SEIZURE

• Seizure


  Excessive abnormal electrical discharge from cortical neurons
• Convulsion


  When a person's body shakes rapidly and uncontrollably
• Epilepsy


  A seizure disorder
• Causes of seizures


  • Idiopathic
  • CNS infection
  • Fever
  • Metabolic disturbance
  • Cerebral trauma
• Complex partial seizures


  • Purposeless behavior is common
  • The affected person may have a glassy stare, may wander about aimlessly, and may speak unintelligibly
  • Psychomotor (temporal lobe) epilepsy may lead to aggressive behavior (e.g., outbursts of rage or violence)
• Complex partial seizures


  • Postictal confusion usually persists for 1-2 minutes after the seizure ends
  • Automatism (e.g., picking at clothes) is common and may follow visual, auditory or olfactory hallucinations
• Generalized seizures


  • Entire brain is involved
  • Motor manifestations are bilateral
  • Diffuse, affecting both cerebral hemispheres
  • Clinical and EEG changes indicate initial involvement of both hemispheres
• Absence (Petit mal) seizures


  • Present as alterations of consciousness (absences) lasting 10-30 seconds
  • Staring (with occasional eye blinking) and loss or reduction in postural tone is typical
  • Enuresis
• Myoclonic seizures


  • Present as involuntary jerking of the facial, limb, or trunk muscles, possibly in rhythmic manner
  • Consist of sporadic jerks, usually on both sides of the body
  • Patients sometimes describe the jerks as brief electrical shocks
  • When violent, these seizures may result in dropping or involuntarily throwing objects
• Clonic seizures


  • Characterized by sustained muscle contractions alternating with relaxation
  • Are repetitive, rhythmic jerks that involve both sides of the body at the same time
• Tonic seizures


  • Involve sustained tonic muscle extension (stiffening)
• Generalized tonic-clonic seizures (grand mal)

  • Cause sudden loss of consciousness
  • The individual becomes rigid and falls to the ground
  • Respirations are interrupted
  • The leg extended, and the back arches; contraction of the diaphragm may induce grunting
  • This tonic phase lasts for about 1 minute
  • A clonic phase follows, marked by rapid bilateral muscle jerking, muscle flaccidity, and hyperventilation
  • Incontinence, tongue biting, tachycardia, and heavy salivation sometimes occur
  • Postictal phase: the individual may experience headache, confusion, disorientation, nausea, drowsiness, and muscle soreness, lasting for hours
• Atonic seizures (drop attacks)


  • Characterized by a sudden loss of postural tone so that the individual falls to the ground
  • Occur primarily in children
• Classification of seizures based on etiology

  • Primary (idiopathic) seizures - have no identifiable cause
  • Secondary seizures (symptomatic or acquired seizures) - occur secondary to an identifiable cause
• Causes of secondary seizures

  • Intracranial neoplasms
  • Infectious diseases (meningitis, influenza, toxoplasmosis, mumps, measles, syphilis)
  • High fever (in children)
  • Head trauma
  • Congenital diseases
  • Metabolic disorders (hypoglycemia, hypocalcemia)
  • Alcohol or drug withdrawal
  • Lipid storage disorders
  • Developmental abnormalities
• Monotherapy


  Treatment with a single anticonvulsant drug
• Multiple-drug therapy


  Treatment with more than one anticonvulsant drug
• Pharmacokinetics of classical antiepileptic drugs

  • Good absorption
  • Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine)
  • Conversion to active metabolites (carbamazepine, primidone, fosphenytoin)
  • Cleared by the liver
  • Plasma clearance is slow
  • At high concentrations phenytoin exhibits zero order kinetics
• Notable adverse effects of antiseizure medications

  • CNS effects (ataxia, dysarthria, insomnia)
  • Decreased serum concentrations of folic acid, thyroxine, and vitamin K with long-term use
  • Fetal hydantoin syndrome (growth retardation, microencephaly, craniofacial abnormalities)
• Strategies for treatment of seizures

  • Modification of ion conductances
  • Increase inhibitory (GABAergic) transmission
  • Decrease excitatory (glutamatergic) activity
• Anticonvulsive drug classification


