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23 Cards in this Set
- Front
- Back
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seizures
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Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
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partial seizures, simple
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consciousness preserved; manifested variously as convulsive jerking, paresthesias, psychic symptoms and autonomic dysfunction
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partial seizures, complex
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impaired consciousness that is preceded, accompanied or followed by psychological symptoms
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tonic-clonic seizures, generalized
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tonic phase (less than 1 minute) involves abrupt loss of consciousness, muscle rigidity and respiration arrest; clonic phase (2-3 minutes) involves jerking of body muscles, with lip or tongue biting and fecal and urinary incontinence; formerly called grand mal
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absence seizures, generalized
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impaired consciousness (often abrupt and brief), sometimes with automatisms, loss of postural tone, or enuresis; begin in childhood (formerly, petit mal) and usually cease by age 20 years
In kids |
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myoclonic seizures
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single or multiple myoclonic muscle jerks
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status epilepticus
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a series of seizures (usually tonic-clonic) without recovery of consciousness between attacks;
it is a life threatening emergency |
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Seizure risk factors
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Risk factors (~1-2% cumulative incidence)
•Children: fever, mental retardation, cerebral palsy, genetics •Adults: trauma, tumors •Elderly: Alzheimers, stroke |
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Relationship between preclinical drug screens, clinical efficacy and suspected mechanism(s) of action
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1st generation drugs effective in the treatment of generalized tonic-clonic and partial seizures:
•Many rate-dependently prolong inactivation of voltage-sensitive Na channels (similar to lidocaine MOA in local anesthesia; a good basis for some selectivity). •Others potentiate GABA by any of several mechanisms. •1st generation drugs effective against other generalized (absence) seizures: •Thought to block T-type Ca channel-mediated current in thalamic neurons. Many current drugs were identified by activity in rodent electroshock test or pentylenetetrazol-induced seizures. Newer drugs being identified through: •Newer phenotypic models (mutant mice, models of kindling or neuropathic pain). •Targeting of defined biochemical mechanisms (e.g. GABA uptake, metabolism, receptor effects). •Novel AED targets: include Glu receptors, K or Ca channels Broader spectrum of action of a given drug may be due to multiple mechanisms of action and/or novel mechanisms of action. |
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Drugs for partial and generalized tonic-clonic seizures
DOC: Phenytoin (Dilantin) |
•Oldest nonsedative antiseizure drug (was known as diphenylhydantoin)
•Blockade of Na channels strongest (not only) effect @ therapeutic concentrations •Absorption highly dependent upon the formulation (multiple available) •Soluble prodrug fosphenytoin facilitates i.m. or i.v. administration •Elimination via liver dose-dependent, must increase dose gradually •Toxicity: nystagmus early, diplopia and ataxia dose-limiting, gingival hyperplasia and hirsutism common long-term •Idiosyncratic reactions rare •Although considered by some a 2nd line drug, still one of most widely used drugs in world |
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Drugs for partial and generalized tonic-clonic seizures
DOC: Carbamazepine (Tegretol) |
•A tricyclic compound related to certain antidepressants. Also effective in the treatment of bipolar disorder, trigeminal neuralgia. Use in drug abuse?
•May exacerbate myoclonic and absence seizures •Sodium channel blockade a likely primary effect •Significant microsomal induction; may have to adjust dose of this and other drugs with time •Toxicity: diplopia and ataxia dose-related; idiosyncratic blood dyscrasias in elderly •Side effects may be decreased with extended release formulation •Stevens-Johnson syndrome a rare but serious side effect- may be predicted largely by presence of a specific HLA allele; 10X risk in Asians; clinical testing now recommended by FDA |
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Drugs for partial and generalized tonic-clonic seizures
DOC: Valproic acid (Depakene) |
•Accidental discovery
•Efficacious against with partial seizures, generalized tonic-clonic, myotonic, atonic, and combination seizures; also bipolar disorder •related to blockade of Na channels? •GABA effects also relevant? (GAD, GAT, GABA-T) •Histone deacetylase inhibition (increases gene expression); Potentiation of Sp TF family •Also highly efficacious against absence seizures (effects on Ca channels?) •Broad spectrum presumably related to multiple MOA •Serious side effects uncommon, but may not be used as first drug of choice by some due to rare but severe idiosyncratic hepatoxicity (requires monitoring of liver function) •Divalproex sodium extended release (Depakote ER) once daily for complex partial or absence seizures or migraine |
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Alternative drugs for partial and generalized tonic-clonic seizures (with exception of phenobarbital, these are second generation AEDs)
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•Phenobarbital (Luminol): GABA; sedative effects can be limiting; rapid effect, safety profile and cost can make it a DOC for some
•Lamotrigine (Lamictal): additional mechanisms of action implied by broad spectrum of activity; shown as effective as DOC (may now be considered one); rare but life-threatening dermatitis possible in infants •Levetiracetam (Keppra): binds SV2A!; very good for adult/child refractory seizures; well tolerated, another possible DOC •Gabapentin (Neurontin): non-GABA MOA, binds voltage-gated Ca channel subunit; Approved for neuropathic pain and postherpetic neuralgia, migraine, restless legs syndrome; just shown useful for refractory chronic cough (‘12); NB: FDA ruling that company illegally marketed drug for many off-label uses (CNS disorders) with poor documentation of efficacy •Topiramate (Topamax): multiple mechanisms? Broad spectrum; THE hot drug for off-label (refractory migraine, bipolar, etc); has typical CNS side effects, plus memory problems, plus side effecs of carbonic anhydrase inhibitor |
