Status epilepticus is a prolonged seizure that lasts longer than typical self-limiting seizures and often does not resolve without medical intervention.
It is the most common neurological emergency in children. Although prolonged status epilepticus is associated with substantial morbidity and mortality, timely and effective therapy may improve the outcome of these children. The purpose of this article is to summarize measures to prevent status epilepticus in high-risk children and effectively interrupt prolonged seizures.
| Definitions |
Historically, status epilepticus was defined as a seizure lasting more than 30 minutes or as multiple consecutive seizures over 30 minutes with no return to neurological baseline between seizures. (1) The current definition, however, recognizes greater complexity by creating three main categories: early status epilepticus, established status epilepticus, and refractory status epilepticus.
Early status epilepticus refers to a seizure that lasts more than 5 minutes. This duration is based on data showing that seizures lasting longer than 5 minutes are unlikely to stop without medical intervention. (1)(2) Therefore, early status epilepticus represents a critical window for frontline providers to intervene.
Established status epilepticus describes a seizure that persists for more than five minutes despite treatment with a benzodiazepine. Refractory status epilepticus refers to a prolonged seizure that did not respond to 2 doses of different antiseizure medications (eg, 1 benzodiazepine and 1 nonbenzodiazepine antiseizure medication). (3)(4)
Status epilepticus can also be characterized by the type of seizure that occurs. The most common and most life-threatening is convulsive status epilepticus. (5) However, clinicians should be aware of less common types of status epilepticus, such as focal status epilepticus without impairment of consciousness, focal status epilepticus with impaired consciousness, and absence status epilepticus.
Focal status epilepticus without impaired consciousness, as well as isolated focal motor seizures, was previously known as a simple partial status. Focal status epilepticus with impaired consciousness was previously known as complex partial status. Absence status epilepticus is a type of generalized seizure that presents with prolonged altered consciousness, but patients may retain intermittent responsiveness. (6)
Focal state and absence state are defined as seizures lasting more than 10 minutes, rather than the 5 minutes used for bilateral tonic-clonic seizure state. Finally, febrile seizures are common and a major cause of status epilepticus in children between 6 months and 5 years. (7) Complex febrile seizures – lasting more than 15 minutes, occurring multiple times in 24 hours, or having focal features – account for almost 20% of febrile seizures.
Here the authors emphasize convulsive status epilepticus in infants and older children. Neonatal seizures often have different etiologies and unique pathophysiological mechanisms compared to seizures in infants and older children and therefore require a different treatment approach.
Similarly, nonconvulsive status epilepticus (NCSE), whether due to focal motor seizures, nonmotor seizures, or absence seizures, is an important consideration that is briefly discussed in the differential diagnosis section. EENC represents unique situations requiring more individualized treatments beyond the scope of this review.
| Pathogenesis |
The pathophysiology of status epilepticus is not completely understood, but is probably related in part to failure of g-aminobutyric acid (GABA)-mediated inhibitory pathways and hyperactivity in glutamate-mediated excitatory pathways. (8)(9)
This state of failed neuronal regulation can cause neuronal damage, cell death, and alterations in brain networks. (1)
There is some evidence that status epilepticus lasting more than 30 minutes represents the onset of neuronal damage with self-perpetuating dysregulation. (10) A prolonged seizure leads to internalization of GABAA receptors, reducing synaptic inhibition as well as responsiveness to benzodiazepines. For this reason, second-line medications for status epilepticus do not target GABAA receptors. (8) (11)
In addition to changes in neurotransmitters and receptors, prolonged seizures lead to multiple physiological changes that are responsible for some of the complications of status epilepticus.
Status epilepticus leads to increased levels of epinephrine and norepinephrine, which promotes peripheral vasoconstriction to improve continuous perfusion and oxygenation of the muscles and brain. This is why patients often have cyanosis and decreased oxygen saturation measured by peripheral pulse oximetry.
The longer the seizure lasts, however, there is an increasing risk of compensatory failure resulting in decreased perfusion, oxygenation, and glycemia. Animal models demonstrate a high rate of decompensation with cardiovascular collapse after 20 to 40 minutes of convulsive attacks. (8)
| Differential diagnosis of status epilepticus |
Convulsive status epilepticus typically presents as continuous bilateral tonic-clonic seizures, or what was previously known as generalized tonic-clonic or grand mal seizures .
This presentation is usually obvious, but other disorders can mimic it, such as prolonged psychogenic nonepileptic seizures (PNES). Clinical observation and careful bedside evaluation are essential to help differentiate an epileptic seizure from PNES.
