Status Epilepticus in Children Definitions • Status Epilepticus: 30 minute duration of seizures (or two or more sequential seizures without full recovery of consciousness between seizures). For practical purposes, start treatment earlier • Seizure: paroxysmal event characterized by a change in behavior of the patient; it is caused by abnormal and excessive activity of a group of cortical neurons. • Epilepsy: occurrence of two or more unprovoked seizures Status epilepticus • Common in children, particularly in children less than 2 years old • Particularly common in children with epilepsy (9-27% over time have at least one episode of status) • High morbidity and mortality Complications • • • • • • Hypoxemia Acidemia Glucose alterations Blood pressure disturbances Increased intracranial pressure Morbidity – Neurologic sequelae – – – – – • Mortality – 3-4% Focal motor deficits Mental retardation Behavioral disorders Chronic epilepsy Acute and chronic MRI changes Assessment of the Patient with Status Epilpeticus 1. 2. 3. 4. Determine if patient is having a seizure Determine type of seizure Determine possible etiology of seizure Treat underlying etiology of seizure if pertinent 5. Stop the seizure Differential Diagnosis Is patient having a seizure?? • Movement Disorder – Drug induced dystonic reaction – Paroxysmal dyskinesias – Sandifers syndrome • Breathholding spell • Syncope • Spasm – Secondary to increased ICP • Psychogenic seizure • Narcolepsy (cataplexy) Classification of seizures Generalized Partial • loss of consciousness • whole brain at onset • no loss of consciousness • focal onset Convulsive Complex Partial • tonic clonic • tonic • clonic • change in level of consciousness Nonconvulsive • • • • absence atypical absence myoclonic atonic Simple Partial • no change in consciousness Partial Seizure evolving to secondary generalization Etiology of Status Epilepticus • • • • • Acute symptomatic Remote symptomatic Progressive encephalopathy Febrile Cryptogenic/Idiopathic Acute Symptomatic Seizures • Fever • Infectious – Meningitis – Abscess – Encephalitis • Neurovascular – Ischemic stroke – Hemorrhagic stroke (AVM, aneurysm, etc) • Trauma • Tumor • Metabolic – Hypoglycemia – Hypocalcemia – Hyponatremia Management of Status Epilepticus in Children--Initial Approach Status Epilepticus Working Party, 2000 (mostly) • Initial assessment – – – – A, B, Cs Rapid neurologic examination Brief history Give high flow oxygen • Measure rapid blood glucose – More to avoid glucose infusion than the uncommon hypoglycemic seizures • Confirm epileptic seizure – Not all events are epileptic!!!! • Laboratory Studies – – – – – Glucose, electrolytes, calcium, magnesium ABG CBC Serum anticonvulsant drug levels (if indicated) Toxicology screening Rapid Neurologic Evaluation • Observation – What is the patient doing • • • • What are the movements? Which extremities involved? Stiff or floppy? What are eyes doing? Head? Is patient at all responsive? • Mental Status – Can you get the patient to respond? Verbal? Noxious stimuli (not too noxious!)? Appropriate withdrawal? • Cranial Nerves – Pupil reactivity, extraocular movements • Motor/Sensory: – What parts of body are moving? What parts withdraw to nailbed pressure Brief history • • • • Has the child ever had a seizure before? History of trauma? Fever? Ingestion? Was the child his usual self prior to this event? What medications (including nonprescription) does the child take? • Any medical problems? • Any neurologic/developmental problems? • If child has known epilepsy – Name and dosage of medications!!! Calculate if this is appropriate