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Drugs used against generalized (absence) seizures
DOC: Ethosuximide (Zarontin) |
•First line drug for absence seizures only
•T-type channel MOA •Good absorption, complete metabolism, good relationship between dose and plasma levels •Toxicity: well tolerated; primarily dose-related gastric distress, (rashes, psychosis more rarely reported |
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Drugs used against generalized (absence) seizures
DOC: Clonazepam (Klonopin) |
•Efficacious not only in absence seizures, but some cases of myoclonic and atonic seizures and infantile spasms
•But may be less effective than above two drugs in absence seizure •Use is limited by typical benzodiazepine side effects of sedation, development of tolerance, withdrawal syndrome |
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Drugs used against generalized (absence) seizures
AND Drugs for partial and generalized tonic-clonic seizures DOC: Valproic Acid (Depakene) |
•Accidental discovery
•Efficacious against with partial seizures, generalized tonic-clonic, myotonic, atonic, and combination seizures; also bipolar disorder •related to blockade of Na channels? •GABA effects also relevant? (GAD, GAT, GABA-T) •Histone deacetylase inhibition (increases gene expression); Potentiation of Sp TF family •Also highly efficacious against absence seizures (effects on Ca channels?) •Broad spectrum presumably related to multiple MOA •Serious side effects uncommon, but may not be used as first drug of choice by some due to rare but severe idiosyncratic hepatoxicity (requires monitoring of liver function) •Divalproex sodium extended release (Depakote ER) once daily for complex partial or absence seizures or migraine |
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Treatment of status epilepticus
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•Generalized tonic-clonic status epilepticus is a life-threatening emergency
•Standard to use iv diazepam or lorazepam followed by iv fosphenytoin or phenobarbital (but watch out for synergistic CNS depression) •RAMPART (Welch WSU ‘12) showed i.m. midazolam by EMS as good or better than i.v. lorazepam |
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Other aspects of antiseizure drug therapy
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Other aspects of antiseizure drug therapy:
Teratogenicity •Important issue; Difficult to assess due to seizure and medication heterogeneity •Most pregnant patients on these drugs deliver normal infants •Phenytion: fetal hydantoin syndrome? •valproate: 1-2% risk of spina bifida; perhaps effect on IQ •Apparent overall 2X increase risk congenital malformations when on drugs, but no increased risk if off drugs during pregnancy •If remain on drug (typical), use the lowest effective dose of monotherapy Drug withdrawal •Withdrawal most difficult for benzodiazepines, barbiturates •~70% of people with epilepsy, enter remission (>5 yrs seizure-free) while on meds •For these, ~75% can be successfully (gradually) withdrawn from meds Other •2X normal increase suicide risk, decreased bone density on chronic use |
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Other aspects of antiseizure drug therapy
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Ketogenic diet:
•Fasting was used to treat epilepsy from ancient times until 1920’s •Lost favor because is seemed based on antiquated medical theories; practical difficulties •Ketogenic diet was developed in 1920s, but rapidly displaced by new drug development •Hollywood and Meryl Streep •Low cal diet, with 4 gm fat/gm protein or carbs •Diet creates ketones by fat metabolism, mimics fasting •Ketones replace glucose as brain fuel •Mechanism(s) of action? •Strict adherence required (initial hospitalization for children) •For treatment refractory seizures in children including Lennox-Gastaut syndrome |
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Other aspects of antiseizure drug therapy: Surgeries
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Surgeries for antiseizure drug therapy:
•Anterior temporal lobectomy: for the most common partial seizure of adults, if seizures refractory and harmful majority of patients seizure free for 5 yr •Corpus callosotomy: for Lennox-Gastaut •Hemispherectomy: for other severe childhood forms eg Rasmussen or Sturge-Weber syndromes •Vagus nerve stimulation: (NeuroCybernetic) for refractory complex partial/generalized seizures, poor surg. candidates gd response (seizure reduction) in 30-75% subjects; now tested in children long known to work; MOA unclear (also used in depression, anxiety, etc) •Case-by-case cost/benefit analysis |
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Future pharmacotherapies of antiseizure therapy
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•Large number of candidate drugs being identified by high-throughput screening.
•Some have novel mechanism(s) of action. Should improve treatment of refractory epilepsies. • Improved understanding of the genetic/cellular bases of epilepsy will lead to more precisely targeted therapeutics and, importantly, novel strategies to delay or prevent epileptogenesis. |
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Therapeutic principles for the management of epilepsy
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Therapeutic principles for the management of epilepsy
•Ascertain cause of seizure if at all possible •For children ‘wait and see’ after a single unprovoked seizure •Use a drug of choice appropriate to seizure type •Since the therapeutic index of most antiseizure drugs is low and toxicity not uncommon, it is important to ensure an adequate trial of a single drug with monitoring of plasma levels •For treatment failure (as many as one-half of patients), try monotherapy with another first line drug •In cases of pharmacological treatment failure (20-30%), consider epilepsy surgery or vagal nerve stimulation. •NEJM study (‘12) supports surgery ASAP after failure of two first-line drugs (rather than waiting >10 years after treatment failure as is seen now) |
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•Case study: During a clerkship in an outpatient setting, you see an adolescent who’s being treated with carbamazepine (Tegretol) for what was thought to be a clear-cut case of generalized tonic-clonic seizures. Although he seemed to respond initially to treatment, his seizure frequency is increasing after some weeks of treatment. Knowing that Dr. Bannon just covered this topic in his scintillating lecture, the pediatrician asks you for your advice- should she: send the child for neuro testing to confirm the diagnosis? switch to another AED? add a second drug as an adjunct to Tegretol?
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Case study answer:
monotherapy! Do NOT add on a second drug. Check plasma levels of the Tegretol to make sure the right dosage is being given. |
