Pediatric Status Epilepticus 

Updated: Oct 06, 2014
Author: Rajesh Ramachandrannair, MBBS, MD, FRCPC; Chief Editor: Timothy E Corden, MD 

Overview

Practice Essentials

Status epilepticus (SE) is defined as a seizure that lasts more than 30 minutes. The annual incidence of convulsive SE among children in developed countries is about 20 per 100,000 population.

Essential update: Researchers identify new genes for severe childhood epilepsies

In a large international collaborative study of 356 patients with severe epilepsies and their parents, researchers identified 429 new synaptic transmission genes. 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.[1]

Signs and symptoms

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

  • Phase 1: Discrete partial seizures or, less frequently, generalized seizures; blood pressure usually remains within the reference range

  • Phase 2: Discrete SE events fuse and partial seizures become secondarily generalized; 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

Patients with absence SE present 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 sometimes 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

When the patient's situation stabilizes, look for lymphadenopathy, which suggests catscratch fever.

See Clinical Presentation for more detail.

Diagnosis

Every patient who presents with SE requires an EEG; however, treatment should not be delayed to wait for EEG results. When a seizure persists longer than 30-60 minutes, making immediate arrangements for an EEG is advisable. Features of testing and procedures are as follows:

  • Laboratory testing should proceed concurrently with stabilization

  • Lumbar puncture with opening pressure measurement is performed for prolonged SE of unknown etiology and in immunocompromised patients

  • Obtain imaging studies based on likely etiologies; stabilize all children before performing CT scanning or other imaging studies

SE persisting beyond 24 hours 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:

  • Urine organic acids, porphyrins (porphyria), and sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency)

  • Serum T4, T3, thyrotropin, and antiperoxidase antibody (autoimmune epilepsy)

  • Serological markers for collagen-vascular disorders

  • Serum and CSF NMDA-R antibody, ultrasound/CT/MRI of testes and abdomen to look for solid tumors (anti NMDA-R antibody encephalitis)

  • Other paraneoplastic antibodies (anti Hu, Yo, Ri)

See Workup for more detail.

Management

Treatment of SE should be based on an institutional protocol, such as the following:

  • Attend to the ABCs before starting any pharmacologic intervention

  • Place patients in the lateral decubitus position to avoid aspiration of emesis and to prevent epiglottis closure over the glottis

  • Make further adjustments of the head and neck if necessary to improve airway 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

  • In the first 5 minutes of seizure activity, before starting any medications, try to establish IV access and to obtain samples for laboratory tests and for seizure medication

  • 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)

  • 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

  • If the seizure fails to stop within 4-5 minutes, prompt administration of anticonvulsants may be indicated

A treatment algorithm is shown in the image below.

Treatment algorithms for convulsive status epilept Treatment algorithms for convulsive status epilepticus.

Anticonvulsant selection can be based on seizure duration, as follows:

  • 6-15 min: Lorazepam (0.05-0.1 mg/kg IV or IO slowly infused over 2-5 min); or diazepam per rectum at 0.5 mg/kg, not to exceed 10 mg

  • 16-35 min: Phenytoin (Dilantin) or fosphenytoin, not to exceed infusion rate of 1 mg/kg/min; do not dilute in D5W; if unsuccessful, phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); increase infusion rate by 100 mg/min; phenobarbital may be used in infants before phenytoin

  • 45-60 min: Pentobarbital anesthesia (patient already intubated); or midazolam, loading dose 0.1-0.3 mg/kg IV followed by continuous IV infusion at a rate of 0.1-0.3 mg/kg/h

Pentobarbital anesthesia is administered as follows:

  • 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

Other specific 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.

Background

Status epilepticus (SE) is defined as a seizure that lasts more than 30 minutes, constituting a neurological emergency.[2] 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 Reference 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 Reference 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 Reference 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 Reference 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 Reference 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 Clinical). 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).[#IntroductionPatientEducation]

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Seizures Emergencies, Seizures in Children, and Epilepsy.

Pathophysiology

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 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.

Etiology

The etiology of 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)

Epidemiology

The annual incidence of convulsive 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.[7] 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).

Prognosis

Several factors affect prognosis in patients with 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.[8] 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.[8, 9] 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.[8] 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.[10]

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.[11]

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.[8]

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.[12]

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.

 

Presentation

History

In the initial presentation of status epilepticus (SE), a directed history suffices. Obtain a more detailed history after stabilization, including the following details about the current seizure activity:

  • Time and nature of onset of seizure activity

  • Involvement of extremities or other body parts

  • Nature of movements (eg, eye movements, flexion, extension, stiffening of extremities)

  • Incontinence

  • Cyanosis (perioral or facial)

  • Duration of seizure activity prior to medical attention

  • Mental status after cessation of seizure activity

  • Postictal neurologic deficit

Other important information to elicit in the history includes the following:

  • Fever or intercurrent illnesses

  • Prior history of seizures - If present, specify medications, anticonvulsant use, and compliance.

  • Head injury (recent and remote)

  • Central nervous system (CNS) infection or disease (eg, meningitis, neurocutaneous syndrome)

  • Intoxication or toxic exposure (see Etiology for examples)

  • Other CNS abnormality (eg, ventricular-peritoneal shunt, prior CNS trauma)

  • Birth history and developmental delay (eg, anoxic encephalopathy, cerebral palsy)

  • Other medical history (eg, acquired immunodeficiency syndrome, systemic lupus erythematosus, type 1 diabetes mellitus)

Phases of convulsive status epilepticus

Generalized tonic-clonic SE (GTCSE) has 3 phases. In phase 1, discrete partial seizures or, less frequently, generalized seizures can be observed both clinically and on electroencephalography (EEG). Blood pressure usually remains within the reference range, but metabolic acidosis may be observed in association with elevated serum lactate and glucose levels.

In phase 2, discrete SE events fuse and partial seizures become secondarily generalized. The main outward manifestation of continuous clinical and EEG seizure activity consists of a tonic phase (sustained muscle contraction) followed by clonic jerks (alternating contraction and relaxation of the 4 limbs). Phase 2 may include altered blood pressure.

