Seizures in the Critically Ill

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65

Seizures in the Critically Ill

Seizures complicate the course of about 3% of adult patients admitted to intensive care units (ICUs) for non-neurologic conditions1 and occur more frequently in specialized neuroscience ICUs.2 The medical and economic impact of seizures in these patients confers a significance on these events out of proportion to their incidence. Seizures are often the first indication of a central nervous system (CNS) complication in these patients, making their rapid etiologic diagnosis mandatory. Furthermore, because epilepsy is a common disorder (affecting about 2% of the general population), patients with preexisting seizure disorders will occasionally require ICU admission for intercurrent conditions. The intensivist usually manages the initial treatment of these patients, so he or she must be familiar with the indications and risks of the potential therapies as they affect the already critically ill patient. In addition, the patient who develops status epilepticus (SE), whether already in the ICU or not, will often require the care of a critical care specialist in addition to a neurologist.

History

Although seizures have been recognized at least since Hippocratic times, their relatively high rate of occurrence in critically ill patients has only recently been recognized. Seizures as a side effect of critical care treatments (e.g., as a complication of lidocaine infusion for ventricular arrhythmias) are also a recent phenomenon.

The first recorded description of SE is by Gavasetti in 1586.3,4 Sir Thomas Willis described the complications of untreated SE in 1667:

… as to what further belongs to the prognostication of the Disease, if it end not about the time of ripe age, neither can be driven away by the use of medicines, there happens yet a diverse event in several sick Patients, for it either ends immediately in Death, or is changed into some other Disease, to wit, the Palsie, stupidite, or melancholly, for the most part incurable. As to the former, whenas the fits are often repeated, and every time grow more cruell, the animal functions are quickly debilitated; and from thence, by the taint, by degrees brought on by the Spirits, and the Nerves serving the Praecordia, the vital function is by little and little enervated, till at length, the whole body languishing, and the pulse is loosned, and at length ceasing, at last the vital flame is extinguished.5

Attempts at treating SE in the nineteenth century included bromide,6 morphine,7 and ice applications. Barbiturates were introduced in 1912, followed by the identification and use of phenytoin in 1937; these were the first rational treatments for SE.8 Paraldehyde gained brief prominence in the next decades.9 The most recent major improvement is the use of benzodiazepines, pioneered by the French in the 1960s.10

Epidemiology

Few data are available concerning the epidemiology of seizures in ICU patients. A 10-year retrospective study of all ICU patients at the Mayo Clinic reported approximately 7 patients with seizures per 1000 ICU admissions.11 In a 2-year prospective study of a medical ICU, we acquired approximately 35 patients with seizures per 1000 admissions.1 These analyses are not strictly comparable, because the patient populations and methods of detection differed. The incidence of seizures is probably higher in pediatric ICUs than in medical ICUs.12–14

Certain ICU patients appear to be at increased risk for seizures, but the degree of that increased risk has not been quantified. Patients with renal failure or with an altered blood-brain barrier who receive imipenem-cilastatin are an obvious example, but other patients receiving this antibiotic (or γ-aminobutyric acid [GABA] antagonists such as penicillin) occasionally seize. Cefepime has emerged as a cause of nonconvulsive seizures and SE, especially in patients with renal insufficiency.15 Transplant patients, especially those receiving cyclosporine, appear to have an increased risk for convulsions. Patients who rapidly become hypo-osmolar from any cause are also at risk. Nonketotic hyperglycemia patients have a high likelihood of partial seizures; this is a rare instance of a metabolic disorder producing focal neurologic syndromes.16 Less commonly, diabetic ketoacidosis may also produce partial seizures.17

The epidemiology of SE is somewhat better understood. Estimates of the incidence of generalized convulsive SE in the United States range from 50,000 cases/year18 to 250,000 cases/year.19 Some portion of this discrepancy may be due to differences in definitions. The larger estimate comes from the only population-based data available and may be more accurate. Similarly large variations occur in mortality rate estimates, from 1% to 2% in the former study to 22% in the latter. This disagreement stems, at least in part, from a conceptual discordance: the smaller number attempts to determine mortality rate that the authors directly attribute to SE, while the larger figure reflects the overall mortality rate for SE patients, in whom death was frequently a consequence of the cause of the underlying disease rather than SE itself. In the latter study, for example, anoxia was the cause of SE in adults with the highest mortality rate. In many of the reports surveyed in the earlier review, these patients were not included.

A number of important risk factors have emerged from the Richmond study. When SE lasted longer than 1 hour, the mortality rate was 32%; when it lasted less than 1 hour, the mortality rate was only 2.7%. SE caused by anoxia was associated with a mortality rate of about 70% in adults, but the corresponding rate in children was less than 10%. After the age of 12 months, the mortality rate of SE rose with increasing age. In their study, the commonest cause of SE in adults was stroke, followed thereafter by withdrawal from anticonvulsant drug therapy; cryptogenic (or idiopathic) SE; and SE related to ethanol withdrawal, anoxia, and metabolic disorders. Systemic infection was the most commonly diagnosed cause of SE in children; this was followed by congenital abnormalities, anoxia, metabolic disorders, anticonvulsant drug withdrawal, CNS infections, and trauma. Although brain tumors seldom caused SE in children, such patients experienced a nearly 50% mortality rate.

Towne and colleagues demonstrated that 8% of an unselected series of comatose medical ICU patients had unsuspected nonconvulsive status epilepticus (NCSE).20 In septic ICU patients, Oddo and colleagues showed that about 30% have periodic epileptiform activity or NCSE when recorded for 24 hours or longer.21

Hospital-based series of SE patients are usually subject to considerable selection bias regarding cause. The data in Table 65.1, based upon 20 years of experience in San Francisco, are of great interest because almost all patients with SE in the city of San Francisco who began to seize outside the hospital are included.22–24

Between 6% and 12% of epilepsy patients present with SE,25 and about 20% of seizure patients will experience an episode of SE within 5 years of their first seizure.11

Nosology and Semiology

Numerous systems have evolved for the classification of seizures; the most frequently used today is that of the International League Against Epilepsy26 (Box 65.1). This schema allows classification based primarily on clinical criteria, without inferences about cause. Although a more recent proposal for terminology has been published, it is not yet widely accepted.27 It is important because of its predictive value for cause, prognosis, and treatment decisions in ICU patients. Simple partial seizures arise focally in the cerebral cortex, without taking over either the limbic system or subcortical nuclei. The patient remains aware of the environment during the ictus, and except for the seizure itself appears unchanged. Bilateral limbic system dysfunction results in a complex partial seizure; the patient’s awareness and ability to interact with the environment are diminished (but not always completely abolished). Automatisms are movements that the patient seems to make without being aware of them; typical automatisms include swallowing, masticatory movements, and fumbling with nearby items. Secondary generalization implies invasion of either the other hemisphere (with loss of consciousness) or, more commonly, subcortical structures, with the development of a generalized convulsion.

Box 65.1

International Classification of Epileptic Seizures

I Partial seizures (seizures beginning locally)

II Primary generalized seizures (bilaterally symmetric, without localized onset)

III Unclassified seizures

From Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.

Primary generalized seizures seem to arise from the entire cerebral cortex and the diencephalon at the same time; there are no visible focal phenomena. Consciousness is lost from the start of the seizure. True absence seizures are usually confined to childhood; they consist of the abrupt onset of a blank stare usually lasting 5 to 15 seconds, without lateralizing phenomena, from which the patient abruptly returns to normal. Atypical absence is usually seen in children who have the Lennox-Gastaut syndrome. Myoclonic seizures begin with brief, bilaterally synchronous jerks without an initial change in consciousness, followed by a generalized convulsion. They occur in several of the genetic epilepsies, but in the ICU are more commonly the consequences of anoxia or metabolic disturbances.28 Clonic seizures involve repetitive movements; they may be generalized (synchronous movements of all extremities and both sides of the face) or partial (e.g., one side of the face and the arm of the same side). Tonic seizures are episodes of tonic extension of the arms, legs, and trunk; they must be distinguished from decerebrate rigidity and from tetanic spasms.29 Tonic-clonic seizures begin with tonic extension, followed by a brief phase of rapid vibration of the extremities, evolving into bilaterally synchronous clonus, and concluding with a postictal phase in which incontinence is common and brief apnea is occasionally noted. They may be primarily generalized or, more commonly, occur as the manifestation of spread of a partial seizure. Only those seizures that are known to involve progression through the tonic and clonic stages should be called tonic-clonic.

When seizures occur in ICU patients, clinical judgment is required to apply this system. Patients whose consciousness is already altered by drugs, hypotension, sepsis, or intracranial disease may be difficult to diagnose regarding the “simple” or “complex” nature of their partial seizures.

SE is classified by a somewhat similar system, with alterations to match the observable clinical phenomena (Box 65.2).30 Again, the ability to use clinical observation without inferences about cause is important. Generalized convulsive SE (GCSE) is the type most commonly encountered in ICUs, and poses the greatest risk to the patient. GCSE may be either primarily generalized, as in the intoxicated patient, or may represent secondary generalization, as in the patient with a brain abscess who develops GCSE. Tonic SE is usually seen in children or adolescents with a history of severe CNS dysfunction. Nonconvulsive SE (NCSE) in the ICU is most commonly the consequence of partially treated GCSE. Some authors use this as a general term for any SE involving altered consciousness without convulsive movements. Although conceptually useful, this blurs the distinctions among absence SE, partially treated GCSE, and complex partial SE (CPSE), which have different causes and treatments. Epilepsia partialis continua (EPC) is a special form of partial SE in which a small area of the body makes repetitive movements, sometimes for months or years following a CNS insult.

Box 65.2

Clinical Classification of Status Epilepticus (SE)

Adapted from Ettinger AB, Shinnar S: New-onset seizures in an elderly hospitalized population. Neurology 1993;43:489.

Pathogenesis

Clinical SE has a large variety of causes. The relative frequencies of causes depend upon the definition of SE employed (e.g., if repetitive, stereotyped myoclonic activity after a cardiorespiratory arrest is considered SE, then the frequency of such arrests as a cause of SE will rise).

The reported “causes” of SE can be separated, if imperfectly, into predispositions and precipitants. Predispositions are relatively fixed conditions that increase the likelihood of SE, such as a brain tumor, in the presence of a precipitant. Precipitants, in contrast, are transient conditions that can produce SE in most, if not all, people but will tend to affect those with predispositions at lesser degrees of severity (e.g., barbiturate withdrawal).

For experimental purposes, the nosologic division of SE into partial (focal) or generalized based on the type of seizure produced works well, as does the recognition of convulsive and nonconvulsive seizure types. One must recognize that these are models of acute SE; they are not chronic conditions that occasionally produce SE, as are many of the afflictions of patients. Nevertheless, they have substantial explanatory power for understanding the neuronal and systemic processes of SE, for studying its consequences, and for predicting responses to therapy.

Pathophysiology

The causes and effects of SE at the cellular, brain, and systemic levels are interrelated, but their individual analysis is useful for understanding them and their therapeutic implications. One must first understand the consequences of a single seizure and then contrast this information with the effects of prolonged or frequent seizures merging into SE. Longer durations of SE produce more profound alterations with an increasing likelihood of permanence, and of becoming refractory to treatment. Figure 65.1 illustrates the variety of processes involved in a single seizure and in the transition to SE.31

The ionic events of a seizure follow the opening of ion channels coupled to excitatory amino acid (EAA) receptors. Although the endogenous ligands of these channels are glutamate and aspartate, the channels are named for synthetic compounds that potently activate them. From the standpoint of the intensivist concerned with SE, three channels are particularly important because their activation may raise intracellular free calcium to toxic concentrations. The first channels primarily conduct sodium ions (the AMPA [amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] channels). The second are the N-methyl-D-aspartate (NMDA) channels, which admit sodium and calcium when the cell has been depolarized (which relieves the resting blockade of the ionophore by magnesium). The third, the metabotropic or ACPD (aminocyclopentane-trans-1,3-dicarboxylic acid) channels, mobilize calcium from intracellular stores via coupling to G-protein-linked second messengers.

These EAA systems are normally crucial for learning and memory. Many drugs that block these systems, such as ketamine, are too toxic to use as chronic anticonvulsants. However, the deleterious consequences of SE, and the brief period during which they would be needed, suggest that similar agents may prove to have a role in the management of SE. Counterregulatory ionic events are also triggered by the epileptiform discharge; the most important is activation of inhibitory interneurons, which feed back to the bursting cells via GABAA synapses.

The cellular consequences of the excessive EAA channel activation include (1) accumulation of toxic concentrations of free intracellular calcium; (2) activation of autolytic enzyme systems; (3) production of oxygen-derived free radicals; (4) generation of nitric oxide, which both enhances subsequent excitation and serves as a toxin; (5) phosphorylation of several enzyme and receptor systems, making seizures likely; and (6) increasing intracellular osmolality, thereby producing neuronal swelling. If adenosine triphosphate (ATP) production should fail (because the substrate becomes inadequate or is diverted into EAA-related events), membrane ion exchange systems stop functioning, and the neuron swells further. These events are responsible for the neuronal damage associated with SE.

Many other important biophysical and biochemical alterations occur during and after SE. The intense neuronal activity activates immediate-early genes and produces heat shock proteins, providing strong indications of the deleterious effects of SE and insight into the mechanisms by which neurons protect themselves.32 Wasterlain’s group summarized the many mechanisms through which SE damages the nervous system.33

Absence SE is an exception among these conditions. It appears to consist of rhythmically increased inhibition and does not produce clinical sequelae or neuropathologic abnormalities.

The mechanisms that terminate seizure activity are uncertain. Given the relative rarity of SE in a population in which at least 1 in 50 patients has had a seizure, one must infer that these mechanisms are generally effective. The leading candidates for seizure terminating systems are inhibitory mechanisms, primarily GABAergic neuronal aggregates. This hypothesis receives strong support from the clinical observation that human SE frequently follows withdrawal from GABA agonists (e.g., benzodiazepines).

The electrical phenomena of SE at the whole brain level, as seen in the scalp electroencephalogram (EEG), reflect the seizure type that initiates SE (Fig. 65.2). Thus, absence SE begins with a generalized 3-Hz wave-and-spike EEG pattern. During the course of SE, there will usually be some slowing of this rhythm, but the wave-and-spike characteristic persists. In contrast, GCSE goes through the sequence of EEG changes outlined in Table 65.2. The initial high-frequency discharge becomes progressively less well formed over minutes; this pattern implies that neuronal activity is less synchronous. Whether this indicates that inhibitory systems are attempting to terminate SE, a progressive decay in the ability of synaptic mechanisms to maintain synchrony, or global deterioration in neuronal function remains to be determined.

Table 65.2

Electrographic-Clinical Correlations in Generalized Convulsive Status Epilepticus

Stage Typical Clinical Manifestations* Electroencephalographic Features
1 Tonic-clonic convulsions; hypertension and hyperglycemia common Discrete seizures with interictal slowing
2 Low- or medium-amplitude clonic activity, with rare convulsions Waxing and waning of ictal discharges
3 Slight, but frequent, clonic activity, often confined to the eyes, face, or hands Continuous ictal discharges
4 Rare episodes of slight clonic activity; hypotension and hypoglycemia become manifest Continuous ictal discharges punctuated by flat periods
5 Coma without other manifestations of seizure activity Periodic epileptiform discharges on a flat background

*The clinical manifestations may vary considerably, depending on the underlying neuropathophysiologic process (and its anatomy), systemic diseases, and medications. In particular, stages of the electrographic progression may be sufficiently brief to be overlooked. Partially treating status epilepticus may dissociate the clinical and electrographic features.

The repetitive firing that characterizes SE alters the extracellular microenvironment. The most important change is probably the elevation of the extracellular potassium concentration. Although extruding potassium is an effective strategy to maintain normal electronegativity, the excessive amounts of potassium ejected during SE overcome the ability of astrocytes to buffer it. Patients with cerebral edema, glial scarring, or alien tissue lesions have extracellular space abnormalities that impair the potassium buffering ability of glial cells. Raising extracellular potassium is a potent epileptogenic stimulus.

The tremendously increased cellular activity of SE elevates tissue demand for oxygen and glucose. To meet this demand, cerebral blood flow initially increases threefold or greater. However, after about 20 minutes, energy supplies become exhausted. This accentuates the demand for local catabolism in order to support ion pumps (in a vain attempt to restore the internal milieu during the flood of sodium and calcium). Many researchers believe that this is the major cause of epileptic brain damage in GCSE. Other forms of SE may not be subject to such severe hypercatabolism, but still pose a risk.

When partial seizures generalize, subcortical structures begin to play an active role in the clinical phenomena observed. Spread of the electrical activity into the substantia nigra and other subcortical regions appears to be necessary before a tonic-clonic convulsion occurs.

The brain contains intrinsic systems that terminate seizure activity; both local GABAergic interneurons and inhibitory thalamic neurons are involved. Whether these systems have evolved, at least in part, for protection against seizures, or whether this effect is an epiphenomenon of some other physiologic function, is unresolved.

SE can produce cerebral edema, which follows ictal damage to the blood-brain barrier.

Prolonged SE produces chronic neuropathologic changes. Prior to the 1970s, these changes were often attributed to the systemic effects of SE (e.g., hypoxia and hyperthermia). However, SE itself produces these changes even in patients who are paralyzed, ventilated, and maintained at normal temperature and blood pressure. The hippocampus, which is one of the most important areas for memory function, contains the most susceptible neurons, but the cerebral cortex is also vulnerable. These regions express high densities of EAA receptors, and may be relatively deficient in systems for handling unusual elevations of free intracellular calcium. Cells that contain nitric oxide synthase seem relatively protected.

In addition to damaging the CNS, GCSE produces serious, often life-threatening, systemic effects.34 Pressures in the systemic arterial system (under sympathetic control) and in the pulmonary arterial system (raised via efferents from pontine and medullary centers) are dramatically elevated from the moment of seizure onset. Epinephrine and cortisol release prompts further elevations of systemic arterial pressure, and also produces hyperglycemia. Increased muscular work raises the circulating lactate concentration. Respiration becomes ineffective; both airway obstruction and diaphragmatic contraction impede air movement. The consequent hypoxia further elevates lactate levels. Ventilatory failure impairs CO2 excretion while CO2 production increases markedly, adding a respiratory component to the acidosis. In GCSE, the arterial blood pH frequently falls below 7.0. The muscular work accelerates heat production; when coupled with decreased dermal blood flow (produced by sympathetic stimulation), GCSE can quickly raise the core temperature to 40° C or higher.

If GCSE is not completely controlled within the first 20 minutes, motor activity begins to diminish in intensity, and ventilation usually improves. Therefore, even without treatment, the metabolic acidosis improves. Core temperature may continue to climb, however, probably reflecting hypothalamic dysfunction. The initial hyperglycemia diminishes; after an hour or more, hepatic gluconeogenesis may fail, and hypoglycemia develops.

GCSE patients frequently suffer secondary complications as well. Aspiration of oral or gastric contents commonly produces chemical pneumonitis, with bacterial pneumonia often following. Rhabdomyolysis is common, and is occasionally followed by acute renal failure. Compression fractures, joint dislocations, and tendon avulsions are other common sequelae of GCSE.

Clinical Manifestations

Recognition of Seizures

Because of the close observation patients receive in the critical care setting, most seizures are witnessed. The partial onset of a secondarily generalized convulsion, a finding of important diagnostic significance, is more likely to be seen and properly described in the ICU than on regular hospital floors or in the community. Three problems occur in ICU seizure recognition: (1) complex partial seizures in patients with already impaired awareness, (2) seizures in patients receiving neuromuscular junction blockade, and (3) the misinterpretation of movement disorders and psychiatric disturbances as seizures. (In any ICU patient who develops abnormal movements or unexplained changes in awareness, thiamine deficiency should be excluded immediately by giving thiamine.)

ICU patients often have altered awareness in the absence of seizures, reflecting their underlying condition, complications of those conditions (such as septic encephalopathy35), and drugs that depress alertness (intentionally or not). Although clonic motor activity in these patients remains visible, it may be difficult to tell whether a subsequent further decline in alertness reflects a seizure or some other process. In this situation, an EEG is required to make the diagnosis of a complex partial seizure. Although the detailed interpretation of EEGs is beyond the scope of this chapter, the intensivist can easily learn to recognize basic seizure types and other important EEG abnormalities in critically ill patients.36

Patients receiving neuromuscular junction blocking agents will not manifest any of the usual signs of seizures. Because most such patients receive concomitant sedation with GABA agonists (e.g., benzodiazepines), the likelihood of seizures is small. The autonomic signs of seizures (hypertension, tachycardia, pupillary dilation) are not readily distinguished from the effects of pain or the patient’s response to inadequate sedation. Thus, any patient who manifests these findings and who has a potential reason for seizures (e.g., intracranial disease) should have an EEG to exclude this possibility.

Many sorts of abnormal movements occur in patients with severe metabolic disturbances or anoxic brain damage. Some of them can be distinguished from seizures by observation; such movements are frequently evoked or exacerbated by sensory stimuli and can sometimes be suppressed by changing the patient’s posture. However, Hirsch and colleagues have demonstrated that seizures in ICU patients may be induced by external stimuli37; if any doubt about the nature of such movements persists, an EEG should be performed.

During therapeutic cooling for patients in a coma after cardiac arrest, seizures may be difficult to detect clinically, especially when neuromuscular junction blockade is used.38 EEG monitoring should be performed.39

Manifestations of Status Epilepticus

The neurologic manifestations of SE depend on the type of SE and, for the partial forms, the area of cortex from which the abnormality arises. Box 65.2 summarizes the types of SE encountered in clinical practice. This section will focus on the varieties of SE seen most frequently among ICU patients.

Primary GCSE usually begins as tonic extension of the trunk and extremities, without any preceding focal ictal activity. If the patient was awake before onset, no aura is reported, and consciousness is immediately lost. After several seconds of tonic extension, the extremities begin to vibrate; this phase gives way to clonic (rhythmic) extension of the extremities, with flexion occurring during each brief relaxation. Usually, this clonic phase will wane in intensity over 1 to 3 minutes. The patient developing SE may then repeat the cycle of tonic activity followed by clonic movements, or may continue to have intermittent bursts of clonic activity without recovery between. Less commonly encountered forms of GCSE are myoclonic SE, in which bursts of brief myoclonic jerks increase in intensity until a convulsion occurs, and clonic-tonic-clonic SE, in which a period of clonic activity precedes the first tonic contraction. Myoclonic SE is particularly common in patients with anoxic encephalopathy or metabolic disturbances, particularly renal failure.

Secondarily generalized SE in the ICU begins with a partial (focal) seizure, which progresses to a tonic-clonic convulsion. Even under the watchful eye of the ICU staff, the initial focal clinical activity may be overlooked. Because this type of seizure is very strong evidence of a structural brain lesion, care should be taken to elicit evidence of any lateralized movement. Tonic SE is almost always confined to patients (usually children) with serious preexisting cerebral disorders. Its importance in critical care practice follows from the observation that benzodiazepines may precipitate tonic SE; paradoxically, these agents are also used to treat it.

There are several forms of generalized NCSE. Of greatest importance to intensivists is NCSE as a sequel of inadequately treated GCSE. In this circumstance, a patient with GCSE is treated with one or more anticonvulsants, often in inadequate doses, after which visible convulsive activity stops. However, the patient does not awaken (or otherwise return to baseline), and SE is actually continuing. As a rule, patients are expected to begin to awaken within 15 to 20 minutes after the successful termination of SE; many will regain consciousness much faster. Those who have not begun to awaken after 20 minutes should be assumed to have entered NCSE. This form of SE is sometimes termed subtle SE, and careful observation will often reveal low-amplitude clonic activity in some part of the body (most commonly, the face or the hands). Most investigators view NCSE as an extremely dangerous problem, because the neuronally destructive effects of SE continue unabated, often for several hours. This condition requires emergent treatment under EEG monitoring to prevent further cortical damage. There are no clinical criteria, which indicate when therapy has finally become effective.

The usual form of partial SE in the ICU follows a stroke or is seen in patients with rapidly expanding cerebral masses (e.g., abscesses). Although clonic motor activity is the most easily recognized form, the seizure will take on the functional characteristics of the adjacent functional tissue. Thus, somatosensory or special sensory manifestations may occur; the ICU patient who is already neurologically impaired may not be able to report these symptoms. Aphasic SE may occur if the seizure begins in a language area; this must be distinguished from a stroke. Physical examination usually reveals at least some mild lateralizing findings.

EPC is a special type of partial SE in which repetitive movements are confined to a small portion of the body (typically the thumb), and may last for months or years. This type of SE is most commonly associated with nonketotic hyperosmolar hyperglycemia and does not respond to conventional anticonvulsant treatment.

CPSE presents with a state of diminished awareness, although frank loss of consciousness is rarely noted. The patient may exhibit automatisms, but commonly the diagnosis comes as a surprise when an EEG is obtained.

Diagnostic Approach

The Intensive Care Unit Patient with New-Onset Seizures

When a patient already in an ICU has a seizure, the staff has a natural tendency to try in some way to stop the ictus. This may, unfortunately, lead to both diagnostic obscuration and iatrogenic complications. Beyond trying to protect the patient from harm, very little can be done with sufficient rapidity to influence the course of the seizure. In particular, padded tongue blades (or similar items) should not be placed in the mouth, because they are more likely to obstruct the airway than to preserve it. Similarly, most patients have stopped seizing before any medication, even administered into a preexisting intravenous line, can reach the brain in an effective concentration. A common scenario is the administration of intravenous diazepam (DZ), which begins to take effect after the seizure is over; the patient is now both postictal and pharmacologically sedated and becomes apneic.

The most important “intervention” during a single seizure is careful observation. This is the best time to collect evidence of a partial onset, which implies structural brain disease. The postictal examination is similarly valuable; language, motor, sensory, or reflex abnormalities after an apparently generalized convulsion should also be viewed as evidence of focal disease.

In addition to the standard historical information to be requested from patients and family members after a seizure, the ICU patient has several special predispositions that must be investigated. Medications are an important cause of ICU seizures, especially in patients with diminished renal or hepatic function, or with damage to the blood-brain barrier. Imipenem-cilastatin is a common cause of seizures in this setting, but other antibiotics may also be offenders. The neurotoxic desmethyl metabolite of meperidine accumulates in renal failure; it also may produce seizures in patients with normal renal function. A complete list of potentially epileptogenic drugs is beyond the scope of this chapter; the medications of any patient who seizes should be reviewed with this possibility in mind.

Drug withdrawal is another common problem. Although ethanol withdrawal is the most common offender, discontinuing any hypnosedative agent (e.g., barbiturates, benzodiazepines, other sedatives) may prompt convulsions 24 to 96 hours later. This may be a particular problem in the ICU, where such agents may be withheld from patients because the staff is afraid that the drug’s effects will obscure the neurologic examination.

The physical examination should be conducted with special emphasis on the points mentioned earlier for the postictal examination. In addition, evidence of cardiovascular disease (as a source for cerebral emboli) and systemic infection should be sought. Careful examination of the skin and fundi are sometimes revealing. The presence of papilledema is obviously important, but its absence does exclude increased intracranial pressure.

In addition to routine biochemical studies, screening for drugs of abuse should be performed on patients with unexplained seizures. Cocaine has emerged as a prominent cause of seizures in many urban hospitals.40 One area of controversy involves the importance of divalent cation disturbances in adult seizures. Hypocalcemia is rarely a cause of seizures beyond the neonatal period, and its discovery should not be the end of the diagnostic workup. Hyperparathyroidism has been linked anecdotally to seizures, with the inference that parathormone is neurotoxic. Similarly, hypomagnesemia has an unwarranted reputation as a cause of seizures, especially in the malnourished alcoholic patient.

In our prospective study of neurologic complications in medical ICU patients, 38 of 61 patients (62%) with seizures had a vascular, infectious, or neoplastic explanation for their fits.1 Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed on all ICU patients with new seizures, with a few exceptions. Hypoglycemia and nonketotic hyperosmolar hyperglycemia will commonly produce seizures (even partial seizures), and such patients might be treated for their metabolic disturbance and observed if there is no other indication of neurologic disease. With currently available technology, there are almost no patients who cannot be transported to undergo CT scanning. Although MRI is preferable diagnostically in most situations, the magnetic field precludes infusion pumps and other metallic devices (nonferromagnetic ventilators are available). The decision whether to administer contrast agent for a CT or MRI scan depends on the clinical setting and on the appearance of the plain scan.

The EEG is a vital diagnostic tool for the seizure patient. Partial seizures usually have EEG abnormalities, which begin in, and may remain confined to, the area of cortex producing the seizures. Primary generalized seizures, in contrast, appear to start over the entire cortex at once. Areas of postictal slowing or depressed amplitude provide clues to the focal cause of the seizures, and interictal epileptiform activity helps to classify the type of seizure and guide the patient’s subsequent treatment. In patients who do not begin to awaken soon after seizures have apparently been controlled, an emergent EEG is necessary to exclude NCSE.

The need for a lumbar puncture (LP) depends on the clinical situation. In view of the common causes of seizures in the critical care setting, those who need cerebrospinal fluid (CSF) analysis will usually require a CT scan before the LP. If a CNS infection is suspected in such patients, empiric antibiotic treatment should be strongly considered while these studies are being performed, rather than waiting for the scan to be performed and CSF results to be obtained.

The Patient Presenting with or Developing Status Epilepticus

In contrast to the ICU patient with a single or a few seizures, the SE patient will require concomitant diagnostic and therapeutic efforts. The first issue is to make a diagnosis of SE. Because most seizures stop within 5 to 7 minutes,41 it is reasonable to begin treatment after 5 minutes of continuous seizure activity or after the second or third seizure occurring without recovery between the spells. The available treatments are discussed later.

SE has a limited differential diagnosis. GCSE might rarely be confused with decerebrate posturing, but the evolutionary nature of the former and the stimulus sensitivity of the latter make their clinical distinction straightforward. Generalized tetanus patients are awake during their spasms, and almost always flex their arms rather than extending them.20 The distinction of seizures from movement disorders and psychiatric conditions is discussed earlier.

EEG monitoring is frequently useful in SE,42 but treatment should not be delayed to obtain it when the diagnosis is apparent. A variety of EEG findings may be present, depending on the type of SE and its duration (see Table 65.2). The most typical pattern early in SE is that of rhythmic, high-frequency (>12 Hz) activity that increases in amplitude and decreases in frequency, finally terminating abruptly and leaving postictal low-amplitude slowing in its wake. CPSE patients often lack such organized discharges, but may instead have waxing and waning rhythmic activity in one or several head regions. Such a pattern requires a high index of suspicion in order to correctly diagnose CPSE; a diagnostic trial of an intravenous benzodiazepine is often necessary. Patients who develop refractory SE or experience seizures during neuromuscular blockade will require continuous EEG monitoring. The technology to perform such monitoring outside specialized epilepsy centers is only now becoming available.

Management Approach

The Intensive Care Unit Patient with New-Onset Seizures

Deciding whether to administer anticonvulsants to an ICU patient who experiences a single seizure or a few seizures requires a provisional etiologic diagnosis, an estimate of the likelihood of seizure recurrence, and an understanding of the utility and limitations of available anticonvulsants. For example, the patient who seizes during ethanol withdrawal will probably not benefit from chronic anticonvulsant treatment, and the administration of phenytoin (PHT) will not prevent more withdrawal convulsions during the same episode. Such a patient may need prophylaxis against delirium tremens with benzodiazepines, but the seizures themselves seldom require treatment. The patient who seizes during barbiturate or benzodiazepine withdrawal, in contrast, should usually receive short-term treatment (usually with lorazepam [LRZ]) to prevent the development of SE. Seizures due to drug intoxications or metabolic disturbances should similarly be treated for a brief period, but do not indicate chronic anticonvulsant therapy.

The ICU patient with CNS disease who has even a single seizure should usually be started on a chronic anticonvulsant regimen, with the decision to continue medication reviewed prior to hospital discharge. It is now apparent that initiating anticonvulsant therapy after the first unprovoked (e.g., not drug- or withdrawal-related) seizure helps delay the onset of subsequent seizures, but does not change their eventual incidence.43 Starting treatment after the first seizure in a critically ill patient who has a condition predictive of seizure recurrence may be even more important if the patient’s problems include coagulopathies, myocardial ischemia, or other conditions that would be seriously complicated by a convulsion.

The Neurocritical Care Society recently published extensive guidelines for the treatment of SE,44 which should be consulted for detailed information about the drugs discussed briefly here.

In the ICU setting, PHT (20 mg/kg loading dose, no faster than 50 mg/minute, followed by an initial maintenance dose of 5 mg/kg/day) is often chosen to prevent subsequent seizures because of its relative ease of administration. Slowing the infusion rate to less than 25 mg/minute can usually prevent hypotension and cardiac arrhythmias that may complicate its rapid intravenous administration. Because of the possible precipitation of third-degree atrioventricular (AV) block, an external cardiac pacemaker should be available when patients with conduction abnormalities receive intravenous PHT. Patients who are not actively seizing can be loaded enterally over 6 to 12 hours. Although fosphenytoin is safer than PHT, if it extravasates, this agent does not have less cardiovascular toxicity. Fosphenytoin can also be used for intramuscular loading; PHT (pH 12) should not be administered intramuscularly because it produces myonecrosis.

The total PHT serum concentration should be kept in the “therapeutic” range of 10 to 20 µg/mL while the patient is in the ICU, unless further seizures occur; the level may then be increased until signs of toxicity occur. If the patient is unable to express these signs (e.g., ataxia) because of his or her underlying condition or its treatment, failure to prevent seizures at a concentration of 25 µg/mL is usually an indication to add phenobarbital (PB) (see later). Although the usual goal of chronic anticonvulsant treatment is to administer the smallest dose of a tolerated single agent that completely controls seizures, such an approach is often impossible in the critical care environment. When the patient is more stable, an attempt to decrease minor side effects or to convert to monotherapy may then be made.

PHT is normally about 90% protein bound. Patients with renal dysfunction will have lower total PHT levels for a given dose because the drug is displaced from its binding sites, but the “free” (unbound) level is not affected. Thus, in renal failure patients, and perhaps in others who are receiving highly protein bound drugs (which will compete for PHT binding sites), it may be advantageous to measure free PHT levels. Because only the free fraction is significantly metabolized, the dose need not be altered with changing renal function. Calculations of the unbound concentration based on the serum albumin concentration are unreliable. The half-life for PHT clearance in patients with normal liver function varies from about 20 hours for the intravenous form and the oral solution to over 24 hours for the extended-release oral capsules. Hence, a new steady-state serum concentration will take 4 to 6 days to establish. The drug need not be given more often than every 12 hours; the dosage interval for the enteral forms depends on the preparation but may be even longer. Hepatic dysfunction will mandate a decrease in the maintenance dose; if the serum albumin is very low, the loading dose can be reduced as well.

Hypersensitivity to PHT is the major adverse effect of concern to the intensivist. This allergy may be manifested solely as fever, but more commonly includes a rash and eosinophilia. Febrile reactions appear to be more common with intravenous than with enteral loading. The Stevens-Johnson syndrome occurs rarely. The diagnosis and management of adverse reactions to PHT and other anticonvulsants have been reviewed.45 PHT is associated with a number of long-term adverse effects in patients with subarachnoid or intracerebral hemorrhage.46

PB (10-20 mg/kg loading dose, followed by an initial maintenance dose of 1.5 mg/kg/day) remains useful as an anticonvulsant for patients who cannot tolerate PHT, or who have breakthrough seizures after adequate PHT loading. The target level for PB in ICU patients should be 20 to 40 µg/mL. Either hepatic or renal dysfunction may affect PB metabolism. The half-life for PB clearance is about 96 hours. Thus, maintenance doses of this agent need be given only once a day, and a steady-state level will take about 3 weeks to be established. Sedation is the major adverse effect; allergy is rare.

Carbamazepine, one of the most useful chronic anticonvulsants, is seldom introduced to critically ill patients because its insolubility has precluded a parenteral formulation. Oral loading with carbamazepine in conscious patients may produce coma lasting several days. It should be recalled as a cause of hyponatremia in patients receiving it chronically.

Valproate should be avoided in settings in which liver disease or hyperammonemia may be problems but is otherwise a useful drug available both orally and intravenously. A loading dose of 30 mg/kg is reasonable.

The place of the newer anticonvulsants in critical care is not well established. Levetiracetam has gained substantial popularity because of its limited drug interactions; it is predominantly excreted by the kidney, so the dose must be adjusted in renal insufficiency. The usual dose for seizure prevention is between 500 and 1500 mg/day, although doses up to 6 g/day have been employed. The role of serum concentrations for assessment of efficacy or toxicity is not yet established. Lacosamide is also available intravenously and is started at a dose of 200 mg twice daily.

Status Epilepticus

The patient in GCSE has an obvious medical emergency; unfortunately, the NCSE and CPSE patients also require emergent treatment but are less straightforward to recognize. In a patient with any of these three conditions, the clinician must move quickly to stop seizures in order to prevent further brain destruction.47 A suggested management protocol for these conditions is presented in Box 65.3, and Figure 65.3 shows a management algorithm for SE. Patients with simple partial SE or EPC appear to be at substantially less risk of developing widespread cerebral damage and also appear less likely to respond to the aggressive approach outlined in Box 65.3. In this group, correction of underlying problems, if possible (such as nonketotic hyperosmolar hyperglycemia), is most important. Of the available anticonvulsants, PB seems most likely to be efficacious. These patients are often loaded with PHT in the hope that this agent will prevent secondary generalization, but the actual value of this practice is unknown.

Box 65.3   Suggested Therapeutic Sequence for Terminating Status Epilepticus (SE)

I Establish airway.

    Often the most rapid way to accomplish this is to rapidly terminate SE. If endotracheal intubation under neuromuscular junction blockade is necessary, use a nondepolarizing agent such as rapacuronium (1.5 mg/kg) or vecuronium (0.1 mg/kg). If increased intracranial pressure is a concern, premedicate with lidocaine (1 mg/kg) or thiopental (4-5 mg/kg). If these agents are used, the patient should be considered still to be in SE until neuromuscular transmission is reestablished, or until an EEG demonstrates that SE is no longer present.

II Determine blood pressure.

    If the patient is hypotensive, begin volume replacement and/or vasoactive agents as clinically indicated. Patients with GCSE who present with hypotension will usually require admission to a critical care unit. (Hypertension should not be treated until SE is controlled, because terminating SE will usually substantially correct it, and many of the agents used to terminate SE can produce hypotension).

III Unless the patient is known to be normo- or hyperglycemic, administer dextrose (1 mg/kg) and thiamine (1 mg/kg).

IV Terminate SE.

    We recommend the following pharmacologic protocol (see text for discussion of these and alternative agents). Be cognizant of the potential of these drugs to eliminate the visible convulsive movements of GCSE while leaving the patient in nonconvulsive SE. Patients who do not begin to respond to external stimuli 15 minutes after the apparent termination of GCSE should be considered at risk for nonconvulsive SE and undergo emergency EEG monitoring.

A Administer LRZ 0.1 mg/kg at 0.04 mg/kg/min.

    This drug should be diluted in an equal volume of the solution being used for intravenous infusion, because it is quite viscous. Most adult patients who will respond have done so by a total dose of 8 mg. The latency of effect is debated, but lack of response after 5 minutes should be considered a failure.

B Give MDZ if SE persists.

    Administer MDZ 0.2 mg/kg as a bolus, followed by an infusion of 0.1-2.0 mg/kg/hr to achieve seizure control (as determined by EEG monitoring). We routinely intubate patients at this stage if this has not already been accomplished. Patients reaching this stage should be treated in a critical care unit.

C Give propofol if MDZ is not effective.

    Should the patient’s SE not be controlled with MDZ, administer propofol at a dose of 50-250 µg/kg/min. Prolonged infusions of propofol have hemodynamic consequences similar to those with pentobarbital. Alternative agents include valproate, ketamine, and levetiracetam.

D Give pentobarbital if propofol is not effective.

    If propofol fails, use pentobarbital 12 mg/kg at 0.2-0.4 mg/kg/min as tolerated, followed by an infusion of 0.25-2.0 mg/kg/hr as determined by EEG monitoring (with a goal of burst suppression). Most patients will require systemic and pulmonary arterial catheterization, with fluid and vasoactive therapy as indicated to maintain blood pressure. Other complications of this treatment are discussed in the text.

V Prevent recurrence of SE.

    The choice of drugs depends greatly on the contributing/causative disorder and the patient’s medical and social situation. In general, patients who have not previously received anticonvulsants whose SE is easily controlled often respond well to chronic treatment with PHT or carbamazepine. By contrast, others (e.g., patients with acute encephalitis) will require two or three anticonvulsants at “toxic” levels (e.g., PB in doses greater than 100 µg/mL) to be weaned from MDZ or pentobarbital, and may still have occasional seizures.

VI Treat complications.

A Rhabdomyolysis

    Rhabdomyolysis should be treated with a vigorous saline diuresis to prevent acute renal failure; urinary alkalinization may be a useful adjunct. If definitive treatment of GCSE takes longer than expected because of hypotension or arrhythmias, neuromuscular junction blockade under EEG monitoring might be considered.

B Hyperthermia

    Hyperthermia usually remits rapidly after termination of SE. External cooling usually suffices if the core temperature remains elevated. In rare instances, cool peritoneal lavage or extracorporeal blood cooling may be required. High-dose pentobarbital generally produces poikilothermia.

C Cerebral edema

    The treatment of cerebral edema secondary to SE has not been well studied. When substantial edema is present, SE and cerebral edema are likely to be manifestations of the same underlying condition. Hyperventilation and mannitol may be valuable if edema is life-threatening. Edema due to SE is vasogenic, so steroids may be useful as well.

EEG, electroencephalogram; GCSE, generalized convulsive status epilepticus; LRZ, lorazepam; MDZ, midazolam; PB, phenobarbital; PHT, phenytoin.

Some frequent errors in the use of medications to terminate SE include (1) use of inadequate doses of potentially effective agents and, conversely, (2) continued administration of drugs that are ineffective in the patient being treated. The first point most frequently applies to PHT; the proverbial “gram of Dilantin” is not adequate for patients weighing more than 50 kg.

Specific Agents

Benzodiazepines

LRZ is emerging as the agent of first choice for terminating SE. A study in the Veterans Affairs medical system compared LRZ, DZ followed by PHT, PHT alone, and PB as first-line agents and demonstrated that LRZ is the definitive agent of first choice.48 The advantages of LRZ over PHT include (1) its longer duration of action against SE (4-14 hours as opposed to 20 minutes) and (2) a higher initial response rate.49 One study concluded that children receiving PHT for SE were far more likely to require intubation for ventilatory failure than comparable children receiving LRZ50; the same was true for all ages in the San Francisco Prehospital Status Study.51 PHT and LRZ remain the only agents in this class with FDA indications for SE. In Europe, midazolam (MDZ) or clonazepam is often used initially. MDZ is exceptionally useful for refractory SE, but it is hampered by tachyphylaxis,52 which occurs because the GABAA receptors bearing benzodiazepine-sensitive subunits are removed from the neuronal cell membrane and replaced with receptors bearing benzodiazepine-insensitive ones.53 Respiratory depression is the major adverse effect of all agents in this class when administered intravenously.

Data from the Veterans Affairs cooperative trial indicate that the use of other conventional agents after failure of the first one is very unlikely to terminate SE.49

Hydantoins

PHT is an effective anti-SE agent but cannot be delivered rapidly enough to be used as a first-line agent. Its major advantage is a very long duration of action once an adequate dose has been administered (the 20-mg/kg loading dose reliably produces a total serum concentration above 20 µg/mL for 24 hours). Concerns about its intravenous administration were discussed earlier. If the patient is no longer in SE during PHT administration, a slower rate should be employed.

PHT is highly insoluble, and it must be dissolved in sodium hydroxide and propylene glycol at a pH greater than 11 to remain in solution. Therefore, extravasation can produce severe necrosis. The drug can also cause thrombophlebitis, which may result in the “purple glove syndrome.”54

Fosphenytoin is a PHT prodrug, which is converted to PHT by phosphatases with a half-life of about 7 minutes. It is prescribed in “PHT equivalents,” so the loading dose remains 20 mg/kg. The maximal recommended rate of infusion is 150 mg/minute, but it should be started more slowly and increased to this rate if tolerated. Because it is water-soluble, extravasation does not pose the problem of skin and soft tissue necrosis.

Hydantoins should not be used in absence SE, as they may worsen the condition.

Barbiturates

PB has long been one of the major anti-SE agents. Some advocate it as a first-line drug,55 but it is rarely used in this role. It has classically been a third-line agent for control of SE, after a benzodiazepine and PHT. Its utility in SE is diminished by the length of time required to obtain a therapeutic effect in patients who have already failed with a benzodiazepine and PHT. It remains an important agent in patients with simple partial SE, and in preparing patients to be withdrawn from high-dose pentobarbital.

Pentobarbital and thiopental are commonly reserved for the control of refractory SE, although thiopental is not currently available in the United States. Although these agents will be effective if used in large enough doses, side effects often limit their use56 or may even be fatal.57 They are important when other rapidly available modalities have failed (see Box 65.3).

Valproate

Intravenous valproate, given in a dose of 20 to 30 mg/kg, has gained popularity for the treatment of SE because it does not produce respiratory depression or marked sedation. It has been successful in case series58,59 but has not been directly compared to the other available agents. Hypotension may occur with large doses.60 This drug should be avoided if the patient has an inborn error of metabolism affecting the liver, as it may precipitate fulminant hepatic failure.61 Valproate has a number of drug interactions that limit its utility in the ICU.62

Propofol

Propofol has been reported effective in refractory SE in doses up to 250 µg/kg/minute64 but has not been directly compared with other drugs. It theoretically offers a lower risk of respiratory depression and more rapid recovery of consciousness after the agent is stopped. We use it in SE patients who have failed or become resistant to MDZ.65 One should observe for evidence of the propofol infusion syndrome and stop the drug should a metabolic acidosis or evidence of muscle injury develop.

Ketamine

Although only anecdotes and small case series are available, ketamine appears to be a useful agent for the termination of refractory SE.66 Its NMDA blocking effect distinguishes it from the other agents discussed here, and it carries theoretical advantages in terms of brain protection.67 Its intrinsic sympathomimetic effect makes it a useful choice in hypotensive patients, and it does not markedly impair ventilation. The appropriate dose in SE has not been established; we use a loading dose of 1 to 5 mg/kg, with an infusion rate of 10 to 50 µg/kg/minute.

Controversial Management Issues

Controversy remains regarding the long-term neurologic consequences of two clinical conditions: periodic lateralized epileptiform discharges (PLEDs) and EPC. PLEDs are an EEG phenomenon usually seen in the setting of large acute strokes or rapidly expanding mass lesions (e.g., tumors or abscesses). Less commonly, acute metabolic or toxic disorders will “reactivate” PLEDs in the vicinity of an old lesion. The EEG activity signifies the repetitive, synchronous firing of large numbers of neurons near the lesion; there is occasionally contralateral myoclonic jerking of the hand or face. Expert opinion is divided regarding the possibly epileptic nature of these phenomena. Patients who have clinical seizures (i.e., other than the myoclonic jerks) should receive anticonvulsants. The myoclonic movements associated with PLEDs are difficult to suppress without resorting to high-dose barbiturates or benzodiazepines. The data available do not suggest that suppressing the electrical phenomenon improves outcome.

EPC is usually diagnosed in a patient who has an isolated repetitive movement (usually of the hand or face), often following an infectious or vascular insult, or in the setting of nonketotic hyperglycemia.73 The movement may persist for months or years. Most patients receive anticonvulsants to prevent spread of the discharge, but these agents seldom affect EPC itself. Attempts at treatment with high-dose barbiturates result in short-term suppression of the movement, but it usually returns as the drug levels decline.

Another area of contention concerns the periodic epileptiform discharges occasionally seen after respiratory or cardiac arrests. Because experimental studies show that neurons in anoxic animals exhibit epileptiform behavior, some have raised the possibility that these discharges are a form of SE and should therefore be treated. Although this possibility has not been systematically studied in humans, the lack even of anecdotes of neurologic improvement with anticonvulsant treatment suggests that currently available anticonvulsant drugs do not improve patient outcome in this condition. If it is associated with myoclonus that the family finds disconcerting, suppression of the movements with neuromuscular junction blockers may be useful. High-dose barbiturates or benzodiazepines will also stop the movements, but they obscure the neurologic examination and complicate the possible diagnosis of brain death. These drugs do not improve prognosis in postanoxic patients.

Prognosis

Wijdicks and Sharbrough reported that 34% of patients experiencing a seizure in any ICU at the Mayo Clinic died during that hospitalization.11 In our prospective study of neurologic complications in medical ICU patients,10 having even one seizure while in the unit for a non-neurologic reason doubled the patient’s in-hospital mortality rate. This effect on prognosis appeared to be due to the effect of the cause of the ictus, rather than the seizure itself.

Three major factors determine the outcome of SE: the type of SE, its cause, and its duration. In general, GCSE carries the worst prognosis for neurologic recovery as a consequence of SE itself; myoclonic SE following an anoxic episode carries a very poor prognosis for survival. CPSE produces some risk of limbic system damage, usually manifested by memory dysfunction. Simple partial SE may produce neuronal damage, but this is difficult to discern from the effect of the lesion that commonly produces this form of SE. At the far end of the spectrum, absence SE does not seem to carry a risk of neurologic deterioration.

Most studies of SE outcome have concentrated on mortality rates in GCSE. Hauser18 summarized the data available in 1990, showing mortality rates for SE to vary from 1% to 53%. The few studies that attempted to distinguish the mortality rate due to SE from that of the underlying disease attributed rates of 1% to 7% to SE and 2% to 25% to its cause. The Virginia Commonwealth University population-based studies have analyzed the mortality risks for various aspects of GCSE.12 SE lasting longer than 1 hour was associated with a 10-fold increase in mortality rate when compared to SE lasting less than 1 hour. Other causes associated with marked increases in mortality rate were anoxia, intracranial hemorrhages, tumors, infections, and trauma.

Very few findings are available regarding the functional status of GCSE survivors, and none reliably allows a distinction between the effects of SE and its causes. A review of intellectual impairment as an outcome of SE concluded intellectual abilities probably did decline as a consequence of SE.74 Survivors of SE frequently have memory and behavioral disorders out of proportion to any structural damage produced by the cause of their seizures. This observation is supported by a wealth of experimental data and argues strongly for the rapid and effective control of SE. The prognosis of CPSE is less certain, but case reports of severe memory deficits following prolonged CPSE have appeared.75

The effect of the treatment of SE on the risk of subsequent epilepsy is uncertain. Experimental studies suggest that SE does lower the threshold for subsequent seizures.76

Key Points

• Seizures lasting longer than 1 hour markedly increase mortality risk compared to seizures lasting less than 1 hour.

• Primary generalized seizures arise from the entire cerebral cortex without evidence of focal point.

• In addition to damaging the CNS, GCSE produces serious, often life-threatening, systemic effects that include cardiovascular, respiratory, and muscular systems.

• Hypersensitivity to PHT is the major adverse effect of concern to the intensivist. This allergy may be manifested solely as fever but more commonly includes a rash and eosinophilia. Rarely Stevens-Johnson syndrome occurs.

• The patient who seizes during ethanol withdrawal will probably not benefit from chronic anticonvulsant treatment, and the administration of PHT will not prevent more withdrawal convulsions during the same episode.

• Errors in the use of medications to terminate SE include (1) use of inadequate doses of potentially effective agents and, conversely, (2) continued administration of drugs that are ineffective in the patient being treated.

• Myoclonic SE following an anoxic episode carries a very poor prognosis for survival.

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