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Overview

Practice Essentials

Status epilepticus (SE) is a period of prolonged seizure activity, either continuous or recurrent, that is a potentially life-threatening emergency requiring coordination between multiple medical professionals to stabilize the patient while terminating the seizure. The modern definition of SE has significantly changed over the past 60 years, from an original subjective definition of "an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epilepticus condition"^[1] to the most recent definition proposed by the ILAE task force on classifications of SE in 2015.^[2] The newest ILAE definition of SE is based on two time points: t1, the duration beyond which a seizure should be considered prolonged and unlikely to terminate without intervention and t2, the time beyond which long-term injury and damage may arise (eg. neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures). Practically speaking, t1 is the point at which rescue or emergency intervention should begin to prevent the patient from ever reaching t2.

The annual incidence of convulsive SE among children in developed countries is approximately 20 per 100,000 population.

Signs and symptoms

Generalized tonic-clonic SE (GTCSE) has 3 phases, which have the following characteristics:

Phase 1: Discrete focal or, less frequently, generalized seizures; blood pressure usually remains within the reference range
Phase 2: Discrete generalized events fuse and focal seizures spread to bilateral hemispheres; the main outward manifestation of continuous seizure activity consists of a tonic phase (sustained muscle contraction) followed by clonic jerks (alternating contraction and relaxation of the 4 limbs); alteration of blood pressure may occur
Phase 3: Clinical seizures may become quite subtle, with brief rhythmic clonic or myoclonic movements often restricted to a single part of the body; rhythmic activity may be observed as myoclonus that affects only the feet, hands, facial muscles, or eyes (as nystagmus); hyperthermia, respiratory compromise, hypotension, and hypoglycemia may be observed

Nonconvulsive status epilepticus has the following characteristics:

Patients appear forgetful and sleepy, behaving as if deaf and blind (“like a zombie”) or drugged
In more severe cases, patients are described as unresponsive
Parents may describe frequent falls, poor motor control, or abnormal balance

Absence SE presents with the following:

Altered consciousness, with or without clonic movements of the eyelids or upper extremities
Automatisms involving the hands and face
A child may continue to perform a motor act that he or she was engaged in before onset of the absence seizure (eg, bouncing a basketball)
In some cases, the patient may answer simple questions, but detailed examination reveals slowed mentation and poor processing of complex information
Episodes of absence SE may last 12 hours or longer

The time points t1 and t2 vary depending on the clincal seizure type. For generalized tonic clonic (or focal to bilateral tonic clonic) SE, t1 and t2 are 5 min and 30 min, for focal SE with impaired awareness, t1 and t2 are 10 min and >60 min and for absence SE, t1 and t2 are 10-15 min and unknown, respectively.

See Presentation for more detail.

Management

Treatment of SE should be based on an institutional protocol based on best practices. Treatment always begins with starting with basic emergency ABCs followed by a concurrent approach to terminate the seizure, treat any complications, initiate the diagnostic work-up and management of the underlying etiology if known.

An example of initial management:

Time the seizure
Attend to the ABCs before starting any pharmacologic intervention
Place patients in the lateral decubitus position to avoid aspiration of emesis, to prevent epiglottis closure over the glottis and make further adjustments of the head and neck to improve airway patency
Maintain appropriate airway position to optimize patency
Immobilize the cervical spine if trauma is suspected
Administer 100% oxygen by facemask
Assist ventilation and use artificial airways (eg, endotracheal intubation) as needed
Suction secretions and decompress the stomach with a nasogastric tube.
Carefully monitor vital signs, including blood pressure
Carefully monitor the patient's temperature, as hyperthermia may worsen brain damage
Obtain rapid bedside glucose administration
In the first 5 minutes of seizure activity, before starting any medications, establish IV access and to obtain samples for laboratory tests and for seizure medication
In children younger than 6 years, use intraosseous (IO) infusion if IV access cannot be established within 5-10 minutes
If serum glucose is low or cannot be measured, give children 2 mL/kg of 25% glucose
Infuse isotonic IV fluids plus glucose at a rate of 20 mL/kg/h (eg, 200 mL D5NS over 1 h for a 10-kg child)
If the seizure fails to stop within 4-5 minutes, prompt administration of anticonvulsants may be indicated

Anticonvulsant selection should be based on seizure duration,^[3] with "t1" as listed above as the time for first line therapy.

The following protocol time points are for convulsive SE:

First Line (5-10 min)

Lorazepam IV or IO (0.05-0.1 mg/kg) max 4 mg, can be repeated once
Diazepam per rectum (0.5 mg/kg), max 20 mg, single dose
Dizepam IV (0.2 mg/kg IV) max 10 mg, can be repeated once
IN diazepam 5 mg (10-19 kg), 10 mg (20-38 kg), 2 X 7.5 mg =15 mg (38-56 kg), 2 X 10 mg = 20 mg (56-74 kg)
Midazolam IM/IV/buccal (0.2 mg/kg) single dose
IN midazolam (0.2/kg) divided dose between nares, can be repeated once.

Second Line (10-30 min)

Fosphenytoin IV or IM (20 mg PE/kg), max 1500 mg/dose
Levetiracetam IV (60 mg/kg), max 4500 mg/dose
Valproic acid IV (40 mg/kg), max 3000 mg/dose
Phenobarbital IV (20 mg/kg), max 1500 mg/dose
Lacosamide IV (8 mg/kg), max 200 mg initial dose. Can be repeated - max 20 mg/kg/day or 400 mg/day, whichever is less.

Third Line (30+ min - failed first two lines of therapy - Refractory Status Epilepticus)

Repeat alternative second line therapies
Transfer to ICU for infusion of IV anesthetics and antiseizure medications. Under EEG guidance, treatment should involve rapid escalation of therapy using repeated boluses, as NCSE is a high risk in these patients.
Preparation for possible endotracheal intubation

Examples of infusions are listed below:

Pentobarbital 5 mg/kg initial load with additional 5 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.5-5 mg/kg/hr titrated to clinical/electrographic seizure control
Midazolam 0.2 mg/kg initial load with additional 0.2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.05-2 mg/kg/hr titrated to clinical/electrographic seizure control
Propofol 1-2 mg/kg initial load with additional 1 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 30-67 mcg/kg/min titrated to clinical/electrographic seizure control. Avoided in pediatrics due to risk of propofol infusion syndrome (highest risk with infusions longer than 48 hr and infusions higher than 67 mcg/kg/min)
Ketamine 1-2 mg/kg initial load with additional 1-2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 1.2 - 7.5 mg/kg/hr titrated to clinical/electrographic seizure control

Note: While phenobarbital is listed as a second line in this algorithm, it, along with levetiracetam, is routinely used as first line in neonatal SE. Recent evidence suggests that phenobarbital is superior to levetiracetam in neonatal SE. ^[4]

Other treatments may be indicated if the clinical evaluation identifies precipitants of the seizures. Selected agents and indications are as follows:

Naloxone - 0.1 mg/kg/dose, IV preferably (if needed may administer IM or SQ) for narcotic overdose
Pyridoxine - 50-100 mg IV/IM for possible dependency, deficiency, or isoniazid toxicity
Antibiotics - If meningitis is strongly suspected, initiate treatment with antibiotics prior to CSF analysis or CNS imaging

See Treatment and Medication for more detail.

Diagnosis

Etiology plays an important role in management and prognosis of SE as mortality and morbidity is increased in acute symptomatic seizures from neurological or systematic insults.^{[5, 6, 7, 8]} Etiology varies significantly throughout the lifespan with cerebrovascular pathology being the most frequent cause of SE in adults and fever/infection being the most common cause in pediatrics.

Treatment of the underlying etiology can be crucial in gaining seizure control and, as such, diagnostic testing should be performed expeditiously. However, not every patient requires the same investigations and the work-up should be guided by history and physiical^[9]. As per the sample management algorithm above, diagnostic work-up (laboratory testing, EEG, imaging) should be performed concurrently with anti-seizure treatments following stabilization of the patient.

Rapid application of EEG (see below)
CBC with differential for signs of infections, while being aware of the transient leukocytosis which can occur in prolonged seizures
Electrolytes, extended electrolytes (magnesium, phosphorus and calcium) - abnormalities can provide clues to a diagnosis or be the SE trigger directly
Full septic work-up, especially in febrile patients, infants, immunocompromised patients and prolonged SE of unknown etiology
If no signs of raised intracranial pressure, lumbar puncture with opening pressure measurement should be performed, especially in febrile patients, infants, immunocompromised patients and prolonged SE of unknown etiology
Drug levels in those taking anti-seizure medications
Urine and blood toxicology screens
Obtain imaging studies based on likely etiologies; stabilize all children before performing CT or MRI studies. Be aware that prolonged seizures can result in transitory MRI changes that can mimic ischemia and inflammation

Refractory and prolonged SE needs further workup if routine blood work, brain MRI, and microbiological studies in serum and CSF do not provide clues to the etiology of the seizures. The following investigations are considered:

Inborn errors of metabolism work-up in patients with history suggestive of a metabolic disorder: unexplained neonatal encephalopathy and developmental delay, neurologic deterioration during an acute illness; unusual odors to the urine; unexplained acidosis or coma. Urine organic acids, serum amino acids, porphyrins (porphyria), sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency), ammonia, lactate, pyruvate, carnitine profile
Genetic testing (whole exome or epilepsy panel) for prolonged/refractory SE
Serum T4, T3, thyrotropin, and antiperoxidase antibody (autoimmune epilepsy)
Autoimmune encephalitis panel - CSF and serum (eg. serum and CSF NMDA-R antibody)
Other paraneoplastic antibodies (anti Hu, Yo, Ri)
Ultrasound/CT/MRI of testes and abdomen to look for solid tumors. If paraneoplastic autoimmune encephalitis is suspected
Serological markers for collagen-vascular disorders

Every patient who presents with SE requires an EEG and making immediate arrangement for an EEG is advisable, however treatment should not be delayed to wait for EEG results.

