Status Epilepticus
AUTHORS
Taryn Taylor, MD, MEd, FAAP, FACEP, Assistant Professor of Pediatrics and Emergency Medicine, Emory University School of Medicine, Atlanta
Bolanle Akinsola, MD, Assistant Professor, Department of Pediatric Emergency Medicine, Emory University School of Medicine, Atlanta
PEER REVIEWER
John Cheng, MD, Pediatric Emergency Medicine Physician, Pediatric Emergency Medicine Associates, LLC, Children’s Healthcare of Atlanta, Wellstar Health System, Atlanta
Status epilepticus (SE) is a condition resulting either from initiation of mechanisms that lead to abnormally prolonged seizures (longer than five minutes), or the failure of the mechanisms responsible for seizure termination. Common causes of SE in children are febrile seizures and metabolic etiologies, such as inborn errors of metabolism and hypoglycemia. Ultimately, the goal of therapy is to terminate both the clinical and electrical seizure activity safely and rapidly. The authors present an approach to the diagnostic evaluation and therapeutic management of neonates and children in SE.
— Ann Dietrich, MD, FAAP, FACEP, Editor
Definition
Historically, SE has been defined as seizures that are continuous for 30 minutes or longer, or repetitive seizures between which the patient does not regain consciousness.1,2 However, this definition is evolving. Many authorities now consider SE to include seizures lasting for longer than five minutes or multiple seizures with no return to baseline in between.
The International League Against Epilepsy revised its definition of SE in 2015 to incorporate both of these time points (five minutes and 30 minutes). It now defines SE as a condition resulting either from initiation of mechanisms that lead to abnormally prolonged seizures (longer than five minutes), or the failure of the mechanisms responsible for seizure termination. It is a condition that can have long-term consequences if it lasts longer than 30 minutes, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.3,4 All seizure types can result in SE.
Epidemiology
Each year, about 150,000 children and adolescents in the United States will seek medical attention for evaluation of a newly occurring seizure disorder of some type, and about 1% of children and adolescents will experience at least one afebrile seizure by 14 years of age.5
The estimated incidence of childhood SE is between 17 and 23 episodes per 100,000 children per year.6,7 Incidence rates and causes of SE vary substantially by age, with the highest incidence in the first year of life. Febrile SE is the most common etiology8; approximately 60% of children are neurologically healthy prior to the first episode of SE.
Ten percent to 20% of children with epilepsy will have at least one episode of SE in their lifetime,9 with SE occurring as the first seizure in 12%. Patients with partial seizures that tend to occur in clusters (three or more within 24 hours, with return to baseline between seizures) have a higher incidence of SE compared to those who do not cluster (47% vs. 13%).10 Risk factors for SE in children with symptomatic epilepsy include focal background electroencephalography (EEG) abnormalities, focal seizures with secondary generalization, occurrence of SE as the first seizure, and generalized abnormalities on neuroimaging.11
Morbidity
Neurologic sequelae from SE usually are caused by the underlying condition rather than the seizures themselves and are associated with younger age, progressive encephalopathy, duration (longer than 24 hours), prior epilepsy, and specific EEG findings. These EEG findings include a suppression of basic activity as well as periodic burst and suppression patterns. A systematic review found that while rates of neurologic sequelae are increased in younger patients with a longer duration of seizures, these factors also are linked to and difficult to separate from the underlying cause. These sequelae include focal motor deficits, cognitive deficits, behavioral disorders, and chronic epilepsy.12-14
Mortality
Like morbidity, mortality results from the underlying condition or from respiratory, cardiovascular, or metabolic complications.15 The underlying etiology is the main predictor of mortality. The reported mortality rates of SE in children vary between 3% and 9%.6,16,17
Etiology
Causes of seizures and epilepsy can be broadly categorized as structural, metabolic, genetic, immune, infectious, and idiopathic. (See Table 1.) All seizure types can result in SE. Therefore, it is important to note the various etiologies of seizure and epilepsy syndromes, because SE may be an acute symptom of medical disease process.8,18 Also, while some causes of seizures can affect children of any age (trauma, central nervous system [CNS] or systemic infections, neoplastic and degenerative diseases), others have a predilection for certain age groups. For example, in the neonatal period, perinatal hypoxic-ischemic injury, intracranial hemorrhage, metabolic disturbances, and CNS or systemic infections are more common causes of seizures (see section on neonatal SE). In older infants and young children, febrile seizures are a common cause of SE. Many of the genetic syndromes also tend to present during this period. In adolescents and young adults, toxic insults and traumatic injuries from increased risk-taking behaviors are seen more commonly.
Table 1. Etiology of Seizures |
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Metabolic Hepatic failure, hypercarbia, hyperosmolality, hypocalcemia, hypoglycemia,* hyponatremia, hypoxia, hypomagnesemia, uremia, inborn errors of metabolism,* pyridoxine deficiency* |
Toxicologic Anticonvulsant, camphor, carbon monoxide, cocaine, heavy metals (lead), tricyclic antidepressants, isoniazid, lithium |
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Infectious Brain abscess, encephalitis, fever,* meningitis, parasites (central nervous system), syphilis |
Traumatic Injuries Cerebral contusion, diffuse axonal injury, intracranial hemorrhage, perinatal hypoxic-ischemic injury |
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Congenital Anomalies/ Dravet syndrome, Angelman syndrome, generalized epilepsy with febrile seizures plus, Lennox-Gastaut syndrome |
Obstetric Complication Eclampsia |
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Oncologic Primary brain tumor, metastatic disease |
Endocrine Addison's disease, hyperthyroidism, hypothyroidism |
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Idiopathic/Cryptogenic* |
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* More common pediatric etiologies |
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Research is emerging about new-onset refractory SE (NORSE). This occurs in patients with no previous diagnosis of an epileptic or neurologic disorder. A subset of NORSE, febrile infection-related epilepsy syndrome (FIRES) occurs between 24 hours and two weeks after a febrile infection and results in refractory SE. FIRES usually occurs in children 3-15 years of age. The pathogeneses of NORSE and FIRES are largely unknown, because there often is no active structural, metabolic, or toxic cause. The prognosis for both conditions generally is poor.
