I. Introduction

Status epilepticus (SE) is a neurologic emergency characterized by continuous or rapidly recurring seizures lasting beyond 5 minutes, without full recovery of consciousness between episodes. Prompt recognition and intervention within this critical timeframe are essential to mitigate neuronal injury and reduce mortality.

• Definition: SE is operationally defined as continuous seizure activity for 5 minutes or more, or two or more discrete seizures between which there is incomplete recovery of consciousness.
• Urgency: Seizures persisting beyond 5 minutes are unlikely to terminate spontaneously and carry a significant risk of irreversible brain damage and systemic complications.

II. Epidemiology and Incidence

The incidence of status epilepticus (SE) exhibits a bimodal distribution, with peaks in neonates/infants and older adults (over 65 years). Incidence rates are notably higher in resource-limited settings, often due to a greater prevalence of CNS infections and limited access to preventative care and antiepileptic drugs.

• Global Incidence: In the United States, an estimated 50,000 to 150,000 cases of SE occur annually. Globally, particularly in low- and middle-income countries, the incidence is higher.
• Age Peaks: The highest incidence rates are observed in the very young (neonates and infants) and in adults aged 65 years and older.
• ICU Cohorts: In critically ill patients, acute symptomatic causes such as central nervous system (CNS) infections, stroke, and traumatic brain injury are predominant etiologies. Nonconvulsive status epilepticus (NCSE) can be particularly challenging to recognize and may account for up to 30% of seizures in the ICU setting.
• Data Gaps: Accurate estimation of SE incidence is hampered by variability in diagnostic definitions, underutilization of electroencephalography (EEG), and inconsistent reporting practices across different healthcare systems.

III. Risk Factors and Precipitating Causes

Status epilepticus often develops as a consequence of an acute neurological or systemic insult, particularly in individuals with underlying vulnerabilities. Common triggers include a history of epilepsy, CNS infections, cerebrovascular events, medication-related issues, and metabolic disturbances.

• Pre-existing Epilepsy: Individuals with a known diagnosis of epilepsy are at higher risk, with up to 25% experiencing an episode of SE during their lifetime.
• Genetic Predisposition: Certain genetic conditions, including channelopathies and inherited metabolic disorders, can predispose individuals to SE, especially in pediatric populations.
• CNS Infections: Encephalitis and meningitis are significant causes of SE, particularly in children and in regions with a high burden of infectious diseases.
• Cerebrovascular Events: Both ischemic and hemorrhagic strokes are common precipitants of SE in adults.
• Medication Nonadherence/Withdrawal: Abrupt cessation of antiepileptic drugs (AEDs) or benzodiazepines, as well as alcohol withdrawal, can trigger SE.
• Metabolic Derangements: Disturbances such as hypoglycemia, hyponatremia, and hypocalcemia can lower the seizure threshold and precipitate SE.
• Other Causes: Traumatic brain injury, brain tumors, and autoimmune encephalitis are also recognized causes.

IV. Pathophysiology

Status epilepticus arises from a critical imbalance between excitatory (primarily glutamatergic) and inhibitory (primarily GABAergic) neurotransmission. This disruption leads to sustained, synchronized neuronal firing and subsequent neuronal injury through various mechanisms.

• Neuronal Hyperexcitability: Excessive release of the excitatory neurotransmitter glutamate, coupled with overactivation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, drives sustained neuronal depolarization.
• GABAergic Failure: During prolonged seizures, inhibitory GABA-A receptors undergo internalization (removal from the cell surface) and alterations in their subunit composition. This process reduces the efficacy of GABAergic inhibition and contributes to benzodiazepine resistance.
• Excitotoxicity: Sustained neuronal firing leads to excessive intracellular calcium (Ca2+) influx. This calcium overload triggers a cascade of detrimental events, including mitochondrial dysfunction, activation of proteases and lipases, and ultimately, apoptotic and necrotic cell death pathways.
• Secondary Injury Mechanisms: Beyond direct excitotoxicity, SE provokes neuroinflammation, oxidative stress, disruption of the blood-brain barrier, and cerebral edema, all of which contribute to ongoing neuronal damage and worsen outcomes.
• Emerging Therapeutic Targets: Research is ongoing to identify novel treatments targeting these downstream pathways, including modulators of inflammation, oxidative stress, and receptor trafficking.

V. Clinical Manifestations

Status epilepticus can manifest in various forms, broadly categorized as convulsive, focal, or nonconvulsive. Nonconvulsive status epilepticus (NCSE) is particularly challenging as its signs can be subtle, requiring a high index of suspicion and EEG confirmation to avoid missed diagnoses and treatment delays.

• Generalized Convulsive SE (GCSE): Characterized by overt, bilateral tonic-clonic movements. Associated features include autonomic instability (tachycardia, hypertension, hyperthermia), risk of respiratory compromise, and a prolonged postictal state. GCSE is a medical emergency requiring immediate intervention.
• Focal SE: Seizure activity is restricted to a specific brain region. Manifestations can be motor (e.g., focal clonic jerking, versive movements, automatisms) or nonmotor (e.g., sensory disturbances, autonomic changes, cognitive symptoms like aphasia). Awareness may be preserved or impaired.
• Nonconvulsive SE (NCSE): Presents primarily with altered mental status, which can range from confusion or lethargy to coma. Other subtle signs may include minor motor phenomena (e.g., eyelid twitching, nystagmus, subtle jerks of a limb), aphasia, or behavioral changes. EEG is essential for the diagnosis of NCSE.

Diagnostic Pitfalls:

• Psychogenic non-epileptic seizures (PNES) can mimic convulsive SE, often leading to diagnostic confusion. Video-EEG monitoring can be invaluable in differentiation.
• Various conditions such as movement disorders, syncope, and metabolic or toxic encephalopathies can masquerade as NCSE, highlighting the need for careful clinical assessment and EEG correlation.

VI. Classification Schemes

Status epilepticus (SE) is classified based on its duration and the type of seizure activity observed. These classification systems are crucial for guiding the urgency of intervention, predicting prognosis, and standardizing research protocols.

A. Duration-Based Classification:

1. Operational (Impending) SE: Continuous seizure activity lasting longer than 5 minutes, or recurrent seizures without intervening recovery of consciousness. This is the point at which first-line therapy should be initiated.
2. Established SE: Seizure activity persisting for longer than 10–30 minutes despite initial therapy, or continuous seizure activity for 30 minutes or more. There is a heightened risk of neuronal injury at this stage.
3. Refractory SE (RSE): SE that continues despite treatment with an adequate dose of an initial benzodiazepine followed by an adequate dose of a second-line antiepileptic drug (AED).
4. Super-Refractory SE (SRSE): SE that persists for 24 hours or longer after the initiation of anesthetic agents, or SE that recurs on attempted withdrawal of these agents.

B. Type-Based Classification:

• Generalized Convulsive SE (GCSE): Involves tonic-clonic movements.
• Focal SE:
  • With impaired awareness (e.g., focal dyscognitive SE)
  • Without impaired awareness (e.g., epilepsia partialis continua)
• Nonconvulsive SE (NCSE): Characterized by altered consciousness and/or behavior with EEG evidence of seizure activity, but without major convulsive movements.

Implications: These classification systems are vital for guiding diagnostic urgency (e.g., need for emergent EEG), selecting and escalating therapies appropriately, predicting patient prognosis, and facilitating enrollment in clinical trials with standardized patient populations.