Characteristic features of PNES include a fluctuating course, retained consciousness despite bilateral seizure activity, asynchronous movements, forced eye closure, lack of postictal labored breathing, and rapid return to baseline function. (12)
Filming the activity of the episode can assist in subsequent diagnosis. (13) Electroencephalography (EEG) is the optimal way to distinguish an epileptic seizure from a non-epileptic event. Importantly, epilepsy is one of the most common comorbid conditions with sPNES, so some people may experience both non-epileptic events and epileptic seizures. (12) The child’s medical history and family description of the episode provide valuable clues to distinguish epileptic seizures from PNES.
Status dystonicus is a rare and life-threatening condition that can be confused with status epilepticus. (14) The dystonic state represents the most severe form of dystonia, a movement disorder that consists of abnormal muscle activation. The dystonic state manifests itself with sustained contractions or abnormal postures, resembling tonic seizure activity.
Patients often have an established history of dystonia that worsens acutely during intercurrent illnesses, medication adjustments, medication withdrawal, or pain. (15) It is important to highlight that these patients remain in their initial mental state.
Because many patients with dystonia have underlying neurological disorders, obtaining a history from a family member or caregiver is essential. In patients with difficulty evaluating changes in mental status, an EEG can rule out seizures but do not show epileptiform activity associated with dystonic movements. The diagnosis is made clinically based on the history and phenomenology of the abnormal movements.
NCSE is a major neurological emergency that can be easily missed due to intermittent responsiveness or preserved partial responsiveness. Signs and symptoms may include altered mental status (e.g., hallucinations, confusion, coma), motor phenomena (e.g., automatisms, ataxia, dysarthria), and autonomic changes (e.g., paleness, vomiting) depending. which region of the brain is affected. (16)
Consequently, the manifestations of NCSE may overlap with those of drug or toxin exposure, infectious or autoimmune encephalitis, metabolic disorders, and psychiatric disorders. Adding to the difficulty of diagnosis, some of these conditions can also cause seizures.
Approximately one-third of children with NCSE have a history of epilepsy or convulsive status epilepticus before developing NCSE. Due to the sometimes subtle nature of the signs and symptoms of NCSE, diagnosis is often delayed.
To rapidly diagnose NCSE, EEG monitoring should be considered in any patient with persistent illness and persistent, unexplained mental status changes. Although clinical symptoms appear milder than in convulsive status epilepticus, NCSE is associated with neuronal injury and increased morbidity even without clinical seizures. NCSE requires urgent intervention with the same medications used in convulsive status epilepticus.
| Epidemiology |
Depending in part on the age of the patient and the definition of status epilepticus, the incidence of status epilepticus in patients aged 1 to 19 years ranges from 10 to 58 per 100,000 per year. (17) (18) (19) (20) The probability of status epilepticus is higher in newborns and infants under 1 year of age, with 156 per 100,000 per year. The highest incidence of refractory status epilepticus also occurs in children under 1 year of age.
Some studies show a male/female predominance of 1.2:1 to 2:1. (21) However, 2 large studies examining status epilepticus diagnoses at US hospital discharge did not demonstrate any differences by sex. (22) (23) No consistent differences were reported by race or socioeconomic status in pediatric status epilepticus.
| Etiology of status epilepticus |
Based on a review of the diagnostic evaluation of 2,093 children with status epilepticus, Riviello et al (18) identified 6 broad etiological categories: acute symptomatic, remote symptomatic, remote symptomatic with acute precipitant, progressive, febrile, and cryptogenic (idiopathic) encephalopathy. Some studies indicate that febrile status epilepticus represents up to 35% of status epilepticus cases, but Riviello et al observed that febrile status epilepticus represented only 22% of cases.
The remote symptomatic, referring to seizures caused by a previous lesion of the central nervous system or chronic encephalopathy, represented 33% of the cases. Acute symptomatic seizures or seizures caused by an acute disease such as meningitis, encephalitis, electrolyte disturbances, sepsis, hypoxia or intoxication represented 26% of the cases reviewed.
Remote symptomatic with acute precipitant, referred to children with previous central nervous system disease with a concurrent exacerbating factor (e.g., illness or hypoglycemia), represented 1% of cases. Progressive encephalopathy, or children with an underlying progressive disorder, accounted for 3% of cases. And finally, cryptogenic or idiopathic status epilepticus represented 15% of all cases reviewed.
Other studies have used the International League Against Epilepsy etiological categories for status epilepticus. These categories divide status epilepticus into electroclinical, unknown/cryptogenic, and known/symptomatic syndromes, which include acute, remote, and progressive categories, similar to those described by Riviello et al.
