Seizure Management and Treatment Flashcards
Seizure
Disorder viewed as a symptom of disturbed electrical activity in the brain
* A disruption of homeostasis of neurons and their stability, which may trigger hyperexcitability
Epilepsy
A chronic disorder of recurrent, unprovoked seizures
What are some medications that may cause seizures?
- Sub-therapeutic anti-epileptic drug (AED) levels
- Withdrawal of CNS depressants
- Antibiotics
- Bupropion
- SSRIs
- Theophylline
- Meperidine (especially with renal dysfunction)
- Overdose
What medications can you overdose to cause seizures?
- Effexor
- Tri-cyclic antidepressants
- Salicylates
- Tramadol
Partial (focal) seizures
- Begin in one hemisphere and result in asymmetric motor manifestation
- Can manifest as changes in motor function, sensory, or somatosensory symptoms, or automatisms
Generalized seizures
Clinical manifestaions tha indicate involvement of both hemisphere
* Loss of consciousness
* There are 6 types
Automatism
A set of brief unconscious behaviors (lip smacking or finger rubbing)
Simple partial seizure
Without loss or change of consciousness
Complex partial seizure
With loss or change of consciousness
Secondary generalization
Partial onset which evolves into generalized tonic-clonic seizure
Absence (Generalized) seizure
- Sudden onset, interruption of ongoing activities, blank stare, possibly brief upward rotation of the eyes
- Commonly occurs in young children through adolescence
Myoclonic (Generalized) seizure
Brief shock-like contractions of the face, trunk, and extremities
Clonic (Generalized) Seizure
Rhythmic contractions
Tonic (Generalized) Seizure
Contraction of muscles into a rigid position
Tonic-clonic (Generalized) Seizure
- Sudden sharp contractions followed by a period of rigidity
- Patients may moan, cry, lose sphincter control, bite the tongue, develop cyanosis
Atonic (Generalized) Seizure
- Sudden loss of muscle tone
- Patients often wear protective head gear
Status Epilepticus (SE)
- A neurologic emergency that can be associated with brain damage and death
- ≥ 5 minutes of continuous seizures, or
- ≥ 2 discrete seizures between which there is incomplete recovery of consciousness
Febrile Seizures
- Occurs primarily in children between 6 months and 6 years (majority between 12-18 months)
- Seizures often develop as the temperature is increasing rapidly but may develop as the fever is declining
- Can occur during both viral and bacterial infections
- Majority have febrile seizures on 1st day of illness
What are the four factors in a prospective cohort study that INCREASE the recurrence risk?
- Young age at onset
- History of febrile seizures in a first-degree relative
- Low degree of fever while in the emergency department
- Brief duration between the onset of fever & initial seizure
Traumatic Brain Injury (TBI)
- Seizures are a complication of TBI
- The more severe the head injury, the longer the patient is at risk for late seizures
Electroencephalogram (EEG)
- Can be an important diagnostic test in evaluating a patient with possible epilepsy/seizures
- Measures the electrical activity of the brain
What is the pathophysiology of seizures?
- From excessive excitation of a large population of cortical neurons (reflects as a sharp wave or spike on the EEG)
- Normal membrane conductance & inhibitory synaptic currents break down
What do the clinical manifestations of seizures depend on?
- Site of focus
- Degree of surrounding brain area irritability
- Intensity of the impulse
What are the mechanisms that may contribute to synchronous hyperexcitability?
- 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
- Changes in extracellular ion concentrations
- Alterations in neurotransmitter uptake and metabolism
- Modifications in the ratio and function of inhibitory circuits
What are the mechanisms of control of abnormal neuronal activity by AEDs?
- Elevating the threshold of neurons to electrical or chemical stimuli
- Involves stabilization of neuronal membranes
- Limiting the propagation of the seizure discharge from the origin
- Depression of synaptic transmission and reduction of nerve conductance
Why should you initiate AED after a 1st seizure?
- Epileptiform abnormalities on EEG
- Remote symptomatic cause, as identified by clinical history or neuroimaging
- Abnormal neurologic examination, including focal findings
- Treatment is generally started after 2nd seizure
- Seizure recurrence indicates on INCREASE risk for additional seizures
How should you discontinue AEDs?