dosage. – Has the child missed dosage of medication • If so, consider loading with that medication – Be aware of paradoxical side effects of ACDS • Phenytoin and carbamazepine toxicity may precipitate SE Management of Status Epilepticus in Children--Initial Approach • Initial assessment – – – – A, B, Cs Rapid neurologic examination Brief history Give high flow oxygen • Measure rapid blood glucose – More to avoid glucose infusion than the uncommon hypoglycemic seizures • Confirm epileptic seizure – Not all events are epileptic!!!! • Laboratory Studies – – – – – Glucose, electrolytes, calcium, magnesium ABG CBC Serum anticonvulsant drug levels (if indicated) Toxicology screening No Caption Found The Status Epilepticus Working Party, et al. Arch Dis Child 2000;83:415-419 Management of Status Epilepticus in Children 1. Stop the seizure 2. Keep seizure from recurring Treatment of Status Epilepticus: 1. STOP the seizure with benzodiazepine – If no IV access: Diazepam 0.5 mg/kg PR • Diastat • IV diazepam, inserted per rectum through butterfly (needle cut off!) – If IV access: Lorazepam • 0.1 mg/kg IV over 30-60 seconds • If seizures continue another 10 minutes, repeat lorazepam – Midazolam: IV, buccal, nasal 2. ADD fosphenytoin (either as second medication if seizure refractory, or to stop from recurring) – 20 PE/kg IV 3. ADD third medication if necessary- Phenobarbital, Valproic acid, Keppra Benzodiazepines • Diazepam vs. Lorazepam • Diazepam – Highly effective in rapidly terminating seizures – However, redistribution into adipose tissue limits anticonvulsant effect to less than 20 minutes – Available in rectal gel, which can be given outside the ED • Lorazepam – – – – Equally or more effective than diazepam Longer duration of action (6-12 hours vs. <1 hour) Less respiratory depression than diazepam Not available rectally Treatment of Status Epilepticus in the Child Step 2 • ADD fosphenytoin:20 PE/kg over 7 min. – If fosphenytoin not available, use phenytoin: 18-20mg/kg over 20 minutes – General rule of thumb: for each 1 mg/kg phenytoin (or 1PE/kg fosphenytoin) expect level to rise by 1) • If already on phenytoin, load with phenobarbital 20mg/kg over 10 minutes Phenytoin vs. Fosphenytoin • • • • • • Phenytoin Can be diluted in NS only! Maximum concentration of 10mg per ml Infusion rate < 1 mg/kg/min (Therefore 18 mg/kg is infused over no less than 18 minutes) Risk of hypotension and cardiac arrythmia Monitor heartrate BP and EKG Extravasation reaction, purple glove syndrome • • • • • • Fosphenytoin Pro drug: converted into phenytoin Can be diluted in commonly used diluents Can infuse 3 times more rapidly than phenytoin (ie, over 7-8 minutes) Decreased risk hypertension and arrhythmia Decreased risk extravasation reactions (pH of 8) Dosed in phenytoin equivalents (PE) which can be confusing. Treatment of Status Epilepticus in the Child Step 3 • ADD third medication if necessary – Phenobarbital 20mg/kg IV (2 mg/kg/min)\ • • may repeat 10mg/kg every thirty minutes Be prepared to intubate as barbituates and benzos potentiate each others effects – Valproic Acid • Not yet approved for initial treatment of SE • Dosage 20-40 mg/kg IV (diluted 1:1 with normal saline or 5% dextrose in water) over 5-10 minutes; may repeat in 10-15 minutes; follow with IV infusion of 5 mg/kg/hr – Keppra • Not approved for initial treatment of SE Refractory Status Epilepticus • Definition: continued seizures after 2 or 3 antiepileptic drugs have failed • Will usually need EEG monitoring at this point; typically titrate to burst suppression Managementof Refractory Status Epilepticus in the