Status Epilepticus

Basics

ALERT
The various forms of status epilepticus (SE) represent critical neurologic conditions associated with significant morbidity and mortality rates, requiring prompt diagnosis and rapid seizure control to minimize permanent neuronal injury.

Description

  • Recently revised definition of SE asserts that SE is a result of failure of the processes responsible for seizure cessation or from the initiation of mechanisms, which lead to abnormally prolonged seizures (T1).
    • T1 defines the time point that is considered “prolonged” and is different depending on the type of SE that is present.
    • T1 determines the earliest time when treatment should be started.
    • For convulsive SE, it is set at 5 minutes; for nonconvulsive SE, it is set at 10 minutes; and for absence SE, it is set at 2 minutes.
  • Furthermore, SE is defined as a condition that can cause permanent brain injury and place patients at risk for systemic cardiopulmonary complications, if not terminated within a set time period (T2), leading to neuronal death, neuronal injury, and/or alteration of neuronal networks.
    • T2 defines the time point at which SE should be controlled to prevent long-term consequences.
    • For convulsive SE, it is set at 30 minutes; for nonconvulsive SE, it is set at 30 to 60 minutes; and for absence SE, it is unknown.
  • SE presents in various forms and revised classification has divided it into the following:
    • SE with prominent motor symptoms: encompassing convulsive SE, characterized by excessive abnormal muscle contractions, which may be sustained or interrupted; generally tonic–clonic in nature
    • SE without prominent motor symptoms: encompassing nonconvulsive SE, characterized without prominent motor symptoms, comprising continuous or fluctuating states of mentation without tonic–clonic activity
    • Refractory SE: seizure activity persisting despite adequate treatment with initial and secondary pharmacologic treatment

Epidemiology

Incidence
  • Overall incidence is 9.9 to 41 cases per 100,000 per year.
    • A recent meta-analysis found the pooled incidence rate to be 12.6/100,000 per year.
  • Results of trend studies show an increase in incidence of SE in the past few decades in the United States.
  • 760,117 hospital discharges with a diagnosis of SE from 1979 to 2010, with SE accounting for 0.07% of all hospital admissions in the United States over this period
  • Predominant sex: male > female (annual relative risk 1.1 in males, P < .0001)
  • Racial differences: blacks (13.7/100,000) > other races (7.4/100,000) > whites (6.9/100,000)
  • Bimodal age distribution: greatest number in those <1st decade of life (14.3/100,000) and >60 years (28.4/100,000)
    • Other prospective population studies show similar bimodal distribution of SE.
    • Elderly subjects with SE had a higher case fatality rate and crude annual incidence rate.

Prevalence
  • 125,000 to 195,000 patients per year present with generalized convulsive SE.
  • Mortality rates in the United States range from 19% to 22% based on two large prospective population-based studies.
    • The overall mortality rates do not show a change in trend over the last few decades.
  • Cost: Mean hospital costs $18,834 in United States and annual direct costs are projected at $4 billion.

Etiology and Pathophysiology

  • Etiologies differ in adults and the pediatric population with anticonvulsant noncompliance being the most common cause of SE in adults and acute symptomatic seizures and remote symptomatic epilepsy being the most common etiology of SE in children.
  • Pediatric consideration:
    • Infection with fever not involving CNS (52% of cases) was the major etiology of SE and then remote CNS insult (39%) and low anticonvulsant levels (21%).
  • Adult consideration:
    • Three major etiologies include low anticonvulsant levels (34%), remote symptomatic epilepsy (24%), and CVA (22%).
  • Geriatric consideration:
    • The most important cause of SE is CVA, followed by acute cardiac, respiratory, or hepatic decompensation, trauma, epilepsy, and dysnatremia.
  • Cerebrovascular diseases:
    • Ischemic stroke, bleeding (intracerebral, subarachnoid), hematoma (subdural, epidural), sinus venous thrombosis, vascular dementia, tumors
  • CNS infections:
    • Meningitis, encephalitis, PML, toxoplasmosis, TB, prion disease, fungal disease, HIV-related disease
  • Neurodegenerative diseases:
    • Alzheimer disease, frontotemporal dementia, etc.
  • Head trauma:
    • Closed, open, penetrating head injury
  • Intoxications:
    • Alcohol (intoxication, withdrawal, Wernicke), drugs, neurotoxins, heavy metals
  • Withdrawal or low antiepileptic drugs levels
  • Cerebral hypoxia or anoxia
  • Metabolic disturbances:
    • Electrolyte imbalance, glucose imbalance, organ failure, acidosis, renal failure, hepatic encephalopathy
  • Autoimmune disorders:
    • Multiple sclerosis (MS), Hashimoto encephalopathy, anti-NMDA encephalopathy, SLE
  • Idiopathic, cryptogenic

