Status epilepticus (SE) is a condition that commonly

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1 Status Epilepticus in the Pediatric Emergency Department Joshua Goldstein, MD Status epilepticus (SE) is a common childhood condition often seen by emergency physicians. It occurs at a frequency of between 17 and 23 per , higher in younger children. Risk factors for SE include an acute symptomatic etiology, and for those children with underlying epilepsy, a remote symptomatic etiology and a younger age of epilepsy onset. Treatment paradigms vary by institution but should be rapid and aggressive. Underdosing of anticonvulsants and excessive lag between doses should be avoided. Identification of nonconvulsive and subclinical SE is often missed and requires a high index of suspicion. Refractory SE often requires an intensive care unit admission and the involvement of a neurologist. Etiologic evaluation should include a broad differential and be focused initially on treatable causes, including central nervous system infections, electrolyte and metabolic disorders, and trauma. Clin Ped Emerg Med 9: C 2008 Elsevier Inc. All rights reserved. KEYWORDS status epilepticus, anticonvulsant, subclinical status epilepticus, nonconvulsive status epilepticus Status epilepticus (SE) is a condition that commonly presents to pediatric emergency care providers across the country, with an incidence of between 17 and 23 per The incidence is higher in younger children, reported to be as high as 51 per [1]. There is a mounting body of scientific evidence suggesting that prolonged seizures are associated with an increased risk of neuronal damage and possible long-term sequelae. Increased recognition of this condition and subsequent aggressive treatment may impact long-term morbidity and improve outcomes. Definitions Status epilepticus has been described in the medical literature for centuries, the term having been coined in Europe in the 19th century [2]. The International League Against Epilepsy defines SE as a seizure that shows no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients or recurrent seizures without interictal resumption of baseline central nervous system function [3]. This definition of SE avoids any specified threshold for seizure length. The 96 length required has decreased over the past decades, initially starting at up to 1 hour and declining to a nadir of 5 minutes [2]. Currently, many neurologists use an operational definition for SE encompassing any seizure or recurrent seizures without return to baseline lasting 20 minutes. The variation in the definitional length reflects the lack of clarity with respect to morbidity both clinically and on a cellular/molecular level as a function of seizure length. Most clinician-scientists believe that longer seizures are worse than shorter ones; however, there is no clear cutoff for a safe length, and thus, no clear threshold has been set for SE. The term status epilepticus is most often used to refer to clinically apparent seizures, namely, convulsive SE. Less common, but still not infrequent, is nonconvulsive SE (NCSE), and probably even less common than NCSE is truly subclinical SE (SSE). These seizure types do not Division of Child Neurology, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL. Reprint requests and correspondence: Joshua Goldstein, MD, Division of Child Neurology, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL. ( jgoldstein@childrensmemorial.org) /$ - see front matter C 2008 Elsevier Inc. All rights reserved. doi: /j.cpem

2 Status epilepticus in the pediatric emergency department 97 involve the classic tonic or clonic rhythmic large amplitude movements of convulsive SE but rather are associated with either subtle motor manifestations or even a complete absence of motor manifestations, presenting with only a clouding of alertness, confusion, or change in mental status. Epidemiology The incidence of SE in children depends to some extent on the defining criteria used for length of seizures. As described above, these criteria have shortened over the past 40 years. The overall incidence of pediatric convulsive SE is around 20 per per year [4]. This number is highly age dependent, with a relatively higher incidence in children younger than 1 year, at 51 per per year, and lowest in adolescents [5]. This incidence is even higher with acute symptomatic etiologies. In one study from England, 1.2% of all emergency department visits were for seizures [6]. Of children with epilepsy, approximately 10% will have at least 1 episode of SE, usually early in their disease course, with a median time of 2.5 years from epilepsy diagnosis to SE. A younger age of epilepsy onset and remote symptomatic etiologies are risk factors for SE in children with epilepsy [7]. The incidence of NCSE or SSE is more difficult to identify. Studies using electroencephalography (EEG) to identify NCSE after acute treatment of convulsive SE have shown that almost one half of SE patients have persistent electrographic seizures after clinically identified seizure cessation and 14% have EEG-documented NCSE [8]. Other studies in the pediatric intensive care unit setting have also identified frequent nonconvulsive seizures and subclinical seizures. It is safe to say, however, that NCSE and SSE are most likely underdiagnosed relative to convulsive SE. Treatment There is no consensus as to a treatment approach to SE with respect