Child • Confirm this is truly an epileptic seizure and continue to look for underlying treatable cause • Call for back up from anesthetist or intensive care specialist Treatment of Refractory Status Epilepticus in the Child • • Inhalational anesthetics Pentobarbital • Propofol • Midazolam • Valproic acid • • Keppra Consider IV pyridoxine • Short acting; Significant side effects: respiratory depression, hypotension, myocardial depression, reduced cardiac output, pulmonary edema, ileus; Intubation and intravascualr monitoring usually required • Thiopental • Active metabolites which can accumulate; Possibly higher adverse reactions than pentobarbital • Intravenous anesthetic; Risk of hypotension, apnea and bradycardia • Contraindicated in child on ketogenic diet • Short half life; IV, IM, intranasal, PO, buccal or rectal • 0.1-0.3 mg/kg IV followed by 1mcg/kg/min IV infusion; increase every 15 minutes as necessary; maximum 8-10 mcg/kg/min • 20-40 mg/kg IV (diluted 1:1with normal saline or 5% dextrose in water) over 5-10 minutes; may repeat in 10-15 minutes. Follow with IV infusion of 5 mg/kg/hr Valproic acid • Not yet approved for initial treatment of SE • Appears effective and safe • Dosage – 20-40 mg/kg IV (diluted 1:1 with normal saline or 5% dextrose in water) over 5-10 minutes; may repeat in 10-15 minutes – Follow with IV infusion of 5 mg/kg/hr Propofol – Intravenous anesthetic – Small number of studies show effectiveness – Risk of hypotension, apnea and bradycardia – Contraindicated in child on ketogenic diet Midazolam – Short half life – IV, IM, intranasal, PO, buccal or rectal – Can be given as continuous IV infusion for refractory SE – Midazolam infusion • 0.1-0.3 mg/kg IV followed by 1mcg/kg/min IV infusion. • Increase every 15 minutes as necessary • Maximum 8-10 mcg/kg/min Pentobarbital • Short acting; used for refractory SE • Significant side effects: respiratory depression, hypotension, myocardial depression, reduced cardiac output, pulmonary edema, ileus • Intubation and intravascualr monitoring usually required • Thiopental – Used for refractory SE – Active metabolites which can accumulate – Possibly higher adverse reactions than pentobarbital Diagnostic assessment Riveillo et al: Practice Parameter: Diagnostic assessment of the child with status epilepticus (an evidence-based review) Neurology 2006;67:1542-1550 • CBC, electrolytes, calcium, glucose • Anticonvulsant levels (if applicable) • LP: only if there is clinical suspicion of meningitis – If this is first febrile seizure, presenting as status, LP will usually need to be performed • Consider toxicology testing • Metabolic and genetic testing: only if specific concern at first seizure (eg: history of recurrent lethargy, etc) • Consider neuroimaging: – MRI better sensitivity, but may not be available – CT better for evaluation of acute blood, skull fractures • Obtain EEG (not in acute period) Disposition • Patient gets admitted for observation for 24 hours Home treatments for Status Epilepticus • Diastat – Dosage: 0.5 mg/kg, round up – DIASTAT AcuDial • 10mg delivery system with a 4.4 cm tip (delivers doses of 5, 7.5 and 10 mg) • 20 mg delivery system with a 6.0 cm tip (delivers doses of 10, 12.5 and 20 mg) • Twin Pack of 2 pre-filled configurations (pharmacist locks in proper dosage) • Intranasal midazolam Neonatal Seizures Neonatal Status Epilepticus Etiology • • • • • • • Hypoxic ischemic encephalopathy CNS infection Intracranial Hemorrhage Cerebral Infarction Chromosomal abnormalities Congenital Brain abnormalities Metabolic Distubances – – – – Hypoglycemia Hypocalcemia Hypomagnesemia Pyridoxine dependency • Inborn errors of metabolism • Drug withdrawal or intoxication Neonatal Seizures Etiology Time of Onset Hypoxic ischemic encephalopathy 12-24 hour Drug withdrawal 24-72 hour Hypocalcemia (nutritional) 3-7 days Aminoaciduria/organic aciduria 3-7 days Differential Diagnosis of Neonatal Seizures by Peak Time of Onset Fenichel, 2nd ed. • 24 hours • 72 hours – 1 week 1. 