Jay K. Varma, MD

DESCRIPTION

Status epilepticus (SE) is defined as an episode of continuous seizure activity for 30 minutes or multiple recurrent seizures without a full return of consciousness in between events in the same span. Clinically, most seizures resolve within 3–5 minutes and those that last longer are less likely to resolve spontaneously; thus treatment should be initiated after 5 minutes of continuous seizure activity.

SE can be divided into convulsive and nonconvulsive forms. Convulsive forms may be generalized or partial; nonconvulsive forms may be absence (electroencephalogram (EEG) shows generalized spike and wave activity) or complex partial (in which the EEG shows localized rhythmic discharges).

EPIDEMIOLOGY

Incidence

• 10–61 per 100,000 per year.
• As with seizures in general, there is a higher incidence among the young and the elderly.

RISK FACTORS

• 30–44% of patients with SE have a history of epilepsy
• Prior SE
• Low levels of anti-epileptic drugs (AEDs)
• Metabolic abnormalities (hypo- or hyper-natremia, hypercalcemia, hyperglycemia, hepatic or renal insufficiency)
• Drugs/toxins: Alcohol abuse, theophylline, penicillins, cocaine, sympathomimetics, isoniazid (INH), amphetamines, baclofen, flumazenil, lithium, carbon monoxide, general anesthetics, antipsychotic medications, antidepressants, anticholinergic medications
• Structural lesions
• Head trauma
• Hypoxic injury
• CNS infection – meningitis, encephalitis, brain abscess
• Autoimmune or paraneoplastic antibodies (e.g. anti-N-methyl D-aspartate receptor antibodies, anti-GABA-B receptor antibodies, anti-voltage-gated potassium channel antibodies)
• Neoplasm (primary CNS or metastatic)
• Vascular lesion (arterio-venous malformation, acute or remote infarct, hemorrhage)

Pregnancy Considerations

Eclampsia is the new onset of generalized seizures during pregnancy or the postpartum period in a woman with signs or symptoms of pre-eclampsia (hypertension and proteinuria). Most older AEDs are pregnancy class D (evidence of risk to the fetus in humans), but the risks of SE to both the mother and fetus usually far outweigh the risks of the medications. Most of the newer medications are Category C (unknown adverse risk to the fetus).

Genetics

Rare genetic diseases may lead to epilepsy and/or a predisposition to developing SE.

GENERAL PREVENTION

Patients with epilepsy should be advised to strictly adhere to their prescribed medication regimen and to avoid factors that may incite seizures (e.g. sleep deprivation or alcohol use).

PATHOPHYSIOLOGY

Seizures are thought to be sustained by a combination of increased neuronal excitation and reduced inhibition. Whereas most seizures resolve spontaneously, SE is thought to be a failure of neuronal inhibition mechanisms, though the exact mechanism is unknown.

COMMONLY ASSOCIATED CONDITIONS

Epilepsy. See “Risk factors”.

[Outline]

• Information
• Description
• Epidemiology
  • Incidence
• Risk Factors
  • Pregnancy Considerations
  • Genetics
• General Prevention
• Pathophysiology
• Commonly Associated Conditions

HISTORY

• The diagnosis of generalized convulsive SE is often straightforward. Patients lose consciousness, develop tonic contraction of the limbs, often with eye deviation or head turning and typically followed by rhythmic clonic movements.
• Partial convulsive SE may present with repetitive clonic movements of a specific muscle group, such as a limb or hand, with or without alteration of mental status.
• Nonconvulsive SE (complex partial or absence) can present with a wide range of alteration of mental status from coma to mild inattention with word finding.

PHYSICAL EXAM

• Neurological examination may reveal altered mental status, repetitive clonic or myoclonic movements or focal deficits suggestive of a structural lesion.

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

• Provoking factors should be ruled out, even in patients with known epilepsy.
• Electrolytes including calcium, glucose, liver function tests (LFTs), and renal function tests as well as serum AED levels, serum and urine drug screens may identify an etiology.
• Lumbar puncture is indicated if meningitis or encephalitis is suspected.
• SE can result in metabolic acidosis; prolonged convulsive SE can lead to rhabdomyolysis and subsequent renal failure.

Imaging

Initial Approach

Noncontrast head CT can quickly diagnose intracranial hemorrhage or tumor if these are suspected. When the patient is stable, brain MRI with gadolinium can better identify structural lesions that may be causing seizures.

Diagnostic Procedures/Other

• EEG can help to establish the diagnosis; in refractory or nonconvulsive SE, continuous EEG recording can help to guide treatment and monitor its effectiveness.
• Lumbar puncture should be performed if subarachnoid hemorrhage, meningitis, or encephalitis is suspected.

DIFFERENTIAL DIAGNOSIS

• The differential diagnosis of convulsive SE, particularly generalized convulsive SE, is limited to psychogenic spells or movement disorders.
• The differential diagnosis for nonconvulsive SE is vast and is essentially the same as for altered mental status, including infectious, metabolic, toxic, autoimmune/inflammatory, trauma, and psychiatric causes.
• Video-EEG monitoring is the gold-standard study to distinguish between psychogenic spells and epileptic seizures.

[Outline]

• History
• Physical Exam
• Diagnostic Tests and Interpretation
  • Lab
    • Initial Lab Tests
  • Imaging
    • Initial Approach
  • Diagnostic Procedures/Other
• Differential Diagnosis

MEDICATION

First Line

• Thamine 100 mg IV should be administered first followed by 50 g of glucose unless the glucose level is known and not low.
• Benzodiazepines are the first-line agents in treatment of SE. The most commonly used agents are lorazepam and diazepam.
  • Lorazepam at 0.1 mg/kg IV up to a maximum dose of 8 mg administered at 2 mg/minute.
  • Diazepam 5–10 mg IV q5 minutes to a maximum of 30 mg in 8 hours.
• If the seizure resolves, begin treatment with phenytoin at 300 mg daily.
• If seizures continue, administer fosphenytoin 20 mg/kg IV at a rate of 150 mg/min. (If fosphenytoin is not available, phenytoin 20 mg/kg IV may be infused at a maximum rate of 50 mg/min.) Valproate may be substituted at 20 mg/kg IV in patients allergic to phenytoin or with hypotension.
  • Fosphenytoin is measured in “phenytoin equivalents”. Pharmacists automatically and universally convert all ordered doses of fosphenytoin to phenytoin equivalents.
• If seizures persist, proceed to 1 of these 4 options. At this point, intubation likely is necessary, especially if proceeding to midazolam or propofol. Continuous EEG recording can help guide treatment, particularly if the goal is suppression-burst.
  • IV valproic acid initiated with a 40 mg/kg loading dose over 10 minutes; continue treatment with 1,000 mg IV q6h.
  • IV phenobarbital initiated at 20 mg/kg infused up to 60 mg/min with maintenance dosing at 1–3 mg/kg/day in 2–3 divided doses.
  • A continuous infusion of midazolam initiated with boluses of 0.2 mg/kg over 2–5 minutes repeated every 5 minutes until the seizures stop up to a maximum dose of 2 mg/kg. The infusion can be started at 0.1 mg/kg/hour increased to a maximum of 2.9 mg/kg/hour until the seizure is controlled.
  • IV propofol beginning with boluses of 1–2 mg/kg IV over 3–5 minutes, repeated every 3–5 minutes until seizures stop up to a maximum of 10 mg/kg. Maintenance infusion can be initiated at 33 mcg/kg/min with the rate increased to a maximum of 250 mcg/kg/min until seizures are controlled.
• If seizures continue, begin continuous IV pentobarbital with a loading dose of 5 mg/kg IV up to 50 mg/min with repeat 5 mg/kg boluses until the seizures stop. Begin maintenance infusion at 0.5 to 10 mg/kg/hour titrating to seizure control or suppression-burst EEG pattern.
• Treatment of nonconvulsive SE is controversial.
• If IV access is not available, diazepam can be administered as a rectal gel or the IV solution (5 mg/mL) can be administered intramuscularly, intranasally, or buccally. Fosphenytoin can be administered IM. Phenytoin should not be administered intramuscularly due to inconsistent absorption.

Second Line

• Newer, nonsedating AEDs may be effective in the treatment of SE:
  • Levetiracetam IV administered with a loading dose of 2,500 mg IV over 5 minutes with maintenance dosing of 3,000–6,000 mg daily in 3–4 divided doses.
  • Lacosamide IV administered with a loading dose of 300 mg IV over 30 minutes with maintenance dosing of 200–300 mg IV or PO q12h.

ADDITIONAL TREATMENT

General Measures

• ABCs: Airway, breathing, and circulation.
• Continuous monitoring of oxygenation, heart rate, blood pressure, and EKG should be initiated early.
• Intubation and mechanical ventilation may be necessary and should occur if continuous benzodiazepine or barbiturate infusion is initiated.
• IV fluids or pressors may be necessary to treat hypotension.

Issues for Referral

Neurological consultation should be considered for all patients with SE.

Additional Therapies

• A ketogenic diet is an experimental treatment that may be a potentially effective treatment of highly refractory SE in combination with AEDs.
• Induced hypothermia is another experimental treatment that may be effective in treating refractory SE.

COMPLEMENTARY AND ALTERNATIVE THERAPIES

A ketogenic diet has been reported to have successfully treated several cases of highly refractory SE in combination with AEDs.

SURGERY/OTHER PROCEDURES

Surgery may be considered in extreme cases of highly refractory SE in patients with a known lesion amenable to resection.

IN-PATIENT CONSIDERATIONS

Admission Criteria

Nearly all patients with SE should be admitted for further observation. Patients should be admitted to the intensive care unit if respiratory or cardiovascular support is necessary.

[Outline]

• Medication
  • First Line
  • Second Line
• Additional Treatment
  • General Measures
  • Issues for Referral
  • Additional Therapies
• Complementary And Alternative Therapies
• Surgery/Other Procedures
• In-Patient Considerations
  • Admission Criteria

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• The patient should be observed closely for 24–48 hours to ensure the resolution of the seizure and the completion of the search for provoking factors. AEDs should be continued, particularly the medication that aborted the seizure. If only benzodiazepines were used to abort the seizure, the patient should be started on AEDs based on comorbidities and side-effect profile of the medications; neurological consultation is recommended.
• Continuous EEG recording can help diagnose nonconvulsive SE or recurrent subtle seizures, which should be suspected in patients with persistent altered mental status or prolonged focal weakness.

PATIENT EDUCATION

• Factors that provoke seizures can also provoke SE. Patients should be counseled regarding the need for medication adherence, avoidance of sleep deprivation, fatigue, and avoidance of physical or emotional stress.
• Patients with a history of SE may be prescribed abortive medications to be used in the pre-hospital setting, i.e. nasal, rectal, or buccal midazolam or oral lorazepam or clonazepam.

PROGNOSIS

• Morbidity from SE typically stems from the underlying cause (hemorrhage, stroke, tumor, etc.) and treatment (ventilator-associated pneumonia, hypotension, sepsis, etc.).
• Mortality from SE is between 10 and 40%, mostly dependent upon the etiology. SE as a result of alcohol withdrawal or intoxication or from low AED levels is associated with a lower mortality than SE due to an acute neurological insult.

COMPLICATIONS

• Many treatments for SE may induce hypotension, including fosphenytoin, phenytoin, midazolam, pentobarbital, phenobarbital, and propofol.
• Phenytoin and fosphenytoin can cause cardiac arrhythmias. Phenytoin is diluted in 40% propylene glycol, and administration can result in metabolic acidosis.
• Pentobarbital infusion can result in gastric stasis, myocardial suppression, thrombocytopenia, and metabolic acidosis (diluted in propylene glycol).
• Propofol infusion can cause hypertriglyceridemia, pancreatitis, and propofol infusion syndrome – a combination of metabolic acidosis, bradycardia, cardiac arrest and rhabdomyolysis.
• Lacosamide may prolong the PR interval.

[Outline]

• Follow-Up Recommendations
  • Patient Monitoring
• Patient Education
• Prognosis
• Complications

• DeLorenzo RJ, Pellock JM, Towne AR, et al. Epidemiology of status epilepticus. J Clin Neurophys 1995;12(4):316–325.
• Lowenstein D, Alldredge BK. Status epilepticus. N Eng Jour Med 1998;338(14):970–976.
• Rosetti AO, Hurwitz S, Logroscino G, et al. Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry 2006;77:611–615.
• Trinka E. What is the evidence to use new intravenous AEDs in status epilepticus? Epilepsia 2011;52(Supp 8):35–38.

ICD9

• 345.00 Generalized nonconvulsive epilepsy, without mention of intractable epilepsy
• 345.01 Generalized nonconvulsive epilepsy, with intractable epilepsy
• 345.3 Grand mal status

• Seizures lasting more than 5 minutes require emergent and aggressive intervention since they are unlikely to resolve spontaneously.
• Underlying provocative causes for status should be sought even in patients with known epilepsy.