What are the definitions of seizure and status epilepticus, their differential diagnoses, and the recommended management?

Seizure and Status Epilepticus: Definitions, Differentials, and Management

Definitions

A seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain 1. Epilepsy is defined by the International League Against Epilepsy (ILAE) as having either: 1) at least two unprovoked seizures occurring more than 24 hours apart, 2) one unprovoked seizure with a probability of recurrence similar to the general recurrence risk after two unprovoked seizures over the next 10 years, or 3) diagnosis of an epilepsy syndrome 1.

Status epilepticus (SE) is defined as unremitting convulsive seizure activity lasting 5 minutes or more, or intermittent seizures without regaining full consciousness 1, 2. The ILAE definition identifies two critical timepoints: t1 (when the seizure does not self-terminate—5 minutes for convulsive SE) and t2 (when ongoing seizure activity risks long-term consequences including neuronal injury—30 minutes for convulsive SE) 2.

Seizures are classified as focal onset (arising within networks of a single cerebral hemisphere), generalized onset (rapidly affecting both hemispheres), or unknown onset 1.

Differential Diagnoses

When evaluating seizures and status epilepticus, emergency physicians must search for treatable underlying causes 1:

Metabolic and Systemic Causes

• Hypoglycemia 1
• Hyponatremia 1
• Hypoxia 1
• Drug toxicity (prescribed medications like tramadol or illicit substances like cocaine can lower seizure threshold) 1

Infectious Causes

• Systemic infection 1
• CNS infection (meningitis, encephalitis) 1
• Autoimmune encephalitis 3

Structural Causes

• Ischemic stroke 1
• Intracerebral hemorrhage 1
• Traumatic brain injury 1, 3
• Brain tumors 1
• Vascular malformations 1
• Developmental abnormalities 1

Other Causes

• Withdrawal syndromes (alcohol, benzodiazepines) 1
• Cardiac arrest 3
• Noncompliance with antiseizure medications 1

Mimics to Consider

• Prolonged psychogenic nonepileptic seizure 4
• Status dystonicus 4
• Nonconvulsive status epilepticus (requires EEG for diagnosis) 3, 4

Management Algorithm

First-Line Treatment: Benzodiazepines

Benzodiazepines are the first-line treatment for status epilepticus and must be administered with optimal dosing 1. Simultaneously, initiate supportive measures including airway management, oxygen, IV access, and assess for treatable causes 1.

Second-Line Treatment: After Benzodiazepine Failure

For patients with generalized convulsive status epilepticus who continue to have seizures despite optimal dosing of benzodiazepines, emergency physicians should administer an additional antiepileptic medication 1. The Neurocritical Care Society recommends urgent control of seizures with any of the following: valproate, levetiracetam, phenobarbital, or phenytoin/fosphenytoin 1.

Valproate (Level B Recommendation)

• Valproate is at least as effective as phenytoin for refractory status epilepticus with potentially fewer adverse effects 1
• Dosing: 20-30 mg/kg IV at a rate of 40 mg/min 1
• Efficacy: 79% seizure control as second-line agent versus 25% with phenytoin (NNT 1.9) 1
• Advantage: No hypotension risk (12% with phenytoin versus 0% with valproate) 1
• Adverse effects: Dizziness, thrombocytopenia, liver toxicity, hyperammonemia 1

Phenytoin/Fosphenytoin (Level B Recommendation)

• Traditionally used but has numerous drawbacks including lower efficacy 1
• Phenytoin dosing: 18-20 mg/kg IV at maximum rate of 50 mg/min 1
• Fosphenytoin dosing: 18-20 PE/kg IV at maximum rate of 150 PE/min 1
• Efficacy: Only 56% success in terminating SE when diazepam followed by phenytoin was used 1
• Adverse effects: Hypotension, cardiac dysrhythmias, soft tissue injury with extravasation, purple glove syndrome 1

Levetiracetam (Level C Recommendation)

• Levetiracetam shows promise as treatment for status epilepticus refractory to benzodiazepines 1
• Dosing: 30-50 mg/kg IV load at 5 mg/kg per minute 1
• Efficacy: 68-73% seizure cessation when compared to valproate 1
• Advantage: Minimal adverse effects (nausea, transient transaminitis in isolated cases) 1
• Limitation: Most studies used levetiracetam as third-line rather than second-line agent 1

Third-Line Treatment: Refractory Status Epilepticus

For refractory SE (continuing despite benzodiazepines and second-line agents), emergency physicians may administer propofol or barbiturates 1. The European Federation of Neurological Societies recommends anesthetic doses of midazolam, propofol, or barbiturates 1.

Propofol (Level C Recommendation)

• Dosing: 2 mg/kg bolus, followed by 5 mg/kg per hour infusion 1
• Efficacy: As effective as pentobarbital but requires fewer mechanical ventilation days (4 versus 14 days) 1
• Advantage: Less hypotension than barbiturates (42% versus 77% requiring pressors) 1

Barbiturates (Level C Recommendation)

• Phenobarbital dosing: 10-20 mg/kg; may repeat 5-10 mg/kg at 10 minutes 1
• Pentobarbital dosing: 13 mg/kg bolus; infusion of 2-3 mg/kg per hour 1
• Efficacy: 92% success with pentobarbital versus 73% with propofol 1
• Limitation: Increased adverse effects including hypotension and respiratory depression 1

Super-Refractory Status Epilepticus

SE that continues despite propofol or midazolam or reemerges after weaning is labeled super-refractory SE 3. Management may include ketamine, additional barbiturates, or non-sedating compounds 3. Continuous video EEG is necessary for management as these cases are almost always nonconvulsive 3.

Critical Management Principles

Condition-specific treatment must be given if a provoking cause is discovered 1. This includes treating hypoglycemia, correcting electrolyte abnormalities, addressing infections, and managing withdrawal syndromes 1.

Continuous EEG monitoring is critical for management of refractory and super-refractory SE 3, 5. Nonconvulsive SE requires EEG for reliable diagnosis 3.

Time is critical: Minimizing time to administration of first- and second-line therapy is necessary to optimize chances of successful seizure termination and minimize neuronal injury 5. Changes in neurotransmission as SE progresses increase excitatory mechanisms and decrease inhibitory mechanisms at the cellular level 6.

Common Pitfalls

Avoid underdosing benzodiazepines as optimal dosing is essential before declaring treatment failure 1.

Do not delay second-line therapy waiting for laboratory results or imaging when SE continues 1.

Recognize that phenytoin has lower efficacy and more adverse effects than valproate despite traditional use 1.

Be aware that prescribed medications can lower seizure threshold and obtain medication history early 1.

Understand that mortality increases with refractoriness: 10% in responsive cases, 25% in refractory SE, and nearly 40% in super-refractory SE 3.