Risk Factors

Risk factors of SE linked to its etiology above; a previous history of SE (recurrence rate in children, 17%; in those with neurologic abnormality, 50%)

Commonly Associated Conditions

Movement disorders, psychogenic; transient ischemic attack (TIA), CVA, migraines, somatoform disorders, Todd paralysis

Diagnosis

History

  • Convulsive SE is a clinical diagnosis, commonly presenting with sustained tonic–clonic motor activity.
    • Assess time of onset and offset, warning signs, parts of body involved in motor activity.
  • The diagnosis of subtle SE or nonconvulsive is challenging, requiring high index of suspicion and a low threshold for obtaining EEG monitoring.
  • Ascertain history of previous seizures, family history, drug history, toxic exposure, prior CVA, history of infection, compliance with mediation regimen, trauma, change in any mentation.

Physical Exam

  • Assess airway, breathing, circulation, and GCS (if <8, proceed to intubation to protect patient’s airway).
  • Vital signs: Look for febrile illness, especially in kids.
  • Detailed neurologic examination:
    • Look for localizing signs of CNS lesion, rule out nonepileptic SE, assess movement activity, look for meningismus, assess pupils.
    • Assess postictal findings: fever, tachycardia, mydriasis, conjugate deviation of eyes, decreased corneal reflex, positive Babinski sign, Todd paralysis, fecal/urinary incontinence, injury (tongue, cheek, lips).

Differential Diagnosis

  • Movement disorders (myoclonus, asterixis, tremor, chorea, tics, dystonia)
  • Herniation syndromes, postanoxic myoclonus
  • Psychiatric disorders (psychogenic nonepileptic seizures, conversion disorder, acute psychosis, catatonia)
  • Any condition leading to decreased mentation

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)
  • Initial diagnostic workup based on Neurocritical Care Society recommendations include the following:
    • Vital sign monitoring, fingerstick glucose (1)[A]
    • Glucose, CBC, BMP, calcium (total and ionized), magnesium, antiepileptic drug level (1)[A]
    • CT brain
  • Tailor workup based on clinical scenario and may require the following based on suspected etiology:
    • Other laboratory tests: liver function tests (LFTs), serial troponins, type and screen, coagulation studies, ABG, comprehensive toxicology panel, UDS, carboxyhemoglobin
    • Brain MRI, EEG, ECG, chest radiography

Follow-Up Tests & Special Considerations
  • If patient is not awake 5 to 30 minutes after a seizure, continuous EEG monitoring must be considered (1)[A].
  • Comatose patients should undergo a minimum of 48 hours of 21 electrode EEG monitoring, whereas noncomatose patients may only require 24 hours.
Diagnostic Procedures/Other
  • Lumbar puncture: if meningitis is suspected
  • EEG: to differentiate nonepileptic seizures; to reveal nonconvulsive SE in comatose or paralyzed patient; to confirm successful treatment
  • Continuous EEG: to follow/manage therapy

Treatment

The most important element of successful termination of seizures is the time elapsed before initiating treatment. Simultaneous goals are to stop the seizure, find the cause, and prevent complications (1)[A].

  • Treatment initiated within 30 minutes of seizure onset is successful in 80% of cases but only 40% beyond the 2-hour window.
  • Mortality doubles with a 24-hour delay in treatment.
  • Support ABCs and monitor vital signs, temperature, ECG, and continuous EEG. Establish two IV lines.
  • Check and treat hypoglycemia immediately.
  • IV, IO, or IM lorazepam is preferred because it is less lipid soluble and does not undergo rapid redistribution into peripheral tissues as with other benzodiazepines, although in the prehospital setting, IM midazolam can also be a first-line therapy (1)[A].
    • Recently, intranasal lorazepam has been proposed as an alternative, with favorable pharmacokinetics and rapid absorption.
    • Buccal midazolam may be an alternative if IV or IM application is not possible.

ALERT
If seizure persists after initial therapy with two drugs, do not delay; move on to refractory treatment with anesthesia/drug coma, typically requiring intubation.

  • Hemodynamic instability may require fluid resuscitation or vasopressors and continue to pursue the underlying cause during treatment.
  • Refractory SE will often require endotracheal intubation and occurs in approximately 1/3 of cases even with adequate initial therapy.

General Measures

Protect from injury, clear/suction airway, prevent tongue laceration.

