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Status Epilepticus

Status Epilepticus. Karim Rafaat, MD. Definition. Single seizure lasting greater than 30 minutes OR Series of seizures lasting 30 minutes or longer without full return of consciousness between seizures. Pathophysiology.

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Status Epilepticus

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  1. Status Epilepticus Karim Rafaat, MD

  2. Definition • Single seizure lasting greater than 30 minutes OR • Series of seizures lasting 30 minutes or longer without full return of consciousness between seizures

  3. Pathophysiology • Status occurs because of failure of the normal mechanisms that limit the spread and recurrence of isolated seizures • Excitation is excessive and/or inhibition is ineffective

  4. Pathophysiology • Excitatory • Glutamate • Major amino acid excitatory neurotransmitter in the brain • Role in the pathogenesis of SE was suggested by an outbreak of illness caused by eating mussels contaminated with domoic acid, an analogue of glutamate • Aspartate • Acetylcholine

  5. Pathophysiology • Inhibitory • Gamma-aminobutyric acid (GABA) • Main inhibitory neurotransmitter in the brain • Antagonists to its effects or alterations in its metabolism in the substantia nigra may contribute to SE • Calcium ion-dependent potassium ion current • Blockage of NMDA channels by magnesium

  6. Subtypes of Status • Convulsive • Primary generalized • Simple of complex partial • Secondary generalized • Nonconvulsive • Absence status • Complex partial status • Atonia (electromechanical dissociation) • “Give Me a Break” • Pseudoseizures

  7. Epidemiology • Status epilepticus occurs in 5-15% of patients with epilepsy • Status is more common in childhood than adulthood • Approximately 10% of children with epilepsy have status on initial presentation • In children the seizure is usually generalized from the onset (often a partial seizure with secondary generalization in adults)

  8. Causes of Status • Reactive • Fever • Metabolic Alterations (hyponatremia, hypocalcemia, hypoglycemia) • Symptomatic • Acute • Infection • Hypoxia • Trauma • Hemorrhage/Stroke • Remote • Perinatal Hypoxic-Ischemic Injury • Trauma • Infection • Congenital Brain Malformation • Idiopathic or Cryptogenic

  9. Physiological Changes During Status Epilepticus • Hypoxia • Responsible for the majority of morbidity and mortality in patients with status • Results from: • impaired mechanical ventilation by muscle spasms • increased salivation and secretions in lungs • increased oxygen consumption with the increased demands from muscle and brain tissue

  10. Physiological Changes During Status Epilepticus • Respiratory Acidosis • Results from impaired ventilation and increased metabolic production of carbon dioxide • Metabolic Acidosis • Predominantly lactic acidosis from impaired tissue oxygenation and perfusion

  11. Physiological Changes During Status Epilepticus • Elevated WBC • Peripheral leukocytosis in 50-60% • CSF pleocytosis in 10-15% • Hyperkalemia • Increased muscle enzymes • Rhabdomyolysis results in myoglobinuria • May result in ATN/acute renal failure

  12. Physiological Changes During Status Epilepticus • Hyperglycemia • Associated with sympathetic discharge and increased hepatic gluconeogenesis • Hypoglycemia • Develops after approximately 60 minutes of seizure activity • Associated with increased consumption by brain and muscles during seizures

  13. Neurological Changes During Status Epilepticus • Most frequent neurological changes • Pupillary changes • Increased or decreased tone • Positive Babinski sign • Result from electrical activity, underlying neurological disease, or metabolic disturbance • May be bilateral or asymmetrical

  14. EEG Changes During Status Epilepticus • Attenuation of background activity • Generalized low voltage fast activity • Epileptic recruiting rhythm with increased amplitude and decreased frequency • Generalized polyspike and slow discharges with repetition rate of 1-4Hz • Diffuse depression of background activity after cessation of seizure

  15. Systemic Changes During Early Status Epilepticus • Hypertension, tachycardia • Caused by massive catecholamine release and autonomic discharge • Cardiac output increases • Mean arterial pressure increases • Hyperpyrexia • Caused by excessive muscle activity

  16. Cerebral Changes During Early Status Epilepticus • Increased ICP • Cerebral blood flow increases 5-7 times • Results from both cerebral vasodilatation and systemic hypertension • Metabolic rate increases 2-5 times • Oxygen and glucose utilization increase

  17. Cerebral Changes as Status Epilepticus Progresses Cerebral blood flow decreases • Cerebral autoregulation is compromised • Brain oxygenation decreases • Brain glucose levels decrease • Metabolic demands are higher than supply • Brain damage generally starts to occur after 30-60 minutes of status • Occurs earlier/more profound with persistent hypoxia

  18. Pharmacotherapy for Status Epilepticus • Ideal medication • Effective against all seizures • Several routes of administration • Potent so small volumes can be given rapidly • Cross blood brain barrier rapidly for fast onset • Long half life for long activity • Safe • No cardiorespiratory depression • No systemic side effects • Remember to treat the underlying cause

  19. Lorazepam (Ativan) • Benzodiazepene/GABA agonist • Dose: 0.05-0.1mg/kg (max 4mg) • Route: IV, ET • Onset of action: 2-3 minutes • Duration of Action: 4-14 hours • Low lipid solubility/small area of distribution • Metabolized by the liver; no active metabolites • Respiratory depression occurs in 10% of pts • Tolerance develops with repeated doses

  20. Diazepam (Valium) • Benzodiazepene/GABA agonist • Dose: 0.2-0.5mg/kg (max 10mg) • Route: IV, ET, IM, PR • Onset of action: 1-3 minutes • Duration of action: 20 minutes • Highly lipophilic/large volume of distribution • Metabolized by the liver/metabolite is N-desmethydiazepam which accumulates • Respiratory depression develops in 10%

  21. Midazolam (Versed) • Benzodiazepene/GABA agonist • Dose: 0.05-0.2mg/kg • Route: IV, IM • Onset of action: 1-5 minutes • Duration of action: 1-2 hours • Continuous drip more effective long-term than bolus doses • Highly lipophilic/large volume of distribution • Metabolized by the liver • Side effects: bradycardia, hypotension

  22. Phenytoin (Dilantin) • Dose: 18-20mg/kg • Route: IV • Onset of action: 10-30 minutes • Duration of action: 12-24 hours • Maximal infusion rate: 50mg/min • Cardiac arrythmias and hypotension can result from rapid administration • Risk of thrombophlebitis and tissue necrosis with infiltration • Highly lipid soluble, but not water soluble • Metabolized by the liver

  23. Fosphenytoin (Cerebyx) • Prodrug of phenytoin • Phosphate ester group is removed from drug once in enters bloodstream • Same dose, onset of action, duration of action as phenytoin • Route: IV, IM • Maximal infusion rate: 150mg/min • Water soluble • Less risk of thrombophlebitis, tissue necrosis with extravasation • 10 times more expensive than phenytoin

  24. Phenobarbital (Luminal) • Loading dose: 10-20mg/kg • Route: IV, IM, PO • Onset of action: 15-60 minutes • Duration of action: 24-96 hours • Maximal infusion rate: 100mg/min • Side effects: sedation, hypotension, respiratory suppression • Dose needs to be adjusted in renal or hepatic failure

  25. Thiopental (Pentathol) • Loading dose: 12mg/kg • Continuous dose: 3-5mg/kg/hr • Onset of action: 20-60 minutes • Hypotension is common/pressors often needed • Infiltrate can cause tissue necrosis • Tolerance develops • Intermittent EEG should be followed • Metabolized to pentobarbital by the liver • Thiopental and pentobarb levels are followed

  26. Pentobarbital (Nembutal) • Barbiturate/GABA agonist • Loading dose: 5-12mg/kg • Continuous dose: 0.5-1mg/kg/hr • Onset of action: 10-20 minutes • Hypotension is common/pressors often required • Ileus/feeding intolerance is common • Requires intermittent EEG monitoring to assess sedation

  27. Isoflorane (Forane) • Liquid anesthetic agent • Route: inhaled • Onset of action: 1-2 minutes • Eliminated by exhalation/little to no risk of hepatotoxicity (unlike halothane) • May cause hypotension requiring pressors • Impractical in ICU setting since it requires facilities for administration of continuous inhaled anesthetic