  • Barbiturates
  • Hydantoins
  • Succimides
  • Oxazolidinediones
  • Benzodiazepine
  • Miscellaneous
• Indications for anticonvulsive drugs

  • GTC and partial seizures (valproic acid, carbamazepine, phenytoin)
  • Absence seizures (ethosuximide, valproic acid)
  • Myoclonic seizures (clonazepam, valproic acid)
  • Status epilepticus (diazepam, lorazepam, phenytoin)
  • Febrile seizures (phenobarbital)
  • Tonic clonic seizures (lamotrigene, VPA, topiramide)
• Drug selection for partial seizures

  • Carbamazepine, phenytoin
  • Valproic acid, lamotrigine, gabapentin, benzodiazepines, barbiturates
  • Adjunct: Tiagabine, topiramate, levetiracetam, zonisamide
• Drug selection for generalized tonic-clonic (grand mal) seizures

  • Carbamazepine, phenytoin
  • Valproic acid, lamotrigine, gabapentin, benzodiazepines, barbiturates
  • Adjunct: Topiramate, zonisamide
• Drug selection for absence (petit mal) seizures

  • Ethosuximide
  • Valproic acid (when absence seizures coexist with tonic-clonic seizures)
  • Clonazepam
  • Adjunct: Lamotrigine, benzodiazepines
• Drug selection for myoclonic syndromes

  • Valproic acid
  • Clonazepam and other benzodiazepines
  • Adjunct: levetiracetam
• Status epilepticus


  Treatment is intravenous diazepam or lorazepam followed by intravenous fosphenytoin (or phenytoin) or phenobarbital
• Mechanisms of action of anticonvulsant drugs

  • Inhibition of voltage-gated Na+ channels to slow neuron firing
  • Enhancement of the inhibitory effects of the neurotransmitter GABA
  • Inhibition of calcium channels
• Sodium channel blockers


  • Phenytoin (Dilantin)
  • Fosphenytoin (Cerebyx)
  • Carbamzepine (Tegretol)
  • Oxcarbazepine (Trileptal)
  • Valproic Acid (Valproate; Depakene, Depakote)
  • Lamotrigine (Lamictal)
  • Topiramate (Topamax)
  • Zonisamide (Zonegran)
  • Lacosamide (Vimpat)
  • Rufinamide (Banzel)
• Phenytoin (Dilantin)


  • Oldest nonsedative antiepileptic drug
  • MOA: closes Na channels
  • Adverse effects: CNS effects (ataxia, nystagmus, diplopia), connective tissue effects (hirsutism, gingival hyperplasia), dermatological effects (maculopapular rashes, SJS, lupus erythematosus)
  • CyP450 inducer (carbamazepine, valproate, warfarin, OCPs)
  • Displaced from protein binding by aspirin, sulfonamides
  • Elimination converts from first-order to zero-order at high therapeutic levels
• Congenital heart disease


  Microcephaly, growth and mental retardation
• Dermatological effects


  Maculopapular rashes sometimes with fever, SJS, and lupus erythematosus
• CYP450 inducer


  Carbamazepine, valproate, warfarin, OCPs
• Displaced from protein binding

  Aspirin, sulfonamides
• 10


  1/24/24
• Elimination of phenytoin


  Converts from first-order elimination (proportional to its concentration) to zero-order elimination (a fixed amount per unit time), usually at high therapeutic levels
• Phenytoin (Dilantin)


  • Na+ Channel Blocker
• Adverse Effects of Phenytoin


  • CNS effects - ataxia (limiting side effect), dysarthria, and insomnia
  • Transient hyperkinesia may follow IV phenytoin infusion
  • Decreased serum concentrations of folic acid, thyroxine, and vitamin K with long-term use
  • "Fetal hydantoin syndrome" - includes growth retardation, microencephaly, and craniofacial abnormalities (e.g., cleft palate) and is possibly due to an epoxide metabolite of phenytoin
• Fosphenytoin


  Prodrug rapidly converted to phenytoin in the blood, providing high levels of phenytoin within minutes, may also be administered intramuscularly (IM)
• Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis