Pediatric Status Epilepticus

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

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

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

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

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

Types of status epilepticus

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

• Focal motor SE

• Focal with impaired awareness SE

• Absence SE

• Nonconvulsive SE

• Myoclonic SE

Focal motor and focal sensory status epilepticus

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

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

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

See also the Medscape Drugs and Diseases topic Partial Epilepsies.

Focal with impaired awareness status epilepticus

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

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

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

Absence seizures SE

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

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

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

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

See also the Medscape Drugs and Diseases topic Absence Seizures.

Nonconvulsive status epilepticus

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

Myoclonic seizures

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

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

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

Etiologic classifications of status epilepticus

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

• Acute symptomatic (26%) – Episodes caused by an acute infection, head trauma, hypoxemia, electrolyte disturbance, hypoglycemia, intoxication or drug withdrawal

• Progressive encephalopathy (3%) – SE occurring with an underlying progressive CNS disorder, such as mitochondrial disorder, Rasmussen encephalitis, CNS lipid storage diseases, aminoacidopathies, or organic acidopathies

• Remote symptomatic SE (33%) – Episodes secondary to static conditions (eg, remote cerebral insult in the perinatal period)

• Remote symptomatic with an acute precipitant (1%) – SE in a patient with a chronic encephalopathy but precipitated by an acute event such as those in acute symptomatic SE

• Febrile (22%) – SE for which the only provocation is a febrile illness, after excluding a direct CNS infection

• Unknown (15%) – SE without identifiable cause

Diagnosis and management of status epilepticus

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

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

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

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

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

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

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

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

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

• Hypoxia

• Hypercarbia

• Hyperthermia

• Tachycardia

• Hypertension

• Hyperglycemia

• Hyperkalemia

• Lactic acidosis

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

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

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

• Birth injury

• Febrile convulsions (6 mo to 6 y)

• Infection

• Metabolic disorders

• Trauma

• Neurocutaneous syndromes

• Cerebral degenerative diseases

• Tumors

• Idiopathic

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

• Sequelae of Birth injury

• Trauma

• Infection

• Epilepsy with inadequate drug levels

• Cerebral degenerative disease

• Tumor

• Toxins

• Idiopathic

Toxins and medications that can cause SE include the following:

• Topical anesthetics (eg, lidocaine)

• Anticonvulsant overdose

• Camphor

• Hypoglycemic agents (eg, insulin, ethanol)

• Carbon monoxide

• Cyanide

• Heavy metals (eg, lead)

• Pesticides (eg, organophosphate)

• Cocaine

• Phencyclidine

• Belladonna alkaloids

• Nicotine

• Sympathomimetics (eg, amphetamines, phenylpropanolamine [recalled from US market])

• Tricyclic antidepressants (eg, bupropion)

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

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

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

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

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

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

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

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

• Medication changes - 20%

• Metabolic precipitants - 8%

• Congenital precipitants - 7%

• Anoxia - 5%

• CNS infection - 5%

• Trauma - 3.5%

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

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

• Lennox-Gastaut syndrome

• Dravet syndrome

• Myoclonic-astatic epilepsy

• Childhood and juvenile absence epilepsy

• Localization-related epilepsy (focal impaired awareness seizures)

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

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

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

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

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

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

Sex- and age-related differences in incidence

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

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

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

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

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

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

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

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

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

Mortality

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

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

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

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.[10]

Hyperthermia, respiratory compromise, hypotension, and hypoglycemia may be observed. If not promptly identified, these physiologic disturbances can significantly 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.

Perform a rapid, directed physical and neurologic examination during status epilepticus (SE), followed by a detailed examination when the child is stabilized. During the initial physical examination, seek signs of sepsis, meningitis, 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

• Tachycardia

• Hypoperfusion (eg, weak pulses, delayed capillary refill, how urine output)

• Hypotension

• Respiratory distress

• Cyanosis

• 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.

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 convulsive SE 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 focal (eg, one hand or even one finger) clonic or myoclonic 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 convulsive SE is brain injury 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 compromise

• 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.

