Status epilepticus (SE) is a true neurologic emergency (1). Both convulsive and nonconvulsive SE affect people of all ages, although it is more common and carries greater morbidity and mortality in infants and the elderly (2–5). Recent large population studies have revealed an incidence 2 to 2.5 times greater than previously recognized (6). Large, hospital-based studies have disclosed that SE is underrecognized and is the cause of coma in a significant number of patients who demonstrate no overt seizure activity (7,8). In addition, the economic burden of SE has been estimated at $4 billion. The direct patient care costs are quite high compared to the direct costs of other major health conditions such as acute myocardial infarction and congestive heart failure (9). Prompt recognition and management certainly lead to the best chance for a successful outcome. Supported by the refractory nature of seizures lasting longer than 7 minutes and because of the potentially significant morbidity and mortality, there are strong arguments to shorten the functional definition of SE so as to encourage earlier intervention in this important public health issue (10). Several recent advances in treatment have occurred, including improved prehospital care for acute and acute repetitive seizures, new anticonvulsant formulations, the use of emergency electroencephalography (EEG), and improved emergency room and intensive care management. These approaches with a particular focus on the treatment of acute seizures as well as a deeper understanding of the pathophysiology and prognosis of SE are discussed.

DEFINITION AND CLASSIFICATION

Although the malady had been recognized for centuries, in 1824, Calmeil first used the term état de mal (status epilepticus) to describe the state in which grand mal (generalized tonic–clonic) seizures occurred in rapid succession without recovery between convulsions (11). The International League Against Epilepsy (ILAE) and the World Health Organization currently define SE as a “condition characterized by an epileptic seizure that is so frequently repeated or so prolonged as to create a fixed and lasting condition” (12). The lack of recovery for a fixed period, possible frequent repetition, prolongation, and possible propagation of further seizures are inherent in the definition. Status epilepticus is defined functionally as a seizure lasting more than 30 minutes or recurrent seizures lasting more than 30 minutes from which the patient does not regain consciousness (13). The classification of individual episodes of SE should be based on observation of clinical events combined with electrographic information when possible (Table 39.1). Clinical care requires intervention for seizures lasting longer than 5 minutes, recognizing that any type of seizure can develop into SE (Table 39.2). The current definition of 30 minutes is not, as described earlier, universally accepted, and several clinical studies have been published using durations of 10 or 20 minutes. Shinnar and colleagues demonstrated that the majority of pediatric seizures lasting 7 minutes or more had not stopped without active treatment by 30 minutes (14). DeLorenzo et al confirmed a nearly 10-fold greater mortality for seizures lasting 30 minutes or greater compared to those lasting 10 to 29 minutes (15).

This chapter deals primarily with convulsive tonic-clonic SE that is primarily or secondarily generalized using the 30-minute definition. This is the most commonly recognized form of SE in children. Focal seizures that evolve to SE most commonly are secondarily generalized convulsive seizures and may occur at any age but probably account for the overwhelming majority of adult cases. SE also encompasses several nonconvulsive entities, including focal with loss of consciousness, focal without loss of consciousness, and absence seizures. Focal SE usually is characterized by an epileptic twilight state in which there is a cyclical variation between periods of partial responsiveness and episodes of motionless staring and complete unresponsiveness accompanied, at times, by automatic behavior (7,16,17). Focal SE characterized by focal seizures that are not associated with loss of awareness may also persist or be repetitive. When this condition lasts for hours or days, it is termed epilepsia partialis continua. Absence, or petit mal, status has also been referred to as spike-wave stupor. This type of nonconvulsive SE may be extremely difficult to differentiate from focal SE associated with loss of consciousness without the aid of an EEG evaluation. Classically, in absence status, there is a continuous alteration of consciousness without cyclical variations. In absence status, the EEG recording exhibits prolonged, sometimes continuous, generalized synchronous 3-Hz spike-and-wave complexes rather than focal ictal discharges that characterize focal SE (7,18). The child presenting with a prolonged confused state, fluctuating level of consciousness, or prolonged unconsciousness needs both clinical and EEG evaluations in addition to other studies.

TABLE 39.1

Myoclonic, generalized clonic, and generalized tonic SE are seen primarily in children. Such children usually are those with encephalopathic epilepsies (3,7,19), and their consciousness seems to be preserved throughout the attacks. The EEG pattern is bilaterally symmetric with polyspike discharges coinciding with the myoclonic jerks. The term myoclonic SE should not be used when children with severe encephalopathy exhibit repetitive myoclonic jerks not accompanied by ictal discharges on EEG. These patients have subtle, generalized, convulsive SE as defined by Treiman (7). About one-half of the cases of generalized clonic SE occur in normal children and are associated with prolonged febrile seizures; the other half is distributed among those with acute and chronic encephalopathies (20). Generalized tonic SE appears most frequently in children, particularly those with Lennox–Gastaut syndrome.

EPIDEMIOLOGY

Status epilepticus is usually a manifestation of symptomatic epilepsy with preexisting neurologic dysfunction or a manifestation of acute disease primarily or secondarily affecting the central nervous system (CNS). In infants and young children, it is uncommon for SE to occur in the unstressed patient with idiopathic epilepsy. A child who has prolonged resistant seizures should receive a full diagnostic evaluation for all etiologies of seizures, along with a search for those precipitating events listed in Table 39.2. There is evidence for a genetic predisposition for SE (21,22). The major causes vary with age, such as febrile SE in children 1 to 2 years of age and remote symptomatic etiologies in the 5- to 10-year range (23). Acute symptomatic etiologies most commonly lead to prolonged SE lasting over 1 hour (24,25). Similarly, recurrent SE is more frequent in children with remote symptomatic etiologies or progressive degenerative disease (23,26).

TABLE 39.2

CNS, central nervous system.

A prospective population-based study of SE revealed the incidence of SE to be 41 patients per year per 100,000 population, resulting in a total of 50 episodes of SE per year per 100,000. It is projected that between 102,000 and 152,000 events occur in the United States annually, an incidence 2 to 2.5 times greater than that previously proposed by DeLorenzo et al. (6) and Hauser et al. (27). Approximately one-third of the cases of SE present as the initial seizure of epilepsy occur in patients with previously established epilepsy, and one-third occur as the result of an acute isolated brain insult. Among those previously diagnosed as having epilepsy, estimates of SE occurrence range from 0.5% to 6.6%. Hauser reported that up to 70% of children who have epilepsy that begins before the age of 1 year experience an episode of SE. Also, within 5 years of the initial diagnosis of epilepsy, 20% of all patients experience an episode of SE. A greater incidence of SE was reported by Shinnar from a cohort of patients with childhood-onset epilepsy. One-third of the patients experienced SE over a 30-year period, 50% presenting as the first seizure and an additional 22% occurring within 12 months of onset of epilepsy. In this group, SE occurred in 44% of those with remote symptomatic epilepsy and 20% of those with idiopathic or cryptogenic epilepsy (28).

Although adults with SE as their first unprovoked seizure are likely to develop subsequent epilepsy (27), a prospective study of children with SE found that only 30% of those initially presenting with SE later developed epilepsy (24). Hesdorffer et al. have presented more recent data indicating a greater likelihood of epilepsy following SE in a group of 95 people, one-third of whom were children. Over the ensuing 10-year period following a symptomatic bout of SE, there was a 41% risk of an unprovoked seizure (29).

Among children, SE is most common in infants and young toddlers, with more than 50% of cases of SE occurring in those younger than 3 years of age (30). Seizures account for 1% of all emergency department visits (31). In the Richmond, Virginia, study, total SE events and incidence per 100,000 individuals per year showed a bimodal distribution with the highest values during the first year of life and after 60 years of age (6,20,32). Infants younger than 1 year of age represent a subgroup of children with the highest incidence of SE whether events, total incidents, or recurrence is counted. The recurrence rate of SE in the Richmond study was 10.8% (6), but 38% of patients younger than 4 years old had repeat episodes, and findings are supported by the Finnish study (28). In another cohort of pediatric epilepsy patients followed by Berg and coworkers for 5 years, only 4.3% had their first episode of SE, whereas 19.6% of those who presented with status epilepticus had one or more episodes of SE (33). More recently, but again from the prospective pediatric epilepsy cohort in Connecticut, Berg and Shinnar reported on factors influencing SE following a diagnosis of epilepsy. In this study, only 10% of the children experienced SE over a median 8-year follow-up period, compared to 20% in the report of Hauser et al and the 22% incidence in the previously described Finnish study. SE occurring prior to the epilepsy diagnosis, younger age, and symptomatic etiology influenced the risk of later SE (34).

Extrapolating these figures worldwide, more than one million cases of SE occur annually. SE is a neurologic emergency that requires immediate, effective treatment to prevent residual neurologic complications or death. SE poses a substantial health risk. Mortality rates as high as 30% have been reported in overall studies. Children have a far lower mortality rate than do adults, with the exception of those in the first year of life (35). Age, etiology, and duration correlate directly with mortality (4,6,36). Multiple studies confirm the lower mortality rate in most children following adequate emergency treatment (24,30,37–39). Treatment of prolonged seizures is often delayed and results in longer seizure duration (40,41).

PATHOPHYSIOLOGY

The cellular physiology and neuropathology of SE has been reviewed recently (42,43) and is discussed in earlier chapters of this book. The mechanisms by which chronic seizures evolve to SE remain unclear (3). There seems to be a loss of inhibitory mechanisms, and neuronal metabolism is not able to keep up with the demand of continuing ictal activity. The pathophysiologic changes that accompany SE can be divided into neuronal (cerebral) and systemic effects. Continuing seizures lead to both biochemical changes within the brain and systemic derangements that further complicate these cerebral changes.

Prolonged convulsive seizures can lead to excito-toxic brain injury. Glutamate, the primary excitatory amino acid neurotransmitter, binds to several neuronal receptors, including the N-methyl-D-aspartate (NMDA) receptor, which is activated by depolarization. The resulting calcium influx causes further depolarization and perpetuates seizures. Glutamate also activates receptors that open channels that conduct sodium and calcium into the cell. Further neuronal damage results through this excessive excitatory neurotransmission. Although gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the brain, excessive GABA may in fact increase activity on both GABA_A and GABA_B receptors. Activation of the presynaptic GABA_B receptors can provide feedback inhibition of GABA_A receptors and paradoxically exacerbate seizures. Other neurotransmitters that may be important in the initiation and maintenance of SE include acetylcholine, adenosine, and nitric oxide (42). Neuropeptides such as dynorphin, substance P, and galanin are potent modulators of the process and may affect the maintenance phase of SE (42).

Neuronal injury and cell death from SE are most prominent in areas that are rich in NMDA glutamate receptors, including the limbic region. The increase in intracellular calcium concentration is critical to cell death. Calcium activates proteases and lipases that degrade intracellular elements, leading to mitochondrial dysfunction and cellular necrosis. Laminar necrosis and neuronal damage after prolonged seizures are similar to those following cerebral hypoxia. Although young animals may be less likely to develop brain damage from SE (44,45), studies using alternative models demonstrate hippocampal cellular injury even in immature rodents (46). It is believed that the glutamate-initiated calcium-dependent cascade is similar to the mechanism of NMDA receptor-mediated cell death during cerebral ischemia. Absence SE associated with excessive inhibitory influences generated by GABA_B-mediated hyperpolarization and activation of folinic T-type calcium channels does not cause cerebral injury (47). Furthermore, evidence suggests that acute and long-term changes in gene expression may occur following prolonged seizures and may contribute directly to hyperexcitability (48).

Systemic metabolic abnormalities increase the risk of brain damage in convulsive SE. These include alterations of blood pressure, heart rate, acidosis, hypoxia, respiratory function, body temperature, leukocytosis, and/or rhabdomyolysis, as well as heightened demands on cerebral oxygen and glucose utilization (49). Circulating catecholamine concentrations increase during the initial 30 minutes of SE, resulting in a hypersympathetic state. In some patients, there is truly massive catecholamine release, resulting in the formation of cardiac contraction bands, ultimately representing the cause of death (50). Tachycardia, sometimes associated with severe cardiac dysrhythmias, occurs and (rarely) also may be fatal (51). Furthermore, cardiac output diminishes and total peripheral resistance increases along with mean arterial blood pressure, possibly because of the sympathetic overload. Hyperpyrexia may become significant during the course of SE, even without prior febrile illness, in both children and adults, and may contribute to neuronal injury (52).

Hypoventilation leads to hypoxia and respiratory acidosis. In addition, serum pH and glucose levels are frequently abnormal as lactic acidosis develops following increased anaerobic metabolism. A leukemoid reaction of peripheral blood frequently occurs in the absence of infection. Rhabdomyolysis, which is not uncommonly seen, may compromise renal function. Recovery from this complicated derangement of metabolism is time dependent. More prolonged seizures produce further neuronal injury and death.

PROGNOSIS

The morbidity and mortality of SE are direct consequences of its basic pathophysiology and the efficiency of treatment. Previously, overall mortality figures for SE were quoted as 10% to 30% (36,53,54). The mortality rate for the Richmond, Virginia, population was 22% overall. Based on this study, which includes all age groups, there are approximately 126,000 to 195,000 SE events, with 22,000 to 42,000 deaths, per year in the United States. However, the mortality rate in children was only 3%, and most of the pediatric deaths occurred between the ages of 1 and 4 years (Table 39.3). The pediatric and aged populations had an increased number of recurrences of SE following a single episode. In general, children had chronic neurologic disabilities but rarely died. Among those patients who died, death rarely occurred during the acute episode of SE. Rather, most patients succumbed 15 to 30 days later. Children with chronic epilepsy and low levels of anticonvulsant drugs have the lowest mortality rate overall. This latter finding, as well as additional confirmation of a 3% SE-related mortality, was reported by Chin et al. from the prospective North London Status Epilepticus in Childhood Surveillance Study. This study did not contain morbidity data but did reveal the highest reported early SE recurrence—16% within 1 year of the initial episode (55).

TABLE 39.3

The morbidity of SE in children was examined in the same database from Virginia. Before their SE event, 81% of children with no prior history of seizures were neurologically normal, in contrast to only 31% of children with seizure histories. Of the neurologically normal children with no prior seizures, more than 25% deteriorated after their first SE event, in comparison to less than 15% of neurologically normal children with a seizure history. Children who were neurologically abnormal without prior seizure deteriorated further in 6.7%, compared to 11.3% of the abnormal children with a seizure history. Morbidity was determined at the time of hospital discharge. In some children, the abnormalities improved, which was attributed to the acute therapies or clinical changes after prolonged seizures. Determining whether language deficits and school performance difficulties were transient or more permanent was much more difficult. In the prospective study, 11% to 15% had significant morbidity after an episode of SE (Table 39.3). These findings suggest a neurologic morbidity substantially lower than the “greater than 50 percent” rate previously reported in children having SE (53), but the morbidity and mortality of very sick infants is higher than in older children (35). A study of neurodevelopmentally normal children with acute neurologic disorders, including electrographic seizures and electrographic status epilepticus, were found to have worse adaptive behaviors and trends toward worse behavioral-emotional and executive function (56).

Hesdorffer and colleagues in Rochester, Minnesota, have demonstrated a 41% 10-year risk of having an unprovoked seizure following an acute seizure with SE. This 95-person cohort included 17 individuals younger than 1 year of age and 17 individuals from 1 to 19 years of age. This risk was increased 18.8-fold for SE as a result of anoxic encephalopathy, 7.1-fold for structural causes, and 3.6-fold for metabolic causes over the risk in a population of patients who experienced a less prolonged acute symptomatic seizure (29). Electrographic and biochemical markers for increased morbidity and mortality in SE exist. The duration of the individual seizure, especially if it evolves to nonconvulsive SE (NCSE), has been directly correlated with death or poor outcome as defined by an inability to return to prehospital level of function (57). Serum and CSF levels of neuron-specific enolase (NSE) rise above normal after both brief and prolonged seizures. Serum levels following SE are significantly higher and are at their highest in patients following NCSE, where levels higher than 37 ng/mL correlate with poor outcome (58). CSF lactate is certainly elevated following SE, and levels three times greater than the accepted normal have been associated with poor outcomes, whereas those elevated 2-fold or less had better outcomes. Elevated CSF proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 have been documented following SE (59). CSF lactate dehydrogenase (LDH) and creatinine kinase do not appear to be valid indicators of prognosis in SE (60). CSF pleocytosis also does not appear to be a valid indicator of prognosis in SE. In all ages, it is typically related to the acute illness or injury precipitating the seizure. More than 6 white blood cells (WBCs)/mm³ or any polymorphonuclear lymphocytes (PMNs) in the adults or more than 8 WBCs/mm³ (and greater than 4 PMNs/mm³) in children should prompt a search for an etiology other than the seizure itself (61,62).

Radiographic findings following SE, typically reversible focal magnetic resonance imaging (MRI) T2-weighted abnormalities, have been recognized for years (63). It had been assumed these findings were benign. The variations in peri- and postictal changes on anatomical and functional imaging examinations have been recently reviewed (64). However, there is a growing collection of case reports suggesting that there is brain injury despite radiographic normalization, as evidenced by persistent EEG abnormalities and proton MR spectroscopy abnormalities (65,66). One report describing hyperintensities in anterior cerebral white matter suggests that a biphasic clinical course of SE, followed by clinical improvement and then early seizure recurrence, increases the odds for neurologic sequelae (59). Similar changes, particularly evolving mesial temporal sclerosis, are being carefully explored in febrile SE, which represents the single largest etiologic subgroup (67,68). There is also strong evidence that structural brain injury in the form of ischemic stroke has a synergistic effect with SE, leading to increased mortality (69).

THERAPY

Extrapolating the statistical figures worldwide, more than one million cases of SE occur annually. As a true neurologic emergency, it requires mobilization of significant personal and medical resources and qualifies as a substantial public health concern. With mortality rates as high as 30% reported in all-age-inclusive studies, immediate effective treatment is necessary to prevent residual neurologic complications or death. Age, etiology, and duration correlate directly with mortality (4,6). The highest mortality is seen in the elderly; fortunately, children have a far lower mortality rate than do adults (4,24,27,36). Some of this improved prognosis is probably a result of fewer coexisting medical conditions. Multiple studies confirm a lower mortality rate in children following adequate emergency treatment (24,30,37–39).

Acute Seizure Management

SE begins as either a prolonged seizure or continuing acute-repetitive seizures. These usually occur away from a medical center. Treatment is required when the seizure duration is 5 minutes or more. Studies have demonstrated the associated consequences of prolonged seizures, including correlation of respiratory support with longer seizure duration (41) and seizure on arrival increasing the risk for apnea in pediatric patients (40). It is paramount that families become educated on seizure first aid and have a seizure action plan. The time of seizure onset is essential to providing support to a patient having a seizure. Many times this support will include at-home benzodiazepine administration, usually in the form of rectal diazepam, but sometimes oral lorazepam or diazepam if consciousness is retained and the patient can safely swallow liquids. Appropriate first-aid recommendations are discussed here for completeness. The Epilepsy Foundation of America (EFA) recommends that the first responders:

The EFA also recommends that first responders:

The Practices in Emergency and Rescue Medication for Epilepsy Managed With Community Administered Therapy (PERFECT™) initiative was created to gain a better understanding of how prolonged convulsive seizures in children are managed in the prehospital setting. A survey of health care professionals found clear gaps that need to be addressed in the prehospital treatment of prolonged seizures (71). The neurologic emergency of SE requires maintenance of respiration, general medical support, and specific treatment of seizures while the etiology is sought (1,72,73). Treatment of seizures varies by region, and there is no standard protocol followed (41). One typical, and unfortunately frequent, mistake made in the treatment of SE is that inadequate doses of drugs are given initially, and physicians wait for more seizures to occur before administering the necessary total dose (41,72,74). Additionally, given that febrile seizures are common and such patients regularly present to emergency rooms for evaluation, the progression from prolonged simple febrile seizure to febrile SE is often missed (75). The ideal antiepileptic drug (AED) for the treatment of SE should have the following properties: rapid onset of action, broad spectrum of activity, ease of administration (including intravenous [IV], intramuscular [IM] and intranasal preparations), minimal redistribution from the CNS, and wide therapeutic safety margin. With confirmed safety and efficacy data (76) and particularly because it is longer acting, lorazepam (LZP) has become more popular in many centers as the initial agent (77). Recent studies in both children and adults also support the use of midazolam (MDZ). Its rapid absorption from varied sites of administration and rapid onset of anticonvulsant activity make MDZ a very attractive agent for use in multiple settings. It has been studied as both an IM and intranasal medication (78,79). If SE continues after the initial dosing of a benzodiazepine, and persists after a primary AED such as phenytoin (PHT) (as fosphenytoin, FOS) or phenobarbital (PB) is given, a second dose of the same AED should be administered before switching to alternative medications. SE refractory to these established agents carries a graver prognosis (73). Numerous studies suggest that additional bolus administration followed by titrated IV infusions of diazepam (DZP), MDZ, pentobarbital, or the anesthetic agents lidocaine or propofol may break these seizures. The use of IV valproic acid (VPA) in the treatment of SE has expanded greatly in the past few years. There are reports, as well, supporting the safety and efficacy of topiramate and levetiracetam (LEV) in the treatment of refractory SE.

The primary goal of treatment is to stop the convulsive discharges in the brain. Table 39.4 lists the steps of the emergency management of SE (72,80). A patient presenting in SE must have cardiorespiratory function assessed immediately by vital sign determination, auscultation, airway inspection, arterial blood gas determination, and suction if necessary. Although spontaneously breathing on presentation, hypoxic injury may have occurred with respiratory or metabolic acidosis from apnea, aspiration, or central respiratory depression (1). The need for ventilator support depends not only on respiratory status at the time of presentation but also on the conditions before arrival and the ability to maintain adequate oxygenation throughout ongoing seizures and during the IV administration of drugs, all of which cause some amount of respiratory depression. Elective intubation and respiratory support are urged in the neurologically depressed patient. In most patients with placement of an oral airway, nasal cannula, or both, oxygen is insufficient as the respiratory drive is depressed. Significant hypoxia is a principal factor determining morbidity and mortality (6). Rapid assessment of vital signs and general neurologic examination give clues to the etiology of SE. Blood drawn to determine blood gases, glucose, calcium, electrolytes, complete blood count, AED levels, culture, and virologic and toxicologic studies help with the overall determination of etiology. Similarly, urine for drug and metabolic screens should be collected. The roles of CSF NSE, cytokines, and lactate, as well as serum NSE, in the prognostication of outcomes in SE were discussed previously.

Intravenous fluids should be administered judiciously, with appropriate corrections for fever, suction, and chemical abnormality. Fluid restriction is rarely necessary. In the case in which IV access cannot be established, the intraosseous route has been shown efficient for both fluid and medication administration (81). The high incidence of febrile SE resulting from CNS infection in infants requires a lumbar puncture to be performed early in the course of management, but not necessarily during the initial phase of stabilization. It is rarely necessary to wait to perform the lumbar puncture until imaging is performed. If lumbar puncture is deferred for any reason, appropriate antimicrobial coverage for possible meningitis or encephalitis should be considered. Electrocardiographic (ECG) and EEG monitoring is desirable when available (73).

TABLE 39.4

EEG monitoring is extremely useful in both the initial and the subsequent management of SE (80,82–84). The classification of SE, clues to etiology, and prognosis may be suggested from the EEG and its response to therapy. The use of EEG is mandatory in the presence of neuromuscular blockade, or whenever recurrence of seizures cannot be documented on a clinical basis (1,80).

An electroclinical dissociation may exist after large doses of AEDs have been given, so that the clinical manifestations are absent while electrographic seizures continue. The recognition of EEG patterns, such as paroxysmal lateralized epileptiform discharges (PLEDs), periodic epileptiform discharges (PEDs), and evidence of continued post-SE ictal discharges without clinical correlation while the patient remains in a coma, may require ongoing therapy and may be helpful in establishing the etiologic diagnosis and prognosis (8). One recent study of 50 patients with SE reported poor outcomes, including death or persistent vegetative states, in 44% of those whose records demonstrated PEDs, compared to 19% without PEDs (85). ECG alterations seen in adults during and after SE range from ischemic changes to tachyarrythmias. These changes must be promptly and appropriately treated (49,86). Practical limitations include EEG not being readily available. Urgent use of EEG monitoring must be considered when patients do not regain consciousness or when seizures are continuous or recurrent.

DRUG THERAPY OF STATUS EPILEPTICUS

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