Status Epilepticus

Kimberly S. Bennett

Colin B. Van Orman

KEY POINTS

Classification

SE is classified by seizure type: generalized convulsive, focal, myoclonic, or nonconvulsive.

Most pediatric SE is generalized convulsive.

Nonconvulsive SE requires a high degree of suspicion and electroencephalographic (EEG) monitoring for diagnosis.

18%-33% of children with unexplained alteration in consciousness, or a prolonged postictal state, have nonconvulsive SE.

Any type of SE that fails to remit after treatment with two agents is considered refractory (RSE) and carries a greater risk of morbidity and mortality.

Epidemiology

SE is a medical emergency that carries a mortality of 3%-7% in children.

Most cases of SE occur in children without a known seizure disorder.

Common inciting events that require concomitant therapy include central nervous system (CNS) infection and metabolic abnormalities.

Mechanism of Disease

Seizures result from increased neuronal excitation and/or decreased inhibition.

Prolonged SE can lead to altered regulation of γ-aminobutyric acid (GABA) receptors and pharmacologic resistance.

SE (either convulsive or nonconvulsive) lasting >30-60 minutes is sufficient to cause neuronal injury.

Patients with concurrent neurological insults are likely more vulnerable to seizure-induced injury.

Clinical Presentation

Any type of SE can become nonconvulsive if prolonged.

Early SE lasts up to 30 minutes and is associated with intact compensation to attenuate seizure-induced injury (i.e., increased catecholamines, tachycardia, hypertension, increased cerebral blood flow).

Late SE is marked by failure of compensatory mechanisms and seizure-associated injury (i.e., hyperthermia, hypotension, hypoglycemia, lost cerebral autoregulation).

Clinical Management

Prompt, goal-directed therapy, including respiratory and hemodynamic support, rapid cessation of seizure activity, and treatment of underlying etiology, is indicated.

The goal of therapy should be seizure cessation within 30 minutes of presentation.

Lorazepam is the preferred first-line anticonvulsant for most pediatric SE.

Phenobarbital is the first-line agent for neonatal SE.

Second-line agents include fosphenytoin, phenobarbital, and valproate.

For RSE, pharmacologic coma should be induced promptly.

Midazolam is the agent of choice with progression to pentobarbital if seizures persist.

For certain etiologies of RSE, therapies other than pharmacologic coma should be considered (e.g., Fever-induced refractory epileptic encephalopathy in school-aged children or antibody-mediated encephalitis).

Status epilepticus (SE) is a medical emergency of varied etiologies that requires prompt recognition and intervention. Children with prolonged seizures are at risk for brain injury, respiratory or hemodynamic compromise due to both prolonged convulsions and high anticonvulsant dosing, and even multiorgan dysfunction. The pediatric intensivist must be familiar with the clinical presentation, causal pathophysiology, clinical evaluation, diagnostic monitoring techniques, potential complications, and goal-directed therapy of SE in infants and children.

DEFINITION

The classical definition of SE is seizure activity, either continuous or episodic, without complete recovery of consciousness, which lasts for at least 30 minutes. The evolution of SE can be conceptualized in stages (1,2): (a) premonitory or prodromal SE, characterized by an increasing frequency of serial seizures with recovery of consciousness between episodes; (b) incipient SE, defined as continuous or intermittent seizures that last up to 5 minutes without full recovery of consciousness; (c) impending or early SE, marked by seizure activity that persists 5-30 minutes; and (d) established SE, defined as seizures that last longer than 30 minutes. When SE lasts longer than 30-60 minutes, subtle SE usually develops. Subtle SE is characterized by progressive electromechanical dissociation, in which clinical signs diminish yet electroencephalographic (EEG) seizure activity persists. Finally, nonconvulsive SE (NCSE) refers to ongoing EEG seizure activity without associated clinical signs.