Medication

ALERT
Begin therapy with two drugs: (i) a benzodiazepine to stop seizure and (ii) an antiepileptic drug to prevent recurrence or stop continuing seizure activity.

First Line
  • Emergent initial therapy to stop seizure
    • Lorazepam (Ativan) IV: preferred benzodiazepine (1,2)[A]
      • 0.1 mg/kg per dose, max dose 4 mg IV at 2 mg/min
      • May repeat q5–10min × 2 doses
      • Pediatric: 0.1 mg/kg IV at <2 mg/min to a maximum dose of 4 mg
    • Diazepam (Valium) (1,2)[A]: IV/PR (Avoid IM because it’s painful.)
      • 0.15 to 0.20 mg/kg per dose, max dose 10 mg IV
      • May repeat dose q5–10min × 2 doses
      • PR dose 0.2 to 0.5 mg/kg, max dose 20 mg per dose
      • Pediatric: 0.3 mg/kg at <2 mg/min IV up to 10 mg; may repeat q5min × 3 doses
      • Pediatric 2 to 5 years PR dose: 0.5 mg/kg; 6 to 11 years: 0.3 mg/kg; >12 years: adult dose
    • Midazolam (Versed) (1)[A]: IM 10 mg for >40 kg, 5 mg for 13 to 40 kg, single dose; IV 0.2 mg/kg; also can give buccal, intranasal
  • Urgent control therapy to prevent recurrence or to stop continuing seizure
    • Fosphenytoin (Cerebyx) (1)[B]
      • 20 mg phenytoin equivalents (PE) per kg IV, IM, or IO at 100 to 150 mg PE/min (follow BP, ECG); max dose 1,500 mg PE per dose
      • 5 mg PE/kg IV/IM can be given 10 minutes after the loading dose if seizures persist.
      • Maintenance: 4 to 6 mg PE/kg/day in divided doses IV/IM
      • Pediatric: same doses as for an adult at <3 mg PE/kg/min
      • Goal serum level (measured as phenytoin) of 10 to 20 mg/dL
    • Valproic acid (preferred over phenytoin and levetiracetam) (1)[A]
      • 20 to 40 mg/kg administered at 5 mg/kg/min; max dose 3,000 mg per dose
      • Maintenance: 3 to 6 mg/kg/min
      • Pediatric: 1.5 to 3.0 mg/kg/min
    • Phenytoin IV (1)[B]: 20 mg/kg IV at 25 to 50 mg/min; cardiac monitoring required
      • Goal serum level of 15 to 20 mg/dL
      • More cardiovascular side effects than fosphenytoin
    • Alternatives if contraindication to above
      • Levetiracetam: 60 mg/kg; max dose 45,000 mg per dose IV at 500 mg/min
      • Phenobarbital: 15 to 20 mg/kg IV at 50 mg/min
      • Midazolam infusion: 0.1 to 0.2 mg/kg/hr
  • For refractory SE
    • Consider transfer to a neuro ICU, intubation, and induction with anesthetics/drug coma with continuous EEG; titrate EEG to burst suppression.
    • Maintain anesthetic for 24 hours and then taper gradually over 12 to 24 hours while adjusting maintenance anticonvulsant therapy.
    • Drug choices (use one)
      • Propofol (Diprivan) (1)[B]
        • 1 to 2 mg/kg IV bolus at rate of 2 mg/min (in elderly, halve initial dose)
        • Follow with 33 to 167 μg/kg/min IV; titrated to EEG
      • Midazolam (Versed) (1)[B]
        • 0.2 mg/kg slow IV bolus injection, can repeat q5min up to 2 mg/kg total dose
        • Follow with 0.1 to 0.2 mg/kg/hr IV; max 0.4 mg/kg/hr
        • Recommended drug in hemodynamically unstable patient
      • Pentobarbital (1)[B]
        • 10 mg/kg IV loading dose at 50 mg/min
        • Follow by continuous infusion of 1 to 4 mg/kg/hr; adjust based on EEG.
      • Additional considerations if seizures persist
        • Topiramate (1)[C]
        • Ketamine (1)[C]
        • Magnesium
        • Lacosamide
  • Contraindications:
    • Propofol in allergy to soybean oil, egg, lecithin, or glycerol
    • Barbiturates in acute intermittent porphyria
    • Valproic acid in hepatic disease, coagulopathy, and pregnancy (risk of neural tube defects)
  • Precautions:
    • Propofol: propofol infusion syndrome (lactic acidosis, lipemia, cardiac and renal failure, systemic collapse, and death); not approved in the United States for children <3 years
    • Diazepam IV: may cause thrombosis/phlebitis
    • Fosphenytoin (Cerebyx) and phenytoin
      • Abrupt withdrawal may precipitate SE. Overdose may cause paradoxical inefficacy.
      • Monitor for arrhythmias, prolonged QT interval, and hypotension. Use caution in liver disease, hyperglycemia, the elderly, and pregnancy.
    • Phenytoin: Infiltration may cause local ischemia (purple glove syndrome).
    • Valproic acid: may decrease platelet function and cause hyperammonemic encephalopathy, pancreatitis, or hepatotoxicity