EEG is crucial in differentiating between the various classifications of SE: generalized or focal convulsive SE, nonconvulsive SE (NCSE) and absence SE. While convulsive SE occurs with clear clinical signs (tonic, tonic-clonic, clonic motor movements), nonconvulsive and absence status epilepticus (NCSE) is associated with altered awareness without overt clinical signs, or altered awareness with subtle motor signs, such as minimal eyelid blinking. Ongoing ictal activity in NCSE can be missed without EEG monitoring and since the risk of brain injury increases with the length of SE, timely recognition of ongoing seizures is vital^[10].

Furthermore, an EEG done at the time of SE can determine if the electrographic discharges are focal or generalized (increasing the importance of imagine in patients with focal discharges as well as helping to decide on optimal therapy) as well as distinguish an epileptic event from a nonepileptic event (paroxysmal non-epileptic seizures), changing the management needed.

See Workup for more detail.

Background

One of the earliest definitions of status epilepticus (SE) was entirely subjective: "an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epilepticus condition."^[1] Over the subsequent decades, there has been an effort to quantify the point at which SE could be diagnosed, with definitions of SE seizure activity lasting 30 to 60 minutes or longer being proposed. This longer time limit and subsequent delay in treatment may be a primary reason for the higher incidence of neurological sequelae in older studies, including following prolonged febrile seizures.^{[11, 12]}

With the recognition of the importance of timely treatment in SE, there has been focus on early intervention, both pre-hospital and within the ED/ICU setting.^[13] That SE is essentially a race against time is reflected in the definition proposed by the ILAE task force on SE classifications in 2015: "a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures."^[2]

The ILAE definition of SE is based on two time points: t1, the duration beyond which a seizure should be considered prolonged and unlikely to terminate without intervention and t2, the time beyond which long-term injury and damage may arise (eg. neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures). Practically speaking, t1 is the point at which rescue or emergency intervention should begin to prevent the patient from ever reaching t2.^[14] For convulsive SE, those time points are 5 and 30 min, respectively.

An important point is that for practical purposes, there is no difference between a single continuous seizure and a series of seizures without recovery of consciousness in between. The rationale for equating intermittent seizures without recovery of consciousness with continuous seizures is twofold. First, in animal models, intermittent seizures were quite powerful agents in causing neuropathological changes (see Pathophysiology). Second, in cases of prolonged status epilepticus, outward motor manifestations may become intermittent or less prominent over time without necessarily indicating decreasing intensity of electrical seizure activity in the brain.^[10]

For more information, see the Medscape Drugs and Diseases topic Status Epilepticus.

Types of status epilepticus

Most of the literature on SE deals with convulsive/tonic-clonic SE, and the terms SE, convulsive SE, and generalized tonic clonic SE (GTCSE) are often used synonymously. This article primarily addresses focal to bilateral and generalized tonic clonic SE; however, when appropriate, comments on other types of SE are included. Other types of SE include the following:

Focal motor SE
Focal with impaired awareness SE
Absence SE
Nonconvulsive SE
Myoclonic SE

Focal motor and focal sensory status epilepticus

In focal motor SE, seizures may be quite sustained, especially when associated with brain lesions. Focal motor seizures may be tonic (sustained muscle contraction of part of the body) or clonic (alternating muscle contraction and relaxation). Prolonged focal motor seizures (often motor and clonic) are frequently termed epilepsia partialis continua and can be associated with acute inflammatory lesions (eg, Rasmussen's encephalitis) as well as genetic syndromes such as POLG.^[15]

Focal seizures do not cause major impairment of consciousness. However, they may be accompanied by recurrent subjective feelings, bodily sensations, or visual hallucinations.

Focal motor seizures are not necessarily associated with diffuse brain damage, unless they become focal impaired awareness SE or are associated with focal to bilateral tonic clonic SE.

See also the Medscape Drugs and Diseases topic Partial Epilepsies.

Focal with impaired awareness status epilepticus

Episodes of focal with impaired awareness status epilepticus are characterized by major alteration in consciousness, lack of recollection for the event associated with stereotypic automatisms, staring, and, in some cases, vocalization. Most patients are described as confused (one third of cases) or unresponsive (one third of cases).

Focal with impaired awareness SE episodes have been followed by cognitive deficits in some cases; recognizing this post-ictal impairment is important.

See also the Medscape Drugs and Diseases topic Complex Partial Seizures.

Absence seizures SE

Absence SE are prolonged episodes of altered awareness/responsiveness with poor or no recollection for events. They can last for hours or even days. Typical absence seizures that exceed 30 minutes in duration should be treated because of the risk of evolution into convulsive seizures. However, prolonged absence SE has been described that were not associated with subsequent neurologic deterioration.

Occasionally. the alteration of consciousness may not be severe, as patients can perform simple automatic behaviors like combing their hair, playing video games, and even driving. Behavioral changes that have resolved with antiepileptic drug therapy have been reported. In some cases, myoclonic jerking of the eyelids (eyelid myoclonia) provides an overlooked clue to absence SE.

Absence seizure status may occur in teenagers and adults who were thought to have outgrown conditions such as Childhood Absence Epilepsy or Junvenile Absence Epilepsy. Occasionally, absence status can be triggered by inappropriate anti-seizure drug therapy (typically the addition of sodium channel blockers carbamazepine and/or phenytoin).^[16]

Absence SE and atypical absence SE can be a feature in syndromes such as Lennox Gastaut Syndrome and Angelman's Syndrome, among others.^[17]

See also the Medscape Drugs and Diseases topic Absence Seizures.

Nonconvulsive status epilepticus

Many studies combine cases of focal impaired awareness and absence SE under the name nonconvulsive SE (NCSE). This is because of the similarity in the seizure semiology, despite the divergent EEG patterns (focal vs generalized discharges at onset). In children, about two thirds of nonconvulsive SE cases have generalized EEG changes suggestive of either typical or atypical absences with or without a myoclonic component.

Myoclonic seizures

Myoclonic seizures are characterized by quick, often repetitive, jerks that randomly involve the limbs. Seizures are often repetitive and, in some cases, may be unabated for lengthy periods.

Some patients with myoclonic epilepsies may sustain repetitive myoclonus that persists for days with or without altered consciousness. Myoclonic SE is a term sometimes used to describe these patients' condition.

See also the Medscape Drugs and Diseases topics Myoclonic Epilepsy Beginning in Infancy or Early Childhood and Juvenile Myoclonic Epilepsy.

Etiologic classifications of status epilepticus

Most studies of SE epidemiology and outcome have used the following classification of episodes:

Acute symptomatic (26%) – Episodes caused by an acute infection, head trauma, hypoxemia, electrolyte disturbance, hypoglycemia, intoxication or drug withdrawal
Progressive encephalopathy (3%) – SE occurring with an underlying progressive CNS disorder, such as mitochondrial disorder, Rasmussen encephalitis, CNS lipid storage diseases, aminoacidopathies, or organic acidopathies
Remote symptomatic SE (33%) – Episodes secondary to static conditions (eg, remote cerebral insult in the perinatal period)
Remote symptomatic with an acute precipitant (1%) – SE in a patient with a chronic encephalopathy but precipitated by an acute event such as those in acute symptomatic SE
Febrile (22%) – SE for which the only provocation is a febrile illness, after excluding a direct CNS infection
Unknown (15%) – SE without identifiable cause

Diagnosis and management of status epilepticus

Perform a rapid, directed history, physical examination, and neurologic examination during SE, followed by a detailed examination when the child is stabilized (see Presentation). Laboratory testing should proceed concurrently with stabilization, with the choice of laboratory studies based on age and likely etiologies (see Workup). The principles of treatment are to terminate the seizure while resuscitating the patient, treating complications, and preventing recurrence (see Treatment).

For patient education information, see Seizures Emergencies, Seizures in Children, and Epilepsy.

Pathophysiology

Seizures are caused by dysfunction between the normal inhibitory and excitatory processes in the brain, resulting in abnormal repetitive electrical discharges from cerebral neurons. In SE, there is further failure of the normal factors that serve to terminate a typical seizure. Sources of this failure include changes in gamma-aminobutyric acid (GABA) receptor composition (resulting in a loss of benzodiazepine efficacy), excessive glutamate excitation, and activation of drug resistance genes, likely all happening in parallel.^[18]

GABA receptor–mediated inhibition plays a major role in the normal termination of a seizure. In experimental models, a subset of GABA_A receptors internalize, leading to a reduced number of receptors within the synapse. In one in vivo model of SE, tthere was a 50% reduction in the number of functional GABA_A receptors per synapse within one hour.3 Benzodiazepines, the frst line therapy in SE, are allosteric modulators of GABA_A and this reduction in the surface density of the receptors during prolonged seizures results in benzodiazepine pharmacoresistance.^[19]

Conversely, surface expression of the receptors to the excitatory neurotransmitter glutamate (required for the propagation of seizure activity) actually increase during prolonged seizures, with an almost 40% increase in the N -methyl-D aspartate (NMDA) receptors noted in an in vivo model of prolonged SE after one hour and abundance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors also increasing.^[20]

In adolescent baboons, brain damage can be observed after 90 minutes of sustained seizures, with the neocortex, thalamus, and hippocampus most affected.^{[21, 22]} In the neocortex, small pyramidal cells in layers 3, 5, and 6 were most affected, and resultant lesions tended to be more prominent in the occipital lobe. In this animal model, in which seizures were induced by bicuculline or pentylenetetrazol (PTZ), intubation/ventilation and chemical paralysis did not improve these types of CNS lesions, suggesting that excessive excitation causes neuronal injury and cell death directly via excitotoxic injury.

