Status Epilepticus

James J. Riviello Jr.

Status epilepticus (SE) is a life-threatening medical emergency that requires prompt recognition and immediate treatment. SE is not a disease in itself but rather a manifestation of either a primary central nervous system (CNS) insult or a systemic disorder with secondary CNS effects. It is important to identify and specifically treat the precipitating cause to prevent ongoing neurologic injury and seizure recurrence. Basic neuroresuscitation principles—the ABCs (airway, breathing, circulation)—must be rigorously adhered to. A team approach, with an organized and systematic treatment regimen, planned in advance, is needed, including one for patients with refractory status epilepticus (RSE). Although the initial approach is standard, once a patient is stabilized, management must be individualized.

DEFINITION

Gastaut defined SE as “an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epileptic condition” (1). This definition, without a specific duration, at first seems vague and cumbersome, but allows a dynamic interpretation. Subsequently, a time duration was specified (2,3). The Working Group on Status Epilepticus of the Epilepsy Foundation of America (Working Group) defined SE as longer than 30 minutes of either continuous seizure activity or two or more sequential seizures without full recovery of consciousness between seizures (4).

Classification begins with seizure type, using the International Classification of Epileptic Seizures, which categorizes seizures according to onset—either partial (focal) or generalized (5, 6, 7, 8, 9). The revision is based on semiology (10). A modified SE system is also based on semiology (11): convulsive (generalized tonic clonic) SE, nonconvulsive SE (absence or complex partial), or simple partial (focal) SE. Nonconvulsive SE may occur with either generalized (absence) or focal (partial complex) epilepsy. SE occurs with any seizure type or epileptic syndrome. In a Netherlands study (1980-1987) of 458 patients (12), generalized convulsive SE occurred in 346 (77%), nonconvulsive SE in 65 (13%) (13), and simple partial SE in 47 (10%) (14). Of the 65 patients with nonconvulsive SE, 40 (62%) had complex partial SE and 25 (38%) had absence SE.

Generalized convulsive SE consists of continuous tonic and/or clonic motor activity, which may be symmetric or asymmetric and overt or subtle and is associated with marked impairment of consciousness with bilateral, although frequently asymmetric, electroencephalogram (EEG) ictal discharges (11,15). Subtle generalized convulsive SE has no obvious signs, despite marked impairment of consciousness and bilateral EEG discharges (15), and may evolve from prolonged convulsive SE or follow unsuccessful treatment; the division between generalized convulsive SE and nonconvulsive SE may not be obvious, because nonconvulsive SE may follow convulsive SE in the same episode. In the Netherlands study, within the nonconvulsive SE classification, focal signs occurred more often with complex partial SE, a fluctuating consciousness was more common with absence SE, and the majority of patients in both groups had prior epilepsy (13). With simple partial SE, 46 patients had somatomotor features and one had aphasia with hallucinations (14). Classification must include pseudoseizures, because pseudostatus epilepticus occurs in adults (16) and children (17,18). Pseudostatus epilepticus occurs even as an expression of Munchausen syndrome (factitious disorder by proxy) (19).

STAGES OF STATUS EPILEPTICUS

The clinical stages of SE include premonitory (prodromal) stage; incipient stage (0 to 5 minutes); early stage (5 to 30 minutes); transition to the late or established stage (30 to 60 minutes); refractory stage (longer than 60 to 90 minutes)
(20); and postictal stage (Table 41.1). The premonitory stage consists of confusion, myoclonus, or increasing seizure frequency; the early stage consists of continuous seizure activity; and the refractory stage can consist of either subtle generalized convulsive SE or nonconvulsive SE. If a premonitory stage is identified, treatment should be initiated. SE should not be considered refractory if therapy has been inadequate.

TABLE 41.1 STAGES OF STATUS EPILEPTICUS

Premonitory
Incipient:	0 to 5 minutes
Early	5 to 30 minutes
Transition	From early to established
Established (late)	30 to 60 minutes
Refractory	After 60 minutes
Postictal

A predictable sequence of EEG progression occurs during these stages in experimental models and humans: (a) discrete seizures with interictal slowing; (b) waxing and waning of ictal discharges; (c) continuous ictal discharges; (d) continuous ictal discharges punctuated by flat periods; and (e) periodic epileptiform discharges (PEDs) on a flat background (Fig. 41.1) (21). Treatment response depends on stage: In the discrete stage, all seizures were controlled with diazepam (6 of 6 patients), whereas in the PED stage, seizures stopped in only 1 of 6 patients and overt clinical seizures were converted to subtle or electrographic seizures in 5 of 6 patients (21). Every episode of SE does not pass through every one of these defined stages, however (22) (Fig. 41.2). The PED stage may also consist of either lateralized (PLED) or bilateral (PBED) patterns (23).

Figure 41.1 A: Continuous ictal discharges. B: Periodic epileptiform discharges on a flat background.

TRENDS IN PATIENTS WITH STATUS EPILEPTICUS

The overall trend in patients with SE has been to decrease the time duration required for diagnosis of the disorder and to treat as soon as possible when a seizure is unlikely to cease. Although the Working Group defined SE as a seizure duration of longer than 30 minutes, treatment was recommended after only 10 minutes (4). Lowenstein and colleagues proposed operational and mechanistic definitions (24). The operational definition of generalized convulsive SE in adults and older children (i.e., older than 5 years of age) is 5 minutes or longer of either a continuous seizure, or two or more discrete seizures, between which there is incomplete recovery of consciousness. In treatment studies, the Veterans Affairs Cooperative Study (25), which compared various first-line antiepileptic drugs (AEDs), used 10 minutes, and the San Francisco Prehospital Treatment study used 5 minutes (26).

Figure 41.1 (continued)

Clinical and experimental data support these trends. A typical clinical seizure rarely lasts as long as 5 minutes. A typical generalized tonic-clonic seizure, on the other hand, lasts 31 to 51 seconds, with a postictal phase of a few seconds to 4 minutes (27). In an inpatient study, mean seizure duration was 62 seconds, with a range of 16 to 108 seconds (28). In one analysis of seizures in children, partial seizures had a duration of 97 seconds (29). In a prospective study of seizures in children, seizure duration was divided into two groups, one with a mean of 3.6 minutes (76% of cases) and the other with a mean of 31 minutes (24% of cases); if the seizure duration was 5 to 10 minutes, it was unlikely to cease spontaneously within the next few minutes (30).

In patients with SE, when first-line AEDs fail to control seizures, the Veterans Affairs Cooperative Study showed only a 5.3% response to a third AED (20), whereas in the Columbia Study, the response rate was higher (58%) when a third AED was administered earlier (31). The San Francisco Prehospital Treatment Study even showed a response to low-dose lorazepam (2 mg) administered by paramedics for out-of-hospital SE in adults (26). Experimental models also show a time-dependent treatment efficacy. In a self-sustaining model of SE induced by intermittent perforant path stimulation, both diazepam and phenytoin prevented SE when given prior to perforant path stimulation, but the efficacy of both decreased when administered later on (32). A loss of inhibitory γ-aminobutyric acid-A (GABA_A) receptors occurs over time in patients with partial SE (33), and in the lithium-pilocarpine model, there is a functional change in GABA_A receptors, which explains the decreased benzodiazepine response (34,35). This decreased benzodiazepine response also has been demonstrated in young animals (36).

PATHOPHYSIOLOGY

Mechanistically, SE occurs when there is a failure of factors that “normally” terminate seizures (24,37). What are the pathophysiologic mechanisms behind this? Seizures result from excessive cerebral excitation, decreased cerebral inhibition, or a combination of both. Excessive excitation itself may cause neuronal injury and cell death, referred to as excitotoxic injury. This has been demonstrated in experimental models, such as in kainic acid-induced limbic seizures (38), but its occurrence in humans had been questioned. An outbreak of poisoning from domoic acid, an excitotoxic agent, with acute symptoms, including SE, was associated with neuronal loss and astrocytosis that was greatest in the hippocampus and amygdala; this was similar to the seizures induced by kainic acid (39,40). A survivor developed epilepsy and, after death, autopsy revealed hippocampal sclerosis (41).

Figure 41.2 Same patient, different seizure A: Continuous ictal discharge. B: Continuous ictal discharges punctuated by flat periods.

Prolonged seizures in anesthetized baboons cause irreversible neuronal injury (42,43). Lothman outlined the alterations in systemic and brain metabolism occurring with prolonged SE (44): decreased brain oxygen tension, mismatch between the sustained increase in oxygen and glucose utilization and a fall in cerebral blood flow, and depletion of brain glucose and oxygen. Initially, brain compensatory mechanisms may protect against neuronal injury; at some point, however, there is a transition from the ability to compensate to the risk for neuronal injury. This compensation, however, requires adequate airway and good breathing, circulation, and cerebral blood flow.

EPIDEMIOLOGY OF STATUS EPILEPTICUS

There have been two large, population-based studies—from Richmond Virginia, and Rochester, Minnesota (45,46). SE accounts for 1% to 8% of hospital admissions for epilepsy. Between 4% and 16% of patients with epilepsy will have at least one episode of SE, with one-third of the cases occurring as the presenting symptom in patients with a first unprovoked seizure, one-third in patients with established epilepsy, and one-third in those with no history of epilepsy (47). These two studies estimate that 60,000 to 150,000 cases of SE occur per year (45,46). The incidence varies: in Richmond, it is 41 per 100,000 (45) and in Rochester, it is 18 per 100,000 (46), but in California, the overall rate is lower (6.2 per 100,000), with higher rates in children younger than 5 years of age (7.5 per 100,000) and the elderly (22.3 per 100,000) (48). Approximately 55,000 deaths occur per year (49). In children, SE is most common in the very young, especially those younger than 2 years of age (50); in this population, more than 80% have either a febrile or an acute symptomatic etiology. SE occurs within 2 years of the onset of epilepsy onset in most of these children (51), and recurrent SE is more likely with an underlying neurologic disorder (52).

ETIOLOGY OF STATUS EPILEPTICUS

Seizures are also classified according to etiology, and SE classification has been expanded to include symptomatic, remote symptomatic, remote symptomatic with acute precipitant, progressive encephalopathy, cryptogenic, idiopathic, and febrile SE (53).

In several studies of adult SE, trauma, tumor, and vascular disease were the most frequently identified causes, although idiopathic and unknown causes were also quite common (54, 55, 56, 57). Etiology also differs among centers and by ages. In San Francisco, noncompliance with AEDs and alcohol withdrawal were the two most common etiologies (Table 41.2) (56,57), whereas cerebrovascular damage was the most common etiology in Richmond (58). The Richmond study included adults and children, so etiologies were better compared (Table 41.3). In adults, cerebrovascular disease was the most common etiology, occurring in 25.2% versus only 3.3% in children, whereas in children, fever or infection was the most common cause, occurring in 35.7% versus only 4.6% in adults. Medication change was a major cause in both adults and children—20% in children versus 19% in adults (58). The incidence of tumors was higher in older studies (54,55).

TABLE 41.2 ETIOLOGY IN THE SAN FRANCISCO STUDIES: CHANGES OVER TIME

	Number of Cases
Etiology	1980	1993
Anticonvulsant withdrawal	27	48
Alcohol-related	15	43
Drug intoxication	10	14
Central nervous system infection	4	12
Refractory epilepsy	—	10
Trauma	3	8
Tumor	4	7
Metabolic disorders	8	7
Stroke	15	6
Cardiac arrest	4	6
Unknown	15	8
Data from Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657-666, and Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483-488.

TABLE 41.3 COMPARISON OF ETIOLOGY IN CHILDREN AND ADULTS IN THE RICHMOND STUDY

Etiology	% of Children (Younger than Age 16 Years)	% of Adults (Older than Age 16 Years)
Cerebrovascular	3.3	25.2
Medication change	19.8	18.9
Anoxia	5.3	10.7
Ethyl alcohol/drug-related	2.4	12.2
Metabolic	8.2	8.8
Unknown	9.3	8.1
Fever/infection	35.7	4.6
Trauma	3.5	4.6
Tumor	0.7	4.3
Central nervous system infection	4.8	1.8
Congenital	7.0	0.8
Adapted from DeLorenzo RJ, Towne AR, Pellock JM, Ko D. Status epilepticus in children, adults, and the elderly. Epilepsia 1992;33 (Suppl 4):15-25.

PROGNOSIS OF PATIENT WITH STATUS EPILEPTICUS

The prognosis of SE depends on etiology, duration (3), and age (50). The mortality rate in modern, generalized convulsive SE series ranges from 4% (59) to 37% (60) and is higher with an acute precipitant (60). An acute precipitant is more likely when there is no prior history of epilepsy (60,61), but may also be responsible for death in persons with known epilepsy with SE. In one series, 63% of patients survived, 28.6% died from the underlying cause, 6.6% died from other causes, and 1.8% died from the SE itself (60). The mortality rate was 21% (14 of 85) in the Columbia study, and was higher with acute symptomatic seizures and older ages (62). A high incidence of symptomatic cases also occurs in the very young, less than age 2 years (50). The mortality was the highest—61% (25 of 41)—in de novo SE occurring in patients already hospitalized (63). With metabolic abnormalities, frequent precipitants—hypoxia, electrolyte imbalance, hepatic encephalopathy, and sepsis—occurred in 23 patients (56%), and 11 (27%) were being treated with theophylline at the time SE developed.

Short-term versus long-term mortality was compared using data from the Rochester study (64, 65, 66); mortality was 19% (38 of 201) within the first 30 days, but cumulative mortality was 43% over 10 years (66). The long-term mortality risk increased with an SE duration longer than 24 hours, acute symptomatic etiology, and myoclonic SE; mortality was not higher with idiopathic/cryptogenic SE (66). Specifically with respect to duration, the mortality rate in the Richmond study was 32% when the duration was longer than 60 minutes versus only 2.7% when the duration was 30 to 59 minutes (67). Other factors associated with a high mortality rate include duration longer than 1 hour, anoxia, and older age, whereas a low mortality rate was associated with alcohol and AED withdrawal (67). Elevated cerebrospinal fluid (CSF) lactate levels may indicate a poor prognosis (68).

The mortality rate in pediatric SE ranges from 4% to 11%, and is also related to etiology and age (59,69, 70, 71, 72, 73, 74). In one study, the mortality was 4%, occurring only with acute symptomatic or progressive symptomatic etiologies (69). Specifically analyzing the age in children, the overall mortality rate in the Richmond study was 6%. However, within the first year, the mortality rate was 17.8%, but in the first 6 months, the mortality rate was 24%, compared with 9% in those ages 6 to 12 months, with the difference caused by a higher incidence of symptomatic SE in the youngest children (75). With respect to morbidity, a Canadian study of SE reported 34% of 40 children with an SE duration of 30 to 720 minutes had subsequent neurodevelopmental deterioration (76). Even in children with febrile SE, speech deficits have been reported (77).

In the Netherlands study (12), prognosis of patients with generalized convulsive SE was related to treatment adequacy. A favorable outcome occurred in 263 (76%) of 346 patients, with outcome related to cause, duration longer than 4 hours, more than one medical complication, and quality of care. To analyze the treatment effects, therapy was classified as insufficient when the wrong AED dose or route was used, if an unnecessary delay occurred, if mechanical ventilation was not used despite respiratory insufficiency or medical complications, or if neuromuscular paralysis was used without electroencephalograph monitoring (to detect seizure activity). The most common reason for classifying therapy as insufficient was an inadequate AED dose. In the patients with a favorable outcome (n=263), therapy was classified as good or sufficient in 85.6% and insufficient in only 10.3%; in those with sequelae (n=45), therapy was inadequate in 22.2%. When the morbidity was from SE itself, insufficient therapy occurred in 50% of patients. With the occurrence of death (n=38), therapy was sufficient in 44.7% of patients, and in cases of death caused by SE itself, therapy was considered insufficient in 62% of patients (12).

An increase in morbidity and mortality occurs with nonconvulsive SE, which is related to SE duration (36 hours to longer than 72 hours) (78). The increased morbidity with nonconvulsive SE is controversial (79, 80, 81). Following cardiopulmonary resuscitation, SE, status myoclonus, and myoclonic SE are predictive of a poor outcome (82). On the EEG, burst-suppression (83) and PEDs are predictive of a poor outcome (84), whereas a normal EEG is associated with a good prognosis (85).

MANAGEMENT OF STATUS EPILEPTICUS

The initial management of patients with SE begins with the ABCs—airway, breathing, and circulation (Table 41.4). Diagnostic studies are then selected, depending on a patient’s history and physical examination (not all studies are obtained in every patient). Serum glucose should be checked immediately with Dextrostix (Bayer Corporation, West Haven, CT) to rapidly diagnose hypoglycemia. A complete blood count may be helpful for diagnosing infection, although leukocytosis may occur with SE. Electrolytes, calcium, phosphorous, and magnesium values may also be helpful. Lumbar puncture (LP) should be considered in the febrile patient. However, if concern exists about increased intracranial pressure or a structural lesion, LP can be deferred until neuroimaging is performed. If there is evidence of infection, antibiotics can be administered prior to LP, although CSF pleocytosis may occur without infection, presumably as a result of a breakdown in the blood-brain barrier (86). In one study, the highest CSF white blood cell count from SE alone (no acute insult) was 28 × 10⁶/L (87). Low AED levels may contribute to the development of SE in both adults and children (88,89).

Neuroimaging options include cranial computed axial tomography (CAT) scan and magnetic resonance imaging (MRI). CAT scans are readily available on an emergency
basis and should identify all disorders demanding immediate intervention, such as tumor or hydrocephalus, but may not show the early phases of infarction. CAT scan and MRI may detect focal changes, which may be transient (90), secondary to a focal seizure (suggesting the origin of the focus), with MRI the more sensitive technique. Although lesions may mimic those of ischemic stroke, they are reported to cross-vascular territories (91). Changes in diffusion-weighted images and the apparent diffusion coefficient (ADC) may occur, suggesting both cytotoxic and vasogenic edema (92). Progressive changes also occur, such as hippocampal atrophy and sclerosis, or global atrophy (93,94). In a fatal case of unexplained SE, high signal lesions in the mesial temporal lobes and hippocampal neuronal loss were reported (95). In general, neuroimaging should be performed in all patients with new-onset SE, especially if there is no prior history of epilepsy.

TABLE 41.4 IMMEDIATE MANAGEMENT OF STATUS EPILEPTICUS

The ABCs:

Stabilize and maintain the Airway; position head to avoid airway obstruction

Establish Breathing (i.e., ventilation): administer oxygen by nasal cannula or mask

Maintain the Circulation: start intravenous (IV) line

Monitor the Vital Signs: pulse (electrocardiogram monitoring), respiratory rate, blood pressure, temperature, pulse oximetry, check Dextrostix

Start IV line:

Use normal saline

Consider thiamine 100 mg; followed by 50 mL of D 50W

Determine what studies are needed:

Consider complete blood cell count, electrolytes, calcium, phosphorus, magnesium; antiepileptic drug (AED) levels, toxicology

Lumbar puncture (especially if febrile)

Neuroimaging, cranial computed axial tomography scan or magnetic resonance imaging

Electroencephalography, if diagnosis initially in doubt

Points from history:

Has an AED been given (prehospital treatment or inpatient), is patient on any AEDs (especially phenobarbital or phenytoin), or does patient have any allergies?

Characteristics of past seizures: is there a history of status epilepticus?

Are treatable causes present (any acute precipitants)?

Fever or illness, head trauma, possible electrolyte imbalance, intoxications, toxin exposure?

Are chronic medical conditions present or is patient on steroid therapy? (If so, patient needs stress coverage.)

Intoxication with certain agents, particularly theophylline (61,63,96) and isoniazid (INH) (97), which may involve acidosis (98) and is treated with pyridoxine (vitamin B₆) (99), may predispose individuals to generalized convulsive SE or nonconvulsive SE. Cyclosporine (100) and ifosfamide (101) may predispose individuals to nonconvulsive SE, which may also occur when phenytoin or carbamazepine are used in patients with idiopathic generalized epilepsy (102); lithium (103), tiagabine (104), and amoxapine (105) might also be implicated. Fatal SE has occurred with flumazenil, therefore caution should be exercised in patients with a history of seizures, chronic benzodiazepine use, or when a mixed overdose is suspected (106).

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