In phase 3, clinical seizures may become quite subtle, with brief rhythmic clonic or myoclonic movements often restricted to a single part of the body. During this period, the patient's EEG findings start to show slow-frequency discharges similar to periodic lateralizing epileptiform discharges (PLEDs). Rhythmic activity may be observed as myoclonus that affects only the feet, hands, facial muscles, or eyes (as nystagmus).

As the episode progresses, a motionless patient's EEG may reveal generalized or PLED-like discharges. This type of activity is thought to represent a burned-out form of SE. This conclusion is supported by cases in which positron emission tomography (PET) scanning revealed hypermetabolism of the mesiotemporal region in patients with abnormal mental status and PLED-like discharges after an episode of SE.

Hyperthermia, respiratory compromise, hypotension, and hypoglycemia may be observed. If not promptly treated, these metabolic, cardiovascular, and respiratory complications can exacerbate the patient's clinical condition and neurologic deficit.

Nonconvulsive status epilepticus

Patients with nonconvulsive SE are described as appearing forgetful and sleepy, behaving as if deaf and blind (“like a zombie”), or having the appearance of being drugged. In more severe cases, patients are described as unresponsive. Sometimes parents describe the motor component of frequent falls, poor motor control, or abnormal balance.

Physical Examination

Perform a rapid, directed physical and neurologic examination during SE, followed by a detailed examination when the child is stabilized. During the initial physical examination, seek signs of sepsis or meningitis and of head trauma or CNS injury.

Signs of sepsis or meningitis include the following:

  • Temperature above 38.5°C; in patients younger than 2-3 months, above 38.0°C

  • Respiratory distress

  • Cyanosis

  • Poor peripheral perfusion

  • Bulging fontanelles in infant

  • Meningismus (in children >12-18 mo)

  • Presence of petechiae or purpura, herpetic vesicles

When the patient's situation stabilizes, look for lymphadenopathy, which suggests catscratch fever.

Evidence of head or other CNS injury includes the following:

  • Bradycardia, tachypnea, and hypertension (Cushing triad for signs of increased intracranial pressure)

  • Poor pupillary response

  • Asymmetry on neurologic examination

  • Abnormal posturing

  • Gross deformity or soft tissue injury to head

Hallmarks of neurocutaneous syndromes (eg, port wine stain) may also be found.

Patients with GTCSE usually have bilateral and synchronous movements of the extremities. Although asynchronous alternating movements of the extremities are often thought to be caused by pseudoseizures, a similar pattern can be observed in cases of frontal lobe epilepsy. Epilepsia partialis continua manifests by unilateral and, at times, focal (eg, one hand or even one finger) clonic activity (ie, twitching).

Patients with absence SE present with altered consciousness, with or without clonic movements of the eyelids or upper extremities, and automatisms involving the hands and face. A child may sometimes 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.

In patients who present to the emergency department (ED) after an episode of prolonged seizure, carefully observe for signs of subtle seizures or SE, such as clonic or myoclonic rhythmic movements involving the limbs or face and eyes. These movements often are easy to recognize in overt generalized tonic-clonic seizures and in SE. Clonic activity may start focally then spread to the hemibody and finally become generalized. Focal clonic activity may assume the form of rhythmic facial muscle contractions, or it may involve the limbs.

Complications

The most feared complication of GTCSE is brain damage associated with neuronal loss mediated by sustained electrical seizure activity in the brain. Other complications of prolonged seizures may include the following:

  • Aspiration

  • Fluid, electrolyte, and metabolic disturbances

  • Trauma

  • Cardiopulmonary problems

  • Complications as a result of the underlying cause

Fluid, electrolyte, and metabolic complications include lactic acidosis, dehydration, and hypotension. Myoglobinuria caused by muscle breakdown during a seizure may lead to renal dysfunction.

Traumatic complications of SE include oral trauma, both internal (eg, biting the tongue or oral mucosa) and external (eg, hitting the lips). Many patients incur closed head or facial injuries during the clonic phase of seizures. Posterior shoulder dislocation is a classic complication and is difficult to diagnose in the unconscious patient

Pulmonary edema and cardiac arrhythmias may be complications of SE or its treatment.

Disseminated intravascular coagulation in association with significant leukocytosis and mild cerebrospinal fluid pleocytosis may produce a clinical picture similar to sepsis or CNS infection. In these cases, patients are often treated for a severe infection until sepsis or meningitis/encephalitis can be safely ruled out.

 

DDx

Diagnostic Considerations

Always consider the possibility of infections in pediatric patients presenting with generalized tonic-clonic status epilepticus (GTCSE). Sources of infection often, but not always, are obvious (eg, otitis media, pneumonia). Treat these infections appropriately because they contribute to lowering the seizure threshold in predisposed patients.

Infections can be the precipitating factor for both GTCSE and nonconvulsive status epilepticus (NCSE). Patients with CNS infections and mental status changes should not be assumed to have infection-related neurologic dysfunction before EEG findings rule out NCSE.

Catscratch disease

Consider catscratch disease, particularly in a school-aged child with a cat or kitten at home who presents with a history of unexplained mental status changes, status epilepticus (SE) of unknown etiology, prolonged seizures, or persistent fatigue. Catscratch fever is an infection acquired from cats (often from kittens) infected with Bartonella henselae via the cat flea. Although the disease may be transmitted by any close contact with a cat, scratches or bites cause 75% of cases.

Psychogenic seizures

Occasionally, nonepileptic seizures can be confused with GTCSE. They may occur in patients with a previous diagnosis of epilepsy.[13]

Patients with nonepileptic seizures can reproduce an outward clinical seizure pattern as a manifestation of an unresolved psychological conflict (psychogenic seizure), or the seizure may be a manifestation of malingering, providing the patient with a clear secondary gain. Pediatric patients rarely fake a seizure, however. Symptoms of true psychogenic seizures resemble conversion symptoms.

In many cases, details of the presentation can help differentiate nonepileptic seizures from GTCSE. Features suggesting nonepileptic seizures include the following:

  • No loss of consciousness in the presence of bilateral movements

  • Asynchronous, side-to-side, and out-of-phase movements

  • Pelvic thrusting

  • Inconsistency of movement patterns and waxing and waning patterns

  • Persistent eye closure

  • Crying during the seizure

On the other hand, no loss of consciousness in the presence of bilateral movements, pelvic thrusting, and asynchronous and thrashing movements can also be part of frontal lobe seizures, which may lead to SE in some cases. Only careful observation of the patient (eg, video) with simultaneous EEG (ie, EEG video monitoring) allows the physician to differentiate between sustained nonepileptic seizures and GTCSE.

Differential Diagnoses

 

Workup

Approach Considerations

Every patient who presents with SE requires electroencephalography (EEG); however, treatment should not be delayed to wait for EEG results. When a seizure persists longer than 30-60 minutes, making immediate arrangements for an EEG is advisable.

Likewise, laboratory testing should proceed concurrently with stabilization. Although routine laboratory studies are not always useful in assessing patients with brief seizures who present to the emergency department (ED), children with generalized tonic-clonic status epilepticus (GTCSE) require a more aggressive workup. Lumbar puncture with opening pressure measurement is performed for prolonged SE of unknown etiology. It is also indicated in immunocompromised patients.

Stabilize all children before CT scanning or other imaging studies are performed. Obtain imaging studies based on likely etiologies

Lab Studies

The choice of laboratory studies is based on age and likely etiologies. They may include the following:

  • Blood glucose level

  • Complete blood count (CBC)

  • Electrolyte levels

  • Calcium and magnesium levels, particularly in neonates

  • Arterial blood gases

  • Toxicology screen

  • Anticonvulsant levels (if indicated by history of ingestion or known therapy[14] )

Stabilization phase studies

While attending to the patient’s airway, breathing, and circulation (ABCs) and inserting an intravenous (IV) line, obtain a CBC and tests for levels of anticonvulsant medication, electrolytes, blood urea nitrogen (BUN) and creatinine, calcium, and magnesium.

Serum glucose measurement is particularly important if the child or another household member uses insulin or other hypoglycemic agents; hypoglycemia may be a contributing factor or cause of seizures. Glucose measurement should be performed with a fast bedside assay (eg, Dextrostix).

The CBC may show elevation of the white blood cell (WBC) count in patients with infection. However, an elevated WBC count may be due to demargination, returning to reference ranges over 12-24 hours.

Calcium and magnesium measurement may be important, especially for infants fed with cows' milk. It is also valuable in older patients with disorders that may produce imbalances in these elements (eg, renal failure, hypoparathyroidism).

Other necessary tests may include urine/serum toxicology, especially in teenagers with unexplained seizures. If school-aged children who have cats (particularly kittens) at home present with unexplained mental status changes and prolonged seizures, evaluate for catscratch fever by measuring indirect fluorescent antibody titers to Bartonella henselae. A lumbar puncture is commonly indicated in children with GTCSE, especially those with unexplained fever or mental status changes preceding or following the seizure episode.

Continued evaluation

Continue evaluation after seizures are controlled. Basic tests recommended by the Epilepsy Foundation Working Group on Status Epilepticus include liver function tests (LFTs), toxicology screen, and brain imaging.[15]

After an SE episode, perform a lumbar puncture for individuals with fever or other evidence of CNS infection. Remember that febrile convulsive status may be associated with CNS infection without typical meningeal signs. Brain imaging should be part of the workup for status epilepticus prior to lumbar puncture for patients with acute neurologic changes suggesting increased intracranial pressure.

A treatment algorithm is shown in the image below.

Treatment algorithms for convulsive status epilept Treatment algorithms for convulsive status epilepticus.

Imaging Studies

Imaging studies are indicated in patients with GTCSE once they are stabilized. A head CT scan is the best diagnostic imaging study, particularly if intracranial hemorrhage, midline shift, or mass lesion is suspected.

In many centers, head CT scanning is available on an emergency basis. If CT scanning is unavailable and the patient is stable and has no signs of increased intracranial pressure, CT scanning can be temporarily deferred.

Perform an imaging study for all patients who have histories of neurologic (including mental status) changes and for patients who have actual deficits on the neurologic examination that persist after cessation of seizures.

Brain imaging should be part of the workup for SE prior to lumbar puncture for patients with acute neurologic changes suggesting increased intracranial pressure.

Children with complex partial seizures preceding or leading to the episode of GTCSE should undergo brain MRI. In many centers, CT scanning is performed in the ED because MRI services are often unavailable after hours. If not immediately available, MRI should be performed in the following days.

Brain imaging may be unnecessary for patients who have already had MRI performed as part of a workup for epilepsy or when the cause or precipitant for their episode of SE is obvious (eg, low anticonvulsant levels, acute infection).

On follow-up, many patients with documented a priori normal MRI findings may develop an increased T2, diffusion and fluid attenuated inverted recovery (FLAIR) signal. This is especially true in cases of prolonged partial seizures leading to secondary GTCSE. Most of these changes are due to transient vasogenic or cytotoxic edema.

Electroencephalography

The EEG helps in differentiating convulsive SE from pseudoseizure (nonepileptic or psychogenic seizure). Nonconvulsive status epilepticus (NCSE) may need to be differentiated from postictal state–related depression and unresponsiveness from metabolic encephalopathies (renal and hepatic) as well as anoxic encephalopathies. This is especially the case when treatment with anticonvulsant medication does not improve the patient’s alertness.

Patients who ultimately require continuous infusion with a barbiturate or benzodiazepine should undergo continuous EEG monitoring.

During a prolonged seizure, EEG manifestations follow a sequence of partial (focal) EEG seizures, leading to discrete generalized tonic-clonic seizures that eventually become fused (ie, continuous EEG seizure). Rhythmic lateralized or generalized discharges later appear to slow in frequency and may appear similar to periodic lateralizing epileptiform discharges (PLEDs).

A patient who arrives at the ED may be at any of these EEG stages; historical information concerning seizure progression usually correlates somewhat with stage. Patients at the later stages of EEG with GTCSE may be more difficult to treat.