Most definitions of SE do not distinguish between uninterrupted seizures and intermittent seizures without recovery of consciousness. This concept is supported by the finding that the pattern of brain damage in animals with repetitive seizures induced by allyl glycine (glutamic acid decarboxylase inhibitor) included hippocampal sclerosis (at times asymmetrical or unilateral), cortical gliosis, and ischemic cell-type damage. Lesions in the cortex sometimes were restricted to the occipital cortex or watershed zones, a pattern very similar to that observed in prolonged sustained seizures.

Consumption of oxygen, glucose, and energy substrates (eg, adenosine triphosphate [ATP], phosphocreatine) in cerebral tissue increases significantly during seizures and SE is a state of high metabolic demand. In addition to the direct effect of excess excitation on neurons, prolonged seizures are associated with cerebral hypoxia, hypoglycemia, hypercarbia, and with progressive lactic and respiratory acidosis. When cerebral metabolic needs exceed available metabolic substrates, irreversible neuronal injury can occur.

Massive sympathetic discharge with status epilepticus (SE) may have the following consequences:^[20]

Hypoxia
Hypercarbia
Hyperthermia
Tachycardia
Hypertension
Hyperglycemia
Hyperkalemia
Lactic acidosis

In addition to the neocortical, hypothalamic, and thalamic injury seen in SE, cerebellar damage can also be observed; however, because it is more prominent in the watershed zones of arterial blood supply, cerebellar damage is felt to be related to secondary ischemia and/or hyperthermia.^[23]

Protection against these injuries relies on optimal delivery of these metabolic substrates to cerebral tissue. The longer the brain and body can compensate, the less likely that permanent injury will result. Maintenance of airway, breathing, adequate cardiac output, and intravascular fluid volume are critical to minimize any permanent cerebral injury. See the Cardiac Output calculator.

Etiology

The etiology of status epilepticus (SE) tends to vary by the age of the child (ie, younger than versus older than 6 years). Causes of SE in early childhood (< 6 y) may include the following:

Birth injury
Febrile convulsions (6 mo to 6 y)
Infection
Metabolic disorders
Trauma
Neurocutaneous syndromes
Cerebral degenerative diseases
Tumors
Idiopathic

Causes in children and adolescents (> 6 y) may include the following:

Sequelae of Birth injury
Trauma
Infection
Epilepsy with inadequate drug levels
Cerebral degenerative disease
Tumor
Toxins
Idiopathic

Toxins and medications that can cause SE include the following:

Topical anesthetics (eg, lidocaine)
Anticonvulsant overdose
Camphor
Hypoglycemic agents (eg, insulin, ethanol)
Carbon monoxide
Cyanide
Heavy metals (eg, lead)
Pesticides (eg, organophosphate)
Cocaine
Phencyclidine
Belladonna alkaloids
Nicotine
Sympathomimetics (eg, amphetamines, phenylpropanolamine [recalled from US market])
Tricyclic antidepressants (eg, bupropion)

Unfortunately, the incidence of accidental and intentional ingestions of illicit drugs continues to rise, especially among toddlers. Opioids, methamphetamine, cocaine, and MDMA habe been reported to cause SE in children.

The etiologies of SE episodes can be classified as (1) acute symptomatic, (2) chronic-progressive neurologic disorders, and (3) remote symptomatic status epilepticus.

Acute symptomatic status epilepticus may be caused by an acute infection, head trauma, hypoxemia, hypoglycemia, or drug withdrawal. Acute symptomatic SE is the most common etiologic category in children, accounting for as many as 35% of cases. Idiopathic SE the second most common category, with a frequency of 30%; febrile SE constitutes 25% of cases.

Meningitis is a common cause of convulsive SE;^[24] fever is present in 17% of the cases in children. In patients with febrile convulsive SE, the classic signs of meningitis may not be present.

Chronic-progressive neurological disorders represent just 5% of cases. Remote symptomatic SE, referring to SE secondary to static conditions (eg, when a cerebral insult that occurred in the perinatal period causes SE later in childhood), constitutes 10-15% of cases.

The use of cephalosporin antibiotics (cefepime and ceftazidime) has been associated with the precipitation of SE. This association is especially important in patients with impaired renal function.