Pathophysiology
Seizure activity involves hypersynchrony of neuronal discharges with cerebral manifestations, including increased blood flow, increased oxygen and glucose consumption, and increased carbon dioxide and lactic acid production. Systemic alterations (from a massive sympathetic discharge) also occur, such as tachycardia, hypertension, and hyperglycemia. This combination gives rise to the failure of adequate ventilation, leading to hypoxia, hypercarbia, and respiratory acidosis. Prolonged skeletal muscle activity (with convulsive seizures) results in lactic acidosis, rhabdomyolysis, hyperkalemia, hyperthermia, and hypoglycemia.
SE occurs because of the failure of the normal mechanisms that limit the spread and recurrence of isolated seizures.19,20 This failure occurs because excitation is excessive and/or inhibition is ineffective. The following section describes some of the mechanisms believed to be involved in this process.
Glutamate is the major excitatory amino acid neurotransmitter in the brain. It is thought that excessive activation of excitatory amino acid receptors by glutamate has a role to play in SE. Other excitatory neurotransmitters that contribute to SE include aspartate and acetylcholine.21
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and antagonists to its effects or alterations in its metabolism in the substantia nigra may contribute to SE.22 This was demonstrated in an animal model where the rate of GABA synthesis in the substantia nigra declined significantly during induced SE.23 Other inhibitory mechanisms include the calcium ion-dependent potassium ion current and blockage of N-methyl-D-aspartate channels by magnesium.
Classification
SE, like seizures, is classified by clinical presentation into four major types based on whether the seizure is focal or generalized and whether it is convulsive or nonconvulsive. (See Table 2.)
Table 2. Classifications of Status Epilepticus |
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SE: status epilepticus |
Clinical Features/Systemic Complications
Clinical features will vary based on the type of SE, either convulsive or nonconvulsive.
Convulsive SE usually presents with continuous muscle contractions that could be tonic-clonic, tonic, or clonic movements. It usually is associated with alteration in consciousness. These prolonged, generalized muscle contractions may lead to elevated body temperature and rhabdomyolysis. Rhabdomyolysis can cause hyperkalemia, increased release of muscle enzymes, and myoglobinuria, which can precipitate acute renal failure.
Another systemic change associated with prolonged seizures/SE is hypoxemia, which may lead to respiratory acidosis.24 Further metabolic disturbances include an alteration in brain glucose levels, lactic acidosis, and depletion of brain adenosine triphosphate. Severe hypoxemia and acidosis result in impaired myocardial function, reduced cardiac output, and hypotension, further disrupting cellular function.
Other systemic effects noted include changes in blood pressure, heart rate, and central venous pressures. At the start of SE, there is an increase in these parameters from the massive release of catecholamine and sympathetic discharge. This increase is accompanied by a large increase in cerebral blood flow, thought to compensate for the brain’s increased metabolic needs.25 However, with the persistence of SE, blood pressure declines, resulting in hypotension. There also is a decline in cerebral blood flow, with the inability to meet the increased demands for substrates and oxygen.
Intracranial pressure is increased during SE. This further interferes with the supply of substrates and oxygen and results in cerebral edema. Factors that contribute to increased intracranial pressure include metabolic acidosis, hypoxemia, and hypercarbia with compensatory cerebral vasodilatation and increased cerebral blood flow.26
Nonconvulsive SE with or without alteration in awareness will have similar features without the generalized muscle contractions and its effects.
Differential Diagnosis
Seizures resulting in SE often are due to an underlying cause, such as toxins, neoplasms, and infections. However, an additional consideration in the differential diagnosis is psychogenic nonepileptic seizures (PNES). Patients with PNES usually present with a prolonged episode of generalized, atypical-appearing motor activity and a prompt return of consciousness. PNES is seen more frequently in teenage patients with underlying psychiatric disorders, such as affective and anxiety disorders, and it is less common in younger children.27,28 A family history of seizures or a friend or acquaintance with seizures usually is present in patients with PNES.
Important distinguishing features of PNES from SE are fluctuating course, asynchronous movements, pelvic thrusting, side-to-side head or body movements, ictal eye closure, ictal crying, memory recall, and absence of postictal confusion.29 In addition, patients with PNES typically are unresponsive to standard anticonvulsant medications. PNES is best distinguished from true seizures by capturing the event on a video EEG monitor.
Additional considerations in the differential diagnosis for seizures and SE are medication-induced dystonic reactions, conversion disorder, syncope, and arrhythmias.
Management
There are three principal goals in the management of a patient in SE. The initial steps are summarized in Table 3. The first priority is to address airway, breathing, and circulation. The second priority is to stop any ongoing seizure activity (both clinical and EEG seizure activity). Finally, it is important to consider reversible causes and initiate the indicated treatment, as well as diagnose the underlying etiology of the seizure episode. This requires astute history gathering and may require ancillary testing.
