Status Epilepticus

See Also

Epidemiology

Prevalence: 152,000 cases per year in United States
Age (Bimodal distribution)
1. Adults: Highest Incidence after age 60 years
2. Children: Highest Incidence under age 1 year

Definitions

Status Epilepticus Diagnostic criteria (2015)
1. Single unremitting Seizure lasting >5 minutes OR
2. Frequent clinical Seizures (>=2) without inter-ictal return to baseline lasting longer than 5 minutes
3. Trinka (2015) Epilepsia 56(10): 1515-23 [PubMed]
Older classical Status Epilepticus diagnostic criteria (deprecated, do not use)
1. Continuous Seizure activity longer than 30 minutes or
2. Two or more sequential Seizures
  1. No recovery of consciousness between Seizures

Pathophysiology

Excessive excitation (excess Glutamate)
Ineffective inhibition (inadequate GABA)
1. GABA aminobutyric receptors are also targeted by Benzodiazepines, Propofol
With prolonged Seizures
1. GABA Receptors (inhibitory) decrease on cell surface (Seizure becomes refractory)
2. NMDA receptors (excitatory) increase on cell surface

Types

Convulsive Status Epilepticus
1. Rhythmic jerking and generalized tonic clonic activity with Altered Mental Status
NonConvulsive Status Epilepticus
1. Electrographic (EEG) Seizure activity without clinical Seizure activity
Refractory Status Epilepticus
1. Persistent clinical or EEG Seizure activity despite 2 antiepileptic agents
2. Affects 10-40% of children with Status Epilepticus

Causes

See Seizure Causes
Poor Medication Compliance with low anticonvulsant drug levels
Alcohol Withdrawal
Drug Overdose (e.g. INH Overdose)
Toxin Ingestion
Intracranial Infection
1. Meningitis
2. Encephalitis
Intracerebral Hemorrhage
Cerebral Neoplasm
Metabolic disorder
1. Electrolyte disturbance (especially Sodium, Calcium and Phosphorus)
2. Inborn Errors of Metabolism
3. Vitamin B6 Deficiency

Signs

See definition above
Witnessed persistent Seizure
Consciousness not regained within 5 minutes of Seizure
Signs may be subtle (e.g. tonic Eye Deviation)

Labs

Bedside Glucose
Serum Electrolytes (e.g. Basic Metabolic panel with additional labs)
Hepatic panel
Venous Blood Gas
Antiepileptic drug levels
Urine Tox Screen
Complete Blood Count

Differential Diagnosis

See Altered Level of Consciousness
See causes as above
Rapidly reversible causes (with specific treatments)

Diagnostics
Indicated for refractory Status Epilepticus

Management
Initial

See ABC Management
Control airway
1. Nasal Airway
2. Consider intubation
Obtain IV Access with Normal Saline to keep open
Administer Supplemental Oxygen
Treat reversible causes (see below)
Monitor Vital Signs closely
1. Especially Temperature
2. Telemetry
3. Electrocardiogram

Management
Rapidly Reversible Causes

DONT Mnemonic (Dextrose, Oxygen, Naloxone, Thiamine)
Treat Hypoglycemia if present (based on bedside Glucose - consider if Glucose <80 mg/dl)
1. Neonate: 0.5 mg/kg (5 ml/kg) D10W
2. Child: 0.5 mg/kg (2 ml/kg) D25W
3. Adult: 50 ml IV of D50W
Consider Thiamine in Alcoholism or nutritional deficiency
1. Thiamine 100 mg IV or IM or
2. Thiamine 500 mg IV every 8 hours is used in Wernicke's Encephalopathy
Infants under age 2 years (empiric for Autosomal RecessivePyridoxine dependent Seizures)
1. Pyridoxine 10-15 mg/kg up to 100 mg IV
Severe Hyponatremia (typically in infant <3 months mistakenly fed free water)
1. Hypertonic Saline 5-10 cc/kg 3% saline over 10 minutes
Eclampsia
1. Magnesium Sulfate load 4 to 6 grams IV over 15-20 minutes, then maintain 2 to 3 g/hour
Alcohol Withdrawal
1. See Alcohol Withdrawal
2. Benzodiazepines or Phenobarbital Single Agent Alcohol Withdrawal Protocol
Isoniazid Overdose
1. Pyridoxine 70 mg/kg (up to 5 g) IV over 3 to 5 minutes
2. Benzodiazepines
Other serious causes with specific emergent management to consider
1. Meninigitis or Encephalitis
2. Intracerebral Hemorrhage