An operational definition that best helps to direct our treatment of SE, is to pragmatically define the condition as seizure

activity lasting longer than 5 minutes. This duration also corresponds to initiation of therapy during impending or early SE, and recognizes the fact that prompt intervention is crucial. In children, unprovoked, afebrile seizures typically last less than 4 minutes, and seizures that last longer than 5 minutes are unlikely to remit spontaneously (3). Additionally, prolonged SE is associated with development of pharmacologic resistance and worse outcome (4). Indeed, children with SE that lasts longer than 30 minutes are less likely to respond to anticonvulsants (4). Consequently, treatment recommendations in this chapter will be based on a definition of SE as either continuous or intermittent seizure activity that lasts at least 5 minutes without full recovery of consciousness.

CLASSIFICATION

SE is commonly classified by seizure type. For the purpose of the pediatric intensivist, SE can be considered as convulsive or nonconvulsive (Table 63.1). Additionally, the pediatric intensivist should be familiar with the characteristics of refractory SE (RSE) and neonatal SE.

Generalized Convulsive Status Epilepticus

Generalized convulsive SE (GCSE) constitutes 73%-98% of pediatric SE (5) and is characterized by tonic, clonic, or tonicclonic

seizure activity that involves all extremities. In primary GCSE, seizure onset cannot be localized to one brain region by either clinical or EEG findings. In secondary GCSE, which is more common, seizures begin focally but spread to involve the entire brain. Early in the course, focal signs may persist on EEG; however, during prolonged GCSE, distinguishing secondary from primary GCSE often becomes difficult.

Focal motor SE, also called simple complex SE, somatomotor SE, or epilepsia partialis continua, is characterized by involvement of a single limb or side of the face. Focal motor SE is less common than GCSE and is frequently associated with focal brain pathology (Table 63.2).

TABLE 63.1 CLASSIFICATION OF STATUS EPILEPTICUS

▪ CONVULSIVE	▪ NONCONVULSIVE
Generalized convulsive	Absence
Focal motor	Complex partial
Myoclonic	NCSE with coma
NCSE, nonconvulsive status epilepticus

TABLE 63.2 COMMON ETIOLOGIES OF FOCAL MOTOR STATUS EPILEPTICUS

Brain Tumor
	Astrocytoma Oligodendroglioma Glioblastoma
Infection
	Brain abscess Viral encephalitis Cysticercosis Tuberculosis
Vascular
	Cortical vein thrombosis Arteriovenous malformation Cerebrovascular accident
Trauma
	Posttraumatic cyst Chronic subdural hematoma Focal gliosis

Myoclonic SE is characterized by irregular, asynchronous, small-amplitude, repetitive myoclonic jerking of the face or limbs. Myoclonic SE is more common in comatose patients and is associated with several specific conditions, particularly anoxia or cardiac arrest (Table 63.3).

TABLE 63.3 COMMON ETIOLOGIES OF MYOCLONIC STATUS EPILEPTICUS

Anoxic Injury
	Cardiac arrest Cardiopulmonary bypass Carbon monoxide poisoning CO₂ narcosis
Infection
	Viral encephalitis Acute demyelinating encephalomyelitis Subacute sclerosing panencephalitis Opportunistic infection
Injury
	Heat stroke Lightning Intracranial hemorrhage
Metabolic
	Hepatic failure Renal failure Hypoglycemia Hyponatremia Nonketotic hyperglycemia Thiamine deficiency
Toxins
	Tricyclic antidepressants Anticonvulsants Antibiotics (β-lactam, carbapenem, quinolone) Opiates Lithium Heavy-metal poisoning
Genetic/Epilepsy Syndromes
	Juvenile myoclonic epilepsy Lennox-Gastaut syndrome Absence epilepsy Degenerative myoclonus epilepsy Angelman syndrome

Nonconvulsive Status Epilepticus

NCSE is characterized by continuous nonmotor seizures and

requires EEG confirmation for diagnosis. NCSE may occur in ambulatory or comatose patients. The most common type of NCSE in ambulatory children is absence SE, which is characterized by altered consciousness and a generalized 3-Hz symmetric spike-and-wave pattern on EEG. In contrast, complex partial SE in ambulatory patients is marked by altered consciousness and focal activity on EEG, usually involving the temporal lobe. In comatose patients, NCSE may be difficult to diagnose and should be considered in any patient with prolonged obtundation after seizure cessation or with coma of unclear etiology (6,7).

The diagnosis of NCSE in critically ill patients requires a high degree of suspicion. Recognition is increasing as continuous EEG (cEEG) monitoring becomes more widely applied in critically ill patients. Pediatric-specific reports reveal nonconvulsive seizures in 16%-46% (8,9,10,11,12) and NCSE in 18%-33% (9,10,12,13) of critically ill children with unexplained alterations

of consciousness and/or suspected SE. Nonconvulsive seizures and NCSE are more common among younger children, particularly those 1 month to 1 year of age, and are frequently associated with structural lesions (e.g., infarction, subdural hematoma, or intracerebral hemorrhage), anoxic injury, and acute infections (e.g., meningitis or encephalitis) (11,13). Although NCSE and nonconvulsive seizures occur in children with preexisting cerebral insults and epilepsy, more than 40% of children with nonconvulsive seizures are previously healthy (11).

Refractory Status Epilepticus

SE of any classification that fails to remit despite treatment with adequate doses of two anticonvulsants is termed refractory

status epilepticus (RSE) (1). RSE develops in 30%-40% of adult patients and is associated with greater mortality than is more responsive SE (14,15). In children, 10%-40% of SE becomes refractory (4,16). Mortality for pediatric RSE is 13%-30%, and 33%-50% of survivors have neurologic sequelae (17,18). Almost half (46%) of neonates with SE develop RSE, and only 10% have good neurodevelopmental outcomes at 1 year of age (19).

Super-refractory SE is an important subtype of RSE. Super-refractory SE is defined as the persistence or recurrence of seizures despite at least 24 hours of pharmacologic coma, including the occurrence of breakthrough seizures during tapering of anesthetic medications (20). Super-refractory SE may occur in patients with severe brain injury or in those who are previously healthy with no apparent cause of SE. Super-refractory SE is important to recognize, as additional diagnostic testing and targeted therapy are often necessary.

Neonatal Status Epilepticus

SE presents differently in neonates than in older infants and children. Neonates are unlikely to demonstrate GCSE or continuous seizure activity; however, frequent, serial seizures without recovery of consciousness can occur. Neonatal seizures are frequently poorly organized and polymorphic and may involve rapid extensor or flexor posturing, tremor of extended extremities, apnea, eye deviation, or automatisms (2,17). Because of such atypical manifestations, most types of bizarre or unusual transient events in the neonatal period may be seizures, particularly if they are stereotypic, insensitive to stimuli, unaltered by restraint or limb displacement, and recur periodically. Neonatal SE is difficult to diagnose, and both clinical and EEG criteria are often required (17). Conditions commonly associated with neonatal SE are presented in Table 63.4.

TABLE 63.4 COMMON ETIOLOGIES OF NEONATAL STATUS EPILEPTICUS

Perinatal or Acute Insults
	Hypoxia-ischemia Intracranial hemorrhage Cerebral vascular accident
Infection
	Meningitis Encephalitis Abscess
Metabolic
	Hypoglycemia Hypocalcemia Hyponatremia Hypomagnesemia Bilirubin encephalopathy
Inborn Errors of Metabolism
	Phenylketonuria Nonketotic hyperglycemia Pyridoxine deficiency Histidinemia Hyperammonemia Homocitrullinemia Maple syrup urine disease Leucine-sensitive hypoglycemia
Toxins
	Antibiotics (β-lactam, carbapenem, quinolone) Anesthetics Drug withdrawal Heavy-metal poisoning
Cerebral Malformations
	Neuronal migration defect Neurocutaneous syndrome
Degenerative Diseases
	Leigh encephalopathy Leukodystrophies Alpers’ disease Sandhoff disease Tay-Sachs disease
Benign Familial Syndromes
	Benign familial neonatal seizures Benign neonatal sleep myoclonus

EPIDEMIOLOGY

Using the classic definition of continuous or intermittent seizure activity that lasts at least 30 minutes without recovery of consciousness, reported incidences for SE in children aged 1 month to 16 years are 17-38 per 100,000 individuals per year (4,16,21). More than 40% of pediatric SE occurs in children <2 years of age (22). Reported age-specific incidences for SE are 51 per 100,000 for children <1 year of age, 29 per 100,000 for those 1-4 years old, 9 per 100,000 for those 5-9 years old, and 2 per 100,000 for those 10-15 year old (16). Racial influences may be important in SE, with a greater incidence in nonwhites than whites (21). Although mortality due to SE has decreased with improved supportive care, pediatric SE remains a medical emergency with overall mortality

rates of 3%-7.2% (16,18,23).

Twenty-five percent to 40% of pediatric SE occurs in children with known epilepsy (24). In other words, 9.5%-27% of children with epilepsy will experience at least one episode
of SE (5,25). Risk factors for SE in epileptic children include epilepsy induced by a known neurologic insult (symptomatic epilepsy) and previous episodes of SE (25). Other associated factors include use of multiple anticonvulsant medications, psychomotor retardation, generalized background abnormalities on EEG, and tapering of anticonvulsant medications. That being said, 60% of SE episodes among epileptic children occur despite therapeutic anticonvulsant drug levels and without any identifiable inciting event, such as fever or concurrent illness (26).

Conversely, more than half of SE occurs in patients without

a prior diagnosis of epilepsy. In fact, 12% of children with new-onset unprovoked seizures present with SE (3,5). SE as the presentation of new-onset seizures is more common in younger children (22). Importantly, 17% of children with new-onset SE have associated, treatable inciting events, such as electrolyte

abnormalities or central nervous system (CNS) infections (16).

Recurrent SE occurs in 13%-55% of pediatric patients, usually within 2 years of the first SE episode (5,16,18,27). The median interval between the first episode and recurrence is 25 days (range, 0-463 days) (16). Risk factors for recurrent SE are age <6 years, focal seizures, and an acute or remote CNS injury (5,18). In fact, children with a preexisting neurologic abnormality are 3-24 times more likely than previously healthy children to experience recurrence (16,18).

No population-based data are available to estimate the incidence of neonatal SE. Seizure type and brain maturation are influenced by gestational age, and studies suggest that neonatal SE is more common in full-term than preterm infants (17). In neonates with asphyxial injury, the duration of seizures has been “independently associated with brain injury” (17), emphasizing the need for prompt recognition and treatment in neonates.

ETIOLOGIES

Although initial supportive and anticonvulsant therapies are similar regardless of cause, diagnostic tests and adjunctive treatments are guided by suspected etiology. The etiologies of SE are commonly classified as cryptogenic, remote symptomatic, febrile, acute symptomatic, or progressive encephalopathic (Table 63.5) (22). Etiologies for pediatric SE vary by report: 30%-50% febrile, 24%-28% remote symptomatic, 8%-28% acute symptomatic, 15% cryptogenic, and 1%-5% progressive encephalopathies (22,28). The etiology of pediatric SE is age dependent (22), and variations likely reflect different age distributions or sampling biases of the studies.

TABLE 63.5 ETIOLOGIC CLASSIFICATION OF STATUS EPILEPTICUS (SE)

▪ ETIOLOGY	▪ DEFINITION
Cryptogenic (idiopathic)	SE in the absence of an acute precipitating central nervous system insult or metabolic dysfunction in a patient without a preexisting neurologic abnormality
Remote symptomatic	SE in a patient with a known history of a neurologic insult associated with an increased risk of seizures (e.g., traumatic brain injury, stroke, static encephalopathy)
Febrile	SE provoked solely by fever in a patient without a history of afebrile seizures Acute symptomatic SE during an acute illness involving a known neurologic insult (e.g., meningitis, traumatic brain injury, hypoxia) or metabolic dysfunction (e.g., hypoglycemia, hypocalcemia, hyponatremia)
Progressive encephalopathy	SE in a patient with a progressive neurologic disease (e.g., neurodegeneration, malignancies, neurocutaneous syndromes)
Adapted from Shinnar S, Pellock JM, Moshe SL, et al. In whom does status epilepticus occur: Age-related differences in children. Epilepsia 1997;38:907-14.

Febrile or acute symptomatic etiologies are most common in younger children and account for more than 80% of SE among children <2 years of age (22). Two-thirds of episodes during the second year of life are due to febrile SE (22). In some cohorts, febrile SE continues to be a common etiology among children >3 years of age (28). However, cryptogenic and remote symptomatic etiologies account for more than 60% of SE in children >4 years of age (22). Tapering or withdrawal of anticonvulsant medications is a common inciting event among older children (23).

CNS infection, metabolic abnormalities, traumatic brain injury, and anoxic brain injury are the most common specific etiologies of acute symptomatic pediatric SE (22). Other reported inciting events are listed in Table 63.6. Meningitis is more frequent in infants. Anoxia is more common in children <5 years old. Among children who present with newonset SE and fever, 12% have acute bacterial meningitis and 8% have viral CNS infections (16). Hypoxic-ischemic injury is the most prevalent cause of neonatal SE in developed countries, but electrolyte abnormalities continue to be more common in developing regions (17). Although rare, antibiotic-related SE is reported with the use of β-lactam antibiotics (particularly third- or fourth-generation cephalosporins and carbapenem), or quinolones in critically ill patients who have received high doses, have hepatic dysfunction, renal failure, or CNS lesions (29,30).

Identification and understanding of SE associated with fever and CNS inflammation in the absence of identified infection is increasing. Termed acute encephalopathy with inflammationmediated status epilepticus (AEIMSE), the three most recognized disorders are idiopathic hemiconvulsive-hemiplegia syndrome in infancy (IHHS, age 0-4 years), fever-induced refractory epileptic encephalopathy in school-aged children (FIRES, age 4 years to adolescence and also known as acute encephalopathy with refractory, repetitive partial seizures [AERRPS]) and new-onset RSE (NORSE, age 20-50 years) (31,32). These disorders typically involve fever that may abate several days before seizure onset, often present as limbic encephalopathy (e.g., confusion or behavioral changes, movement disorders, and limbic seizures) and can be difficult to distinguish from other etiologies of RSE (31,32). Mortality is high (12%) and, among survivors, refractory epilepsy and
significant cognitive disability are typical (31,32). Prompt recognition is important, as optimal diagnostic testing and treatment differ from other etiologies of SE.

TABLE 63.6 POTENTIAL ETIOLOGIES OF ACUTE SYMPTOMATIC STATUS EPILEPTICUS

	▪ NEWBORN		▪ 1-2 MONTHS OLD	▪ INFANCY AND CHILDHOOD
Acute insult	Hypoxic-ischemic CNS infection Intracranial hemorrhage		CNS infection Subdural hematoma Anoxia VP shunt dysfunction	CNS infection Intracranial hemorrhage Anoxia VP shunt dysfunction
Genetic and metabolic	Hypoglycemia Hypernatremia Hyponatremia Hypocalcemia Hypomagnesemia Hyperbilirubinemia Organic acidemia Urea cycle defects		Hypoglycemia Hypernatremia Hyponatremia Hypocalcemia Organic acidemia Urea cycle defects Phenylketonuria Uremia Riley-Day syndrome	Hypoglycemia Hypernatremia Hyponatremia Hypocalcemia Lysosomal defects Urea cycle defects Hepatic failure
		Nonketotic hyperglycemia Congenital lactic acidosis
	Pyridoxine dependency
Malformation	Neuronal migration defect Chromosomal anomaly		Sturge-Weber syndrome Neurofibromatosis Tuberous sclerosis
Other	Toxins		Cocaine toxicity	Febrile convulsion
	Drugs		Drugs	Drugs
	Narcotic withdrawal		Narcotic withdrawal		Tricyclic antidepressants Anticonvulsants Calcineurin inhibitors Antibiotics (β-lactam, carbapenem, or quinolone) Opiates
				Narcotic withdrawal

MECHANISM OF DISEASE

The mechanisms of SE and the relationship between seizure activity, neuronal injury, and functional outcome are multifactorial and complex. Isolating the specific effects of seizures from those of underlying etiology and associated systemic influences remains difficult. Much of the current understanding of pathogenesis has been gleaned from experimental models. In many instances, experimental findings have been confirmed in patients with epilepsy.

Laboratory Models and Experimental Data

Experimental models of SE commonly use chemical convulsants or electrical stimulation to induce self-sustaining seizures. These models provide insight into the mechanisms of seizure initiation, propagation, and termination, as well as patterns of cerebral development that affect seizure development and SE.

Behavioral and Electroencephalographic Manifestations

The progression of both clinical and experimental convulsive SE (CSE) may be divided into five stages (33). The first stage is characterized by discrete seizures, which are typically focal with secondary generalization and manifest as generalized tonic-clonic convulsions. In the second stage, continued discrete seizures merge to produce an EEG pattern of asymmetric sharp-and-spike waves with waxing and waning amplitude accompanied by either generalized convulsions or serial tonic or clonic seizures involving one or more extremities. The third stage is characterized by cEEG seizure discharges and either clonic jerks or subtle clonic convulsive activity. In the fourth stage, flat periods of EEG activity interrupt continuous seizure discharges, and behavioral clonic convulsions may be overt, subtle, or absent. During the fifth stage, the EEG shows monomorphic, repetitive, sharp waves, called periodic lateralized epileptiform discharges (PLEDS), on a flat background, and accompanying motor manifestations are absent. In the immature (vs. the adult) brain, the EEG progression through all five stages is less consistent and behavioral manifestations less discrete (34). Treatment with anticonvulsants can interrupt both EEG and behavioral progression of SE.

Seizure Initiation and Progression

Seizure initiation and propagation involve a failure of γ-aminobutyric-acid (GABA)-mediated inhibition and/or an

increase in glutamate-mediated excitation. A seizure begins with an intrinsically firing neuron, which, facilitated by inadequate inhibition, recruits adjacent neurons (35). Aberrant neuronal excitation commonly originates near regions of cerebral injury or scarring but may arise from uninjured neurons (36). As adjacent neurons begin firing, excitatory mediators, including glutamate, are released. Glutamate activates N-methyl-D-aspartate (NMDA) receptors and is thought to facilitate local neuronal synchronization, as well as seizure spread. In experimental models, NMDA receptor antagonists block seizure progression (37).

The mechanisms that enable the self-sustained seizures necessary for SE remain poorly understood. Localized
“feed-forward” excitatory circuits are identified in experimental models of self-sustaining hippocampal seizures (2). Aberrant excitatory circuits created by injury-induced axonal sprouting are associated with neuronal hyperexcitability and acquired epilepsy (36). The pathogenic contribution of such excitatory circuits to SE remains controversial, but they are unlikely to be a sufficient cause.

Other putative mechanisms that promote self-sustaining seizures include a reduction of inhibitory interneuron activity (36) and receptor trafficking changes that favor excitability (1). In seizure models, synaptic GABAA receptors are downregulated, whereas NMDA receptors are upregulated, promoting neuronal excitability (1). These seizure-induced alterations of GABA and glutamate activity may facilitate seizure continuation and spread, as well as hinder seizure termination. A predominance of inhibition is required for seizure termination and may be achieved by augmenting inhibition or blocking excitation. Mechanisms implicated in seizure termination include a predominance of GABA activity, membrane stabilization by acidic extracellular pH, magnesium blockade of NMDA channels, activation of the sodium-potassium adenosine triphosphatase (Na/K-ATPase) pump system, and activation of potassium (K⁺) conductance to allow membrane repolarization (38). Adenosine, an endogenous neuroprotectant, is thought to regulate basal neural inhibition (39) and may also prove important for seizure termination. Treatment with adenosine antagonists, such as caffeine or aminophylline, is proconvulsant. Conversely, adenosine-releasing stem cells attenuate seizure activity in epilepsy models (40).

Refractory Status Epilepticus

The mechanisms that underlie the pharmacologic resistance that characterizes RSE remain unclear and are likely multifactorial. Putative mechanisms include alterations in anticonvulsant drug targets and failure to achieve efficacious drug levels in the brain (1,41). Changes in receptor composition or membrane trafficking may be induced by prolonged seizure

activity or chronic anticonvulsant therapy. For example, seizure-induced downregulation of GABAA receptors may reduce the efficacy of benzodiazepines in RSE (1). Similarly, extrusion of anticonvulsants across the blood-brain barrier (BBB) may limit anticonvulsant activity. Overexpression of the transporter’s multidrug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1

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