Table 3. Initial Management of Status Epilepticus in Children |
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Timeline |
Assessment |
Supportive care |
Seizure therapy |
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0 to 5 minutes |
Obtain initial vital signs, including temperature |
Open airway |
Benzodiazepine: |
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Identify airway obstruction and hypoxemia |
Place continuous cardiorespiratory monitors and pulse oximetry |
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Identify impaired oxygenation or ventilation |
Perform bag-valve-mask ventilation, as needed Prepare for RSI* |
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Obtain rapid bedside blood glucose and other studies, as indicatedΔ |
Establish IV or IO access |
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Evaluate for signs of sepsis/meningitis |
Treat hypoglycemia (IV dextrose |
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Evaluate for signs of head trauma |
Treat fever (acetaminophen |
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5 to 10 minutes |
Reevaluate vital signs, airway, breathing, and circulation |
Maintain monitoring, ventilatory support, and vascular access |
Benzodiazepine: second dose |
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Evaluate for signs of trauma, sepsis, meningitis, or encephalitis |
Give antibiotics if signs of sepsis or meningitis◊ |
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10 to 15 minutes |
Reevaluate vital signs, airway, breathing, and circulation |
Maintain monitoring, ventilatory support, and vascular access |
Levetiracetam 40 mg/kg IV or IO |
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Place second IV |
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RSI potentially indicated* |
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15 to 30 minutes |
Reevaluate vital signs, airway, breathing, and circulation |
Maintain monitoring, ventilatory support, and vascular access |
Fosphenytoin¶ (if not already given) 20 mg PE per kg IV or IO◊ |
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Obtain continuous EEG monitoring, if available |
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IV: intravenous; IO: intraosseous; IM: intramuscular; O2: oxygen; RSI: rapid sequence endotracheal intubation; PE: phenytoin equivalents; * Rapid sequence intubation should be performed if airway, ventilation, or oxygenation cannot be maintained and if the seizure becomes prolonged. |
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Perform a brief physical examination to assess respiratory and circulatory status. Establish an adequate airway immediately (e.g., reposition, suction, or use adjunctive airway equipment, such as an oropharyngeal airway or nasal pharyngeal airway, as needed). If there is respiratory compromise, institute supportive therapy (e.g., administration of oxygen, positive pressure ventilation, or mechanical ventilation) as needed. Secure parenteral access (intravenous [IV] catheter or intraosseous [IO]) as soon as possible to obtain blood samples and administer medications. Monitor ongoing vital signs. A rapid neurologic examination should be performed to provide a preliminary classification of the type of SE. A brief history obtained from a parent or caregiver may help determine the cause or precipitants of the seizure.
The second priority is to stop any ongoing seizure activity (both clinical and EEG seizure activity). The first-line treatment for SE is benzodiazepines because they can rapidly control seizures.30 Diazepam, lorazepam, and midazolam are the three benzodiazepines most commonly used to treat SE. Historically, lorazepam has been the first drug of choice because of its long half-life and safety profile.30 It is important to note that benzodiazepines can be given via intramuscular (IM), rectal (PR), intranasal (IN), and IO routes if IV access is not readily available. However, there is evidence that IV-administered agents abort seizure activity more rapidly.31-33 If IV access is not readily available, PR diazepam, IM midazolam, IN midazolam, and buccal midazolam can be considered.
Lorazepam is administered at a dose of 0.1 mg/kg IV, up to a maximum of 4 mg; its effect is assessed over five to 10 minutes.34 Diazepam is administered at a dose of 0.2 mg/kg IV up to a maximum dose of 8 mg.35 If seizures continue after five minutes, give additional doses of lorazepam or diazepam. It is important to remember that the risk of respiratory depression increases with administration of repeated doses of benzodiazepines.36,37 Be prepared to establish a definitive airway in those situations.
If seizures continue for 10 minutes after administration of at least two doses of a benzodiazepine, a second-line treatment with a long-acting antiseizure medication is indicated. Phenytoin/fosphenytoin, levetiracetam, and valproic acid (VPA) are the recommended options in this setting.38 Levetiracetam is a preferred choice over phenytoin because of its ease of use, more rapid administration, and equivalent efficacy.39,40 The recommended dose is 40 mg/kg IV. The recommended loading dose of fosphenytoin is 20 mg phenytoin equivalents (PE)/kg IV. If seizures persist, an additional 5 to 10 mg PE/kg IV of fosphenytoin can be given 10 minutes after the loading dose. The dose for phenytoin and fosphenytoin is the same. VPA is an alternative and should be considered as an initial therapy in children who did not respond to levetiracetam or fosphenytoin in previous episodes of SE, in children with a hypersensitivity to phenytoin or fosphenytoin, in cases of toxin-induced SE, or in children on chronic VPA therapy who are known to have had recent nonadherence and in whom VPA levels are suspected to be low.41 The recommended IV loading dose of VPA is 20-40 mg/kg. An additional 20 mg/kg can be administered after 15-20 minutes, if needed.
If convulsive SE persists for 30 minutes after first- and second-line treatments are instituted, it is considered refractory SE and a third-line treatment is recommended. The drugs most commonly used in refractory SE are midazolam, pentobarbital, and propofol, usually administered as a continuous infusion.42-44 Midazolam is given as continuous infusion of 0.05 to 2 mg/kg/hour; for breakthrough seizures, additional 0.1 to 0.2 mg/kg boluses can be given and the continuous infusion rate increased by 0.05 to 0.1 mg/kg/hour every three to four hours. Pentobarbital is given as an initial bolus infusion of 5 to 15 mg/kg IV followed by a continuous infusion of 0.5 to 5.0 mg/kg per hour. Propofol may terminate seizures rapidly, but it is rarely used in children because of its Federal Drug Administration black box warning regarding propofol infusion syndrome. The duration of the continuous infusion is dependent on achieving a suppression-burst pattern on continuous EEG for 24 to 48 hours (usually in the intensive care unit setting).
The third priority in the management of a patient with SE is identifying reversible causes (i.e., electrolyte imbalances or toxic insults) and initiating prompt, specific treatment to stop the seizures.
Treatment of Reversible Causes
Hypoglycemia
For symptomatic hypoglycemia, one should give an initial bolus of 2 mL/kg of dextrose 10% (0.2 g dextrose/kg of body weight). If glucose fails to increase after 15 to 20 minutes, repeat the bolus. Higher concentrations of dextrose are not recommended as an initial bolus because they frequently result in hyperglycemia with a subsequent insulin surge, triggering further hypoglycemia. After the initial bolus, start a dextrose infusion to prevent recurrent hypoglycemia. Neonates should be started on D10 containing isotonic maintenance fluids. Because older children have lower glucose requirements, they should be started on D5 containing isotonic fluids at maintenance rate.
Hyponatremia
Cerebral edema is a potential complication of symptomatic hyponatremia with seizures. The risk of morbidity from delayed therapy is greater than the risk of complications from too rapid correction and osmotic demyelination. Therefore, aggressive initial correction is recommended.
In children with acute, symptomatic hyponatremia, an initial hypertonic (3%) saline dose of 3 to 5 mL/kg IV should be administered over 10 to 15 minutes.45 If the seizures persist, recheck serum sodium levels and repeat the infusion. Once the seizure has been abated, if hyponatremia persists, the child’s clinical status and serum sodium level can guide further IV fluid replacement.46 The targeted goal is to raise the serum sodium not more rapidly than 8 to 9 mEq/L over the initial 24 hours.47-50 Patients with persistent SE secondary to hyponatremia likely will be refractory to antiepileptic medications if the underlying hyponatremia has not been addressed.
Hypocalcemia
IV calcium is indicated to treat symptomatic hypocalcemia. The recommended regimen is 100 to 200 mg/kg/dose of calcium gluconate, administered intravenously over five to 10 minutes. This should be given slowly because of the risk of serious cardiac dysfunction, including systolic arrest.51 Although calcium chloride also can be used for correction, it is more likely to cause tissue necrosis if extravasated.
Hypomagnesemia
Hypocalcemia is difficult to correct in the setting of concurrent hypomagnesemia. If administering magnesium in the form of magnesium sulfate, the appropriate dose is 25 to 50 mg/kg/dose IV every four to six hours for two to three doses with a maximum dose of 2,000 mg/dose. Continue magnesium repletion as long as the serum magnesium concentration is less than 0.8 mEq/L (1 mg/dL).
Toxic Insults
In the management of toxic insults, benzodiazepines are a temporizing measure at best. Definitive therapy would include the antidote for a given poisoning. Examples include seizures resulting from methanol or ethylene glycol toxicity, for which one should administer fomepizole, which acts to inhibit the enzyme alcohol dehydrogenase. Pyridoxine should be administered in suspected isoniazid toxicity. It is highly recommended that providers contact the local poison control center in these situations for additional recommendations.
The third priority in the management of SE includes diagnosing the underlying etiology of the seizure episode. A parent or caregiver may provide a history to help determine the cause or precipitants of the seizures. It is prudent to obtain information about the seizure episode, any preceding events (e.g., history of trauma, fever, headache or vomiting, toxin exposure or ingestion), underlying seizure disorder, current medications, and any history of missed medication. Inquire about surgical history (e.g., ventriculo-peritoneal shunt placement), family history, and travel history. A thorough physical examination must be performed, checking for evidence of an infectious or traumatic etiology. Examine the skin for rashes or other congenital skin lesions, dysmorphic features, or stigmata of underlying hepatic, renal, or endocrinologic disorders.
Laboratory Studies
Table 4 highlights priorities for laboratory testing in children with SE. Blood and urine should be obtained for the following: a rapid “finger-stick” glucose, serum electrolytes (including calcium, phosphate, and magnesium levels), venous or arterial pH and pCO2, urinalysis and a complete blood count, urine and blood toxicology, and serum anticonvulsant drug levels. Of note, patients with an infection may have an elevated white blood cell count (WBC). However, an elevated WBC also may be due to demargination, in which case it will return to reference ranges in 12-24 hours. Although institutional panels for limited and extended toxicology screens may vary, substances such as ethanol, cocaine, amphetamines, methamphetamines, lysergic acid diethylamide (LSD), and phencyclidine (PCP) have been reported to cause SE and should be explored if clinically indicated. Blood cultures should be obtained if there is evidence of systemic infection. Similarly, cerebrospinal fluid studies via a lumbar puncture (LP) should be obtained if there is concern for a CNS infection. Children with known epilepsy have a decreased seizure threshold during infections because of the increased metabolic stress. When patients present in SE, they may have a localizing source of their infection, in which case the clinician must use their best judgment to determine if an LP is indicated. A renal function panel, creatine phosphokinase, and urinalysis can be obtained to monitor for complications of SE, such as rhabdomyolysis.
