interferes with normal function. Epilepsy repeated
occurrence of any of the various forms of seizures. Prodrome mood
or behavior changes that precedes a seizure. Aura localized symptom
that be the first part of a seizure Tonic A sustained muscular
contraction Clonic- intermittent muscular contractions and
relaxation
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Seizures Can cause involuntary changes in body movement,
sensation, awareness, or other functions Sudden attacks of
involuntary movements or convulsions, brief losses of awareness
Auras precede an impending seizure; patient may just not feel right
or may have other symptoms: abnormal smell, taste or visual
symptoms Postictal symptoms headache, confusion, generalized muscle
ache, drowsiness, incontinence
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Incidence Between 0.3-0.7% of the US population >200,000
Americans have a seizure more than once a month Generalized
seizures are more common in children; partial seizures are more
common in adults. Incidence of partial seizures remains constant at
20 per 100,000 population from infancy until age 65 years when it
increases sharply.
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Pathophysiology Initially a small number of neurons will fire
abnormally, however, there is a break down of normal membrane
conductance and inhibitory mechanisms which leads to the spread of
the excitability either to a local area or widespread generalized
area. Dramatic increase in metabolic needs. The brain will consume
more oxygen than the vasculature can supply which can lead to brain
damage.
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Factors Leading to Membrane Instability Ion channel
abnormalities Abnormal Potassium conductance Defective voltage
sensitive ion channels Deficiency in membrane sodium potassium
pumps Increase in Neurotransmitters that enhance excitability
Acetycholine, glutamate, norepinephrine, histamine, aspartate.
Deficiency in Inhibitory Neurotransmitters Dopamine, GABA
Abnormalities in serum pH can lead to seizures due to the fact that
normal neuronal activity depends on adequate supplies of glucose,
electrolytes, oxygen and amino acids.
Classification of Seizures Generalized seizures (absence,
myoclonic, generalized tonic-clonic) - widespread regions of the
brain Partial (focal) seizures - originate in a localized area of
the cerebral cortex Further, seizures can be divided into simple or
complex seizure depending on whether consciousness is altered
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Generalized Seizures Absence patients are usually unaware of a
lapse in concentration or awareness Myoclonic single, rapidly
recurrent, bilaterally shock-like jerks to the face, trunk and
extremities Tonic Clonic (grand mal) - vision, taste, smell, or
sensory changes, hallucinations, or dizziness before the seizure;
muscle rigidity, followed by violent muscle contraction, and loss
of consciousness. * Other symptoms that occur during the seizure
may include: - Biting the cheek or tongue - Clenched teeth or jaw -
Loss of urine or stool control (incontinence)
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Partial Seizures Originate in single area of one hemisphere.
May progress to generalized seizures Simple Last 10-20 seconds.
Consciousness is not impaired Presence of automatisms Complex
Consciousness is lost Lasts 1-2 minutes May experience an aura More
likely to progress to generalized seizures.
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Absence Seizures Characterized by short frequent lapses in
Consciousness Motor and speech activity Last 5-20 seconds Typically
present in children ages 4-8 Occur more frequently in girls than
boys. Child will typically present with history of decline in
school work.
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Myoclonic Seizures Bilateral synchronous single jerk of the
extremities. Typically occurs in the arms Most often occurs while
falling asleep or waking up.
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Tonic-Clonic Seizures Sudden loss of consciousness Contractions
Perioral cyanosis Loss of bladder control Post ictal state Deep
sleep Headache Lasts 30-60 minutes
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Atonic Seizures Sudden loss of muscle tone and subsequent
falling or dropping to the floor unprotected. Drop attacks
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Infantile Spasms Characterized by Recurrent brief myoclonic
seizures lasting ~ 2 seconds. Flexion, extension or a mixed pattern
involving the trunk, neck and limbs Unknown cause Male predominant
May be a family history Presents during the first year of life
Prognosis is poor Can be misdiagnosed as the colic because the
seizures cause flexion at the waist.