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

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

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

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

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

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

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

Furthermore, an EEG done at the time of SE can determine if the electrographic discharges are focal or generalized (making early imaging more important with focal discharges and helping to decide on optimal therapy) as well as distinguish an epileptic event from a nonepileptic event (pseudoseizures or paroxysmal non-epileptic seizures), changing the management needed. 

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)[43]

• Full septic work-up including lumbar puncture 

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. Rapid bedside glucose measurement is essential.

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.[44]

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.

Imaging studies are indicated in patients with convulsive status epilepticus (CSE) after stabilization. A head CT scan is the preferred initial study due to its rapid accessibility and ability to identify life-threatening conditions such as intracranial hemorrhage, cerebral edema, midline shift, fracture, hydrocephalus, or mass lesion.

If increased intracranial pressure is suspected, CT imaging should be obtained prior to lumbar puncture. 

Once stabilized, a brain MRI (with and without gadolinium contrast) can be performed. MRI evaluation is of particular importance in patients with histories of neurologic (including mental status) changes or who have deficits on the neurologic examination that persist after cessation of seizures. All children with focal seizures preceding or leading to the episode of CSE should undergo brain MRI. 

Brain imaging may be unnecessary for patients who have already had MRI performed as part of a work-up 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.

While acute stabilization and initial seizure management should not be delayed while awaiting EEG electrode placement, a patient should have EEG monitoringin place as soon as possible, as it plays a crucial role in management of SE. 

During a prolonged convulsive seizure, EEG manifestations often follow a sequence of repetitive focal seizures progressing into discrete diffuse tonic-clonic seizures that eventually become fused (ie, continuous EEG seizure). Eventually, in prolonged SE, the EEG can progress through a variety of rhythmic, repetitive, and periodic patterns. A patient who arrives at the ED may be at any of these EEG stages; historical information concerning seizure progression usually correlates with stage. 

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

As SE progresses and is complicated by increasing doses and numbers of sedating medications, the EEG can become more difficult to interpret, with various degrees of suppression, slowing, rhythmicity, and periodicity that are not always clearly ictal. Knowing when not to escalate treatment further is an important part of SE management, and the EEG is crucial in deciding when someone's seizure has stopped.

Several possibilities exist to explain persistent decreased consciousness following the end of a clinical seizure: nonconvulsive status epilepticus (NCSE), postictal state–related depression and unresponsiveness from metabolic (renal and hepatic) or anoxic encephalopathies. Without EEG monitoring, it can be impossible to differentiate these etiologies.

In 2021, the American Clinical Neurophysiology Society published an updated guideline on Standardized Critical Care EEG Terminology[45]  to help standardize critical care EEG reporting. While a detailed discussion of that topic is beyond the scope of this article, clinical examination (state changes, autonomic changes) combined with careful interpretation by a trained electroencephalographer is required to help guide ICU management. 

Finally, EEG recording of the ictal events helps in differentiating convulsive status epilepticus (SE) from non-epileptic seizures (paroxysmal non-epileptic seizures - PNES) and pseudoseizures. 

Seizures not responding to the first- and second-lines drugs (initial doses of benzodiazepines, IV phenytoin/fosphenytoin, Keppra, valproic acid, phenobarbital) should be considered refractory status epilepticus (RSE). Prolonged refractory status epilepticus (seizures persisting beyond 24 h) needs further work-up 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. 

Ongoing work-up for refractory SE may include:

• Screens for inborn errors of metabolism in patients with history suggestive of a metabolic disorder: unexplained neonatal encephalopathy and developmental delay, neurologic deterioration during an acute illness; unusual odors to the urine; unexplained acidosis or coma. Urine organic acids, serum amino acids, porphyrins (porphyria), sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency), ammonia, lactate, carnitine profile

• Genetic testing  (whole exome or epilepsy panel) for prolonged/refractory SE

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

• Autoimmune encephalitis panel - CSF and serum (eg, serum and CSF NMDA-R antibody)

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

• Ultrasound/CT/MRI of testes and abdomen to look for solid tumors - associated with paraneoplastic antibodies and autoimmune encephalitis

• Serological markers for collagen-vascular disorders

• Repeat MRI brain with gadolinium

• Cerebral angiography (CT angiography or conventional 4-vessel angiography) to look for evidence of vasculitis if an autoimmune disorder is suspected

• CSF neurotransmitters

If these investigations do not identify the etiology of seizures within a week, a brain biopsy should be considered.