  28. Etomidate (Adimate) • IV anesthetic agent • Dose: 0.3mg/kg • Route: IV continuous infusion • Onset of action: 1-2 minutes • Metabolized by the liver • Patients may develop myoclonus or muscle twitches unassociated with epileptic activity • Long term infusion results in adrenal suppression • Corticosteroids are required

  29. Propofol (Diprivate) • IV anesthetic agent • Loading dose: 1.5mg/kg/hr • Maintenance dose: 6-10mg/kg/hr • Onset of action: 1-2 minutes • Rapidly metabolized by the liver • Patients may develop involuntary muscle twitches unassociated with EEG activity • Marked lipidemia occurs with prolonged use • No adrenal side effects

  30. Treatment Protocol for Status Epilepticus • <1 minute • Establish airway • Assess respirations and blood pressure • Establish IV access • Draw labs • Chem 7, divalents, CBC, accucheck in all • AED drug levels, tox screen, cultures when appropriate • <2 minutes • Lorazepam 0.05-0.1mg/kg IV (ET if n • Diazepam PR, midazolam IM if needed

  31. Treatment Protocol for Status Epilepticus • <15 minutes • Phenytoin or fosphenytoin load • Slow infusion rate if hypotensive, arrythmias • Phenobarbital load if allergic to phenytoin • <60 minutes • Midazolam load/drip if seizures persist • Titrate to seizure cessation or burst suppression on EEG • Correct any metabolic disturbances found • >60 minutes • Pentobarbital load/drip if seizures persist • Titrate to burst-suppression on EEG

  32. Complications • Neuronal cell damage/death • Aspiration pneumonia • Neurologic pulmonary edema • Rhabdomyolysis • Hyperthermia • Cardiac arrythmias • Medication complications: • Respiratory depression • Hypotension • Bradycardia • Ileus

  33. Recurrent Seizures • Risk factors for recurrent seizures : • 1st seizure is status epilepticus • Remote symptomatic etiology • Abnormal EEG • Seizure during sleep • History of prior febrile seizure • Todd’s paresis

  34. Neurologic Sequelae • Variable rates of neurologic sequelae • Neurologic outcome depends primarily on the underlying condition • One review demostrated 6 to 15 percent rate of encephalopathy and neurologic deficits

  35. Age and Prognosis • Overall children have better outcomes than adults • Poorer prognosis at extremes of age • Adult mortality rate 25% • Pediatric mortality rate 5% • Age under 1 year: 25% • Age 1-3 years: 10% • Differences in outcomes thought to be based on different etiologies in these age groups

  36. Outcomes in Status Epilepticus • Mortality is related to underlying cause • 90% of patients with status from AED withdrawal, alcohol abuse, or trauma do well • 33% of patients with status from stroke, anoxia, or major metabolic disturbance do well • Majority of morbidity results from hypoxia • More closely related to duration of hypoxia rather than duration of seizure activity • But patients who seize for more than 60 minutes have worse outcomes than those who seize for less

  37. Refractory Status Epilepticus • Persistent seizure activity despite appropriate therapy • Associated with high mortality and morbidity • Retrospective review of 22 pts tx’d 1992-2000 with high-dose anesthetic agents for 2 to 146 days (median 16.5 days) • Mortality was 32% • Greater in younger patients and in those with multifocal or generalized abnormalities on EEG • All except one survivor developed active epilepsy and none with a normal neurologic status prior to the event returned to their baseline

  38. Adjunctive Therapy: the Ketogenic Diet • High fat (80-90% of calories), low protein, very low carb diet developed in 1900’s • Ketosis is induced by starvation for 1-2 days, then perpetuated by ketogenic diet • Diet alters metabolism to replace glucose with fats as the body’s main energy source • Ketone bodies may have an antiepileptic effect (mechanism not understood) • Many observation studies report good results • 1/3 sz resolution; 1/3 sz improved; 1/3 unchanged • No randomized clinical trials in the literature

  39. Future Potential Therapy • NMDA antagonists and other calcium entry channel blockers • Glutamine antagonists • Limited secondary to psychiatric effects

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