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Lennox-Gestaut Syndrome Presents in preschool age children
Mixture of seizure types Myoclonic, generalized, tonic-clonic,
absence, partial, atonic High seizure frequency Difficult to
control High incidence of status epilepticus 40-80 % will be
severely mentally retarded.
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Status Epilepticus Any seizure lasting more than 5 minutes or
two or more discrete seizures between which there is incomplete
recovery of consciousness. Pediatric neurological emergency May
occur as a result of acute cerebral insult or as the first
manifestation of a ongoing seizure disorder. Early treatment is
essential The longer the seizure persist the more difficult it is
to control and the higher the mortality.
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Evaluation of Seizures and Epilepsy History Medical history
Physical examination
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History of the event Descriptive information of a spell -
Prodrome - Loss or alteration of consciousness - Characteristics of
motor movements - Automatism - Tongue laceration, urinary or fecal
incontinence - Duration of event - Postictal symptoms - Confusion -
Duration - Postictal focal neurologic deficits
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Medical History Medical and surgical history Current medication
use Family history of seizures in affected family members Social
history: alcohol and substance abuse
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Electroencephalography (EEG) Samples electrical activity of the
brain Only test of functional excitability of the brain Neuronal
discharges are characterized by spikes and sharp waves. Recording
obtained over 20-30 minutes, patient is encouraged to sleep.
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Goals of Therapy Suppress seizures completely without causing
intolerable side effects Initial treatment with and AED achieves
these goals in 70% of patients Prognosis for seizure control in the
other 30% is less favorable and may require numerous trials of
AEDs, either as monotherapy or combination.
Overview Older AEDs such as carbamazepine, valproic acid, and
phenytoin remain the first line therapy in most seizure types.
Exception is absence seizures Ethosuximide is the drug of choice
New AED are generally used as add on therapy for children who have
refractive seizures. Dosages are adjusted according to patient
response and/or serum concentrations
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Overview Anticonvulsants are thought to carry an increased risk
of suicidal ideation and behavior Patients and caregivers should be
informed of the increased risk of suicidal thoughts and behaviors
and should be advised to immediately report the emergence or
worsening of depression, the emergence of suicidal thoughts or
behavior, thoughts of self-harm, or other unusual changes in mood
or behavior.
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Differences between the Generations First generation - Lack of
tolerability in some patients due to side effects - Neurotoxicity -
Teratogenicity - Therapeutic monitoring - Drug interactions Second
generation - Improved tolerability - Multiple mechanisms - Less
weight gain - Fewer endocrine effects - Less drug interactions
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Limitations with 1st Generation Anticonvulsants Enzyme
Induction/Inhibition Cognitive impairment Metabolic Products
CBZ-epoxide, hyperammonaemia Hematological Disorders bone marrow
depression, thrombocytopenia Cosmetic Side Effects
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2nd Generation Anticonvulsants No required therapeutic
monitoring Fewer Drug Interactions Adjunct therapy &
monotherapy; Indicated for partial seizures with or without
generalization Orally administered Not used for Status Epilepticus
Used Outside of the Box
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Partial Seizures First Line Therapy Carbamazepine or
Oxcarbazepine Given as monotherapy Second Line Therapy Phenytoin or
Depakote Given as monotherapy or in combination with a first line
agent. Adjunct Therapy Gabapentin, Lamotrigine, Topiramate Should
be used after failure with preferred agents
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Absence Seizures First Line Therapy Valproic Acid, Ethosuximide
Second line therapy Clonazepam, Lamotrigine
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Myoclonic Seizures First Line Therapy Valproic Acid Second Line
Therapy Lamotrigine Third Line Therapy Phenytoin, Carbamazepine,