Patients who cannot be aroused following a seizure should have an EEG performed to rule out subclinical SE. An EEG can confirm the seizure pattern and help indicate the most appropriate long-term treatment, if necessary.

Workup for Prolonged Refractory Status Epilepticus

Seizures not responding to appropriate therapy in 60 minutes or to the first- and second-lines drugs (initial doses of benzodiazepines, IV phenytoin/fosphenytoin, and phenobarbital) should be considered refractory status epilepticus. Prolonged refractory status epilepticus (seizures persisting beyond 24 h) needs further workup if routine blood work, MRI of the brain, and microbiological studies in serum and cerebrospinal fluid (CSF) do not provide clues to the etiology of the seizures. The following investigations are considered:

  • Urine organic acids, porphyrins (porphyria), and sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency)

  • Serum T4, T3, thyrotropin, and antiperoxidase antibody (autoimmune epilepsy)

  • Serological markers for collagen-vascular disorders

  • Serum and CSF NMDA-R antibody, ultrasound/CT/MRI of testes and abdomen to look for solid tumors (anti NMDA-R antibody encephalitis)

  • Other paraneoplastic antibodies (anti Hu, Yo, Ri)

If the patient continues to be in refractory status epilepticus beyond 72 hours, additional investigations are suggested, as follows:

  • Repeat MRI brain with gadolinium

  • Cerebral angiography (CT angiography or conventional 4-vessel angiography) to look for evidence of vasculitis

  • CSF neurotransmitters

If the above-mentioned investigations do not identify the etiology of seizures within a week, brain biopsy may be considered.

 

Treatment

Approach Considerations

Status epilepticus (SE) treatment should follow a logical sequence of interventions. Every institution dealing with this problem should design a plan, such as the one outlined below, that is based on current information derived from authoritative sources, as well as on recent reviews of the literature, and the protocol should be communicated to the medical staff. Review the protocol at least annually.

The lack of a structured protocol has been blamed for increased morbidity from SE.[16] Litigation involving patients suffering sequelae of SE is often based on perceptions that treatment deviated from established standards of practice.

Physicians should become familiar with the pharmacology of the drugs used to treat SE. Prudence calls for doses of these drugs to be placed in visible locations within emergency departments (EDs), pediatric units, and nursing stations.

Treatment for generalized SE should be part of a continuum of the management for seizures of shorter duration. Any algorithm for treating seizures should consider the time of onset of the ictal activity (continuous or intermittent without recovery of consciousness) and the number and type of drugs that did not control the seizures, despite appropriate dosages and routes of administration. Remember that seizures of longer duration tend to be more difficult to treat.

Prehospital Care

Supportive care, including management of airway, breathing, and circulation (the ABCs), must be addressed in the prehospital setting. Emergency medical system (EMS) personnel should proceed as follows:

  • Secure the airway

  • Administer supplemental 100% oxygen

  • Infuse isotonic intravenous fluids and dextrose

  • Immobilize the cervical spine in patients with possible trauma

If the seizure fails to stop within 4-5 minutes or if the patient is continuing to seize at the time of EMS arrival, prompt administration of anticonvulsants may be indicated, if permitted by local protocols. Consider rectally administered diazepam (0.5 mg/kg/dose) or intramuscularly administered midazolam (0.1-0.2 mg/kg/dose; not to exceed a cumulative dose of 10 mg).[17]

If persons who know the patient, or who witnessed the onset of the seizures, are present at the scene, EMS providers may be able to collect information that offers clues to the cause of the SE.

Patient Stabilization

As in any medical emergency, attend to the ABCs first, before starting any pharmacologic intervention. Place patients in the lateral decubitus position to avoid aspiration of emesis and to prevent epiglottis closure over the glottis. Further adjustments of the head and neck may be necessary to improve patency of the airways (use care in the setting of potential neck trauma without full radiographic evaluation). 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.

Respiratory depression is a common complication of the management of prolonged seizures. Ensure that equipment is available to deliver supplemental oxygen and positive pressure ventilation when initiating anticonvulsant therapy.

Carefully monitor the patient's vital signs, including blood pressure. Carefully monitor the patient's temperature because hyperthermia may worsen brain damage caused by seizures.

In the first 5 minutes of seizure activity, before starting any medications, try to establish intravenous (IV) access and to obtain samples for laboratory tests and for seizure medication levels (see Workup). Infuse isotonic intravenous fluids plus glucose at a rate of 20 mL/kg/h (eg, 200 mL dextrose 5% in normal saline [D5NS] over 1 h for a 10-kg child).

In children younger than 6 years, use intraosseous (IO) infusion if intravenous access cannot be established within 5-10 minutes . Most available anticonvulsants may be administered intravenously or intraosseously.

If serum glucose is low or cannot be measured, give children 2 mL/kg of 25% glucose. Adults should receive 50 mL of 50% glucose, along with 100 mg of thiamine to avoid Wernicke- Korsakoff syndrome.

Other specific 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 intravenously preferably (if needed may administer intramuscularly/subcutaneously) for narcotic overdose

  • Pyridoxine - 50-100 mg intravenously/intramuscularly for possible dependency, deficiency, or isoniazid toxicity

  • Antibiotics - If meningitis is strongly suspected, initiate treatment with antibiotics prior to cerebrospinal fluid (CSF) analysis or CNS imaging

If the onset of the seizure was witnessed, initiate anticonvulsant treatment only after 5 minutes of seizure duration. Most seizures stop without intervention.

Obtain a history of the prehospital treatment of the seizures. Cumulative doses of benzodiazepine medication (prehospital included) increase the risk of respiratory failure.

In cases of repetitive convulsions without recovery of consciousness, the duration of the seizure is defined as the time elapsed from the onset of the first seizure to the termination of the last.

Call for the pediatric intensive care unit (PICU) service and respiratory therapists (or anesthesiologists) if seizures persist for more than 20 minutes.

The Table below is based on the Emergency Management Guidelines of Children's Hospital and Regional Medical Center. Step 1, which encompasses the first 0-5 minutes of care and thus precedes the actions outlined in this table, consists of addressing the patient's ABCs.