Some anticonvulsants may produce de novo nonconvulsive SE (both absence and complex partial types). Carbamazepine, phenytoin, and tiagabine are commonly implicated. Patients with Lennox-Gastaut syndrome may develop NCSE due to excessive sedation (usually secondary to long-term benzodiazepine use).

Of the many acute precipitants described in children, infection and fever collectively constitute the most common (35.7%). Other common precipitants and their reported frequencies are as follows:

Medication changes - 20%
Metabolic precipitants - 8%
Congenital precipitants - 7%
Anoxia - 5%
CNS infection - 5%
Trauma - 3.5%

No precipitant is found in 8-10% of cases of generalized tonic-clonic SE. Generalized tonic-clonic SE may recur in 17-25% of children. Recurrent SE epilepticus primarily occurs in children with neurologic abnormalities. The risk of recurrence also varies among the etiologic groups. Idiopathic and remote symptomatic groups have the highest recurrence risk (28% in prospective studies). The febrile seizure group has a prospective recurrence risk of 3%.

Nonconvulsive SE is commonly associated with a prior diagnosis of one of the following epileptic syndromes:

Lennox-Gastaut syndrome
Dravet syndrome
Myoclonic-astatic epilepsy
Childhood and juvenile absence epilepsy
Localization-related epilepsy (focal impaired awareness seizures)

In a large international collaborative study of 356 patients with severe epilepsies and their parents, researchers identified 429 new synaptic transmission genes.^[25]These mutations were considered causative in 12% of the patients. DNM1, a gene that carries the code for the structural protein dynamin-1, which is involved in shuttling small vesicles between the body of the neuron and the synapse, was found to be mutated in five patients. De novo mutations in GABBR2, FASN, and RYR3 were found in two patients each. In all, 75% of the mutations detected were predicted to disrupt a protein involved in regulating synaptic transmission.^[25]

Epidemiology

The annual incidence of convulsive status epilepticus (SE) among children in developed countries is about 20 per 100,000 population; however, the rate will vary depending on factors such as the socioeconomic and ethnic characteristics of the population.^[26] Age plays a strong role, as status epilepticus incidence follows a bimodal distribution, with the highest estimates in the first years of life (0-4 years) and after 60 years.^[27]

Although the data are contradictory, SE incidence appears to have increased in recent decades with a systematic review showing incidence of all-age convulsive SE rising from 3.5 (1979) to 12.5 (2010) per 100,000 people per year.^[27] While part of the increase is certainly related to changes in the definitions of SE (shorter time before meeting criteria), the advent of modern antiseizure drugs (ASDs) is implicated as well. Data have showed that 43% of patients taking ASDs when SE occurred had low serum levels of the drugs; in only 38% of cases were a patient's ASD levels all in the therapeutic range.

While the overall percentage of patients with epilepsy who develop status epilepticus varies from 1.3-16%, in children younger than 1 year who are subsequently diagnosed with epilepsy, 70% present with SE as the initial manifestation of their illness. The first seizure lasts longer than 30 minutes in 12.6% of those subsequently diagnosed with epilepsy. However, almost half (48%) of adults who present with SE have no prior history of seizures and among children diagnosed with SE, a history of prior unprovoked seizures was even less common (32%).^[28]

Generalized tonic-clonic SE may be recurrent in 10-25% of children with SE.^[29] Risk of generalized tonic-clonic SE recurrence varies among etiologic groups. The idiopathic and remote symptomatic groups have the highest recurrence risk (ie, 28% in prospective studies). The febrile seizure SE group has a prospective recurrence risk of 3-7%, depending on the clinical features (length, focality, number within 24 hrs).^[28] Of children with febrile seizures, 5% present with status epilepticus. Pediatric patients who present with febrile SE rarely have a history of epilepsy.^[28]

Median healthcare costs related to SE admission were approximately US$8000 per child (0-16 years).^[27]

Sex- and age-related differences in incidence

No sexual predilection or age variation is recognized. However, certain etiologies are more prevalent in selected age groups (see Etiology).

Prognosis

Multiple factors affect prognosis in patients with status epilepticus (SE). These include seizure type (nonconvulsive versus generalized tonic-clonic), duration, etiology, patient age, and systemic complications (respiratory failure and cardiac dysfunction).^{[30, 31]}

Pediatric patients with SE tend to do better than adults,^{[29, 32, 33, 34, 35]} with negative outcomes (death and neurological dysfunction) strongly influenced by etiology. In a prospective study of 193 patients, seven children died within 3 months of having the prolonged seizure and new neurologic deficits were found in 17 (9.1%) of the 186 survivors. However, overall incidence of sequelae was low (1.4%) in patients classified as having idiopathic febrile seizures and remote symptomatic seizures, intermediate (12%) in those with acute symptomatic seizures, and highest (80%) in those with chronic progressive encephalopathy. All of the deaths and 15 of the 17 sequelae occurred in the 56 children with acute or progressive neurologic insults. Only two of the 137 children with other causes sustained any new deficits.^[32] In another prospective study of > 200 pediatric patients, while convulsive SE was found to be associated with substantial long-term neurological morbidity, it was primarily in those who had epilepsy, neurological abnormalities, or both before the episode of CSE. Patients without neurological abnormalities before SE tended to have favorable outcomes.^[33]