Oxcarbazepine Adjunct Therapy Clonazepam, Ethosuximide
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Tonic-Clonic, Atonic Seizures First Line Agents Carbamazepine,
Valproic Acid, Oxcarbazepine Second Line Agent Phenytoin Third Line
Agents Lamotrigine, Topiramate Atonic Seizures Valproic Acid or
Clonazepam
Carbamazepine ( Tegretol ) MOA: limits the influx of sodium
ions Therapeutic Serum Concentrations 4-12 mg/L Administration The
solution should be given 3-4 times a day Tablets may be given 2-4
times a day Do not mix the solution with other medications it may
decrease the effect. Suspension will produce a higher peak level
than tablets at the same dose Start suspensions at the lower dosage
range and titrate slowly to avoid ADE. Side Effects Hyponatremia,
sedation, rash, blood dyscrasias, hepatotoxicity,
photosensitivity
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Oxcarbazepine ( Trileptal ) MOA: B lock Na+ channels inhibiting
repetitive neuronal firing and stabilizing neuronal membranes Cross
hypersensitivity can occur with carbamazepine ( 20-35%) Monitor
sodium levels in person who receive other medications that also
alter sodium levels. Suspension is stable for 7 weeks after opening
the bottle Side Effects Sedation, ataxia, nausea, hyponatremia
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Valproic Acid ( Depakote ) MOA: increases GABA availability and
action Therapeutic Serum Concentrations 50 100 mg/L Should not be
used in children < 2 years. Increased risk of developing fatal
hepatotoxicity Do not substitute Depakote ER for Depakote May take
with food. Do not administer with carbonated drinks Do not give the
tablet with milk Depakote Sprinkles may be sprinkled on food and
swallowed immediately. Do not chew or crush. Side Effects
Hepatotoxicity,, Tremors, Hyperammonemia, alopecia, weight gain,
thrombocytopenia, pancreatitis.
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Phenytoin ( Dilantin ) MOA: Increases efflux or decreases the
influx of sodium across the cell membrane. Therapeutic Serum
Concentrations Neonates 8-15 mg/L Children 10-20 mg/L Use with
caution in neonates Capsules and suspension contain Sodium Benzoate
and may cause gasping syndrome. Food may affect absorption
depending on formulation. High fat meals decrease the rate of
absorption of Dilantin Kapseals and decreases the bioavailability
of generic extended release phenytoin sodium. Administer at the
same time with regard to meals Separate the doses of other
medications or tube feedings by 2 hours. Side Effects Ataxia,
sedation, cognitive impairment, visual disturbances,hirsutism
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Gabapentin ( Neurontin ) MOA: GABA agonist activity
Neuropsychiatric ADEs have occurred in pediatric population
Hostility, aggressive behaviors Do not discontinue abruptly; taper
over at least one week Oral Solution must be refrigerated Side
Effects Somnolence, ataxia, dizziness, weight gain
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Lamotrigine ( Lamictal ) MOA: affects voltage regulated sodium
channels and inhibits the presynaptic release of glutamate and
aspartate Potential to cause rash (Steven-Johnson Syndrome); risk
factors are Young age, concurrent VPA therapy, high initial dose,
rapid titration Occurs as a result of a toxic arene oxide
intermediate metabolite which is produced through the P450
pathway
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Topiramate ( Topamax ) MOA: Thought to block sodium channels,
potentiate GABA and inhibit the activation of glutamate. May cause
an ocular syndrome characterized by acute angle closure glaucoma
Typically occurs within 1 month of initiation of therapy. Advise
patients to report any blurred vision to physician immediately May
cause kidney stones Parents should report any pain upon urination
Tablets may be crushed, mixed with water and administered
immediately Sprinkle capsules should not be chewed.
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Zonisamide (Zonegran) Approved for adjunctive treatment of
partial seizures in adults with epilepsy Blocks sodium channels,
thereby stabilizing neuronal membranes Used off-label in children
Adverse effects: hypothermia and oligohydrosis, kidney stones
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Felbamate ( Felbatol ) MOA: regulates Na, enhances GABA
Asssociated with aplastic anemia and hepatotoxicity. Currently FDA
recommends that it only be used in patients who have failed therapy
with all other AEDs and who have such severe epilepsy that the
benefits outweigh the risk. Weekly or biweekly monitoring of CBC
and Liver Function tests are recommended with use.
