Status Epilepticus Karim Rafaat, MD

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

Pathophysiology Status occurs because of failure of the normal mechanisms that limit the spread and recurrence of isolated seizures 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

Pathophysiology Excitatory Excitatory –Glutamate Major amino acid excitatory neurotransmitter in the brain 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 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

Pathophysiology Inhibitory Inhibitory –Gamma-aminobutyric acid (GABA) Main inhibitory neurotransmitter in the brain Main inhibitory neurotransmitter in the brain Antagonists to its effects or alterations in its metabolism in the substantia nigra may contribute to SE 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

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

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

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

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

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

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

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

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

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

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

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

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

Pharmacotherapy for Status Epilepticus Ideal medication 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 cardiorespiratory depression No systemic side effects No systemic side effects Remember to treat the underlying cause Remember to treat the underlying cause

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Outcomes in Status Epilepticus Mortality is related to underlying cause 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 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 But patients who seize for more than 60 minutes have worse outcomes than those who seize for less

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

Adjunctive Therapy: the Ketogenic Diet High fat (80-90% of calories), low protein, very low carb diet developed in 1900 ’ s 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 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 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) Ketone bodies may have an antiepileptic effect (mechanism not understood) Many observation studies report good results Many observation studies report good results –1/3 sz resolution; 1/3 sz improved; 1/3 unchanged No randomized clinical trials in the literature No randomized clinical trials in the literature

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