In one study, length of SE only played a role in the outcome of the 10% of cases with acute neurological insults;^[32] however, other studies demonstrate a stronger relationship between length of SE and worsening outcome. In a pediatric study of ~600 patients, those with generalized tonic-clonic SE lasting less than 1 hour had a markedly better prognosis than those with more prolonged SE. When SE lasted 30-59 min, mortality was 2.7% and when SE was > 60 min, mortality jumped to 32%.^{[35, 36]}

Sequelae rates for patients with generalized tonic-clonic SE decline with increasing age. Rates were 29% among patients younger than 1 year ,11% for children aged 1-3 years, and fell further to 6% for children older than 3 years.^[37]Although children younger than 1 year have greater incidence of acute symptomatic generalized tonic-clonic status epilepticus, no difference in the etiologic categories among the other age groups was observed.

Patients with refractory SE who require high-dose suppressive therapy (eg, barbiturate coma, midazolam infusion) often need prolonged therapy. The long-term outcome in previously healthy children who survive prolonged barbiturate coma or midazolam infusion for SE is not particularly favorable; these children may have long-term cognitive deficits and recurrent seizures. In one study performed at Boston Children's Hospital, all patients developed intractable epilepsy, and none returned to baseline.^[38]

De novo development of hippocampus sclerosis (ie, mesial temporal lobe sclerosis) is one of the possible complications of SE and possibly the reason that survivors may develop chronic recurrent and refractory focal epilepsy.^{[39, 8, 11, 12, 40]}

Cognitive difficulties recognized after SE may represent as pre-existent but unrecognized problems. Although learning disabilities and cognitive impairment are more common among children with epilepsy than in the general population, cognitive problems often remain undiagnosed until the patient's first seizure and sometimes not until the first prolonged seizure. Occasionally, it is possible to obtain a history of abnormal language development and cognition prior to the seizures.

The relationship between seizure-mediated brain damage and duration of SE is not as clear with focal motor and non-convulsive SE as it is with generalized tonic-clonic SE, as reflected in the longer "t1" and "t2" in the ILAE definitions of SE.^[2]

Mortality

In pediatric patients, death after SE occurs almost exclusively among those in the acute symptomatic or progressive encephalopathy groups. Maytal et al found that the mortality rate for both classifications combined was 12%, whereas there were no deaths among patients in the remote symptomatic, idiopathic, and febrile status groups.^[37]

Reporting on mortality within 8 years following an episode of convulsive status epilepticus, one study noted an overall fatality rate of 11% of the 226 patients studied. Seven children died within 30 days of their episode and 16 during follow-up; 25% of deaths during follow-up were associated with intractable seizures/convulsive status epilepticus, and the rest died as a complication of their underlying medical condition. The mortality rate was 46 times greater than expected and was associated with pre-existing clinically significant neurological impairments; however, children without prior neurological impairment were not at a significantly increased risk of death during follow-up. No deaths were noted in children following prolonged febrile convulsions and idiopathic convulsive status epilepticus. These results suggest that while a high risk of death was realized within 8 years, most deaths were not seizure related; the main risk factor was the presence of pre-existing neurological impairments.^[41]

Most modern pediatric series report that mortality directly related to SE occurs at a rate of 2%, whereas overall mortality rates range from 4% to 6%. This contrast with the much higher mortality rate in adults with SE, which ranges from 16% to 35%, with 1-5% of deaths directly related to status epilepticus. Early treatment of seizures with appropriate first-line medications (benzodiazepines) is thought to be associated with a better outcome, but further testing is required to confirm this statement.

Clinical Presentation

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Pediatric Status Epilepticus. Treatment algorithms for convulsive status epilepticus.

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Table 1. Examples of Medical Treatment of Seizures and Convulsive Status Epilepticus Based on Time Elapsed Since Seizure Onset (Steps 2-4)

Table 1. Examples of Medical Treatment of Seizures and Convulsive Status Epilepticus Based on Time Elapsed Since Seizure Onset (Steps 2-4)

