Etiology

The causes of SE are varied. In addition to epilepsy, any neurologic insult or systemic abnormality capable of inducing a seizure can theoretically cause SE.

The single most common cause of SE is anticonvulsant drug nonadherence or withdrawal. However, planned, physician-supervised medication withdrawal does not seem to confer increased risk of SE in selected patients who are seizure-free for at least 2 years.[9][12] Other common etiologies are: stroke and cerebral hemorrhage; alcohol use or withdrawal; drug withdrawal, overdose, and toxicity; central nervous system infection; cerebral tumors; trauma; metabolic abnormalities; febrile seizure; refractory epilepsy; and cardiac arrest.[13][14][15][16]​​​​ A rare cause of seizures of focal onset is Rasmussen encephalitis, an immune-mediated disease that usually occurs in children <10 years of age (although adolescents and adults can be affected). It is associated with progressive neurologic dysfunction and refractory seizures.[17]

A large number of cases of SE are cryptogenic, the majority of which end up with the diagnosis of epilepsy. New-onset refractory SE (NORSE) is a rare and devastating condition characterized by de novo onset of refractory SE (RSE) without an identifiable acute or active structural, toxic, or metabolic cause.[5][6]​​ NORSE refers to a clinical presentation rather than a specific diagnosis, and in many cases is presumed to have an autoimmune etiology.[5]​ In children, NORSE with a preceding febrile illness is termed FIRES (febrile infection-related epilepsy syndrome) and is a subset of NORSE.[18]

Pathophysiology

The pathophysiology of SE is complex, but is generally understood to occur when intrinsic mechanisms of seizure termination fail (whether due to excess excitation during a seizure, or to a loss of inhibition properties).[19][20] During a prolonged seizure, numerous physiologic changes occur that favor continued seizure activity; the longer a seizure lasts, the less likely it is to terminate on its own due to changes at the molecular level. In the initial seconds after seizure onset, protein phosphorylation and excitatory neurotransmitter release (primarily glutamate) set the stage for ongoing seizure activity.[20][21] This is followed by alterations in receptor expression, with inhibitory Type-A gamma-aminobutyric acid (GABA-A) receptors endocytosed, and excitatory N-methyl-D-aspartate (NMDA) receptors trafficked to the cell surface.[20][22][23][24] As benzodiazepines act through GABA-A receptors, this decrease in GABA-A receptor expression is thought to be the mechanism for decreased benzodiazepine-responsiveness as SE continues.[20][25][26] As a seizure progresses, increased excitatory neuropeptide synthesis and decreased inhibitory neuropeptide expression favors seizure continuation. If SE lasts for days to weeks, epigenetic changes and changes in gene expression occur.[20]

Systemically, clinical manifestations include hyperthermia, hypoxia, lactic acidosis, and hypoglycemia, which all contribute to neuronal injury and ultimately to hippocampal sclerosis.[27]

Classification

The International League Against Epilepsy (ILAE) Task Force: a definition and classification of status epilepticus[7]

This classification of SE is based on the clinical presentation. The two main criteria are:

  • The presence or absence of prominent motor symptoms

  • The degree (qualitative or quantitative) of impaired consciousness.

SE is classified as:

With prominent motor symptoms

  • Convulsive SE

    • Generalized convulsive

    • Focal onset evolving into bilateral convulsive SE

    • Unknown whether focal or generalized

  • Myoclonic SE (prominent epileptic myoclonic jerks)

    • With coma

    • Without coma

  • Focal motor

    • Repeated focal motor seizures (Jacksonian)

    • Epilepsia partialis continua

    • Adversive status

    • Oculoclonic status

    • Ictal paresis (i.e., focal inhibitory SE)

  • Tonic status

  • Hyperkinetic SE.

Without prominent motor symptoms

  • Nonconvulsive SE with coma (including so-called "subtle" SE)

  • Nonconvulsive SE without coma

    • Generalized

      • Typical absence status

      • Atypical absence status

      • Myoclonic absence status

    • Focal

      • Without impairment of consciousness (aura continua, with autonomic, sensory, visual, olfactory, gustatory, emotional/psychic/experiential, or auditory symptoms)

      • Aphasic status

      • With impaired consciousness

    • Unknown whether focal or generalized

      • Autonomic SE.

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