Pediatric Status Epilepticus

Status epilepticus (SE) was previously defined as a seizure that lasts more than 30 minutes, constituting a neurologic emergency. ^[1]  More recently, it is defined as a neurologic emergency in which there is at least 5 minutes of continous seizure activity or recurrent seizures with a return to baseline between seizures. ^[2] Thus, the seizure may be continuous or may be intermittent without recovery of consciousness between seizures.

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. 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.

In the past, the common definition of SE was seizure activity exceeding 60 minutes. This longer time limit (as opposed to the current definition of 30 minutes) may be one of the reasons for the higher incidence of sequelae in older studies. Other factors accounting for outcome differences include improvement in intensive medical care and the retrospective nature of these older studies, which tended to create a bias toward more severe cases.

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

Types of status epilepticus

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

• Simple partial SE

• Complex partial SE

• Absence SE

• Nonconvulsive SE

• Myoclonic SE

Simple partial status epilepticus

In simple partial SE, seizures may be quite sustained, especially when associated with focal brain lesions. Simple partial seizures may be tonic (sustained muscle contraction of part of the body) or clonic (alternating muscle contraction and relaxation). Prolonged simple partial seizures (often motor and clonic) are frequently termed epilepsia partialis continua.

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

Simple partial seizures are not necessarily associated with diffuse brain damage, unless they become complex partial SE or are associated with secondary generalization.

See also the Medscape Drugs and Diseases topic Partial Epilepsies.

Complex partial status epilepticus

Episodes of complex partial 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 or screaming. Most patients are described as confused (one third of cases) or unresponsive (one third of cases).

Complex partial SE episodes have been followed by cognitive deficits in some cases; recognizing the impairment is important.

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

Absence seizures

Typical absence seizures are prolonged episodes of alteration in 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 secondary generalization. However, prolonged absence SE has been described that was not associated with subsequent neurologic deterioration.

Alteration of consciousness may not be severe; automatic behavior sometimes occurs, with patients able to perform customary daily activities such as combing their hair, playing video games, and even driving. Preceding behavioral changes that cleared with antiepileptic drug therapy have been documented in some cases. In some cases, myoclonic jerking of the eyelids (eyelid myoclonia) provides the clue to absence SE.

Absence seizure status may occur in teenagers and adults who were thought to have outgrown the condition.

See also the Medscape Drugs and Diseases topic Absence Seizures.

Nonconvulsive status epilepticus

Many studies combine cases of complex partial and absence SE under the name nonconvulsive SE. This is because of the similarity in the seizure semiology, despite of the divergent EEG patterns. 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

• Cryptogenic (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 the Brain & Nervous System Center, as well as Seizures Emergencies, Seizures in Children, and Epilepsy.

Seizures result from rapid abnormal electrical discharges from cerebral neurons. This presents clinically as involuntary alterations of consciousness or motor activity.

Consumption of oxygen, glucose, and energy substrates (eg, adenosine triphosphate [ATP], phosphocreatine) in cerebral tissue increases significantly during seizures. Optimal delivery of these metabolic substrates to cerebral tissue requires adequate cardiac output and intravascular fluid volume. See the Cardiac Output calculator.

SE occurs with the 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, loss of benzodiazepine efficacy, excessive glutamate excitation, and activation of drug resistance genes.

GABA receptor–mediated inhibition may be responsible for the normal termination of a seizure. In addition, the activation of the N -methyl-D aspartate (NMDA) receptor by the excitatory neurotransmitter glutamate may be required for the propagation of seizure activity. In experimental models, resistance to benzodiazepines and barbiturates may develop during prolonged seizures that may alter the structure and function of GABAa receptors. ^[3]

Prolonged seizures are associated with cerebral hypoxia, hypoglycemia, and hypercarbia and with concurrent and progressive lactic and respiratory acidosis. When cerebral metabolic needs exceed available oxygen, glucose, and metabolic substrates (especially during status epilepticus), neuronal destruction can occur and may be irreversible.

Massive sympathetic discharge with status epilepticus (SE) may have the following consequences:

• Hypoxia

• Hypercarbia

• Hyperthermia

• Tachycardia

• Hypertension

• Hyperglycemia

• Hyperkalemia

• Lactic acidosis

In adolescent baboons, brain damage can be observed after 90 minutes of sustained seizures, with the neocortex, thalamus, and hippocampus most affected. ^{[4, 5]} 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 paralyzation did not improve these types of CNS lesions, suggesting that excessive neuronal discharge caused the damage.

These studies also established that hyperpyrexia may also contribute to CNS damage observed in prolonged seizures. This observation has been confirmed in studies of adult humans. Cerebellar damage can also be observed; however, because it is more prominent in the border zones of arterial blood supply, this type of damage probably relates to ischemia and/or hyperthermia.

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 continuous prolonged seizures.

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 (3 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:

• 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

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 ^[6] ; 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 and tiagabine are commonly implicated. Patients with Lennox-Gastaut syndrome may develop SE 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 absence epilepsy

• Localization-related epilepsy (partial seizures)

In a large international collaborative study of 356 patients with severe epilepsies and their parents, researchers identified 429 new synaptic transmission genes. ^[7] 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. ^[7]

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. ^[8] The percentage of patients with epilepsy who develop status epilepticus varies from 1.3-16%. The first seizure lasts longer than 30 minutes in 12.6% of cases. Among patients with febrile seizures, duration exceeds 30 minutes in 5% of cases.

Almost half (48%) of adults who present with SE have no prior history of seizures. Among children diagnosed with SE, a history of prior unprovoked seizures was even less common (32%); pediatric patients who present with febrile SE rarely have a history of epilepsy.

Although the data are contradictory, SE incidence may have increased since the advent of modern antiepileptic drugs (AEDs). Data have showed that 43% of patients taking AEDs when SE occurred had low serum levels of the drugs. In 19% of cases, some levels were low and other levels were within the therapeutic range. In 38% of cases, all AED levels were in the therapeutic range.

Generalized tonic-clonic SE may be recurrent in 17-25% of children with SE. 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 group has a prospective recurrence risk of 3%.

Of children younger than 1 year who are subsequently diagnosed with epilepsy, 70% present with SE as the initial manifestation of their illness. In children with epilepsy, 20% have SE within 5 years of diagnosis. Of children with febrile seizures, 5% present with status epilepticus.

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).

Several factors affect prognosis in patients with status epilepticus (SE). These include seizure type (nonconvulsive versus generalized tonic-clonic), duration, and etiology and patient age.

After an episode of nonconvulsive SE, at least 60% of patients show some degree of cognitive deterioration. In contrast, one study of children with generalized tonic-clonic SE reported that sequelae occurred in 9% of cases. ^[9] Of these, approximately 58% were motor sequelae only, 29% were motor and cognitive, and 13% were cognitive only.

Patients with generalized tonic-clonic SE that lasts less than 1 hour have a better prognosis than do those with more prolonged SE. The relationship between seizure-mediated brain damage and duration of SE is not as clear with simple partial motor SE as it is with generalized tonic-clonic SE.

Seizure etiology has a strong effect on the frequency of SE sequelae. ^{[9, 10]} Maytal et al reported that the 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.

Sequelae rates for patients with generalized tonic-clonic SE declined with increasing age. Rates were highest among patients younger than 1 year (29%), declined to 11% for children aged 1-3 years, and fell further to 6% for children older than 3 years. ^[9] 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. ^[11]

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 complex partial seizures. ^[12]

Cognitive difficulties recognized after SE may represent pre-existent but unrecognized problems. Although learning disabilities and mental retardation 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.

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. ^[9]

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 preexisting 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 preexisting neurologicalimpairments. ^[13]

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