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Tiagabine (Gabitril) Indicated for the adjunctive treatment of
partial seizures Inhibits the reuptake of GABA, the major
inhibitory neurotransmitter in the CNS. Side Effects: mostly GI
(diarrhea, nausea, abdominal pain)
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Levetiracetam (Keppra) FDA-approved as adjunctive therapy for
adults and children 4 years of age and older with partial seizures
FDA-approved for adults and children 6 years of age and older with
primary generalized tonic-clonic seizures FDA-approved for adults
and adolescents greater than 12 years of age with myoclonic
seizures.
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Vigabatrin (Sabril) Structural analog of GABA and was designed
to inhibit the metabolism of GABA First drug to be FDA approved for
the treatment of infantile spasms Also FDA-approved for adjunctive
therapy in the treatment of adults with refractory complex partial
seizures. Due to the risk of permanent vision loss, vigabatrin is
only available through a restricted distribution program called
SHARE.
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Clonazepam (Klonopin) Benzodiazepine Treats myoclonic, atonic
and absence seizures resistant to other drugs SE: drowsiness,
ataxia Withdrawal symptoms can occur after abrupt
discontinuation
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Pregabalin (Lyrica) Binds to voltage-gated calcium channel and
results in a decrease in the release of several excitatory
neurotransmitters More potent than gabapentin Minimal CNS side
effects; no drug interactions May cause weight gain and edema FDA
approved for fibromyalgia
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Rectal Diazepam (Diastat) Approved for use in the treatment of
increased seizure activity in patients taking other antiepileptic
drugs Diastat AcuDial supplied as a prefilled syringe with either
10mg or 20mg for single-dose administration by the caregiver.
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Treatment of Refractory Epilepsy Epilepsy Surgery
Electroconvulsive Therapy Vagus Nerve Stimulation Ketogenic
Diet
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Status Epilepticus Continuous or intermittent seizures lasting
more than 5 minutes, without full recovery of consciousness between
seizures. Therapeutic principles: time is brain If a treatment
fails, there should be no interval between the end of a failed
protocol and the initiation of next therapy
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First-Line Therapies Benzodiazepines IV diazepam (0.2 mg/Kg
given at 5mg/min) and lorazepam (0.1 mg/kg given at 2 mg/min)
Phenytoin limitation is the rate at which it can be delivered
Fosphenytoin prodrug of phenytoin; can be infused at rates faster
than phenytoin; less vascular irritation; can be given IM
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Other First-Line Therapies Valproate Phenobarbital Works on the
GABA receptors; causes profound respiratory depression and
hypotension
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Refractory Status Epilepticus Failure of adequate amounts of
two IV drugs to stop seizures. Add enough anticonvulsant to reach a
high therapeutic or low toxic serum anticonvulsant concentration
Should be no hesitation to depress respiration and intubate, but
severe arterial hypotension should be avoided since it will curtail
cerebral blood flow.
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Refractory Status Epilepticus Midazolam continuous infusion due
to short duration of action; less hyptonsion Propofol GABA agonist;
immediate suppression of seizure activity Anesthetic Barbiturates
Pentobarbital and thiopental
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Seizure First Aid Remain calm Put pillow under head, turn
person on their side, and loosen tight clothing DO NOT put anything
in mouth DO NOT restrain the person Clear the area
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New Drugs? Rufinamide (Banzel) approved for treatment of
seizures associated with Lennox-Gestaut syndrome in patients 4
years of age and older Lacosamide (Vimpat) IV or PO use as add-on
therapy in adults with partial- onset seizures.
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Role of the Pharmacist Improve compliance - Education - Refer
to patient support groups - Reinforce importance of treatment -
Provide written instructions