- May be considered by a neurologist after a 2-4 year seizure free interval
- Recommend tapering at 25% of the dose monthly
- If patient is one more than one AED, stop the medication that is less appropriate for the seizure type or the agent responsible for ADE
What are some factors that increase the risk of seizure recurrence?
- History of high frequency seizures
- Repeated episodes of status epilepticus
- A combination of seizure types
- Development of abnormal mental functioning
- Identifiable brain disease (e.g., brain tumor, congenital malformation, encephalomalacia)
- Abnormal neurologic examination
- Seizure onset after the first decade
- Poor initial response to treatment
- Combination therapy at the time of withdrawal
- Selected epilepsy syndromes (especially juvenile myoclonic epilepsy)
- Abnormal electroencephalogram (EEG)
- Family history of epilepsy
What are some considerations for the Elderly?
- Drug interactions
- Hypoalbuminemia is common
- Some AEDs (phenytoin, valproic acid, tiagabine) bound to albumin which makes monitor difficult
- Increase in fat, decrease in total body water
- Affect volume of distribution of drugs
What are some considerations for the Neonates/infants?
- Increase in total body water to fat ratio
- DECREASE in serum albumin and alpha-glycoprotein (results in volume of distribution changes)
- Newborn up to 2-3 years have decreased renal elimination and hepatic function
What are some considerations for the Women?
- Highest seizure vulnerability b/c estrogen is a seizure activating effect
- Just before and during the menstruation
- At ovulation
What are some Pregnancy category D medications?
- Phenytoin
- Carbamazepine
- Valproic acid
- Phenobarbital
What drugs affect hormonal contraception?
Enzyme inducing AEDs
Older AEDs:
* Phenytoin, phenobarbital, carbamazepine
Newer agents:
* Felbamate, topiramate, oxcarbazepine
What are some drug inducers?
- Carbamazepine
- Phenytoin
- Phenobarbital
What are some drug inhibitors?
Valproic acid
What are some drug inhibitors and inducers?
- Felbamate
- Oxcarbamazepine
- Topiramate
Clobazam MOA
Benzodiazepine
-Involves potentiation of GABAergic neurotransmission from binding at the benzodiazepine site of the GABA receptor
What is the place of therapy Clobazam?
Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older
What are the adverse effects of Clobazam?
- Somnolence and/or sedation
- WARNING: Abrupt withdrawal should be avoided
What are the counseling points of Clobazam?
- Controlled substance Category IV
- Pregnancy Category C
- Need medication guide
What is the place of therapy of Ethosuximibe?
First line treatment for absence of seizures
What is the therapeutic level of Ethosuximibe?
40-100 mg/dL
What is the adverse effect of Ethosuximibe?
Cutaneous Reaction:
-Urticaria, rash, Stevens-Johnson syndrome, systemic lupus erythematosus
-N/V/D/weight loss
-Aplastic anemia
-Drowsiness, fatigue, ataxia
What is the place of therapy of Ezogabine?
-Adjunctive agent for partial seizures
-Known internationally as Retigabine
What is the adverse effect of Ezogabine?
-Dizziness (32%), somnolence (27%), urinary retention (2%)
Warnings:
-QT-interval prolongation has been reported within 3 hours of administration; monitoring recommended
What are some counseling points of Ezogabine?
- REMS for urinary retention and symptoms of acute urinary retention
- Medication Guide
What is the placeof therapy of Felbamate?
Reserved for patients not responding to other AEDs
What is the adverse effect of Felbamate?
-Aplastic anemia and acute liver failure
* Patient or guardian must sign a consent form
What is the place of therapy of Gabapentin?
-Second line agent for partial seizures +/- generalizations
-Possibly a role in the treatment of less severe seizure disorders such as new onset partial epilepsy
-Highly used for off-label indications: Neuropathic pain, migraines, & bipolar disorder
What is the adverse effect of Gabapentin?
-Fatigue, somnolence
-Weight gain
-Behavior changes (hostility in children)
What is the place of therapy of Lacosamide?
FDA approved for adjunctive treatment of partial seizures
What are the adverse effects of Lacosamide?