Table 4. Laboratory Studies for Children With Status Epilepticus |
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Population |
Studies |
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All patients |
Serum electrolytes; serum calcium, phosphate, magnesium; brain imaging (CT or MRI) |
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Epilepsy patients maintained on anticonvulsants |
Anticonvulsant level |
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Febrile patients |
CBC with differential; blood culture; urinalysis, urine cultures; CSF culture |
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Poisoned patient |
Urine screen for amphetamines, cocaine, PCP; aspirin level; venous or arterial pH and pCO2; ECG when seizures stop |
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Infants younger than 6 months of age |
Blood gas; plasma ammonia; plasma amino acids; PT, PTT; serum AST, ALT, LDH, alkaline phosphatase; blood lactate and pyruvate; urinalysis; urine for reducing substances |
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CT: computed tomography; MRI: magnetic resonance imaging; |
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Neuroimaging. Consider computed tomography (CT)/magnetic resonance imaging (MRI). CT may be performed in the emergency department setting, but MRI has superior yield for determining the underlying etiology. Consider neuroimaging when SE is the first presentation of epilepsy; if there are signs or symptoms of elevated intracranial pressure; if the patient presents with a focal seizure or has a persistent focal neurologic deficit; in the setting of head trauma; in unexplained persistent seizure activity, as well as in children whose recovery from SE does not follow the expected course.36,52 Expert consultation with neurology is helpful in instances of refractory SE.
Other Therapies. Observational data suggest that other antiseizure drugs, including lacosamide and topiramate, may play a role in the management of SE, particularly in the refractory setting. Other emerging therapies include ketamine and the ketogenic diet.53-56 Immunomodulatory therapy including IV corticosteroids and IV immunoglobulin has been used to treat NORSE and FIRES.
Neonatal Seizures
Neonates are a distinct subset of the population, and neonatal seizures warrant special consideration. Seizures in the neonatal period most frequently occur within the first week of life. Newborns at higher risk for seizures are those who are born at a younger gestational age and lower birth weight. The estimated incidence of seizures in this age group is from 1.5 to 5.5 per 1,000.57-65 The etiology, classification, diagnosis, and management of neonatal seizures varies from that of older children.
Etiology
Approximately 85% of neonatal seizures occur as a consequence of a specific identifiable etiology. These are broadly classified as neonatal encephalopathy and hypoxic-ischemic encephalopathy; structural brain injuries, including ischemic and hemorrhagic stroke; metabolic disturbances (most often glucose and electrolyte abnormalities); CNS or systemic infections; drug withdrawal or intoxication; and inborn errors of metabolism.
Neonatal encephalopathy subsequent to hypoxia-ischemia is the most common cause of neonatal seizures.66,67 In a prospective multicenter study of 426 consecutive neonates with seizures, hypoxic ischemic encephalopathy was the most common etiology (38%), followed by ischemic stroke (18%), and intracranial hemorrhage (11%).
Metabolic disturbances resulting in neonatal seizures are potentially treatable and include hypocalcemia, hypomagnesemia, and hypoglycemia. Typically, reversal of these abnormalities is sufficient to treat the acute symptomatic seizures, and anticonvulsant medications usually are not necessary.
Bacterial and viral infections of the CNS also can cause seizures and result in SE.68 For example, prenatal infections — toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus infection (TORCH) — are potential risk factors for seizures. Any neonate with suspected seizures should be considered to have a systemic and/or CNS infection until proven otherwise and should have an immediate evaluation for infection.
Drug withdrawal and intoxication are additional causes of neonatal seizures. Neonates exposed to substances in utero may experience a withdrawal syndrome in the first days of life that can include seizures.
Inborn errors of metabolism also can manifest as seizures, especially in the neonatal period. They should be suspected when seizures begin several days postpartum following a normal pregnancy and delivery, absent postpartum complications.69 Other clues include a family history of consanguinity or early sibling death; physical signs, such as organomegaly, cardiomyopathy, or hematologic abnormalities; and seizures refractory to conventional treatment.
Classification
Seizures in the neonatal period are unique when compared with those of older infants and children. Neonatal seizures are classified according to their motor manifestations into focal clonic, multifocal clonic, generalized tonic, myoclonic, spasms, and motor automatisms.70-77
Subtle seizures are common and are associated with abnormal eye movements, lip smacking, and swimming or pedaling movements.78
Even the most discerning clinician may find it difficult to identify seizure activity in a newborn. This is because neonates, particularly preterm infants, often display normal physical activity that, when occurring suddenly, may resemble seizures. This includes sucking, gagging, coughing, and stretching. Further, many neonatal seizures are subclinical or nonconvulsive. Jitteriness, for example, may resemble a seizure, but is distinguished clinically from clonic seizures by the lack of associated ocular movements and a tremor that is suppressed by flexing the limb. Often, a bedside EEG is required to distinguish these normal events from seizures.72,79,80 The history and physical exam can identify risk factors and provide clinical clues to guide judicious use of testing. They also can help clarify the underlying etiology as either acute symptomatic seizures or neonatal onset of epilepsy.
Maternal History. Specific conditions during pregnancy can predispose infants to illnesses that may manifest as seizure activity. For example, infants born to women who experienced gestational diabetes are at risk for neonatal hypoglycemia. Maternal infections, such as sexually transmitted infections, or even more vague histories of fever and rash may expose infants to in utero transmission of the infection. Maternal use of prescription or illegal substances can lead to seizure activity in the newborn as a result of drug intoxication or withdrawal.
Family History. In addition to confirming if there is a family history of epilepsy, there are additional familial historical clues that can help guide the diagnosis. A family history of consanguinity or early sibling death from unknown causes warrants consideration of inborn errors of metabolism. These errors often lead to electrolyte disturbances, which subsequently can cause seizures.
Physical Exam. Aspects of the physical examination may direct further testing and provide clues to the underlying etiology. One should pay attention to the infant’s head size and fontanelle. Macro- and microcephaly can indicate a structural abnormality, while a bulging fontanelle may suggest meningitis or increased intracranial pressure. Rashes may indicate a TORCH infection. The motor exam can detect asymmetry in spontaneous movements or abnormal tone that may suggest a structural brain lesion or neonatal encephalopathy.
Laboratory Investigation. Infection and sepsis are among the most common causes of neonatal seizure, and often the clinical manifestations can be otherwise subtle. As such, a proper sepsis evaluation should ensue, and the clinician should obtain cerebrospinal fluid and blood and urine cultures in addition to the rest of the septic workup. Additional blood tests that can be helpful are serum electrolytes, magnesium levels, measures of transaminase levels, ammonia, lactate, and an arterial blood gas. Similarly, a urinalysis and toxicology screen may help guide management. Although the results may not be available in the acute setting, serum pyruvate and amino acids, TORCH titers, urine-reducing substances, and urine organic acids can assist with longitudinal diagnosis and management.
Other Testing. Similar to older children, MRI is the neuroimaging modality of choice for neonates presenting with seizures. MRI can detect intracranial hemorrhage, ischemic stroke, brain malformations, and evidence of hypoxic ischemic damage. If vascular pathology is suspected, one can order MRI venography or angiography. If MRI is not readily available, a cranial ultrasound can be used to identify intracranial hemorrhage or hydrocephalus. CT generally should be avoided in young children, especially neonates, since MRI provides superior resolution and does not involve exposure to ionizing radiation.81,82 The gold standard for neonatal seizure diagnosis is multi-channel video EEG monitoring.81
Management
The management goal of neonatal seizures is to stabilize the infant, quickly identify and treat any reversible causes, and administer antiepileptic drugs (AEDs) when necessary. While AEDs may be effective at treating neonatal epilepsy, intractable SE may ensue if there is another underlying cause that has not been properly addressed. This can lead to irreversible brain damage.
Reversible Causes. Infections, particularly those involving the CNS, should be treated promptly with broad-spectrum antibiotics, with doses sufficient to treat meningitis. Herpes simplex virus should be considered in any neonate with seizures and acyclovir administered.
Metabolic Disturbances. Electrolyte abnormalities are common, yet reversible, causes of neonatal seizures.
Hypoglycemia. Correct immediately with 2 mL/kg of D10 administered intravenously. Neonates may require additional boluses; however, once the hypoglycemia has been corrected, maintenance fluids should contain an IV infusion of dextrose, specifically D10.
Hypocalcemia. Treat with 10% calcium gluconate via IV (100 mg/kg or 1 mL/kg) infused over five to 10 minutes. It is important to monitor the heart rate for bradycardia and the infusion site for infiltration during administration. The clinician can repeat the dose in 10 minutes if no response occurs. It is important to note that calcium chloride can be used as an alternative; however, it is associated with tissue necrosis and extravasation when administered through a peripheral IV line.
Hypomagnesemia. In neonates, 50 to 100 mg/kg/dose of magnesium sulfate can be injected intramuscularly or given intravenously over 10 to 15 minutes. It is important to monitor the patient carefully during administration, as apnea from respiratory muscle paralysis can result from transient hypermagnesemia. Cardiac arrest subsequently can ensue; therefore, it also is important to have calcium gluconate immediately available. The dose of magnesium can be repeated every 12 hours as needed until the serum magnesium levels have returned to normal.
Pyridoxine Dependent Seizures (PDS). Although it occurs rarely, pyridoxine deficiency has been shown to cause intractable, recurrent seizures in neonates. These seizures often are resistant to most antiepileptic medications. However, they do respond to the administration of pyridoxine. If given intravenously in the acute setting, pyridoxine should be administered with close cardiopulmonary monitoring, as it is associated with neonatal apnea. Monitoring the patient with continuous EEG during administration also is recommended. Trial doses of 100 mg IV have been recommended, and can be repeated every five to 15 minutes up to a maximum of 500 mg. In rare cases of PDS, infants who did not respond to pyridoxine have had successful abortion of their seizures with leucovorin.83
Antiepileptic Drugs. Phenobarbital is the first-line AED used in the management of neonatal seizures.66,84-87 The initial dose is 20 mg/kg IV given over 15-20 minutes. If necessary, an additional 10-20 mg/kg IV can be administered in 10 mg/kg aliquots until seizure cessation. It is important to note that sedation, respiratory arrest, and hypotension are potential complications of phenobarbital administration.
Acute treatment also can be initiated with a short-acting benzodiazepine. Other antiseizure drugs that can be given intravenously include levetiracetam, fosphenytoin, and lidocaine. (See Figure 1.)
Figure 1. Antiseizure Drug Therapy for Neonatal Seizures |
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EEG: electroencephalography; IV: intravenous; PE: phenytoin equivalents |
Disposition
Patients in SE usually will need to be admitted to the hospital, often to an intensive care unit. Continuous EEG monitoring should be instituted during the inpatient stay to monitor for seizure activity.
Summary
SE is a condition resulting either from initiation of mechanisms that lead to abnormally prolonged seizures (longer than five minutes), or the failure of the mechanisms responsible for seizure termination. Common causes of SE in children are febrile seizures and metabolic etiologies, such as hyponatremia and hypoglycemia. Ultimately, the goal of therapy is to terminate both the clinical and electrical seizure activity safely and rapidly. This can be accomplished by meeting the three principal treatment priorities: addressing airway, breathing, and circulation; stopping any ongoing seizure activity; and considering reversible causes and initiating the indicated treatment, as well as diagnosing the underlying etiology of the seizure episode.