Table 1. Medical Treatment of Seizures and Status Epilepticus Based on Time Elapsed Since Seizure Onset (Steps 2-4) (Open Table in a new window)

Step

Medication

Dose

Alternatives

Step 2 (6-15 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 intramuscularly (IM)*, IV, or intranasally*

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 (16-35 min)

Phenytoin (Dilantin) or fosphenytoin (Cerebyx)†

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)

If seizures persist, administer 5 mg/kg for 2 doses (if blood pressure is within the reference range and no history of cardiac disease is present)

If unsuccessful, administer phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); increase infusion rate by 100 mg/min; phenobarbital may be used in infants before phenytoin; be prepared to intubate patient; closely monitor hemodynamics and support blood pressure as indicated

Step 4 (45-60 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.

Anticonvulsant Selection

The optimal protocol for management of SE begins with a benzodiazepine, either lorazepam or diazepam.[18] In the United States, lorazepam is the drug of choice in patients with intravenous or intraosseous access. Lorazepam (0.05-0.1 mg/kg IV or IO slowly infused over 2-5 min) has rapid onset and long duration of anticonvulsant action. It is preferred over diazepam,[19, 20] although one review found lorazepam and diazepam equally effective for controlling SE in children.[21, 22]

If an IV line cannot be established rapidly in a child who is too old for IO infusion, use per rectum (PR) diazepam. Midazolam (0.1-0.2 mg/kg IM) is the most effective choice when IV or IO access is not immediately available, but IM midazolam is not approved by the US Food and Drug Administration (FDA) for that indication.

Midazolam is the only benzodiazepine that can be administered safely intramuscularly while providing rapid onset equivalent to that of intravenous agents and a moderate duration of action. Intranasal midazolam may also be an option in children with prolonged seizure without an IV access.

In one study, no difference in efficacy was observed between caregiver-administered intranasal midazolam and rectal diazepam for terminating sustained seizures (ie, >5 minutes) in children at home. Caregiver's satisfaction was higher with the inhaled midazolam (easier to administer) and the median time from medication administration to seizure cessation was 1.3 minutes less for inhaled midazolam compared with rectal diazepam.[23]

If the seizures cease, no further drugs are immediately necessary. The etiology of SE epilepticus should then be investigated.

If benzodiazepine therapy proves ineffective, IV or IO fosphenytoin or phenytoin is used. These agents are effective for most idiopathic generalized seizures and for posttraumatic, focal, or psychomotor SE. Fosphenytoin offers the advantage of a potentially rapid rate of administration with less risk of venous irritation and vascular compromise of the infused limb (eg, purple-glove syndrome).

The loading dose of phenytoin is 20 mg/kg IV or IO; for fosphenytoin, it is 20 mg/kg PE IV or IO. A full loading dose should be delivered unless the patient is known to have a current therapeutic level. With phenytoin, use a slow rate of infusion (< 1 mg/kg/min or < 50 mg/min) to avoid hypotension or cardiac arrhythmias. Although respiratory depression that requires endotracheal intubation may occur at any time during treatment of GTCSE, it is especially common during administration of phenytoin/fosphenytoin.

If fosphenytoin or phenytoin is not effective, phenobarbital (20 mg/kg IV/IO) is the third-line therapy. In many pediatric institutions, phenobarbital is the second-line choice, rather than fosphenytoin or phenytoin, especially for febrile and neonatal SE. Phenobarbital's major disadvantages are that it significantly depresses mental status and causes respiratory difficulty. Obtain serum anticonvulsant levels prior to administering additional long-acting anticonvulsants such as phenytoin or fosphenytoin.

For more information, see the Medscape Reference article Antiepileptic Drugs.

Refractory status epilepticus

The term refractory GTCSE has been used when seizures do not respond to benzodiazepines, phenytoin/fosphenytoin, and phenobarbital. Several options are presently available for these patients.

Barbiturate anesthesia is among the most popular treatments, although midazolam infusions (neither is approved by the FDA) have gained growing acceptance in the United States over the past 5 years. In the United States, barbiturate anesthesia is commonly performed with pentobarbital infusions. Pentobarbital is given in a loading dose of 5-10 mg/kg IV or IO, followed by 0.5-3 mg/kg/hr. In the United Kingdom, thiopental (thiopentone) is often used rather than pentobarbital. High-dose phenobarbital has been used in patients with GTCSE. All barbiturates used in anesthetic doses have been associated with such complications as hypotension, cardiac depression, and infections.

Midazolam and propofol are gaining increasing acceptance throughout the world as alternative treatments for refractory GTCSE, thanks to the comparative ease of handling these drugs in a continuous infusion.[24] However, propofol is not currently recommended for long-term control of SE, due to reports of severe acidosis and movement disorder after prolonged use. Also worrisome is the association of propofol-related metabolic acidosis in patients on the ketogenic diet.

Midazolam has been used, even in neonates, and has a reasonably predictable pharmacology, although movement disorders have been reported from prolonged use of midazolam for sedation.[25] Midazolam is given in a loading dose of 0.2 mg/kg IV or IO, followed by 0.75-10 mcg/kg/min.

In a few cases, adding a maintenance anticonvulsant medication to the patient’s regimen may help wean the patient off a continuous barbiturate infusion. Although the experience is still very limited, both IV valproic acid and topiramate via nasogastric tube have been used with that goal.

High-dose topiramate has been used in adults with SE, at doses as high as 1600 mg/day.[26] One pediatric study used relatively lower initial doses of 2-3 mg/kg/day before proceeding within 48-72 hours to a maintenance dose of 5-6 mg/kg/day (in 2 divided doses daily), which terminated the episode of SE.[27] Another study reported a loading dose of 10 mg/kg followed by 5 mg/kg/day maintenance (in 2 divided doses daily).[28] Treatment of SE with topiramate is suggested by the neuroprotective action of this drug in animal models. Nonetheless, further data are necessary to show similar action in humans.

Intravenous valproic acid is used for 3-Hz spike and wave stupor (absence SE) and myoclonic SE in cases of juvenile myoclonic epilepsy and postanoxic myoclonus.[29, 30] Treatment of convulsive status (ie, GTCSE) with IV valproic acid after failure of other drugs (eg, benzodiazepines, phenytoin, phenobarbital) has been rarely reported. Both secondary and primary GTCSE seem to equally respond to IV valproic acid.

A loading dose of 15-20 mg/kg is used, followed by 10 mg/kg every 6 hours. Alternatively, Uberall et al recommend a loading dose of 20-40 mg/kg over 5 minutes, followed by an infusion at a rate of 5 mg/kg/h.[31] After 12 hours of clinical and EEG cessation of seizures, the dose is reduced to 1 mg/kg every 2 hours.

Reports have shown the efficacy of levetiracetam as an add-on therapy in adults with refractory SE, with reported loading doses of 500-3000 mg/day and a maintenance dose of 2000-3000 mg/d. In children, the reported loading dose is 30-40 mg/kg.[32, 33, 34]

In Europe, alternative agents such as paraldehyde, lidocaine (Sweden and United Kingdom), and chlormethiazole (mostly United Kingdom) have been used. Paraldehyde is no longer commercially available in the United States, whereas chlormethiazole is not approved by the FDA. Lidocaine is unpopular in the United States because of its narrow therapeutic index and proconvulsant effect at toxic levels.

Paraldehyde is a very effective drug, despite problems (eg, sterile abscess, pulmonary edema), but was discontinued from the US market in 2008. Respiratory failure and hypotension of sudden onset has been described. Shorvon recommends pediatric doses of 0.07-0.35 mL/kg.[35] The adult dose is 5 mL PR diluted on the same volume of water.

Exposure to air and light causes conversion of paraldehyde to acetaldehyde and then to acetic acid, with subsequent metabolic acidosis when administrated. Paraldehyde dissolves some plastic syringes and tubing if not used immediately.

Approximately 80% of the paraldehyde is absorbed after a single rectal dose. Because of the high solubility of paraldehyde in lipids, the passage through the blood brain barrier may depend more on the cerebral blood flow; this is an attractive quality because of the possibility of a differential absorption concentration of the drug by the regions of the cortex involved in the epileptiform activity because they have higher blood flow than the rest of the brain during seizures.

A therapeutic trial with folinic acid (0.5-1 mg/kg) and enteral pyridoxine (up to 30 mg/kg/day) for a week is worth considering in prolonged refractory status epilepticus.

Further Inpatient Care

Most children with an episode of SE should be admitted for inpatient observation, evaluation, and treatment. Any child with persistent altered mental status (despite cessation of seizure activity) or with prolonged status epilepticus should be admitted to a pediatric critical care unit.

Treat patients with status epilepticus (SE) who have suspected herpes encephalitis with acyclovir until the diagnosis can be confirmed. Suspect herpes virus encephalitis in all patients with fever, mental status changes, and de novo onset of partial seizures, with or without secondary generalization.

Treatment of catscratch disease is not universally efficacious. Rifampin, ciprofloxacin, and trimethoprim-sulfamethoxazole have been successfully used.

Electrolyte disturbances may cause or perpetuate seizures; hypocalcemia and hyponatremia are the most common. Efforts to correct hyponatremia should be performed carefully because quick shifts in serum osmolality may cause irreversible brain damage from central pontine myelinolysis. Correction of hypocalcemia with IV calcium gluconate should be performed under electrocardiographic (ECG) monitoring because of the possibility of cardiac arrhythmias.

Long-Term Antiepileptic Therapy

Although a complete guide for outpatient management of epilepsy is beyond the scope of this article, the Epilepsy Foundation Working Group on Status Epilepticus recommends starting some patients, including those with a history of epilepsy or brain lesion, on long-term antiepileptic therapy after an episode of SE.

No long-term therapy is indicated for SE caused by transient problems (eg, metabolic disturbances such as hyponatremia, intoxications). No consensus has been reached regarding the need for treatment after an instance of febrile SE or when a first unprovoked seizure is an SE episode.

Although many studies have shown that recurrent seizure risk is unrelated to seizure duration, a recurring GTCSE episode is more likely to be a prolonged seizure.

Knowledge of the seizure type and EEG pattern can help confirm the diagnosis of an epileptic syndrome and guide the selection of anticonvulsant medication. Patients with partial seizures respond better overall to carbamazepine, phenytoin, and phenobarbital (infants).

Valproic acid and phenobarbital are better treatments for patients with generalized tonic-clonic seizures, although carbamazepine and phenytoin can also be administered for patients with secondary generalized seizures. Valproic acid carries a higher risk of liver failure in patients younger than 2 years and those on polypharmacy.

Consultations

After initial emergency stabilization, consider consultation with the following specialists:

  • Pediatric emergency or critical care specialist or general pediatrician

  • Pediatric neurologist

  • Pediatric neurosurgeon if needed

Transfer is prudent unless the hospital facility has a pediatric critical care unit and staff familiar with the risks and complications of SE in children.

A child who has a single generalized tonic-clonic seizure for the first time often does not receive long-term anticonvulsant therapy. Consult a pediatric neurologist.

 

Medication

Medication Summary

This section primarily addresses dosages and pharmacologic properties of anticonvulsant medications used to treat generalized tonic-clonic status epilepticus (GTCSE). Benzodiazepines, hydantoins, and barbiturates have anticonvulsant properties. Choose a parenteral preparation with rapid onset and long duration of action and the least amount of sedation and respiratory depression. Titrate for clinical response by waiting an adequate length of time for attainment of therapeutic levels in the brain.

Anticonvulsant Benzodiazepines

Class Summary

This class of medications has long been used to treat generalized tonic-clonic status epilepticus (GTCSE) and is often mentioned as first-line treatment for seizures in general. Diazepam has been advocated as a first-line agent alone or in combination with phenytoin.

Whether a benzodiazepine followed by phenytoin is really the ideal sequence for this combination or if phenytoin (or fosphenytoin) should be followed by a benzodiazepine is unclear. Although the latter sequence appears better in animal models of GTCSE, human data are lacking. Experience with benzodiazepines in the treatment of status epilepticus (SE) is large. This class of drugs has been described as the most potent used in SE management.

