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  Seizures are a relatively common occurrence in the intensive care unit (ICU), but may be difficult to recognize.

  
  
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  Seizures that persist longer than 5 to 7 minutes should be treated to prevent progression to status epilepticus.

  
  
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  Three major factors determine outcome in status epilepticus: type of seizure, cause, and duration.

  
  
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  Electroencephalographic (EEG) monitoring to titrate therapy should be implemented in seizing patients who do not awaken promptly after institution of antiepileptics, even if tonic-clonic motor activity resolves.

  
  
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  Lorazepam is a preferred agent for initial treatment, followed by consideration of additional agents for long-term management or to “break” status epilepticus.

  
  
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  Patients with refractory status epilepticus require intubation, mechanical ventilation, and aggressive treatment with antiepileptics titrated to the EEG.

  
  
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  The underlying cause of the seizure disorder must be sought in tandem with treatment of the seizure disorder itself.

Seizures are a relatively common occurrence in the ICU, complicating the course of about 3% of adult ICU patients admitted for nonneurologic conditions.¹ Status epilepticus (SE) may be the primary indication for admission, or it may occur in any ICU patient during a critical illness. Seizures are second to metabolic encephalopathy as a cause of neurological complications (28.1%).¹ A seizure may be the first indication of a central nervous system (CNS) complication or the result of overwhelming systemic disease. Seizures in the setting of critical illness are often difficult to recognize and require a complex diagnostic and management strategy. Delay in recognition and treatment of seizures is associated with increased mortality,² thus the rapid diagnosis of this disorder is mandatory. Conventionally, status epilepticus referred to a protracted seizure episode or multiple frequent seizures lasting 30 minutes or longer. However more recently, revised definitions have suggested to consider seizures lasting for 5 minutes or longer as status epilepticus,^3-5 and newer guidelines define status epilepticus as five minutes or more of either continuous clinical and/or electrographic seizure activity, or recurrent seizure activity without recovery between seizures.⁶

While most seizures will terminate spontaneously within a few minutes,⁵ only half of seizure episodes lasting 10 to 29 minutes will stop spontaneously⁷ and aggressive treatment should be administered to prevent ongoing SE.⁸

Limited data are available on the epidemiology of seizures in the ICU. A 10-year retrospective study of all ICU patients with seizures at the Mayo Clinic revealed that 7 patients had seizures per 1000 ICU admissions.⁸ Our 2-year prospective study of medical ICU patients identified 35 with seizures per 1000 admissions.¹ The incidence of generalized convulsive SE (GCSE) in the United States is estimated to be up to 195,000 episodes per year,⁹ but it is unknown how many of these patients require care in an ICU. The incidence of SE in the elderly is almost twice that of the general population.¹⁰ Nonconvulsive seizures and NCSE are present in a large proportion of comatose patients with traumatic brain injury, intracranial hemorrhage, sepsis, cardiac arrest, or CNS infection.^11-15 In one series, 8% of hospitalized comatose patients were found to be in electrographic status epilepticus,¹⁵ up to 34% of patients in neurological ICUs,¹⁵ and other series of patients with altered mental status found 37% to have nonconvulsive seizures.¹⁶ Of all patients with status epilepticus, about 80% have nonconvulsive status epilepticus.¹⁷ Seizures are probably even more frequent in the pediatric ICU, as children in the first year of life have the highest incidence of SE of any age group studied.⁸

Table 85-1 summarizes the most common causes of SE in adults and children in the community. An analysis of 204 cases of SE in Virginia revealed that the primary etiology in children was infection with fever, followed by remote symptomatic epilepsy, and subtherapeutic levels of anticonvulsant drugs. In adults, cerebrovascular disease and low antiepileptic drug levels were the most prevalent causes.⁸ A recent study from Brazil found anticonvulsant noncompliance to be the main cause of SE in patients with a prior history of epilepsy, and CNS infection, stroke, and metabolic disturbances predominated in the group without previous seizures.¹⁸ A prospective study of neurologic complications in medical ICU patients determined that two-thirds of patients had a vascular, infectious, or neoplastic explanation for their seizures¹; metabolic and toxic etiologies are common in the ICU as well. A review of 100 cases of nonconvulsive SE (NCSE) demonstrated that 14% were due to acute neurologic events, 28% due to acute systemic causes, and 31% due to epilepsy, with the remainder due to multiple causes or a cryptogenic etiology,¹⁹ and among patients with NCSE in a comatose state, hypoxia (42%) and stroke (22%) were the most common etiologies.¹⁵ In medical ICU patients, electrographic seizures or periodic epileptiform discharges were detected in 22% of patients, with the predominant underlying disease state being sepsis.¹³ It is important to realize that the frequency of diagnosing NCSE will rise with implementation of continuous EEG monitoring by 6% to 8% accounting for the increment of investigations.²⁰