Investigators have developed an automated identification quality measurement for pediatric convulsive SE and refractory convulsive SE (RCSE) that has the potential to allow automated time-to-treatment calculation and assess RCSE quality.[46]

A multidisciplinary team should be convened in the setting of refractory SE to include specialists from Pediatric Neurology, Critical Care, Rheumatology, Genetics, and Infectious Disease.

Status epilepticus (SE) treatment should follow a logical sequence of interventions. Evidence strongly suggests that aggressive early intervention leads to timely seizure termination and improved outcomes.[47]  Institutions caring for pediatric patients should have an SE care pathway plan that is based on current best practice authoritative sources.[3]  Once developed, SE care pathways should be communicated to the medical staff and reviewed annually.

The lack of a structured protocol has been associated with increased morbidity from SE.[48] Litigation involving patients suffering sequelae of SE is often based on perceptions that treatment deviated from established standards of practice.

The lack of a structured protocol has been blamed for increased morbidity from SE.[48] 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. Rapidly accessible resources with anti-seizure dosing regiments should be placed in visible locations within emergency departments (EDs) pediatric units, and pharmacies.

Treatment for convulsive 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.

The following example of a protocol with time points for convulsive SE:

First Line (5–10 min)

• Lorazepam IV or IO (0.05-0.1 mg/kg) max 4 mg, can be repeated once

• Diazepam per rectum (0.5 mg/kg), max 20 mg, single dose

• Diazepam IV (0.2 mg/kg IV) max 10 mg, can be repeated once

• Midazolam IM/IV/buccal (0.2 mg/kg) single dose

• IN midazolam (0.2/kg) divided dose between nares, can be repeated once.

Second Line (10–30 min)

• Fosphenytoin IV or IM (20 mg PE/kg), max 1500 mg/dose

• Levetiracetam IV (60 mg/kg), max 4500 mg/dose

• Valproic acid IV (40 mg/kg), max 3000 mg/dose

• Phenobarbital IV (20 mg/kg), max 1500 mg/dose

• Lacosamide IV (8 mg/kg), max 200 mg initial dose. Can be repeated - max 20 mg/kg/day or 400 mg/day, whichever is less. 

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

• Repeat alternative second line therapies

• Transfer to ICU for infusion of IV anesthetics and antiseizure medications. Under EEG guidance, treatment should involve rapid escalation of therapy using repeated boluses, as NCSE is a high risk in these patients. 

Examples of infusions are listed below:

1. Pentobarbital 5 mg/kg initial load with additional 5 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.5–5 mg/kg/hr titrated to clinical/electrographic seizure control

2. Midazolam 0.2 mg/kg initial load with additional 0.2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.05–2 mg/kg/hr titrated to clinical/electrographic seizure control

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

4. Ketamine 1-2 mg/kg initial load with additional 1–2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 1.2–7.5 mg/kg/hr titrated to clinical/electrographic seizure control

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

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

• Naloxone - 0.1 mg/kg/dose, IV preferably (if needed may administer IM or SQ) for narcotic overdose

• Pyridoxine - 50–100 mg IV/IM for possible dependency, deficiency, or isoniazid toxicity

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

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:

• Timing of the seizure

• 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).[49]

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 status epilepticus (SE).

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 using bag mask ventilatio and endotracheal intubation if 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 non-invasive ventilatory support while preparing for potential intubation 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.

Obtain a rapid bedside glucose determination

In the first 5 minutes of seizure activity, before starting any medications, try to establish intravenous (IV) access and obtain blood 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. Anticonvulsants can be administered via the intravenous or intraosseous route.