Diazepam (Valium, Diastat)

Diazepam depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of gamma-aminobutyric acid (GABA). It is a highly lipophilic drug that quickly crosses the blood-brain barrier but is also rapidly redistributed to lipid-rich tissues. Thus, the duration of seizure control is very short with diazepam, and the drug must be followed by administration of the longer-acting phenytoin or phenobarbital.

Per rectum (PR) diazepam has been found to be effective in the control of cluster and prolonged seizures. Diazepam tends to be more effective when administered within 15 minutes of seizure onset. Do not administer faster than 1-2 mg/min IVP in children or faster than 5 mg/min in adults.

Lorazepam (Ativan)

Lorazepam is a sedative hypnotic with short a rapid onset of action, equivalent to that of diazepam, but a longer effective duration of action against GTCSE (6-8 h) than diazepam. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of CNS, including the limbic and reticular formation. Monitoring of the patient's blood pressure after administering a dose of lorazepam is important. Adjust the dose as necessary.

Midazolam (Versed)

Midazolam depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. IM midazolam is the drug of choice for the child without immediate IV or IO access.

Although midazolam is not approved by the FDA for treatment of seizures in the United States, it has a long record of safety that probably is similar to other benzodiazepines. It is used in at least 2 scenarios: (1) for initial treatment of relatively brief seizures (>5-10 min) as an alternative to diazepam or lorazepam and (2) to treat SE refractory to other benzodiazepines, phenytoin, and phenobarbital.

Because midazolam is water soluble, the peak EEG effect takes approximately 3 times longer than diazepam; thus, 2-3 minutes are required to fully evaluate sedative effects before initiating a procedure or repeating the dose. Commercially available solutions contain 1% benzyl alcohol and 0.01% edetate sodium.

Hydantoins

Class Summary

These agents stabilize neuronal membranes. They may act in the motor cortex, where they may inhibit the spread of seizure activity.

Phenytoin (Dilantin)

Phenytoin slows the rate of recovery of voltage-activated sodium channels in the inactivated state, preventing rapid repetitive firing of neurons. The activity of brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited.

Phenytoin should not be mixed with dextrose-containing solutions because of risk of precipitation; instead, dissolve drug in NaCl 0.9%. Propylene glycol and sodium hydroxide in IV preparation are thought to be responsible for pain during infusion, phlebitis, and local tissue damage.

Approximately 90% of serum phenytoin is bound to protein, mainly albumin, and an increase in unbound phenytoin is observed in patients with lower albumin levels (eg, neonates, people with renal or hepatic failure, nephrotic syndrome, pregnancy, or severe burns). Phenytoin demonstrates fast brain uptake equivalent to that of phenobarbital and diazepam. The cerebrospinal fluid (CSF) concentration is similar to the unbound serum fraction.

Phenytoin is effective for idiopathic, posttraumatic, focal, and psychomotor SE. Individualize doses. Maximal IV infusion rates (1 mg/kg/min in children and 50 mg/min in adults) are to be respected because of the many cardiovascular actions from its quinidinelike effects.

Fosphenytoin (Cerebyx)

A key drug for the treatment of GTCSE, fosphenytoin is a diphosphate ester salt of phenytoin that acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity.

The dose of fosphenytoin is expressed as phenytoin sodium equivalents (PE). Although fosphenytoin can be administered IV and IM, IV is the route of choice and should be used in emergency situations. The drug can be readily dissolved in any of commercially available IV solutions (eg, D5W, isotonic sodium chloride solution). It is prepared with 100 mL of diluent.

Concomitant administration of an IV benzodiazepine is usually necessary to control SE. When patients become alert during infusion, they may report perineal itching. Slow the infusion for individuals appearing uncomfortable and whose seizures have stopped.

Fosphenytoin is three times more avidly bound to serum protein than phenytoin, displacing the latter from its protein-binding sites. It can be infused 3 times faster than phenytoin.

Despite these factors, when comparing the maximum phenytoin infusion rate of 50 mg/min (1 mg/kg/min in children) with that of fosphenytoin 150 mg/min (3 mg/kg/min for children), the rates at which free and total serum phenytoin levels increase show very similar curves that overlap at many points in time. The main advantage of fosphenytoin is its relatively low level of local irritation, avoiding serious local tissue damage with IV extravasation, and potential use in IM injection. Disadvantage is high price.

Barbiturates

Class Summary

These agents have sedative, hypnotic, and anticonvulsant properties. They suppress CNS from the reticular activating system (presynaptic and postsynaptic).

Pentobarbital (Nembutal)

Use pentobarbital anesthesia when seizures persist after 60 min of appropriate treatment. Patient should be already intubated. An advantage of pentobarbital over inhalation anesthetics is that it decreases intracranial pressure whereas the latter tend to increase it.

At concentrations below 10 µmol, pentobarbital potentiates GABA-induced increase in chloride (Cl) conductance and decreases voltage-activated calcium currents in hippocampal neurons. At subanesthetic concentrations, barbiturates decrease glutamate-induced depolarizations (an effect mediated by the AMPA receptors).

At concentrations above 100 µmol, this agent is capable of increasing Cl conductance in the absence of GABA. At high (anesthetic) concentrations, it inhibits sodium (Na) channels that reduce high-frequency rapid repetitive firing. Indirect evidence suggests Na channel blockade may be a main mechanism of general anesthesia.

Pentobarbital decreases cation flux after cholinergic activation of nicotinic receptors. Interaction with nicotinic receptors at the autonomic ganglia and at the neuromuscular junction explains hypotension and potentiation of the action by neuromuscular-blocking agents.

Approximately 35-45% of serum pentobarbital is protein bound. Like all highly lipid-soluble barbiturates, the total terminal half-life of pentobarbital does not have a direct relationship with the duration of its efficacy as an anesthetic because of the redistribution effect.