to medication selection and dosing, with therapy being somewhat variable between institutions and practitioners. In the evaluation and treatment of SE, evaluation of the patient's vital signs and an assessment of airway, breathing, and circulation (with appropriate interventions) should precede anticonvulsant treatment. Simple noninvasive airway maneuvers (eg, midline positioning of the head and neck, jaw thrust, or chin lift), suctioning of excess secretions, and the provision of supplemental oxygen should benefit most actively seizing children and should therefore precede efforts to obtain vascular access. Guiding principles in the medical treatment of SE with antiepileptic drugs (AEDs) include the rapid administration of appropriate medications at appropriate doses. Common errors include medication underdosing, excessive intervals between medications, and inappropriate medication choices and routes of administration. Benzodiazepines including diazepam (Valium; Roche, Nutley, NJ) and lorazepam (Ativan; Bioval, Bridgewater, NJ) are the most commonly used first-line AEDs for SE. Intravenous or rectal routes of administration are usually preferred for these 2 drugs given their fast rectal absorption and more rapid onset of action. Dosing recommendations are highly variable, as are the number of repeated doses, although most recommend giving 2 or 3 doses of benzodiazepines before consideration of other AEDs. A general principle governing the use of benzodiazepines for SE is that drug administration should be rapid (pushed or infused over a few minutes) and the administered dose should be sufficient. Frequent dosing of small or inadequate individual doses should be avoided because this practice only prolongs the time to achieving a therapeutic level of the AED. Rather, higher individual doses should be used either once or twice to allow for the more timely institution of a second AED if needed. Most practitioners now regard fosphenytoin (Cerebyx; Parke Davis, New York, NY) as the second choice for AED treatment of SE. This prodrug of phenytoin (Dilantin; Pfizer, New York, NY) converts to phenytoin within 15 minutes after infusion. Care in dosing is important because it is delivered in phenytoin equivalents (PE units) rather than milligrams. A standard initial loading dose for SE is 20 PE units/kg, although some advocate using lower doses. Advantages of phosphenytoin over phenytoin include lower risk of cardiac dysfunction with acute infusion, lower rates of phlebitis, and less severe tissue necrosis if the medication extravasates from the vein during infusion. Although it can be infused at a significantly faster rate than phenytoin, fosphenytoin should not be infused at a rate greater than 3 PE units/kg/min (or N7 minutes for a 20 PE units/kg load). A loading dose of 20 PE units should provide a serum phenytoin level of around 20 μg/ml. A second dose of 10 PE units/kg (for a total of 30 PE units/kg) is often given if the first loading dose fails to stop clinical seizures. A goal for AED administration for SE (Figure 1) through the first dose of fosphenytoin should be approximately 20 minutes. After appropriate doses of benzodiazepines and fosphenytoin have been given, the selection of alternative treatment options for SE are more varied. At this point, the patient has met the criteria for refractory SE and a neurologist should be consulted if available, and consideration of intensive care unit placement is appropriate. A more detailed review of potential acute symptomatic etiologies should be undertaken at this time. Electrolyte derangements such as hyponatremia or hypoglycemia are notorious for inducing refractory SE that is unremitting in the face of AED treatment. Likewise, infectious diseases of the central nervous system (CNS), trauma, and toxins should be considered. At this point, many neurologists will recommend the use of other routine AEDs such as intravenous phenobarbital, valproic acid (Depacon;

3 98 J. Goldstein Figure 1 Guidelines for administrations of AEDs. Abbott Labs, Chicago, IL), or midazolam or pentobarbital continuous infusions. Phenobarbital is commonly chosen as the next AED for refractory SE given its long history of use and good efficacy and because most practitioners have comfort with it as a familiar medication. Phenobarbital is given via intravenous infusion at an initial dose of 20 mg/kg. It is often highly effective; however, its adverse effects can include significant respiratory suppression, especially after benzodiazepines have been given, often requiring ventilatory support. Phenobarbital's half-life of 24 to 72 hours also makes the ongoing assessment of clinical neurological function difficult for a prolonged time. For these reasons, many clinicians are now avoiding its use in refractory SE, opting for some of the treatments discussed below. Phenobarbital is, however, the medication of choice in neonatal SE based primarily on its long history of use rather than any formal study. Midazolam continuous infusions are usually started at 50 to 100 μg/kg/hr and titrated upwards to a range of 600 to 1200 μg/kg/hr. To avoid tachyphylaxis, the infusion rate increases should be small, reaching maximal dose a few hours after initiation at most. At our institution, we increase by increments of 50 to 100 μg/kg/hr every 15 to 20 minutes. Continuous EEG monitoring should be instituted if available when continuous infusions of AEDs are used.

4 Status epilepticus in the pediatric emergency department 99 Table 1 Common causes of status epilepticus. Metabolic Hyperglycemia and hypoglycemia Hypernatremia and hyponatremia Hypocalcemia Hypophosphatemia Hypomagnesemia Infection Bacterial meningitis Herpes simplex virus or other viral encephalitis Structural/Traumatic Subdural hematoma Epidural hematoma Intraparenchymal hemorrhage Stroke Arteriovenous malformation Tumor Cortical malformation Toxicologic Anticonvulsants Camphor Cocaine Heavy metals Hypoglycemic agents Isoniazid Lithium Methylxanthines Organophosphates Phencyclidine Sympathomimetics Tricyclic antidepressants Topical anesthetics Epilepsy Medication withdrawal Concurrent infection Like midazolam, pentobarbital can also be administered as a continuous infusion for refractory SE. It is usually initiated with a loading dose of 5 to 8 mg/kg, followed by a continuing infusion at a rate of 0.5 to 1 mg/kg/hr and then increased as needed to 3 to 5 mg/kg/hr. Pentobarbital, like phenobarbital, is extremely sedating and has a higher associated rate of hypotension than does midazolam, often requiring pressor support for blood pressure management. Intravenous valproic acid (Depakon) and levetiracetam (Keppra; UCB Pharma, Smyrna, GA) have minimal to no formal evidence for their efficacy in SE. There are, however, some theoretical advantages to these medications. As what are considered broad spectrum anticonvulsants, they should not exacerbate primary generalized epilepsy as can phenytoin. They also are considered less sedating than benzodiazepines, phenobarbital, or phenytoin, allowing for more precise ongoing neurological examinations. More detailed research is needed to determine where in the spectrum of AEDs used for SE these medications fall. Etiologies/Evaluation A broad differential and ensuing evaluation is important in the assessment of etiology for SE (Tables 1 and 2). Etiologies are highly dependent on the age of the patient. In young children younger than 2 years, acute causes are more common than are remote etiologies (eg, prior history of stroke, meningitis, brain tumor, and hypoxic insult), whereas this is reversed in older patients [9]. The most common etiology of acute symptomatic SE is febrile seizure (febrile SE). Febrile SE accounts for approximately 5% of febrile seizures and one third of all episodes of SE in children [10]. Previously, febrile SE was felt to be a fairly benign condition. However, recent studies are beginning to demonstrate long-term sequelae, in particular an increased risk for the development of epilepsy later in life. The diagnosis of febrile SE remains essentially as one of exclusion. The most important etiology to be excluded is a CNS infection. A lumbar puncture should be considered in all children with febrile SE. Another common cause of SE is medication noncompliance. Children with usually well-controlled epilepsy can experience prolonged seizures after missing doses of their medications. A careful medication history can be helpful in discerning this as can anticonvulsant levels if available. Infections of the CNS often present with SE. Meningitis, encephalitis, or meningoencephalitis, either bacterial or viral, can all be implicated. In the setting of SE and a fever at any age, analysis of cerebrospinal fluid via lumbar puncture is warranted unless another etiology is clearly identified. Likewise, empiric treatment with antibiotics and acyclovir should be considered until cerebrospinal fluid analysis excludes herpes simplex virus encephalitis or bacterial meningitis as a possibility. Electrolyte disturbances can also present with SE, usually in the setting of concurrent altered mental status or encephalopathy. Although routine analysis of serum chemistries has been shown to be unhelpful in the evaluation of a new seizure, there is probably a role for screening in the setting of SE. The most common electrolyte abnormalities include hyperglycemia and hypoglycemia and hyponatremia. Hypocalcemia in the neonate is another very common cause of recurrent seizures and SE. Electrolyte abnormalities are also notorious for inducing SE that is refractory to appropriate AED treatment. In this setting, seizures may continue until the underlying abnormalities are corrected. Another important etiology of SE to identify is trauma, often associated with nonaccidental injuries, including the Table 2 Initial studies for status epilepticus without identified etiology. Routine electrolytes: sodium, glucose, calcium, magnesium Computerized tomography Lumbar puncture (if febrile or history of recent fever)

5 100 J. Goldstein shaken baby syndrome. Seizures and SE can often be the presenting symptom of child abuse and in the absence of any external manifestations of injury and/or a suggestive history. In the setting of SE without another clear etiology, computerized tomography of the head should be considered when the child is clinically stabilized. Stroke may present with SE, usually in the presence of a known congenital heart lesion, but may occur without such a history. Likewise, a prolonged seizure and a subsequent Todd paralysis may be mistaken for a stroke. Computerized tomography may often be helpful in identifying new strokes; however, it is important to remember that repeat imaging may be required to identify subtle areas of infarction. Magnetic resonance imaging may provide superior discrimination of small lesion and infarction, provided that the patient's condition permits this longer procedure. A persistent new focal finding on neurological examination should be considered a stroke until proven otherwise. Occult structural abnormalities including cortical dysplasia, CNS tumors, CNS autoimmune processes, and vascular malformations may also present with SE, although the diagnosis of these etiologies is somewhat less urgent and may require imaging with magnetic resonance imaging or serological evaluation not undertaken in the emergent setting. Subclinical/Nonconvulsive Status Seizures without any clinical manifestation or those with very subtle clinical manifestations are more common than previously thought and are thus often missed. As described above, persistent NCSE may occur in up to one half of patients with convulsive SE in adult populations. The percentage with persistent NCSE in pediatric SE is less clear. A recent study of children in an intensive care unit demonstrated that prolonged EEG monitoring captured nonconvulsive seizures (but not necessarily NCSE) in 16% of monitored patients [11]. Diagnosis and identification of subclinical or nonconvulsive seizures rest on a high index of clinical suspicion. Failure to return to baseline mental status in an appropriate amount of time after SE or persistence of subtle movements such as eye deviation, nystagmus, or slight rhythmic twitching of the mouth, face, or limbs should all lead to further empiric treatment of suspected continued SE or an emergent EEG to clarify the diagnosis. Persistent confusional states after convulsive SE may also represent ongoing NCSE and is often treated empirically with benzodiazepines looking for a paradoxical improvement in mental status after administration. Summary Status epilepticus is a common childhood condition accounting for a significant number of visits to the emergency department. The time threshold for consideration as SE has decreased over the past decades and is still not universally agreed upon. The treatment of SE is also not standardized across institutions and likely varies by clinician; however, in general, treatment should use appropriate doses of anticonvulsants in rapid sequence. The goal for AED administration in SE should be to give benzodiazepines followed by fosphenytoin (if required) within 20 minutes, after which the patient is considered to have refractory SE. A high index of suspicion should be maintained for continued subclinical or nonconvulsive seizures after initial SE treatment. Reference 1. Neville BG, Chin RF, Scott RC. Childhood convulsive status epilepticus: epidemiology, management and outcome. Acta Neurol Scand 2007;115: Lowenstein DH. Status epilepticus: an overview of the clinical problem. Epilepsia 1999;40 S1:S3-S8. 3. Blume WT, Lüders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE Task Force on classification and terminology. Epilepsia 2001;42: Respall-Chaure M, Chin RF, Neville BG, et al. The epidemiology of convulsive status epilepticus in children: a critical review. Epilepsia 2007;48: Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368: Smith RA, Martland T, Lowry MF. Children with seizures presenting to accident and emergency. J Accid Emerg Med 1996;13: Berg AT, Shinnar S, Testa FM, et al. Status epilepticus in children with newly diagnosed epilepsy in children. Neurology 2004;63: DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39: Shinnar S, Pellock JM, Moshe SL, et al. In whom does status epilepticus occur: age related differences in children. Epilepsia 1997; 38: Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsion: finding of national cohort study. BMJ 1993;307: Saengpattrachai M, Sharma R, Hunjan A, et al. Nonconvulsive seizures in the pediatric intensive care unit: etiology, EEG, and brain imaging findings. Epilepsia 2006;47: