Introduction

Refractory status epilepticus (RSE) is a common and life-threatening neurologic emergency that is usually managed in the intensive care units (ICUs). Status epilepticus (SE) is prolonged self-sustaining seizures without intervening recovery of consciousness, or a prolonged single continuing seizure lasting for 10 min or longer. Patients who do not respond to standard treatment regimens for SE are considered have in RSE. RSE is mostly defined as persistent seizure activity after initiation of a first-line [intravenous (IV) benzodiazepines] and one second-line (mostly phenytoin, valproate, levetiracetam, or phenobarbital) anti-epileptic drug (AED), while others suggest a duration of SE of more than 60 min. It results in prolonged hospitalization and has a worse prognosis than treatment-responsive SE. After failure of stage I (with benzodiazepines) and stage II treatment (with phenytoin, levetiracetam, or valproic acid), 31–43% of patients enter into stage III or RSE. When treatment with an IV anesthetic for more than 24 h is not successful in controlling SE, patients enter into stage IV and the condition can be termed “super-refractory SE” or “malignant SE.”

Epidemiology

With an annual incidence of 10–40/100,000, SE is the second most frequent neurological emergency after acute stroke. The incidence of SE has a bimodal distribution with peaks in children aged less than a year and the elderly. With estimates of the frequency of RSE in patients with SE ranging from 30% to 45% the annual incidence lies between 5 and 9/100,000 RSE in Europe. The short-term fatality rates for RSE have been estimated between 16% and 39%; when compared to nonrefractory SE, mortality after RSE is about three times higher.

Classification

SE can be classified by semiology, duration, and the underlying cause into the following.

(1) Prolonged convulsions with impaired consciousness constitutes “Generalized convulsive status epilepticus” (GCSE). Characteristic findings of GCSE include rhythmic jerking of the extremities and mental status impairment (coma, lethargy, confusion). (2) “Focal motor status epilepticus,” including epilepsia partialis continua. (3) “Nonconvulsive status epilepticus” (NCSE) is defined as seizure activity seen on electroencephalogram (EEG) without clinical findings associated with GCSE. The semiological spectrum of nonconvulsive seizures is highly variable. Negative symptoms include anorexia, aphasia/mutism, amnesia, catatonia, coma, confusion, lethargy, and staring. Positive symptoms include agitation/aggression, automatisms, blinking, crying, delirium, delusions, echolalia, facial twitching, laughter, nausea/vomiting, nystagmus/eye deviation, perseveration, psychosis, and tremulousness. Two distinct phenotypes of NCSE have been described: (1) the “wandering confused” patient presenting to the emergency department with a relatively good prognosis and (2) the acutely ill patient with severely impaired mental status, with or without subtle motor movements (e.g., rhythmic muscle twitches or tonic eye deviation that often occurs in the setting of acute brain injury); the latter has also been labeled as “subtle status”. NCSE should be considered in the differential diagnosis of coma.

Cause

The causes of SE are varied. Together with age, cause has been consistently identified as the principal independent outcome predictor. AED withdrawal is an acute cause that is often related to good outcome; ischemic stroke or hemorrhage, central nervous infection, and intracranial tumors are remote causes associated with a bad prognosis. A longer duration of untreated SE may also render its control more difficult. The cause of SE should be diagnosed and treated as soon as possible. The occurrence of RSE has been mostly associated with acute, severe, and potentially fatal underlying causes, such as encephalitis, massive stroke, or rapidly progressive primary brain tumors and may be accompanied by severe impairment of consciousness. Risk factors predisposing patients to RSE include delay in receiving treatment, infections of central nervous system, metabolic encephalopathy, and hypoxia. The patient at risk for malignant SE is typically young and suffers from encephalitis. Table 17.1 shows the potential underlying cause of RSE for adults.

Pathophysiology

According to a new definition, SE is the failure of the mechanisms responsible for seizure termination or the initiation of mechanism, which leads to abnormally prolonged seizures that might have long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. An imbalance of the inhibitory activity of the neurotransmitter γ-aminobutyric acid (GABA) and the excitatory activity of the neurotransmitter glutamate is suspected as the underlying pathophysiology of seizure perpetuation in SE. SE-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N -methyl d -aspartate (NMDA) receptors and triggers receptor-mediated calcium influx. This results in a cascade of events and cell death. Apoptosis is likely to play a role in cell death during SE. Another important aspect of self-sustaining SE is the progressive, time-dependent development of pharmacoresistance. As a result of sympathetic overdrive, the body responds to GCSE with both systemic and cerebral effects, whereas in NCSE, systemic effects are more limited. GCSE can cause many systemic complications, including cardiac arrhythmias, temperature disturbances, electrolyte and glucose imbalance, rhabdomyolysis, and pulmonary edema. Initially during SE, blood pressure, glucose, and lactate increase and pH decreases. Initially there is increased cerebral blood flow to meet the elevated demands; as the cerebral blood flow diminishes, there is a mismatch between blood supply and the utilization of oxygen and glucose, resulting in a lower energy state and metabolic–substrate mismatch. In fact, after approximately 30 min, a second phase begins during which blood pressure and glucose normalize, lactate normalizes, and respiratory compromise and hyperthermia ensue. Hyperthermia causes damage to the hippocampus and cortex. When SE is refractory, subcellular maladaptive changes with internalization of postsynaptic GABAa-receptors to the cytoplasm and changes in chloride homeostasis make GABAergic drugs less efficacious or eventually ineffective. The excitatory neurotransmitter glutamate plays a major role in seizure perpetuation via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at this stage. The likelihood of returning to baseline functional status after RSE is as low as 21% as opposed to 63% for nonrefractory SE. Also, the need for admission to acute rehabilitation facilities for surviving patients doubles after RSE.