Step	Medication	Dose	Alternatives
Step 2 (5-10 min)	Diazepam (Valium)	5-20 mg IV slowly; not to exceed infusion rate of 2 mg/min; pediatric dose is 0.3 mg/kg	If IV line is unavailable, use rectally administered (PR) diazepam at 0.5 mg/kg (not to exceed 10 mg) or midazolam (Versed) at 0.2 mg/kg IM, IV, or intranasal
Step 2 (5-10 min)	Lorazepam* (Ativan)	2-4 mg IV slowly*; not to exceed infusion rate of 2 mg/min or 0.05 mg/kg over 2-5 min; pediatric dose is 0.05-0.1 mg/kg
Step 3 (10-30 min)	Phenytoin (Dilantin) or fosphenytoin (Cerebyx)†	Phenytoin:20 mg/kg IV over 20 min; not to exceed infusion rate of 1 mg/kg/min; do not dilute in 5% dextrose in water (D5W) Fosphenytoin: 15-20 mg/kg IV; not to exceed infusion rate of 2 mg/kg/min or 150 mg/min whichever is slower; dilute in D5W or NS	Sodium valproate 40 mg/kg IV, max 3000 mg or levetiracetam 60 mg/kg IV, max dose 4500 show equal efficacy to fosphenytoin. If unsuccessful, administer phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); phenobarbital may be used in infants before phenytoin; be prepared to intubate patient; closely monitor hemodynamics and support blood pressure as indicated.
Step 4 (30+ min)‡	Pentobarbital anesthesia (patient already intubated)	Loading dose: 5-7 mg/kg IV; may repeat 1-mg/kg to 5-mg/kg boluses until EEG exhibits burst suppression; closely monitor hemodynamics and support blood pressure as indicated Maintenance dose: 0.5-3 mg/kg/h IV; monitor EEG to keep burst suppression pattern at 2-8 bursts/min	Midazolam* infusion loading dose: 100-300 mcg/kg IV followed by IV infusion of 1-2 mcg/kg/min; increase by 1-2 mcg/kg/min every 15 min if seizures persist (effective range 1-24 mcg/kg/min); closely monitor hemodynamics and support blood pressure as indicated; when seizures stop, continue same dose for 48 h then wean by decrements of 1-2 mcg/kg/min every 15 min Propofol* initial bolus: 2 mg/kg IV; repeat if seizures continue and follow by IV infusion of 5-10 mg/kg/h, if necessary, guided by EEG monitoring; taper dose 12 h after seizure activity stops; closely monitor hemodynamics and support blood pressure as indicated With phenobarbital-induced anesthesia, repeated boluses of 10 mg/kg are administered until cessation of ictal activity or appearance of hypotension; closely monitor hemodynamics and support blood pressure as indicated
*Not approved by the FDA for the indicated use. †Doses for fosphenytoin administered in phenytoin equivalents (PE). ‡An alternative third step preferred by some authors is midazolam administered by continuous IV infusion with a loading dose 0.1-0.3 mg/kg followed by infusion at a rate of 0.1-0.3 mg/kg/h.

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Author

Marvin H Braun, MD, PhD Assistant Professor of Neurology, Neuroscience Institute, Geisinger Commonwealth School of Medicine; Pediatric Neurologist, Janet Weis Children’s Hospital, Geisinger Medical Center

Marvin H Braun, MD, PhD is a member of the following medical societies: American Epilepsy Society, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Coauthor(s)

Frank A Maffei, MD, FAAP Professor of Pediatrics, Geisinger Commonwealth School of Medicine; Chair of Pediatrics, Division Chief, Pediatric Critical Care, Geisinger Janet Weis Children's Hospital

Frank A Maffei, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Dale W Steele, MD, MS Professor of Emergency Medicine, Pediatrics, and Health Services, Policy, and Practice, Warren Alpert Medical School of Brown University; Attending Physician, Department of Pediatric Emergency Medicine, Rhode Island Hospital

Dale W Steele, MD, MS is a member of the following medical societies: American Academy of Pediatrics, American Statistical Association, Society for Medical Decision Making

Disclosure: Nothing to disclose.

Additional Contributors

Marcio Sotero de Menezes, MD Clinical Associate Professor, Department of Neurology, Division of Pediatric Neurology, Seattle Children's Hospital, University of Washington School of Medicine; Director, Pediatric Neuroscience Center and Genetic Epilepsy Clinic, Swedish Neuroscience Institute

Marcio Sotero de Menezes, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society

Disclosure: Received salary from Novartis for speaking and teaching; Received salary from Cyberonics for speaking and teaching; Received salary from Athena diagnostics for speaking and teaching.

Ednea Simon, MD Consulting Staff, Swedish Pediatric Neuroscience Center

Ednea Simon, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Rajesh Ramachandrannair, MBBS, MD, FRCPC Associate Professor, Michael G DeGroote School of Medicine, McMaster University; Staff Neurologist, McMaster Children's Hospital, Canada

Disclosure: Nothing to disclose.

Acknowledgements

G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami, Leonard M Miller School of Medicine; Medical Director, Palliative Care Team, Director, Pediatric Critical Care Transport, Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Manager, FEMA, Urban Search and Rescue, South Florida, Task Force 2; Pediatric Medical Director, Tilli Kids – Pediatric Initiative, Division of Hospice Care Southeast Florida, Inc

G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society