Additional Therapies

  • In suspected alcoholism: thiamine, 100 mg IV/IM (before or promptly after dextrose)
  • If hypoglycemic: D50 dextrose IV
    • Pediatric: Use D25W; give 2 mL/kg slowly.
  • If pupils are miotic or opioid overdose is suspected: naloxone (Narcan); may require continuous infusion
  • If suspected eclampsia of pregnancy: magnesium
  • If hyponatremia, 100 mL 3% NaCl when appropriate (see “Hyponatremia”)

Admission, Inpatient, and Nursing Considerations

All SE patients need to be admitted. Discharge when seizures controlled; therapeutic anticonvulsant levels

Ongoing Care

Patient Education

Reinforce importance of continuing anticonvulsant medications and avoiding alcohol.

Prognosis

  • Prognosis is largely dependent on the etiology of SE with poor prognoses associated with anoxia (60–100% mortality), CVA (20–60%), and metabolic disorders (10–35%).
  • Age also impacts prognosis with reported mortality 19–27% in adults, 3–19% in children, extremely high in neonates, and up to 76% in the elderly.
  • With seizure duration >1 hour, mortality is 37%; >4 hours, 50%; >12 hours, 80%

Complications

Morbidity/mortality is usually related to underlying etiology, complications from repeated seizures, or complications of treatment instituted.

Additional Reading

See Also

Seizure Disorders ; Seizures, Febrile

Codes

ICD-10

  • G40.011 Local-rel idio epi w seiz of loc onset, ntrct, w stat epi
  • G40.101 Local-rel symptc epi w simp part seiz, not ntrct, w stat epi
  • G40.111 Local-rel symptc epi w simple part seiz, ntrct, w stat epi
  • G40.201 Local-rel symptc epi w cmplx prt seiz, not ntrct, w stat epi
  • G40.211 Local-rel symptc epi w cmplx partial seiz, ntrct, w stat epi
  • G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus
  • G40.311 Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus
  • G40.401 Oth generalized epilepsy, not intractable, w stat epi
  • G40.411 Oth generalized epilepsy, intractable, w status epilepticus
  • G40.501 Epileptic seiz rel to extrn causes, not ntrct, w stat epi
  • G40.801 Other epilepsy, not intractable, with status epilepticus
  • G40.811 Lennox-Gastaut syndrome, not intractable, w stat epi
  • G40.901 Epilepsy, unsp, not intractable, with status epilepticus
  • G40.911 Epilepsy, unspecified, intractable, with status epilepticus

ICD-9

  • 345.00 Generalized nonconvulsive epilepsy, without mention of intractable epilepsy
  • 345.10 Generalized convulsive epilepsy, without mention of intractable epilepsy
  • 345.3 Grand mal status
  • 345.80 Other forms of epilepsy and recurrent seizures, without mention of intractable epilepsy

SNOMED

  • 13973009 grand mal status (disorder)
  • 230456007 Status epilepticus (disorder)
  • 230459000 Non-convulsive simple partial status epilepticus (disorder)
  • 434201000124105 Grand mal status epilepticus, refractory (disorder)
  • 434211000124108 Grand mal status epilepticus, non-refractory (disorder)
  • 434501000124107 Complex partial status epilepticus, refractory (disorder)
  • 434511000124105 Complex partial status epilepticus, non-refractory (disorder)
  • 442512002 Nonconvulsive status epilepticus (disorder)

Clinical Pearls

  • SE is life threatening; begin treatment immediately even before etiology is known and start with IV lorazepam or IM midazolam and add antiepileptic urgently.
  • If not controlled with first-line drugs and second-line drugs, intubate, induce general anesthesia/drug coma, and admit to ICU.

Authors


Muhammad Durrani, DO, MS
Amy Ondeyka, MD

Bibliography

  1. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48–61.  [PMID:26900382]
  2. Prasad K, Krishnan PR, Sequeira R, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014;(9):CD003723. [PMID:25207925]


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