Serum pentobarbital levels achieved in adults and adolescents range from 5-100 mg/L. Some authors emphasize the need to reach burst-suppression pattern on EEG, whereas others have shown that this pattern is neither necessary nor sufficient because breakthrough seizures may occur coming out of this pattern. It is much easier to teach burst-suppression pattern recognition than to diagnose seizures on EEG. EEG monitoring is often used to adjust infusion to keep the burst-suppression pattern within 2-8 bursts/min. Some authors recommend continuous EEG monitoring for the first 6 hours, followed by 10-minute samples every 30 minutes.

Patients requiring pentobarbital anesthesia after prolonged seizures lasting 16 hours to 3 weeks may have poor outcome, which may be related to underlying pathology (eg, cancer, drug overdose) rather than to use of pentobarbital. Pentobarbital anesthesia is also effective in children with SE refractory to other medications, but pediatric experience is limited, and prognosis may be somewhat better than in adults. Vasopressors are commonly needed during pentobarbital anesthesia in children.

Thiopental (Pentothal)

Thiopental differs from other barbiturates because of a sulfur replacement of the oxygen on the C2 position, which confers increased lipid solubility, faster onset of action, and accelerated degradation. This agent is widely used to treat refractory SE in Europe and Australia, but is less frequently used in the United States. The elimination half-life is directly proportional to the duration of infusion. Thiopental is slowly metabolized by the CYP450 microsomal enzyme system in the liver. The CSF concentration is more variable than that of pentobarbital.

Burst-suppression pattern is observed on EEG when serum levels above 30-40 mg/L are reached, although higher levels may be necessary in patients undergoing prolonged treatment. EEG silence is usually observed with levels above 70 mg/L. Other factors that influence the effectiveness of thiopental include protein binding, pH-dependent changes of nonionized fraction of drug, and blood flow distribution.

An effective IV anesthetic dose of 2.5% thiopental induces loss of consciousness in 10-20 s; maximal brain concentration is achieved in 30 s, and consciousness regained in 20-30 minutes after single dose. Nonetheless, when a single dose is injected IV, effects last only a few min because of redistribution to less vascular tissues (eg, muscle, fat) leading to a drop in CNS concentrations.

Prolonged administration and use of doses greater than 1 g may be associated with prolonged recovery (hours to days) because of saturation of lipid stores. Monitor levels daily during thiopental infusions.

Phenobarbital (Luminal)

Phenobarbital is effective for febrile and neonatal SE. Many pediatric neurologists and pediatricians use phenobarbital (instead of phenytoin) as a second-line treatment for seizures in infants and toddlers that did not respond to benzodiazepines. No controlled studies have demonstrated superiority of either phenobarbital or phenytoin to treat seizures.

Phenobarbital's site of action may be post-postsynaptic (eg, cortex thalamic relay nuclei, pyramidal cells of cerebellum, substantia nigra) or pre-presynaptic in the spinal cord. This agent's inhibitory action relates to interaction with the GABAa receptor, increasing duration of opening bursts of chloride channel. Barbiturates increase binding of GABA to the GABAa receptor but use a binding site different from the site to which benzodiazepines attach. Phenobarbital promotes binding of benzodiazepines to the GABAa receptor.

The efficacy of phenobarbital is similar to that of diazepam plus phenytoin and lorazepam. When administered after benzodiazepines, phenobarbital creates significant risk for respiratory impairment.

At concentrations greater than 200-300 µmol, phenobarbital is capable of increasing chloride conductance in the absence of GABA. At high concentrations, it decreases voltage-activated calcium currents in hippocampal neurons. The presence of cardiovascular complications appears to be related to the rate of rise in levels rather than to absolute values.

Given IV, phenobarbital may require approximately 15 minutes to attain peak levels in the brain. If injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that required to control seizures, resulting in subsequent toxicity. Thus, it is important to use the minimal amount required and wait for anticonvulsant effect to develop before administering a second dose.

Restrict IV use to situations in which other routes are not possible, either because patient is unconscious or because prompt action is required. IV administration should be at a rate less than 50 mg/min. The parental product contains 68% propylene glycol. Ensure monitoring for hypotension, bradycardia, and arrhythmias upon administration.

If the IM route is chosen, administer into areas where there is little risk of encountering a nerve trunk or major artery (eg, gluteus maximus, vastus lateralis). A permanent neurologic deficit may result from injecting into or near peripheral nerves.

General Anesthetics

Class Summary

General anesthetics used in SE include pentobarbital, thiopental, and propofol. Pentobarbital and thiopental are discussed under Barbiturates, above. Propofol is a phenolic compound unrelated to other types of anticonvulsants. It has general anesthetic properties when administered IV.

The development of propofol infusion syndrome, an irreversible chain of events associated with significant morbidity and mortality, is a concern. Propofol infusion syndrome was first described in 1992 by Parke et al.[36] Since then, numerous case reports and reviews have been published.[37, 38, 39, 40, 41]

Administration of general anesthesia to control SE is performed in a pediatric critical care unit. All children must be intubated and paralyzed and must have continuous cardiorespiratory and EEG monitoring. Pentobarbital may be required when seizures persist despite appropriate administration of other antiseizure agents.

Propofol (Diprivan)

The use of propofol anesthesia to treat SE has been subject of many reports in the European literature in the past decade. Although not approved by the FDA for this purpose, it now gaining acceptance in the United States. The advantages of propofol include relatively low toxicity for short-term use, quick onset of action, and fast recovery upon discontinuation. Reports of severe acidosis and movement disorder after propofol use in infants have caused a significant decrease in its use within that age group.

Metabolic acidosis may be a complication related to prolonged use of propofol, explaining the rarity of this complication in short surgical anesthesia. In contrast, metabolic acidosis in children with prolonged propofol use for sedation and treatment of SE has been reported. Also worrisome is the association of propofol-related metabolic acidosis in patients receiving the ketogenic diet.

Propofol is only slightly soluble in water, but highly soluble in lipids. CNS penetration primarily depends on cerebral blood flow. Emergence from anesthesia is faster than with thiopental, even with prolonged infusions. Accumulation effect after continued use is a theoretical risk not often observed in practice. Even though respiratory depression is likely in the doses used to treat SE, hypotension tends to be only mild.