2. 3. 4. 5. 6. 7. Meningitis/Sepsis Direct drug effect Hypoxic-ischemic encephalopathy Intrauterine infection Laceration of tentorium or falx Pyridoxine dependency Subarachnoid hemorrhage • 24-72 hours 1. 2. 3. 4. 5. 6. 7. 8. 9. Familial neonatal seizures Cerebral dysgenesis Cerebral infarction Hypoparathyroidism Intracerebral hemorrhage Kernicterus Nutritional hypocalcemia Methylmalonic/ propionic acidemia Urea cycle abnormalities 1. 2. 3. 4. 5. 6. 7. 8. 9. Meningitis/sepsis Drug withdrawal Cerebral contusion/SDH Cerebral dysgenesis IVH in newborns Pyridoxine dependency Subarachnoid hemorrhage Urea cycle abnormalities Hypoparathyroidsm-hypocalcemia • 1 week- 4 weeks 1. 2. 3. 4. 5. 6. 7. 8. Neonatal adrenoleukodystrophy Cerebral dysgenesis Fructose dysmetabolism Gaucher Type 2 Gm1 gangliosidosis Herpes simplex encephalitis MSUD Urea cycle abnormalities Diagnostic Assessment of Neonatal Seizures • Metabolic testing (screening) – – – – – – • LP – – – – – – • Blood glucose Calcium Ammonia Lactate pH electrolytes Cells Protein/glucose Cultures Herpes PCR Lactate/pyruvate Aminoacids Neuroimaging – – – Head ultrasound Head CT Brain MRI Neonatal Status Epilepticus Treatment • Etiology specific treatment if possible – Hypoglycemia • Correct with 10% glucose solution IV 2cc/kg • Maintenance glucose infusion to max of 8 mg/kg/min – Hypocalcemia • Treat with 10% calcium gluconate (100 mg/kg or 1ml/kg IV over 5-10 minutes while monitoring heart rate and infusion site; or calcium chloride (20mg/kg or 0.2 ml/kg) – Hypomagnesemia • Often associated with hypocalcemia • Treat with 50% solution of magnesium sulfate IM, 0.25 ml/kg – Pyridoxine dependency • Used empirically in infants with refractory seizures • While EEG monitoring, give 100 mg/kg IV Neonatal Status Epilepticus Treatment • Phenobarbital – Usually used first – Prolonged half life—100 hours after day 5-7; therefore watch for toxicity – 20 mg/kg IV (up to 40 mg); repeat 10/kg every 15-30 minutes times two • Phenytoin/Fosphenytoin – 20 mg/kg (over 30-45 minutes) – Half-life 100 hours – Nonlinear kinetics; redistribution, variable rate hepatic metabolism require individuallization of maintenance dosing • Benzodiazepine – Diazepam • 0.25mg/kg IV bolus or 0.5 mg/kg PR – Lorazepam • 0.05 mg/kg IV over2-5 minutes • Midazolam infusion References • • • • • • • Riviello JJ et al: Practice Parameter: Diagnostic assessment of the child with status epilepticus (an evidence based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 2006;67;1542-1550. Appleton et al: Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children, The Cochrane Collaboration, Volume (4), 2006. Fenichel GM: Clinical Pediatric Neurology: A Signs and Symptoms Approach, 5th Edition, Elsevier Suanders 2005, p 1-45. Mizrahi,EM and Kellaway p: Diagnosis and Management of Neonatal Seizures, Lippincott-Raven, Philadelphia, 1998,p. 181. Tharp, Barry: Management of Status Epilepticus in Children, Uptodateonlline.com The Status Epilepticus Working Party: The treatment of convulsive status epilepticus on children, Arch Dis Child 2000;83;415-419. Wolfe et al: Intranasal midazolam therapy for pediatric status epilepticus, American Journal of Emergency Medicine 2006; 24(3);343-346.