Having a younger age of onset and a symptomatic etiology, whether acute, remote, or progressive, increases the risk of status epilepticus. (24)
When separating electroclinical syndromes (e.g. forms of epilepsy such as Lennox-Gastaut syndrome) from other causes of status epilepticus, it has been shown that 10% of children with epilepsy will present with status epilepticus as their first seizure. (17) (21) Furthermore, 25% of children with epilepsy develop status epilepticus during their lifetime. (24)
| Prevention of status epilepticus |
As a general rule, a seizure is easier to stop soon after it starts than after it has become persistent, and stopping the seizure sooner should mitigate the adverse physiological effects of a prolonged seizure.
For these reasons, a seizure action plan should generally include a seizure rescue medication designed to be administered by the patient’s caregivers in an effort to abort the seizure before it progresses to status epilepticus. The exact time frame for administering rescue medication will depend on the patient’s type of epilepsy and the clinical judgment of the patient’s physician.
Commonly used seizure rescue medications include intranasal (IN) or rectal diazepam and IN midazolam. (25) (26) In rare situations where intravenous or rectal medications approved by the Food and Drug Administration (FDA) cannot be administered, orally dissolving oral midazolam or clonazepam tablets may be options. reasonable.
An IN atomizer device can be used to convert intravenous (IV) midazolam to off-label IN midazolam. Clonazepam can also be used for several days as a temporary scheduled, or “bridging,” medication for clusters of seizures exacerbated by illness or medication changes. Bridging usually stops as the disease resolves.
Caregivers should be taught how to properly administer rescue medication and become familiar with its adverse effects. All commonly used rescue medications are benzodiazepines, so the adverse effects are similar. The common adverse effect is sedation. (27) (28)
Caregivers should be aware of the risk of respiratory suppression with benzodiazepine use, particularly in the setting of multiple doses or a dose greater than typical for the patient’s weight. With an adequate dose of weight-based rescue anticonvulsant medication, respiratory suppression is extraordinarily rare and is much more likely to occur from a prolonged seizure. (29) Respiratory suppression is more likely to occur if the patient has taken opioids, barbiturates (including phenobarbital), or alcohol, which could be a concern for older pediatric patients.
| Driving |
The first step in controlling status epilepticus, as with any medical emergency, is to secure airways, breathing, and circulation. (3)(5)
Appropriate positioning, a jaw thrust maneuver, and airway accessories can be used, as appropriate, to ensure a patent airway. Aspiration of secretions or vomit can help protect the airway.
For a prolonged seizure that does not resolve with medications or if there is concern about airway compromise, intubation may also be necessary. Close monitoring of vital signs, including oxygenation, blood pressure, and heart rate, allows for continuous assessment of breathing and circulation. Although less clinical stabilization is needed in NCSE, medication management is similar.
Early intravenous access is essential to administer antiseizure medications (ACMs), as well as to administer fluids to support blood pressure. Laboratory evaluation may include glucose, basic metabolic panel, calcium, complete blood count, and MACs levels, if applicable. The goal of these acute studies is to identify treatable causes of seizures such as hypoglycemia, hyponatremia, and hypocalcemia.
Leukocytosis could suggest an underlying infectious etiology. Subtherapeutic levels of MACs in a patient with known epilepsy may document suboptimal dosing or suggest medication noncompliance. Urine and serum toxicology is appropriate when there is concern for poisoning or substance use. (18)
The initial medication for a prolonged seizure should be a benzodiazepine such as midazolam, diazepam, or lorazepam. (3)(5)(9) All 3 medications can be administered intravenously. Midazolam and diazepam also have IN formulations, diazepam has a rectal formulation, and midazolam can also be administered intramuscularly.
When routes of administration are limited, intraosseous access is an emergency option for all 3 benzodiazepines. A second dose of the same benzodiazepine may be given if the seizure persists. The target time for administering the first dose of benzodiazepine in convulsive status epilepticus is usually 5 minutes.
If the seizure does not stop within 5 minutes after the first benzodiazepine is given, a second dose of the same medication may be given.
Because of the short duration of action of benzodiazepines, a second-line medication is often given, even if the initial drug successfully stopped the seizure. Administering the second dose of benzodiazepines, preparing the second-line medication, and then administering the second-line medication should ideally occur within the first 20 minutes after seizure onset.
Second-line medications include levetiracetam, fosphenytoin, or valproic acid. The Established Status Epilepticus Treatment Trial (ETEE) demonstrated that these three medications are equivalent in terms of efficacy and tolerability. (30) In practice, levetiracetam is usually administered first, partly because it is easier to continue long-term as oral seizure prophylaxis.
If levetiracetam fails to stop the seizure, fosphenytoin and then valproic acid may be added. Phenobarbital is a reasonable alternative if levetiracetam, fosphenytoin, and valproic acid are unavailable or ineffective, but due to higher rates of hypotension and respiratory depression, phenobarbital is often given after the other MAC.
The exception, however, is the use of phenobarbital for neonatal seizures. Although outside the scope of this review, phenobarbital is essential as an initial medication in neonatal seizures. Lacosamide is increasingly used for status epilepticus because it has similar advantages. Lacosamide can be administered intravenously, is generally well tolerated, and there are data supporting efficacy in status epilepticus, at least in adults. (31)
If seizures persist despite benzodiazepines and intravenous MACs, the next step is to administer a continuous intravenous infusion of midazolam, pentobarbital, or ketamine . (3)(5) These agents should be supervised by a physician knowledgeable about their use in children, aided by EEG monitoring. There is no consensus on which third-line infusion should be used. (3)(4) (32) Midazolam and pentobarbital require a safe airway and are often preferred due to more retrospective data and experience among clinicians.
Midazolam and pentobarbital infusions can induce significant hypotension. Ketamine has less effect on blood pressure and does not require intubation, but there is less data supporting the use of ketamine for status epilepticus. (4)
Finally, propofol is used in adults for the treatment of status epilepticus, but is rarely used in pediatric patients due to the risk of propofol infusion syndrome, which causes metabolic acidosis, rhabdomyolysis, heart failure, and death. (33) Additional treatments for refractory status epilepticus include ketogenic diet, corticosteroids, intravenous immunoglobulin, and vagus nerve stimulation. (32)
| Next steps in the INITIAL evaluation |
Diagnostic evaluation of children with status epilepticus may include levels of MACs in children with existing epilepsy and obtaining toxicological and metabolic studies in children with appropriate clinical concern. An EEG is useful in determining the type of epilepsy and when there is concern about PNES. In children whose seizure etiology is unknown, neuroimaging is recommended.
Postictal deficits should also prompt more urgent neuroimaging in a patient without a history of these deficits. In patients without a history of epilepsy who present signs or symptoms of infection and in the case of status epilepticus, it is vitally important to rule out central nervous system infection. Antibiotic treatment should not wait for test results if there is a high suspicion of a central nervous system infection.
Complex febrile seizures can often present as febrile status epilepticus at ages 6 months to 5 years. Prolonged seizures are treated the same in the acute setting whether febrile or not. Patients with focal or prolonged complex febrile seizures may warrant further investigation with EEG and neuroimaging to evaluate the presence of seizure causes. (3. 4)
An urgent EEG can rule out persistent subclinical seizures, help in the treatment of refractory status epilepticus, and distinguish PNES from an epileptic seizure. (3) (12) Some patients with refractory presentations will require medically induced coma with a burst suppression pattern on EEG to rest the brain. EEG monitoring is essential to evaluate subclinical seizures as well as the depth of induced coma.
| Outcome after status epilepticus |
Status epilepticus is associated with substantial mortality and morbidity.
It is estimated that between 2.7% and 5.2% of patients with status epilepticus die during acute hospitalization, and long-term mortality after hospitalization may increase from 3.8% to 17%. (19) (21) (35) (36)
The outcome depends on the duration of the seizure and the underlying etiology. Some of the causes of status epilepticus have high mortality and morbidity rates independent of the seizure, such as near drowning, sepsis, hemorrhagic shock, aspiration, and prolonged mechanical ventilation. (37) Refractory status epilepticus can increase mortality to 32%. (38) (39)
Neurological sequelae may include motor deficits, behavioral and developmental problems, and new-onset epilepsy. For a child presenting in status epilepticus, the chance of experiencing recurrent seizures ranges from 16% to 50%. One third of patients who present with recent onset of refractory status epilepticus subsequently develop epilepsy. (40) The likelihood of recurrent seizures is greater in individuals with an abnormal EEG, a history of febrile seizures, preexisting neurological dysfunction, or immediate postictal deficit. (21) (35) (39)
Patients with status epilepticus are also at risk for focal deficits, behavioral disorders, and cognitive disorders. (21) Patients with symptomatic epilepsy are more likely than patients with epilepsy of unknown cause to have neurocognitive and behavioral problems. Up to a third of patients will develop cognitive and behavioral problems after status epilepticus. (19) (41)
Early age of onset and duration of status epilepticus are the strongest predictors of worse neurocognitive outcomes. (42) Close monitoring of a patient’s development, behavior, and cognition by both the neurologist and the pediatrician is essential after status epilepticus. The American Academy of Pediatrics serves as the National Coordinating Center for Epilepsy, with excellent resources available to both physicians and caregivers on epilepsy and its comorbidities. (43)
The sometimes poor outcome of pediatric status epilepticus combined with the safety of rescue medications contributed to the shift toward earlier intervention. There is a critical interval if status epilepticus is to be stopped before neuronal injury. Often the first doctors to treat children with status epilepticus, pediatricians, play a vital role in improving a child’s outcome by preventing status epilepticus and rapidly initiating acute seizure treatment.
