Although every seizure type can theoretically persist and evolve into SE, a simple 2D SE classification system can be constructed, either generalized or focal to be combined with convulsive or non-convulsive.⁷ While generalized convulsive SE appears straightforward, generalized non-convulsive SE has distinct varieties with different clinical implications. In comatose patients, usually in intensive care unit (ICU) settings and often after cessation of convulsive SE, it may be termed subtle SE.⁸ Generalized non-convulsive SE can also be a manifestation of absence SE in patients with idiopathic generalized epilepsy, in which case the patient is typically encephalopathic rather than comatose. A form of focal convulsive SE characterized by a more or less continuous seizure state affecting a restricted part of the body is also labeled ‘epilepsia partialis continua,’ and focal non-convulsive SE may manifest as prolonged or frequently repeated complex partial seizures.

SE is often the expression of underlying severe disturbances of the central nervous system (CNS), and occurs in 10–41/100,000 persons per year according to population-based studies.^9–12 Refractory SE, defined as resistant to two or more treatments, develops in about 10–40% of SE cases.^13–16

Diagnosis and Differential Diagnosis
Four main criteria contribute to SE diagnosis: clinical presentation, duration, electroencephalogram (EEG), and response to treatment.⁷ However, diagnosis is often not straightforward, because clinical features are extremely variable, seizure onset is often difficult to determine, EEG pattern tends to evolve with time,⁸ and treatment response is not uniform. Imitators of SE are usually characterized by abnormal movements and diminished responsiveness. While classic movement disorders have typical features, post-sedation shivering or posturing in the ICU may sometimes prove hard to differentiate from subtle SE, and so-called diencephalic seizures, also termed paroxysmal sympathetic storm, can include tonic posturing or tremor that may mimic convulsions.¹⁷ However, the most important entity that needs to be positively identified is prolonged psychogenic non-epileptic seizures.¹⁸ These may be frequently mistaken for SE, leading to potentially dangerous medical overtreatment.^19,20

General Outline and Pharmacological Background
There is a general consensus on the need to treat SE as soon as possible in order to prevent potentially deleterious sequelae.^3,6,21,22 The pathophysiological mechanisms occurring during an episode of SE have been well described in animal studies.^1,21,23–29 Briefly, at the beginning there is an imbalance between inhibitory, mostly gamma-amino butyric acid (GABAA), and excitatory, predominantly glutamate, inputs of neuronal circuits. This serves as a rationale to begin SE treatment with benzodiazepines, which are rapidly acting GABA-ergic agents. GABA resistance develops progressively due to GABA receptor internalization and subunit changes; afterwards, a shift towards self-sustaining glutamate-mediated excitotoxicity occurs, resulting primarily from the activation of N-methyl-D-aspartic acid (NMDA) receptors (blocked by magnesium ions under normal conditions). These changes may explain both refractoriness to benzodiazepines and excitotoxic neuronal damage. During the first stage metabolism is hypercompensatory, with arterial hypertension, hyperglycemia, and cerebral hyperperfusion, whereas in the second stage, following a transitional period occurring in experimental animals after 30–60 minutes, there is progressive deregulation leading to cerebral hypoperfusion, lactic acidosis, and multiorgan failure. SE treatment may be conceptually categorized into three phases of, usually intravenous (IV) AED administration. The first consists of benzodiazepines and aims at rapid SE control; the second, using classic AEDs, targets early resistant forms and begins long-term coverage following anticipated control of SE; and the third treatment phase is reserved for refractory episodes and comprises administering general anesthetics. A simple protocol with corresponding timing is proposed in Figure 1. Awareness of the protocol greatly facilitates this practical approach and allows smooth interplay between the different providers (paramedics, emergency or ICU team, and neurologists).