The mainstay in any emergency is to first assess and maintain adequate airway, breathing, and circulation. Next, providers should obtain parenteral access and administer an appropriate dose of benzodiazepine, or in the case of a neonatal seizure, a dose of phenobarbital. One should simultaneously obtain a history to identify any antecedent illness or intoxication, while assessing for any findings suggestive of sepsis or head trauma. The blood glucose level should be obtained rapidly, and other blood samples sent as indicated. If the seizure persists, the patient can be given a second dose of benzodiazepine, being sure to correct any metabolic derangement and administer antibiotics, if warranted. Providers should be prepared to provide additional respiratory and ventilatory support after the administration of multiple doses of benzodiazepines, as respiratory depression commonly ensues. Second- and third-line treatments for SE include the administration of fosphenytoin, levetiracetam, VPA, or continuous infusions of midazolam, pentobarbital, or propofol.
Once the patient is hemodynamically stable and the clinical seizure activity has been terminated, expert consultation with neurology should be considered, and can guide the decision to obtain additional studies, such as neuroimaging and EEG.
REFERENCES
- [No authors listed.] Guidelines for epidemiologic studies on epilepsy. Commission on epidemiology and prognosis, International League Against Epilepsy. Epilepsia 1993;34:592-596.
- Gorelick MH, Blackwell CD. Neurologic emergencies. In: Fleisher GR, Ludwig S, eds. Textbook of Pediatric Emergency Medicine. 6th ed. Philadelphia: Lippincott Williams & Wilkins;2010:1011.
- Trinka E, et al. A definition and classification of status epilepticus — Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015;56:1515-1523.
- Berg AT, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 2010;51:676-685.
- Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35(suppl):S1-S6.
- Chin RF, et al; NLSTEPSS Collaborative Group. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: Prospective population-based study. Lancet 2006;368:222-229.
- Raspall-Chaure M, et al. The epidemiology of convulsive status epilepticus in children: A critical review. Epilepsia 2007;48:1652-1663.
- Singh RK, et al. Prospective study of new-onset seizures presenting as status epilepticus in childhood. Neurology 2010;74:636-642.
- Shinnar S, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216-225.
- Haut SR, et al. The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures. Epilepsia 1999;40:1832-1834.
- Novak G, et al. Risk factors for status epilepticus in children with symptomatic epilepsy. Neurology 1997;49:533-537.
- Raspall-Chaure M, et al. Outcome of paediatric convulsive status epilepticus: A systematic review. Lancet Neurol 2006;5:769-779.
- Kravljanac R, et al. Outcome of status epilepticus in children treated in the intensive care unit: A study of 302 cases. Epilepsia 2011;52:358-363.
- Maytal J, et al. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323-331.
- Lambrechtsen FA, Buchhalter JR. Aborted and refractory status epilepticus in children: A comparative analysis. Epilepsia 2008;49:615-625.
- Novorol CL, et al. Outcome of convulsive status epilepticus: A review. Arch Dis Child 2007;92:948-951.
- Jafarpour S, et al. New-onset status epilepticus in pediatric patients: Causes, characteristics, and outcomes. Pediatr Neurol 2018;80:61-69.
- Watemberg N, Segal G. A suggested approach to the etiologic evaluation of status epilepticus in children: What to seek after the usual causes have been ruled out. J Child Neurol 2010;25:203-211.
- Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-976.
- Hanhan UA, et al. Status epilepticus. Pediatr Clin North Am 2001;48:683-694.
- Teitelbaum JS, et al. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N Engl J Med 1990;322:1781-1787.
- Wasterlain CG, et al. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34(suppl): S37-S53.
- Wasterlain CG, et al. GABA metabolism in the substantia nigra, cortex, and hippocampus during status epilepticus. Neurochem Res 1993;18:527-532.
- Dunn DW. Status epilepticus in children: Etiology, clinical features, and outcome. J Child Neurol 1988;3:167-173.
- Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates. Ischemic cell change and its relation to ictal physiological events. Arch Neurol 1973;28:10-17.
- Gabor AJ, et al. Intracranial pressure during epileptic seizures. Electroencephalogr Clin Neurophysiol 1984;57:497-506.
- Patel H, et al. Nonepileptic seizures in children. Epilepsia 2007;48:2086-2092.
- Kutluay E, et al. Nonepileptic paroxysmal events in a pediatric population. Epilepsy Behav 2010;17:272-275.
- Avbersek A, Sisodiya S. Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? J Neurol Neurosurg Psychiatry 2010;81:719-725.
- Brophy GM, et al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23.
- Chin RFM, et al. Treatment of community-onset, childhood convulsive status epilepticus: A prospective, population-based study. Lancet Neurol 2008;7:696-703.
- Welch RD, et al; Neurological Emergencies Treatment Trials (NETT) Network Investigators. Intramuscular midazolam versus intravenous lorazepam for the prehospital treatment of status epilepticus in the pediatric population. Epilepsia 2015;56:254-262.
- Silbergleit R, et al; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600.
- McTague A, et al. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev 2018;1:CD001905.
- Chamberlain JM, et al; Pediatric Emergency Care Applied Research Network (PECARN). Lorazepam vs diazepam for pediatric status epilepticus: A randomized clinical trial. JAMA 2014;311:1652-1660.
- Chin RF, et al. Treatment of community-onset, childhood convulsive status epilepticus: A prospective, population-based study. Lancet Neurol 2008;7:696-703.
- Chin RF, et al. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. J Neurol Neurosurg Psychiatry 2004;75:1584-1588.
- Glauser T, et al. Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the guideline committee of the American Epilepsy Society. Epilepsy Curr 2016;16:48-61.
- Dalziel SR, et al; PREDICT research network. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): An open-label, multicentre, randomised controlled trial. Lancet 2019;393:2135-2145.
- Lyttle MD, et al; Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI) collaborative. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): A multicentre, open-label, randomised trial. Lancet 2019;393:2125-2134.
- İșgüder R, et al. A comparison of intravenous levetiracetam and valproate for the treatment of refractory status epilepticus in children. J Child Neurol 2016;31:1120-1126.
- Tasker RC, et al; Pediatric Status Epilepticus Research Group. Refractory status epilepticus in children: Intention to treat with continuous infusions of midazolam and pentobarbital. Pediatr Crit Care Med 2016;17:968-975.
- Prasad A, et al. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380-386.
- Harrison AM, et al. Treatment of convulsive status epilepticus with propofol: Case report. Pediatr Emerg Care 1997;13:420-422.
- Brenkert TE, et al. Intravenous hypertonic saline use in the pediatric emergency department. Pediatr Emerg Care 2013;29:71-73.
- Sarnaik AP, et al. Management of hyponatremic seizures in children with hypertonic saline: A safe and effective strategy. Crit Care Med 1991;19:758-762.
- Sterns RH, et al. Neurologic sequelae after treatment of severe hyponatremia: A multicenter perspective. J Am Soc Nephrol 1994;4:1522-1530.
- Berl T. Treating hyponatremia: Damned if we do and damned if we don’t. Kidney Int 1990;37:1006-1018.
- Karp BI, Laureno R. Pontine and extrapontine myelinolysis: A neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 1993;72:359-373.
- Sterns RH. Severe symptomatic hyponatremia: Treatment and outcome. A study of 64 cases. Ann Intern Med 1987;107:656-664.
- Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. The Endocrinologist 1996;6:10.
- Yoong M, et al. The role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus. Dev Med Child Neurol 2012;54:328-333.
- Gaspard N, et al. Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study. Epilepsia 2013;54:1498-1503.
- Cobo NH, et al. The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: Challenges in implementation in the pediatric and neonatal intensive care units. J Child Neurol 2015;30:259-266.
- O’Connor SE, et al. The ketogenic diet for the treatment of pediatric status epilepticus. Pediatr Neurol 2014;50:101-103.
- Cervenka MC, et al. The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit. Neurocrit Care 2011;15:519-524.
- Kellaway P, Hrachovy RA. Status epilepticus in newborns: A perspective on neonatal seizures. Adv Neurol 1983;34:93-99.
- Lanska MJ, et al. A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 1995;45:724-732.
- Ronen GM, et al. The epidemiology of clinical neonatal seizures in Newfoundland: A population-based study. J Pediatr 1999;134:71-75.
- Saliba RM, et al. Incidence of neonatal seizures in Harris County, Texas, 1992-1994. Am J Epidemiol 1999;150:763-769.
- Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013;18:185-191.
- Buraniqi E, et al. Electrographic seizures in preterm neonates in the neonatal intensive care unit. J Child Neurol 2017;32:880-885.
- Scher MS, et al. Electrographic seizures in preterm and full-term neonates: Clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91:128-134.
- Glass HC, Pham TN, Danielsen B, et al. Antenatal and intrapartum risk factors for seizures in term newborns: A population-based study, California 1998-2002. J Pediatr 2009;154:24-28.e1.
- Pisani F, et al. Incidence of neonatal seizures, perinatal risk factors for epilepsy and mortality after neonatal seizures in the province of Parma, Italy. Epilepsia 2018;59:1764-1773.
- Glass HC, et al; Neonatal Seizure Registry Study Group. Contemporary profile of seizures in neonates: A prospective cohort study. J Pediatr 2016;174:98-103.e1.
- Lynch NE, et al. The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia 2012;53:549-557.
- Verboon-Maciolek MA, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008;64:266-273.
- Dhamija R, et al. Epilepsy in children — when should we think neurometabolic disease? J Child Neurol 2012;27:663-671.
- Electroclinical studies of status epilepticus and convulsions in the newborn. In: Drefus-Brisac C, Monod N, Kellaway P, Petersen I, eds. Neurological and Electroencephalographic Correlative Studies in Infancy. New York: Grune & Stanton;1964:250.
- Lombroso CT. The treatment of status epilepticus. Pediatrics 1974;53:536-540.
- Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837-1844.
- Rose AL, Lombroso CT. A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up. Pediatrics 1970;45:404-425.
- Volpe JJ. Neonatal seizures: Current concepts and revised classification. Pediatrics 1989;84:422-428.
- Watanabe K, et al. Electroclinical studies of seizures in the newborn. Folia Psychiatr Neurol Jpn 1977;31:383-392.
- Volpe J. Neonatal seizures. N Engl J Med 1973;289:413-416.
- Berg AT, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 2010;51:676-685.
- Fisher RS, et al. Operational classification of seizure types by the International League Against Epilepsy: Position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58:522-530.
- Murray DM, et al. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008;93:F187-F191.
- Malone A, et al. Interobserver agreement in neonatal seizure identification. Epilepsia 2009;50:2097-2101.
- Shellhaas RA, et al. The American Clinical Neurophysiology Society’s guideline on continuous electroencephalography monitoring in neonates. J Clin Neurophysiol 2011;28:611-617.
- Glass HC, et al. Amplitude-integrated electro-encephalography: The child neurologist’s perspective. J Child Neurol 2013;28:1342-1350.
- Nicolai J, et al. Folinic acid-responsive seizures initially responsive to pyridoxine. Pediatr Neurol 2006;34:164-167.
- Bartha AI, et al. Neonatal seizures: Multicenter variability in current treatment practices. Pediatr Neurol 2007;37:85-90.
- Hellström-Westas L, et al. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr 2015;104:123-129.
- Dilena R, et al. Influence of etiology on treatment choices for neonatal seizures: A survey among pediatric neurologists. Brain Dev 2019;41:595-599.
- Painter MJ, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-459.
The authors present an approach to the diagnostic evaluation and therapeutic management of neonates and children in SE.
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