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Status Epilepticus

Status Epilepticus

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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