-Dizziness (31%)
-Headache (13%)
-Fatigue (9%)
What are the counseling points of Lacosamide?
Schedule V controlled substance
Warning:
-Prolongation of the PR interval may occur. Use caution in patients with conductance problems (second degree heart block or greater)
Medication Guide must be dispensed with each prescription
What is the place of therapy of Lamotrigine?
-Monotherapy after trying other AEDs & adjunctive treatment in patients with partial seizures
-Alternatives agent for myoclonic or absence seizures to avoid VPA use (weight gain, polycystic ovary syndrome)
-Adjunctive therapy in patients with generalized tonic-clonic seizures
What are the adverse effect of Lamotrigine?
-Diplopia, drowsiness, ataxia
-Rash in 5-10% (due to Stevens-Johnson Syndrome)
* Often at 3-4 weeks
* High initial dose, concurrent valproic acid use, rapid escalation
* Can be potentially life-threatening in 1% of patients
What are some counseling points of Lamotrigine?
Drug Interactions:
-Valproic acid INCREASE serum concentration by 200%
* Due to interference with lamotrigine’s metabolic clearance
-Enzyme inducing drugs (Phenytoin, carbamazepine) accelerates metabolism
What is the place of therapy of Levetiracetam?
-For patients with partial seizures who have failed previous therapy; Role as monotherapy is NOT clear
-Adjunctive treatment for myoclonic seizures in patients with juvenile myoclonic epilepsy
What are the adverse effects of Levetiracetam?
Overall best safety profile
Minimal ADEs:
-Somnolence, asthenia, headache, agitation, anxiety
-Behavioral effects in young children (anxiety, agitation, irritability)
What is the place of therapy of Rufinamide?
Adjunctive treatment of generalized seizures of Lennox-Gastaut Syndrome
What are the adverse effect of Rufinamide?
-QT shortening (46-65%)
-Headache (16-27%)
-Dizziness (3-19%)
-Fatigue (9-16%)
Contraindicated in pts with familial short QT syndrome
What are the counseling points of Rufinamide?
Medication Guide for each prescription
What is the place of therapy of Oxcarbazepine?
-Monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children as young as 4 yrs old
-Potential 1st line agent for primary generalized convulsive seizures
How to get the dose from carbamazepine to oxcarbazepine?
CBZ dose per day x 1.5
What are the adverse effects of Oxcarbazepine?
- Dizziness, nausea, headache, ataxia
- CNS effects are more common at doses > 1200 mg/day
- 25-30% carbamazepine cross-sensitivity with rash
- Less rash than carbamazepine
- Hyponatremia in 2.5%
- More common than carbamazepine
- Reduce dose, d/c diuretics, fluid restrict, Na+ replace
What are the counseling points of Oxcarbazepine?
Pregnancy Category C
Drug Interaction:
* DECREASE bioavailability of oral contraceptives
* Less potent inducer than carbamazepine and phenytoin
- Transition from carbamazepine to oxcarbamazepine can lead to toxicity of certain drugs (less enzyme induction)
- Valproic acid, phenytoin, warfarin
What is the place of therapy of Tiagabine?
2nd line agent for partial seizures in patients who failed initial therapy
What are the counseling points of Tiagabine?
Drug Interactions:
* No inhibition or induction of hepatic enzymes
* CYP3A4 substrate
- Phenytoin, carbamazepine, phenobarbital DECREASE serum concentrations
What is the place of therapy of Topiramate?
-First line AED for partial seizures
-Also approved for treatment of tonic-clonic seizures in primary generalized epilepsy and migraine prophylaxis
-Migraine prophylaxis
What are the adverse effects of Topiramate?
- CNS effects: psychomotor slowing, somnolence, irritability, slurred speech, confusion
- Seen with rapid dose titration and higher dose
- Kidney stones (1.5%) 2-4x normal
- Counsel to maintain good fluid intake
- Weight loss
- Glaucoma
What are the counseling points of Topiramate?
Drug Interactions:
* Metabolism INCREASE by 50% when given with enzyme-inducing AEDs
- Drug levels reduced
* Topiramate may DECREASE the levels of oral contraceptives, digoxin
What are the counseling points of Vigabatrin?
- Black Box Warning: Permanent vision loss
- Available only through the SHARE program
- REMS program for permanent vision loss
What is the place of therapy of Zonisamide?
Adjunctive treatment of partial seizures
What are the adverse effect of Zonisamide?
- Most common: fatigue, dizziness, ataxia, anorexia
- Idiosyncratic severe skin rash, Steven Johnson Syndrome
- D/C zonisamide immediately
- Weight loss
- Nephrolithiasis
Contraindication: Sulfa allergy
What is the place of therapy of Medical Marijuana?
Potential alternative for refractory epilepsy in adults and children who do not respond to current medications
What are some advantages of newer AED?
- Lower side-effects rates
- Little or no need for serum monitoring
- Once or twice daily dosing for some agents
- Fewer drug interactions
- Pregnancy category C
What is the FDA alert in 2008?
- Increased suicidality of 11 AED drugs
What is the place of therapy of Phenytoin?
First-line for primary generalized convulsive & partial seizures
What is the PK of Phenytoin?
- Absorption:
- Differences in salt products
- Tube feedings decrease absorption
- Oral absorption is 100%
- Distribution:
- 90% bound to albumin
- Severe burn patients have INCREASE free phenytoin concentrations
- Obesity increases volume of distribution: BWAdj = IBW + ((ACT-IBW) * 0.4)
- Metabolism:
- Zero order kinetics
- Saturates at doses
- Renally eliminated
What is the dosing of Phenytoin?
Loading dose: 15-20 mg/kg IV at rate of ≤ 50 mg/min
* Administer IV slow to avoid venous irritation, pain, and thrombophlebitis
* Administration related hypotension and cardiac arrhythmias may also occur with fast administration
Maintenance: 300 mg/day (5-6 mg/kg/day in 1-3 divided doses)
For oral: 20 mg/kg then divide by 3 & administer divided doses q 2-4 hours
Use adjusted body weight if obese
BWAdj = IBW + ((ACT-IBW)*0.4)
What are some concentration dependent adverse effects of Phenytoin?
- Lethargy
- fatigue
- in-coordination
- blurred vision
- dizziness
- ataxia
- nystagmus
What are some concentration independent adverse effects of Phenytoin?
- Hypertrichosis
- Gingival hypertrophy (50%)
- Thickening of facial features
- Osteomalacia (long term effect)
- Folate deficiency (long term effect)
- Hypersensitivity reactions
Purple Glove Syndrome
- A rare complication of intravenous phenytoin use that typically presents with pain, edema, and discoloration at the injection site that spreads to the distal limb
- Phenytoin
What are some monitoring parameters of Phenytoin?
- BP
- Vital signs with IV use
- Plasma phenytoin levels
- CBC
- Liver function
What is the therapeutic range of Phenytoin?
Total 10-20 mg/L
* Free 1-2 mg/L
Obtain trough levels 2-3 weeks after initiation or change of dose
What is the recommended dose increase if normal renal function?
Steady state PHT Increase by
< 7 mg/L 100 mg/day
7 to < 12 mg/L 50 mg/day
≥ 12 mg/L 30 mg/day
What are the calculations of Phenytoin?
- Correction for Hypoalbuminemia
- C corrected = C observed/ 0.2(Alb + 0.1)
- Correction for renal failure (CrCl < 10mL/min)
- C corrected = C observed/ 0.1(Alb + 0.1)
-Extra LD to achieve desired serum levels; then use table if normal renal function to change maintenance dose
- C corrected = C observed/ 0.1(Alb + 0.1)
- IV dose(mg/kg) = (C desired – C actual) 0.7
(add extra 10% to oral dose)
Fosphenytoin dose
- LD 10-20 mg/kg PE
What is the advantage of Fosphenytoin?
- More advantageous for peripheral IV administration
- Can give IM for those w/o IV access
MOA of Carbamazepine?
-Thought to be due to inhibition of voltage-dependent sodium channels
-Interaction with voltage-gated calcium and potassium channels
What is the place of therapy of Carbamazepine?
First line AED for partial and primary generalized convulsive seizures who are not in an emergent situation
Pregnancy Category D
What is the PK of Carbamazepine?
- Auto-induction of its own metabolism
- Max auto-induction 2-4 weeks after initiation or dose change
- Re-adjust dose at 3-4 weeks due to auto-induction
What is the dose of Carbamazepine?
Starting dose: 200 mg BID
* Weekly increase: 200 mg/day
* Usual dose: 800-1200 mg/day given in 2-4 divided doses (max: 1.6-2.4 g/day)
What is the therapeutic level of Carbamazepine?
4-12 mg/L
What is the concentration dependent ADE of carbamazepine?
- Nystagmus
- Ataxia
- Blurred vision
- Diplopia
- Vomiting
- Sedation
- Dizziness
What is the concentration independent ADE of carbamazepine?
- Leukopenia (10%)
- Hold drug if WBC < 2500 cell/mm^3 and absolute neutrophil count < 1000/mm3.
- Hypersensitivity (rash in 10% SJS)
What do you monitor for carbamazepine?
CBC with platelet count, serum iron at baseline and periodically during therapy
What are the counseling point of Carbamazepine?
FDA Alert:
* Screening of patients for HLA B * 1502 allele
* Strong correlation with the presence of the HLA-B * 1502 allele & serious dermatologic reactions with carbamazepine
- Including Stevens-Johnson syndrome & toxic epidermal necrolysis
- Characterized by skin lesions, blisters, fever, itching
* Patients testing positive for the HLA-B*1502 allele should not be treated with carbamazepine
What are some drug interactions of Carbamazepine?
- Macrolide antibiotics DECREASE the metabolism of carbamazepine which may result in toxicity
- Serum concentrations of warfarin may be DECREASE by carbamazepine resulting in subtherapeutic warfarin
What is the place of therapy of Valproic acid?
-First line AED for primary generalized seizures such as myoclonic, atonic, and absence seizures
-Can be used as monotherapy or adjunctive therapy for partial seizures
-Useful in patients with mixed seizure disorders
What is the dosage of Valproic acid?
LD: 15-20 mg/kg IV
Maintenance:
* Initial 10-15 mg/kg/day in 2-3 divided doses
* Weekly increases 10mg/kg/day
* Target maintenance: 30-60 mg/kg/day in 2-3 divided doses
What is the therapeutic dose of Valproic acid?
Total 50-100 mg/L
What are some dose dependent ADE of Valproic acid?
- GI complaints (20%)
- Alopecia (temporary)
- Thrombocytopenia, platelet dysfunction
What is the dose independent ADE of Valproic acid?
-Hepatotoxicity
* Unpredictable/fatal
* Most common in young children < 2yrs, on polytherapy, within 1st 6-12 months of therapy
* Patients complaining of nausea, vomiting, lethargy, anorexia, and edema early in the therapy course should have liver function tests done
What are some drug interactions of Valproic acid?
- INCREASE carbamazepine metabolite, 10,11 epoxide
- Ethosuximide INCREASE or DECREASE
- INCREASE lamotrigine
- Phenytoin INCREASE free, DECREASE total
- Aspirin INCREASE Valproic free concentration levels (displacement of drug from albumin)
- Carbamazepine, phenytoin, phenobarbital DECREASE valproic acid levels
What are some monitoring parameters for Valproic acid?
-Baseline & periodically throughout therapy: Liver enzymes, CBC w/ platelets
-Serum valproate levels
What is the place of therapy of Phenobarbital?
-Drug of choice for neonatal seizures, but is reserved in other situations for patients who have failed therapy with other AEDs
-May be useful given IV in refractory status epilepticus
What is the dose of Phenobarbital?
LD: 15-20 mg/kg IV
* Avoid rapid administration due to hypotension
Maintenance Dose IV/PO: 50-100 mg 2-3 times daily (1-3 mg/kg/d in 1-2 doses)
What is the therapeutic level of Phenobarbital?
15-40 mg/L (trough)
What are the concentration dependent ADE of Phenobarbital?
- Sedation
- Respiratory depression
- Hypotension
What is the concentration independent ADE of Phenobarbital?
- Hypersensitivity reactions
- Hyperactivity
- Altered concentration
- Altered learning
- Depression