A prospective study of neurologic complications in medical ICU patients showed that having one seizure in the ICU doubled mortality.¹ At least 20% of patients with status epilepticus die,^21,22 and up to 61% of patients developing SE during hospitalization do not survive.²³ SE in and of itself confers a mortality rate of 26% to adults older than 16 years and 38% to those 60 years and older.⁸ Multiple reports corroborate an especially poor outcome in the elderly.^15,24 The mortality rate of SE in children is 3% in the general population and 6% in the ICU,²⁵ and much higher if a preexisting significant neurological deficit is present.²⁶ Factors determining outcome in SE include the type of SE, the cause, and the duration. In a 90-day follow-up study after convulsive SE, longer seizure duration, presence of cerebral insult, and progression to refractory SE were associated with a worse outcome, only 8% of all patients whose SE was characterized by those three factors had a good outcome, as opposed to 65% of patients who had SE but none of those factors.²¹ Based on the combined assessment of previous history of seizures, seizure type, extent of impairment of consciousness, and age, a prognostic score has been recently suggested for outcome prediction (STESS, status epilepticus severity score).²⁷ Better outcomes are observed if the status is convulsive or focal, as opposed to nonconvulsive, and if the underlying etiology is epileptic or toxic.²⁸ Anoxic SE, including myoclonic SE following an anoxic episode carries a very poor prognosis for survival. Survivors of SE may experience impaired cognitive function, motor deficits, and worsening of preexisting epilepsy.²⁹ Particularly, complex partial SE (CPSE) can produce limbic system damage, usually manifested as a memory disturbance.

The mortality of patients with NCSE has been reported between 17% and 57%,² and correlates with the underlying etiology, severity of impairment of mental status, and the development of acute complications (especially respiratory failure and infection). Older age had a positive influence on outcome in one series.¹⁷ Causes associated with increased mortality included anoxia, intracranial hemorrhage, tumor, infection, and trauma. Status epilepticus in the setting of acute ischemic stroke has a very high mortality, approaching 35%.³⁰ Prolonged seizure duration is a negative prognostic factor.³¹ A study of 253 adult SE patients showed a greater than tenfold increase in mortality rate associated with seizures lasting ≥60 minutes compared with those lasting 30 to 59 minutes.³²

In children who are treated for SE in an ICU, the mortality is reported close to 10%. Etiology of SE and prior neurologic abnormalities are predictors of mortality; younger age, etiology, and duration of SE were associated with morbidity.³³

The International League Against Epilepsy’s (ILAE) classification of seizures is generally accepted. The system allows classification on the basis of clinical criteria without inferring cause. Knowledge of interictal or ictal electroencephalographic (EEG) findings is not necessary to classify seizures except for absence seizures, which are not likely to be a problem in the ICU. The classification system divides seizures into two types: partial, which have a focal or localized onset, and generalized, in which the cortex of both cerebral hemispheres is involved simultaneously at onset. Partial seizures can further be categorized as simple, in which consciousness remains intact throughout the event, or complex, in which consciousness is disrupted or altered (but not lost), often resulting in amnesia for the event. Seizures that start locally and then spread to involve the entire cortex are termed secondary generalized. Generalized seizures are of two types: convulsive, in which tonic, clonic, or myoclonic movements are prominent, and nonconvulsive, in which a patient has an altered level of consciousness with or without very subtle motor manifestations.

The clinical manifestation of partial seizures varies with the location of their onset. Motor seizures are usually due to a lesion in the contralateral frontal lobe. Deviation of eyes and head toward the irritative focus is often seen at the onset of seizure activity and is termed versive movement. Careful observation of the direction of this initial movement provides important diagnostic information regarding the location of brain pathology. Muscle contractions may be localized to a small region, such as the face or fingers, or be more extensive, involving the entire hemibody. Movements are usually tonic or clonic, but dystonic posturing is also common. Sensory seizures can be primarily auditory, somatosensory, visual, or consist of vague visceral sensations. Patients with complex partial seizures may demonstrate any combination of the above symptoms and have associated motor automatisms, such as lip smacking or swallowing.

Generalized convulsive seizures are usually of the tonic-clonic type. During the tonic phase, initial extension of the trunk is followed by extension of the arms, legs, neck, and back. The respiratory muscles may be involved in the tonic spasm, resulting in cyanosis and decreased oxygen saturation if the tonic phase is long enough, although this is rare. The clonic phase follows and is manifest by repetitive muscle contractions. Fixed and dilated pupils, tachycardia, and hypertension are well described during tonic-clonic seizures. Incontinence usually follows termination of the seizure. The frequency of the clonus eventually wanes and respiration commences when the seizure stops. Patients may initially be deeply comatose but should begin to regain consciousness within 15 to 20 minutes.

Status epilepticus refers to prolonged or serial seizures without interictal resumption of baseline mental status. Refractory SE refers to SE that is resistant to treatment with first-line measures and requires more aggressive therapy. Super-refractory status epilepticus is refractory SE which is unresponsive to initial anesthetic therapy as it continues or recurs 24 hours or more after the onset of anesthesia, or on the reduction or withdrawal of anesthesia. Description of specific treatment modalities will be reviewed below. Epilepsia partialis continua is a special type of focal motor epilepsy that consists of near constant muscle contractions of a specific muscle group. These movements can last for months or years without generalizing.

There are theoretically as many different types of SE as there are seizures, since SE is a prolonged seizure. However, SE cannot be classified in exactly the same manner as individual seizures, because seizures are discrete time-limited events with symptomatology restricted to the brief duration of their occurrence. SE, on the other hand, can evolve over time and therefore can have a symptomatology that may encompass more than one seizure type. Furthermore, NCSE can have similar signs and symptoms with different EEG signatures and etiologies. The simplest classification divides SE into generalized convulsive SE and nonconvulsive SE, depending on whether convulsive movements are present. Since NCSE includes everything that is not convulsive, it describes a wide variety of clinical entities and scenarios.

The conventional method of subcategorizing NCSE is to divide it into absence SE and complex partial SE. This works well for patients with a previous history of epilepsy. In this context, absence SE denotes confusion, typically mild, in a patient with generalized, approximately 3-Hz spike-wave discharges on EEG and a history of generalized epilepsy. Complex partial SE denotes confusion, typically waxing and waning, or recurrent complex partial seizures associated with focal seizures in a patient with focal epilepsy. As defined herein, both types of NCSE imply that the encephalopathy is due to seizure activity. Historically, NCSE was labeled “absence” type if generalized EEG changes were found and “complex partial” if focal EEG changes were found, regardless of whether a history of epilepsy was present.

Many patients with NCSE do not have a history of epilepsy and do not fit into the conventional categorization elaborated above. For example, in a retrospective study of NCSE, we did not find any association between EEG findings and mortality,¹⁹ emphasizing that this categorization is not very useful. This is particularly a problem in ICU patients in whom there are typically numerous factors contributing to encephalopathy. This nosologic uncertainty has given rise to several terms to describe NCSE arising in the ICU, including ICU status, subtle generalized convulsive status epilepticus, EEG status, and status in the critically ill. An important aspect of ICU status is that encephalopathy often has other causes in addition to the seizure activity.

NCSE is of particular importance to the intensivist when it occurs as a sequela of inadequately treated GCSE. After prolonged generalized convulsions, visible motor activity may stop, but the electrochemical seizure continues. Patients who do not start to awaken after 20 minutes should be assumed to have entered NCSE. NCSE following GCSE is a dangerous problem because the destructive effects of SE continue even without obvious motor activity. NCSE in this setting demands emergent treatment guided by electroencephalographic monitoring to prevent further cerebral damage since there are no clear clinical criteria to indicate whether therapy is effective.

NCSE can occur as a late stage of convulsive SE from any etiology, or as an initial form of SE from another cause. Failure to recognize NCSE is common in patients presenting with nonspecific neurobehavioral abnormalities, such as delirium, lethargy, bizarre behavior, cataplexy, or mutism.³⁴ A high level of suspicion for this disorder should be maintained in patients with unexplained alteration in level of consciousness or cognition who are admitted to the ICU.

Two special circumstances with which the intensivist should be familiar are myoclonus and febrile seizures. Brief, shock-like, involuntary muscle contractions constitute myoclonus. Myoclonic jerks are arrhythmic, of variable amplitude, and involve both small and large muscles. In patients with postanoxic coma, myoclonus may be continuous or evoked by stimuli such a noise or touch. While this disorder has been associated with epileptiform discharges in the EEG,³⁵ not all episodes of myoclonus are epileptic; an EEG can clarify whether it is epileptic in individual cases. Postanoxic myoclonus also occurs in patients who have regained consciousness (the Lance-Adams syndrome); in this setting the myoclonus is probably of cerebellar origin and is not a seizure. Febrile seizures are specific to young children and are usually generalized motor convulsions that occur in association with fever, typically as the temperature is rising. These seizures should not be confused with those that transpire in the setting of fever secondary to infection of the nervous system. Febrile seizures are usually brief, but can be prolonged and recurrent, prompting admission to an ICU.

Clinical judgment is required to classify seizures in the ICU. Patients in whom consciousness has already been altered by drugs, hypotension, sepsis, or intracranial pathology may be difficult to classify using only the ILAE classification because it depends heavily on whether the seizure activity has altered consciousness. However, focal seizure activity on EEG or focal neurologic deficits often helps determine whether the seizure is focal or generalized in onset. The ILAE continues to work toward revising and updating the current classification system. The goal is a multi-axis diagnostic scheme that incorporates anatomic, etiologic, therapeutic, and prognostic implications. For the most recent information regarding this ongoing project, refer to www.epilepsy.org.³⁶

The systemic and cerebral pathophysiology of GCSE can be divided into early and late phases.³⁷ The early phase of systemic manifestations results from an adrenergic surge and excessive muscle activity.³⁸ The adrenergic surge causes tachycardia, hypertension, and hyperglycemia. These are augmented by extreme muscle activity that causes hyperthermia and acidosis and can lead to muscle breakdown, rhabdomyolysis, and secondary acute renal failure. This stage is generally well compensated by homeostatic mechanisms so that the excessive demands are met with increased supply or other compensatory mechanisms.

Most facets of GCSE begin to slow down late in GCSE, so only a rare patient continues to have continuous convulsive motor activity for more than 1 hour. Cessation of continuous motor activity would seem to be a beneficial turn of events, but this is actually coincident with a sharp increase in mortality and in complications. Although systemic factors such as heart rate and blood pressure normalize, they may be inadequate to meet increased demands of intermittent convulsions or electrographic seizure activity, even in the absence of convulsions. Thus mortality increases dramatically for SE lasting longer than an hour.³¹ Death may result from a number of causes, but in a prospective study of cardiovascular changes during GCSE, 58% of patients had potentially fatal arrhythmias.³⁹ Patients with atherosclerotic cardiovascular risk factors may have a gradual deterioration in hemodynamic parameters as their cardiovascular reserve is expended, while other patients decline acutely, presumably from arrhythmias.⁴⁰

SE may cause neuronal injury in surviving patients. Some neuronal injury is caused by systemic factors; for example, hyperthermia causes cerebellar neuronal injury. However, neuronal injury continues during electrographic SE, even without motor manifestations or when physiologic parameters are held in the normal range. This is illustrated most clearly in experimental GCSE. Neuronal injury is prominent in the hippocampus and temporal lobe in primates with experimental GCSE. The injury persisted even when muscle activity was eliminated by paralysis, and pulse, blood pressure, temperature, and oxygenation were kept normal.

Neuronal injury during SE is due in part to the excitotoxic effects of glutamate-mediated neuronal seizure activity.³⁷ Glutamate is the most common excitatory neurotransmitter in the brain. It mediates transfer of information between neurons under normal conditions via several receptors. However, glutamate excessively activates the N-methyl-d-aspartate (NMDA) subtype of receptor in the robust conditions of SE. NMDA receptors have a limited normal function, but during SE they cause very prolonged depolarization of neurons. This results in intracellular accumulation of calcium and other cellular changes that result in both immediate and delayed cell death.³⁷

There are two important clinical implications of the pathophysiology of SE. First, neuronal injury continues during electrical SE even after control of motor manifestations. Therefore it is imperative to exclude ongoing seizure activity if patients are pharmacologically paralyzed after GCSE or do not awaken soon after motor activity stops. These circumstances require EEG monitoring to exclude ongoing seizure activity. Second, pharmacologic treatment is aimed at augmenting inhibition, via drugs that act on γ-aminobutyric acid (GABA), such as barbiturates and benzodiazepines. There will probably also be a role for NMDA antagonists. Ketamine is the only currently available NMDA antagonist, but others are likely to be helpful in the future.

Three problems complicate seizure recognition in the ICU: (1) occurrence of complex partial or nonconvulsive seizures in the setting of depressed consciousness, (2) masking of seizures by pharmacologically induced paralysis or sedation, and (3) misinterpretation of other abnormal movements as seizures. ICU patients often have decreased levels of consciousness in the absence of seizures that are ascribable to the underlying disease and its complications.¹ An encephalopathic patient may be unable to appreciate or report symptoms of seizure. Fluctuations in mental status are frequently subtle and may go unrecognized by staff. A decline in baseline alertness may reflect a seizure; an EEG may be required to confirm that one has occurred.

Patients receiving neuromuscular junction blocking agents do not manifest the motor signs of seizures. Patients with refractory intracranial hypertension, severe pulmonary disease, or other critical illnesses may be both paralyzed and sedated, making identification of seizures particularly challenging. Tachycardia and hypertension are signs of seizure that can be misinterpreted as evidence of inadequate sedation. Continuous EEG monitoring is warranted in this population if seizures are suspected.

Patients with metabolic disturbances, anoxia, and other types of nervous system injury may demonstrate abnormal movements that can be confused with seizure. Asterixis, or flapping tremor, is a brief arrhythmic loss of tone that can appear in the setting of hepatic encephalopathy, hypercarbia, drug intoxication, or CNS pathology.⁴¹ Myoclonus in postanoxic coma has been reported in the presence³⁴ and absence⁴² of epileptiform discharges. Therefore, EEG is absolutely indicated in this setting to evaluate for ongoing seizures. Action myoclonus in a patient recovering from hypoxic encephalopathy is evoked during movements directed at a target, such as an examiner’s finger. It is frequently associated with cerebellar ataxia and postural lapses, which when combined with myoclonus can severely impair ambulation. Myoclonus associated with etomidate is described,⁴³ but whether it is cortically mediated remains unclear. Brain-injured patients may suffer from so-called “hypothalamic seizures.” Tetanus patients do not lose consciousness during their spasms, and describe excruciating pain associated with the sustained whole-body contractions. Psychiatric disturbances in the ICU occasionally resemble complex partial seizures. If doubt about the nature of abnormal movements persists, an EEG should be performed.

The initial approach to seizure management is the same as that for any other acute medical problem: circulation, airway, and breathing. As described above, generalized convulsive status epilepticus often causes apnea and/or poor oxygen saturation. Hypertension and tachycardia may be marked. However, respiratory and hemodynamic dysfunction is transient, and with seizure termination rapidly returns to normal. Padded tongue blades or similar items should not be placed inside the mouth; they are more likely to obstruct the airway than to preserve it. Medication to treat tachycardia and hypertension before the seizure activity stops is not warranted.

When a patient has a seizure, one has a natural tendency to try to stop the event. This leads to both diagnostic confusion and iatrogenic complications. Beyond protecting the patient from harm, very little can be done rapidly to influence the course of the seizure. The seizures of most patients stop before any medication can reach the brain in an effective concentration. Observation is the most important activity to perform when a patient has a single seizure. This is the time to collect evidence of a partial onset in order to implicate structural brain disease. The postictal examination is similarly valuable; language, motor, sensory, or reflex abnormalities after an apparently generalized seizure are evidence of focal pathology.

Seizures in ICU patients have many potential causes that must be investigated. Medical conditions such as hepatic encephalopathy or acute hypothyroidism have been associated with seizures, particularly nonconvulsive status epilepticus.^44,45 Drugs are a major cause of seizures in critically ill patients, especially in the setting of renal or hepatic dysfunction. Imipenem-cilastatin⁴⁶ and fluoroquinolones⁴⁷ have the potential to lower the seizure threshold, particularly in patients with impaired renal function. Similarly, cephalosporins, particularly cefepime, have been associated with NCSE, especially in adult patients with impaired renal function.⁴⁸ Theophylline can provoke seizures or SE if it has been rapidly loaded or if high concentrations of the drug occur; however, these complications can also arise with normal serum drug levels.⁴⁹ Immunosuppressant agents such as cyclosporine or tacrolimus are known culprits for seizures, and as etiology for posterior reversible leucoencephalopathy, which may manifest primarily with seizures, but status epilepticus seems to arise only rarely.^50,51 Accumulation of a metabolite of meperidine, normeperidine, causes seizures, even in patients with normal renal function. Sevoflurane, a volatile anesthetic agent, also causes electrographic and clinical seizures without a history of epilepsy or CNS pathology.⁵² Other, less conventional etiologies include the use of tranexamic acid in cardiac surgery, which was found to be associated with postoperative seizures in patients with renal dysfunction.⁵³

Recreational drugs are frequently-overlooked offenders in patients presenting to the ICU. Acute cocaine or methamphetamine intoxication is characterized by a state of hypersympathetic activity followed by seizures.⁵⁴

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