Management
Protocol

Precautions
1. Ensure ABC Management and reversible cause management (e.g. Hypoglycemia) as above
2. Goal of Status Epilepticus management is definitive Seizure control within 20-60 minutes of onset
3. Seizures are harder to control beyond 20 minutes due to loss of GABA Receptors
4. Post-ictal period and Somnolence may persist longer than typical 30 minutes following Status Epilepticus
5. One third of Status Epilepticus cases are refractory to Benzodiazepines
6. Following Benzodiazepines
  1. No evidence for one antiepileptic over another (Keppra, Phenytoin, Valproic Acid) in adults or children
    1. (2014) Ann Emerg Med 63(4): 437-47 [PubMed]
    2. Kapur (2019) N Engl J Med 381(22):2103-2113 [PubMed]
  2. Second-line agents fail 50% of the time
First: Benzodiazepines (choose one)
1. Precautions
  1. Do not underdose (give full dose early to have best chance to terminate Seizure)
  2. IV Lorazepam and IV Diazepam have equivalent efficacy in Status Epilepticus
  3. Midazolam IM, intranasal or buccal may be more effective than Diazepam IV or rectal
  4. Benzodiazepine effectiveness decreases (and respiratory depression increases) with each subsequent dose
  5. Neonatal Seizure
    1. Call pharmacy at presentation to have Phenobarbital available in case Benzodiazepines fail
2. Lorazepam (Ativan)
  1. IV: 0.1 mg/kg IV (<2 mg/minute) up to 4 mg
  2. Rectal: 0.1 mg/kg up to 4 mg
  3. May repeat once in 5-10 minutes
  4. Avoid more than 2 doses in children due to risk of respiratory depression
  5. Phamacokinetics: Onset in 2-3 minutes with duration of action 12-24 hours
  6. Avoid IM Lorazepam (unreliable in Status Epilepticus)
3. Diazepam (Valium)
  1. IV or IM: 0.1 to 0.3 mg/kg IV up to 8-10 mg/dose maximum
    1. May repeat once in 5 minutes
  2. Rectal: 0.5 mg/kg per Rectum up to maximum of 20 mg
    1. Instill via lubricated Feeding Tube inserted 4-5 cm into the Rectum OR
    2. Via tuberculin syringe (without needle) intra-rectally
    3. Hold buttocks closed after instilling medication
  3. Pharmacokinetics: Onset in 1-3 minutes with duration of action 5-15 minutes
    1. Must be immediately followed with longer acting anticonvulsant (e.g. Fosphenytoin) due to short duration
  4. Efficacy
    1. Diazepam is as effective as Lorazepam in Status Epilepticus
      1. Chamberlain (2014) JAMA 311(16): 1652-60
    2. Diazepam IM dosing is as effective as IV dosing
      1. Silbergleit (2012) N Engl J Med 366:591-600 [PubMed]
4. Midazolam (Versed)
  1. Preferred Intramuscular agent (when no IV Access available)
    1. Alternative when longer acting Benzodiazepines not available or without IV Access (e.g. Ambulance)
    2. Midazolam IM, intranasal or buccal may be more effective and more rapid than Diazepam IV or rectal
    3. Lorazepam and Diazepam are preferred if available for other routes
  2. IV: 0.15 mg/kg up to 4 mg (then infused IV at 1 mcg/kg/min and titrated every 5 min as needed) up to 10 mg
  3. IM: 0.2 mg/kg of the IV formulation up to 10 mg
    1. Weight 13-40 kg: 5 mg IM
    2. Weight >40 kg: 10 mg IM
  4. Rectal: 0.25 to 0.5 mg/kg
    1. May be delivered via tuberculin syringe (without needle) intra-rectally
    2. Commercial preparations are available for home use (Diastat AcuDial at $300 for 2 doses, age >2)
  5. Intranasal
    1. Dose: 0.2 to 0.4 mg/kg up to 10 mg of the IV formulation
    2. Typically given via syringe with MADD atomizer attached (roughly $15)
    3. Commercial preparations are available for home use (Nayzilam at $550 for 2 doses, age>12)
  6. Buccal mucosa: 0.5 mg/kg of the IV formulation
Next (if refractory after 5 minutes): Choose one
1. If Neonatal Seizure skip to Phenobarbital below (due to higher efficacy in this age group)
2. Not effective in Alcohol Withdrawal (continue with Benzodiazepines)
3. Pharmacokinetics: Both agents have onset within 10-30 minutes with a duration of action of 12-24 hours
4. Do not delay starting a second agent if no response to initial Benzodiazepines
5. Fosphenytoin (Cerebyx)
  1. Dose: 20 mg/kg IV or IM (at 3 mg/kg/min up to 150 mg/min) up to 1500 mg maximum
    1. Deliver slowly over 7 minutes
  2. Preferred over Phenytoin
    1. Fosphenytoin can be infused with dextrose
    2. Fosphenytoin has lower risk of Arrhythmia (due to no Ethylene Glycol in base)
    3. Fosphenytoin may be given IM or delivered a faster IV rate (not tissue toxic)
      1. However onset of activity is similar to that with Phenytoin
      2. Fosphenytoin is converted to active Phenytoin form
6. Phenytoin (Dilantin) - Fosphenytoin is preferred instead (see above)
  1. Dose: 20 mg/kg IV (at 1 mg/kg/min up to 50 mg/min) up to to 1500 mg maximum
    1. Deliver very slowly over 20 minutes
  2. May repeat once with Phenytoin 5-10 mg/kg IV
  3. Maintenance with Phenytoin 50 mg/min
7. Levetiracetam (Keppra)
  1. Dosing recommended in Status Epilepticus is higher
    1. Dose: 60 mg/kg IV (up to 4500 mg/dose) for single dose
  2. Typical dosing
    1. Load: 20-30 mg/kg IV at 5 mg/kg/min (may give additional second 20 mg/kg IV dose)
    2. Maximum: 3000 mg (or 80 mg/kg/day)
  3. IV formulation is not FDA approved in children
  4. Keppra is as effective as Phenytoin as second-line after initial Benzodiazepine dosing in children and adults
    1. Noureen (2019) J Clin Neuro 15(4): 468-72 [PubMed]
8. Valproic Acid (Depakote)
  1. Dosing recommended in Status Epilepticus is higher
    1. Load: 20 to 40 mg/kg IV (up to 3000 mg/dose)
      1. Infuse slowly (no faster than 6 mg/kg/min)
    2. Maintain: 5 mg/kg/hour or 4 to 8 mg/kg IV three times daily (adjusting based on serum levels)
  2. Adverse effects
    1. Less sedation, respiratory depression, and cardiovascular effects than any of the other agents
    2. Risk of hepatotoxicity
    3. Risk of hyperammonemia (avoid in age under 2 years, especially if inborn error of metabolism)
Next (if refractory after 30 minutes)
1. Phenobarbital (less commonly used in 2020 - used if second line options not available or Neonatal Seizure)
  1. Dose: 15 to 20 mg/kg IV
    1. May repeat twice with Phenobarbital 5-10 mg/kg IV
    2. Maximal infusion rate: 0.5 to 1 mg/kg/minute up to 50 mg/min
  2. Pharmacokinetics: Onset within 10-20 minutes and duration of 1-3 days
  3. Be prepared to ventilate patient
  4. More effective than Phenytoin as a second line agent in pediatric Seizure
    1. Burman (2019) Front Neurol 10:506 [PubMed]
Next (if refractory after 60 minutes)
1. Preparation
  1. Requires full life support (coma state)
    1. Intubate and ventilate
    2. Rapid Sequence Intubation
      1. Consider Pentobarbital, Benzodiazepines, Ketamine or Propofol for induction agent
  2. Foley Catheter
  3. Electroencephalogram (EEG)
    1. Dosages below titrated based on EEG
    2. Infusion slowed every 4-6 hours to check EEG status
  4. Follow Temperature closely
    1. Treat hyperthermia with rectal Acetaminophen 15 mg/kg up to 650-1000 mg every 6 hours
  5. Pressor support
    1. Often required for next set of medictions
2. Choose one medication (combined post-intubation sedation AND antiepileptic)
  1. See Phenobarbital as above
  2. Propofol (Diprivan)
    1. Load: 1 to 2 mg/kg IV
    2. Maintain: 2-10 mg/kg/hour if Propofol loading dose aborted the Seizure
    3. Anticipate apnea and Hypotension with rapid infusion
    4. Risk of Propofol Infusion Syndrome (esp. children)
      1. Catastrophic outcomes with use >48 hours, esp. at high dose (e.g. 10 mg/kg/h)
      2. Do not use Propofol for extended time, especially in children
      3. Lower risk of Propofol Infusion Syndrome with doses <5 mg/kg/hour
  3. Pentobarbital (Nembutal)
    1. Load: 5 mg/kg IV (up to 15 mg/kg, coma dose)
    2. Maintain: 0.5 to 1 mg/kg/hour (up to 5 mg/kg/hour)
    3. Anticipate myocardial depression with secondary reduced Cardiac Output and Hypotension
  4. Midazolam (Versed)
    1. Load: 0.2 mg/kg IV
    2. Maintain: 1 mcg/kg/min
    3. Titrate: Increase by 1 mcg/kg/min every 15 minutes until burst suppression (up to 0.75 to 10 mg/hour)
    4. Anticipate respiratory depression
  5. Ketamine (alternative agent, Pentobarbital, Midazolam, Propofol are preferred)
    1. Antagonizes NMDA receptors and AMPA receptors
    2. Dose: 1.5 to 2 mg/kg
    3. If Ketamine aborts Seizure, then start Propofol maintenance at dose as above
    4. Case reports of neurotoxicity in adults

Prognosis

Mortality
1. Overall: 22%
2. Children: 3%
3. Adults: 26%
4. Elderly: 38%
5. DeLorenzo (1996) Neurology 46:1026-35 [PubMed]
Morbidity
1. High Incidence of neurologic sequelae
2. Worse outcomes with longer duration of Seizure

Complications
Prolonged Seizure

Anoxic brain injury
Death
Rhabdomyolysis (after 30-60 minutes of Seizure)
Hypoglycemia
Metabolic Acidosis
Aspiration

References

Fuchs and Yamamoto (2012) APLS, Jones and Bartlett, Burlington, p. 191-7
Lu, Claudius and Behar in Herbert (2013) EM:Rap 13(12): 12-3
Morgenstern in Herbert (2020) EM:Rap 20(10):12-4
Nocera, Valente, Amanullah (2018) Crit Dec Emerg Med 32(11): 3-9
(1993) JAMA 270:854-9 [PubMed]
Abend (2008) Pediatr Neurol 38(6): 277-390 [PubMed]
Glauser (2016) Epilepsy Currents 16(1): 48-61 [PubMed]
Hanhan (2001) Pediatr Clin North Am 48(3): 1-12 [PubMed]
Lowenstein (1998) N Engl J Med 338:970-6 [PubMed]
Sirven (2003) Am Fam Physician 68(3):469-76 [PubMed]