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

Status epilepticus (SE) management is a race against time; the goal is to abort a prolonged seizure before injury to the patient occurs. Complicating this is the unfortunate reality that the longer a seizure lasts, the more difficult it can be to abort due to the paradoxical loss of inhibitory and simultaneous increase in excitatory receptors, making medications less effective.[6, 18, 23]  Therefore, the focus of pharmacotherapy should be seizure control with benzodiazepines in the emergent phase, followed by urgent control with the administration of intravenous (IV) anti-seizure drugs if benzodiazepines are unsuccessful as well as to prevent recurrence.[14, 50, 47, 51]

Prospective and retrospective trials and hospital surveys all support the idea that the optimal protocol for management of SE begins with a benzodiazepine, either lorazepam, midazolam or diazepam.[52, 3, 13, 9, 19, 53, 54, 47, 51]  Early and appropriate therapy with a benzodiazepine universally resulted in a significantly shorter time until SE cessation.[47]  In the United States, lorazepam is often 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 with some evidence that it is superior to diazepam. [55, 56]

If IV or IO access cannot be rapidly established there are a number of options available, including rectal diazepam, buccal, IM, and IN midazolam (0.1-0.2 mg/kg), sublingual lorazepam (0.1 mg/kg), and IN diazepam. Midazolam can be administered safely intramuscularly while providing rapid onset equivalent to that of intravenous agents, however, IM midazolam is not approved by the US Food and Drug Administration (FDA) for that indication.

With regards to the absolute best first-line agent for pediatric SE the data is less clear, as multiple studies found similar efficacy between IV lorazepam, rectal diazepam, IN diazepam, and IN and buccal midazolam.[57]  [58, 59, 50, 53, 54, 60, 61, 62]  In practice, since the shorter the time between onset of convulsive SE and treatment initiation is a strong factor in seizure cessation, the best medication to use is the one that can be provided the fastest. In the case of pediatric SE, training caregivers in the use of a rescue medication (eg, rectal or IN diazepam or IN midazolam) often means the difference between early SE cessation and escalation in therapy to second- and third-line agents. Parents typically report higher levels of satisfaction with IN rather than rectally administered medications.[57]

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

If benzodiazepine therapy proves ineffective, IV, IO ,or IM fosphenytoin, IV valproic acid, or IV levetiracetam is used as the second-line in pediatric SE.[3, 19, 63, 64]  These agents are effective for most idiopathic generalized seizures and for posttraumatic, focal, or psychomotor SE.

Fosphenytoin has been used as a second-line agent in SE for many years, with many studies supporting its efficacy. A 2018 review of randomized controlled trials in IV phenytoin in convulsive SE supported its use as a second-line therapy for benzodiazepine-resistant convulsive SE, as well as the use of IV phenytoin immediately after IV diazepam even when seizures have not recurred.[65] 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. 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.

Other agents have gained popularity as second-line agents in SE, particularly levetiracetam and valproic acid. Recent RCTs have supported that in the context of benzodiazepine-refractory convulsive status epilepticus, levetiracetam, fosphenytoin, and valproate had similar levels of seizure cessation with similar incidences of adverse events.[66, 67, 68, 63, 64]  Dosing suggestions from the trials are 40 mg/kg (max 3000 mg) as a single dose for valproic acid and 60 mg/kg (max 4500 mg) as a single dose for levetiracetam when used as second-line agents in SE.

If SE is unresponsive to one of the three first-line agents, use of phenobarbital or lacosamide is reasonable.

Phenobarbital (20 mg/kg IV/IO) is used as therapy in SE at all ages, but particularly in neonatal SE where it has shown to be superior to other agents like levetiracetam.[69, 4]  Phenobarbital's major disadvantages are that it significantly depresses mental status and causes respiratory difficulty and does not appear to have significant benefit over other ages outside of the neonatal period. 

Lacosamide is another antiseizure drug with an IV formulation that allows its use in SE (8 mg/kg with max 400 mg). While there has not yet been a large RCT, multiple small studies show that it is generally well tolerated and has good efficacy.[70]  However, it can make generalized epilepsy worse, thus etiology of the SE should be considered before administration. 

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 and second-line agents (phenytoin/fosphenytoin, levetiracetam, valproic acid and phenobarbital). Several options are presently available for these patients, including a variety of antiseizure agents thatcan be administered as IV infusions. Prior to initiation of these agents, patients should be transferred to an intensive care unit and EEG monitoring should be initiated. Under EEG guidance, treatment should involve rapid escalation of therapy using repeated boluses, as NCSE is a high risk in these patients. 

Barbiturate anesthesia was historically among the most popular third-line treatments, although midazolam infusions (neither is approved by the FDA) have gained growing acceptance in the United States. In the United States, barbiturate anesthesia is commonly performed with pentobarbital infusions. Pentobarbital is given in a loading dose of 5 mg/kg IV or IO, followed by 0.5-5 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.[71] However, propofol is not currently recommended for long-term control of SE due to reports of severe acidosis and movement disorder after prolonged (> 48 h) use. Also worrisome is the association of propofol-related metabolic acidosis in patients on the ketogenic diet.

Midazolam has been effectively used in pediatrics, even in neonates, and has a predictable pharmacology, although movement disorders have been reported from prolonged use of midazolam for sedation.[72] Midazolam is given in a loading dose of 0.2 mg/kg IV or IO, followed by 0.75-10 mcg/kg/min.

Ketamine has a unique mechanism of action (NMDA receptor antagonist) and limited respiratory depression when compared to other infusion agents. Coupled with the recognition that there is increasing neuronal abundance of NMDA receptors likely contributing to SE, ketamine is becoming more commonly used in refractory SE with good efficacy (> 70% response in some studies).[73, 74]

Examples of infusions are listed below:

1. Pentobarbital 5 mg/kg initial load with additional 5 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.5-5 mg/kg/hr titrated to clinical/electrographic seizure control

2. Midazolam 0.2 mg/kg initial load with additional 0.2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.05-2 mg/kg/hr titrated to clinical/electrographic seizure control

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

4. Ketamine 1-2 mg/kg initial load with additional 1-2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 1.2-7.5 mg/kg/hr titrated to clinical/electrographic seizure control

Infusions and the need for repeated boluses require simultaneous EEG monitoring to guide therapy. (See Long term Monitoring.)

Other treatments

High-dose topiramate via nasogastric tube has been used in adults with SE, at doses as high as 1600 mg/day.[75] 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.[76] Another study reported a loading dose of 10 mg/kg followed by 5 mg/kg/day maintenance (in 2 divided doses daily).[77] 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 post-anoxic myoclonus.[78, 79] 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 20-40 mg/kg over 5 minutes is recommended, followed by an infusion at a rate of 5 mg/kg/h.[80] After 12 hours of clinical and EEG cessation of seizures, the dose is reduced to 1 mg/kg every 2 hours.

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.[81] The adult dose is 5 mL PR diluted on the same volume of water. 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 folic 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, especially in neonates. EEG monitoring is required during these vitamin trials to track response. 

The ketogenic diet is increasingly used in super-refractory SE and a number of small studies demonstrate that is practical to achieve ketosis within 2 days of initiation, with minimal adverse effects. Within 7 days of initiation, many of the pediatric patients in ketosis had resolution of seizures and had anesthesia lifted.[82, 83, 84, 85]

Rarely, in super-refractory SE, therapies such as hypothermia, surgery (resective vs palliative - VNS) and electroconvulsive therapy have been tried with varying degrees of success. 

Most children with an episode of status epilepticus (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 SE should be admitted to a pediatric critical care unit.

Treat patients with SE who have suspected infection with antibiotics as appropriate. Treatment with acyclovir in all patients with concern for herpes encephalitis should be continued 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 spread.

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.

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 antiseizure therapy after an episode of status epilepticus (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.

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 focal motor, focal impaired awareness, and focal with bilateral tonic clonic epilepsy respond well to levetiracetam, carbamazepine, oxcarbazepine, lacosamide, phenytoin (avoided in pediatric), and phenobarbital (infants).

Valproic acid, levetiracetam, brivaracetam, topiramate, and phenobarbital are good treatments for patients with generalized epilepsy. Valproic acid carries a higher risk of liver failure in patients younger than 2 years and those on polypharmacy.

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

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

• Pediatric Rheumatology

• Pediatric Infectious Disease

• Genetics

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

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

The use of continuous EEG monitoring in patients who ultimately require continuous anesthetic or anti-seizure infusions is vital. Patients at this stage are often unresponsive and there are a number of reasons why patients cannot be aroused following the end of a clinical seizure: nonconvulsive status epilepticus (NCSE), postictal state-related depression, sedation from medication, and unresponsiveness from metabolic (renal and hepatic) or anoxic encephalopathies. Without EEG monitoring, it can be impossible to differentiate these etiologies and manage them appropriately.

In the case of ongoing seizure activity, EEG monitoring is required to direct escalation of infusions. All infusions should follow a pattern of rapid (every 5 minutes) escalation of therapy with repeated boluses followed by increases in infusion rate until seizure cessation +/- burst suppression is achieved. The choice of titrating therapy to EEG burst suppression vs seizure cessation varies with roughly 50% of centers in a US survey choosing each endpoint. However, there appears to be some evidence for targeting a more suppressed (low-amplitude bursts, prolonged interburst intervals) background rather than simple seizure cessation. In several studies and reviews, there was increased success in weaning IV medications with fewer breakthrough seizures following more pronounced EEG suppression.[86, 87, 88, 89]

As SE progresses and is complicated by increasing doses and numbers of sedating medications, the EEG can become more difficult to interpret, with various degrees of suppression, slowing, rhythmicity, and periodicity that are not always clearly ictal. Knowing when not to escalate treatment further is an important part of SE management, and the EEG is crucial in deciding when someone's seizure has stopped.

This section addresses pharmacologic properties of anticonvulsant medications used to treat status epilepticus (GTCSE) and provides links to the respective Medscape drug monographs. In most cases, choose a parenteral preparation with rapid onset and long duration of action and the least amount of sedation and respiratory depression. Other mechanisms of administration include rectal (diazepam), buccal (midazolam, lorazepam), IM (midazolam, fosphenytoin), G-Tube (topiramate).

Titrate for clinical response by waiting an adequate length of time for attainment of therapeutic levels in the brain. 

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, AcuDial, Valtoco)

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.

Diazepam IV 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.

Per rectum (PR) diazepam has been found to be effective in the control of cluster and prolonged seizures.

More recently, an IN formulation has been shown to have similar efficacy for use in status epilepticus and seizure clusters. Dosing is dependent on the patient's age and weight. 

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 children with 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.

Midazolam intranasal (Nayzilam)

Indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy aged 12 years and older. 

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 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) to avoid cardiovascular adverse effects. Dilute only in NaCl 0.9%; dilutions with dextrose-containing solutions may cause precipitation. Phlebitis, and local tissue damage were reported with IV administration.

Fosphenytoin (Cerebyx)

A key 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. It is indicated for treatment of generalized tonic-clonic status epilepticus and treatment of seizures occurring during neurosurgery in all ages (birth through adult).

The fosphenytoin doses are expressed as phenytoin sodium equivalents (PE). Although fosphenytoin can be administered IV (preferred route) and IM; IV should be used short-term and only in emergency situations. It can be diluted with either NS or D5W. 

Coadministration 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.

Class Summary

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

Pentobarbital

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.

Phenobarbital (Sezaby)

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.

Class Summary

General anesthetics used in SE include pentobarbital, propofol, and ketamine. Pentobarbital is 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.[90] Since then, numerous case reports and reviews have been published.[91, 92, 93, 94, 95]

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 and is prescribed off-label. 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.

Ketamine (Ketalar)

Data are emerging regarding use for benzodiazepine-refractory status epilepticus in children. 

Class Summary

Synaptic vesicle protein 2A (SV2A) ligands have been identified as presynaptic binding sites for certain antiepileptic drugs (eg, levetiracetam). Although the mechanism is not fully understood, it is thought that levetiracetam directly interferes with presynaptic neurotransmitter release. 

Levetiracetam (Elepsia SR, Keppra, Keppra XR, Spritam)

Consider second-line use for status epilepticus. It is indicated for primary generalized tonic-clonic seizures in patients aged 6 years and older. 

Class Summary

May consider these drugs for second line and repeat dosing.

Valproic acid

Consider off-label use as second-line therapy for status epilepticus. Available as IV (sodium valproate) and oral (valproic acid). 

Lacosamide (Vimpat)

Consider use as second-line therapy for status epilepticus. It is indicated as adjuvant therapy for primary generalized tonic-clonic seizures in patients aged 4 years and older. 

Topiramate (Eprontia, Qudexy XR, Topamax)

Consider use as second-line therapy for status epilepticus. It is indicated for primary generalized tonic-clonic seizures in patients aged 2 years and older.