Epidemiology

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.⁹ Our 2-year prospective study of medical ICU patients identified 35 with seizures per 1000 admissions.¹ These two studies are not exactly comparable, as the patient populations and methods of detection differed. A recent series found 8% of comatose patients without clinical signs of seizure activity to be in electrographic status epilepticus.¹⁰

Up to 34% of hospital in-patients experiencing a seizure die during their hospitalization.¹ Our prospective study of neurologic complications in medical ICU patients showed that having even one seizure while in the ICU for a non-neurologic reason doubled in-hospital mortality.¹⁰ Incidence estimates for generalized convulsive status epilepticus in the United States vary from 50,000 cases per year¹¹ to 195,000 cases per year.¹² Some portion of this difference can be accounted for by different definitions; however, the latter estimate represents the only population-based data available and may be more accurate. Mortality estimates similarly vary from 1% to 2% in the former study to 22% in the latter. This disagreement follows from a conceptual discordance: the smaller number describes mortality the authors directly attribute to status epilepticus, whereas the larger figure estimates the overall mortality rate, even though death was frequently caused by the underlying disease rather than by status epilepticus itself. The elderly have an incidence of status epilepticus almost twice that of the general population and the highest associated mortality rate of any age group at 38%.¹³

Table 36-1 summarizes the most common causes of status epilepticus in adults in the community. Almost 50% of the cases were attributed to cerebral vascular disease.¹¹ Garzon and colleagues¹⁴ found antiepileptic drug noncompliance as the main cause of status epilepticus in patients with a prior history of epilepsy, and CNS infection, stroke, and metabolic disturbances predominated in the group without previous seizures.

TABLE36-1 Causes of Status Epilepticus in Adults Presenting from the Community

CNS, central nervous system.

Three major factors determine outcome in patients with status epilepticus: the type of status epilepticus, its cause, and its duration. Generalized convulsive status epilepticus has the worst prognosis for neurologic recovery; myoclonic status epilepticus following an anoxic episode carries a very poor prognosis for survival. Complex partial status epilepticus can produce limbic system damage, usually manifested as a memory disturbance. Causes associated with increased mortality included anoxia, intracranial hemorrhages, tumors, infections, and trauma. The mortality of patients with nonconvulsive status epilepticus has been reported as high as 33%¹⁵ and correlates with the underlying cause, severe impairment of mental status, and the development of acute complications, especially respiratory failure and infection.¹⁶ Data strongly suggest that prolonged seizure duration is a negative prognostic factor. A study of 253 adult status epilepticus patients demonstrated a 30-day mortality rate of 2.7% in patients with seizures lasting 30 to 59 minutes, compared with 32% in those with seizures of 60 minutes or longer.¹⁷

Limited data are available concerning the functional abilities of generalized convulsive status epilepticus survivors, and no data reliably permit a distinction between the effects of status epilepticus and effects of its causes. One review concluded that intellectual ability declined as a consequence of status epilepticus.¹⁸ Survivors of status epilepticus frequently seem to have memory and behavioral disorders out of proportion to the structural damage produced by the cause of their seizures. Case reports of severe memory deficits following prolonged complex partial status epilepticus have been published.¹⁹ Conversely, one prospective study of 180 children with febrile status epilepticus demonstrated no deaths and no cases of new cognitive or motor handicap.²⁰ Experimental animal²¹ and human epidemiologic²² studies suggest that status epilepticus may be a risk factor in the development of future seizures. Whether treatment of prolonged seizures reduces the risk of subsequent epilepsy remains uncertain.

Classification

The most frequently used classification scheme is that of the International League Against Epilepsy (Box 36-1).²³ This scheme allows classification on clinical criteria without inferring cause. Simple partial seizures start focally in the cerebral cortex without invading other structures. The patient is aware throughout the episode and appears otherwise unchanged. Bilateral limbic dysfunction produces a complex partial seizure; awareness and ability to interact are diminished (but may not be completely abolished). Automatisms (movements a patient makes without awareness) may occur. Secondary generalization results from invasion by epileptic electrical activity of the other hemisphere or subcortical structures.

Primary generalized seizures arise from the cerebral cortex and diencephalon at the same time; no focal phenomena are visible, and consciousness is lost at the onset. Absence seizures are frequently confined to childhood; they consist of the abrupt onset of a blank stare that usually lasts 5 to 15 seconds, after which the patient abruptly returns to normal. Atypical absence seizures occur in children with the Lennox-Gastaut syndrome. Myoclonic seizures start with brief synchronous jerks without alteration of consciousness, initially followed by a generalized convulsion. They frequently occur in patients with genetic epilepsy; in the ICU, they commonly follow anoxia or metabolic disturbances.²⁴ Tonic-clonic seizures start with tonic extension, evolve to bilaterally synchronous clonus, and conclude with a postictal phase. Clinical judgment is required to apply this system in the ICU. In patients in whom consciousness has already been altered by drugs, hypotension, sepsis, or intracranial pathologic lesion, the nature of partial seizures may be difficult to classify.

Status epilepticus is classified by a similar system that has been altered to match observable clinical phenomena (Box 36-2).²⁵ Generalized convulsive status epilepticus is the most common type encountered in the ICU and poses the greatest risk to the patient. It may either be primarily generalized, as in the drug-intoxicated patient, or secondarily generalized, as in the brain abscess patient who develops generalized convulsive status epilepticus. Nonconvulsive status epilepticus in the ICU frequently follows partially treated generalized convulsive status epilepticus. Some practitioners use the term for all cases of status epilepticus that involve altered consciousness without convulsive movements; this blurs the distinctions among absence status epilepticus, partially treated generalized convulsive status epilepticus, and complex partial status epilepticus, which have different causes and treatments. Epilepsia partialis continua (a special form of partial status epilepticus in which repetitive movements affect a small area of the body) sometimes continues for months or years.

The International League Against Epilepsy 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.²⁶

Pathogenesis and Pathophysiology

The causes and effects of status epilepticus at the cellular, brain, and systemic levels are interrelated, but their individual analysis is useful for understanding them and their therapeutic implications. The ionic events of a seizure follow the opening of ion channels coupled to excitatory amino acid receptors. From the standpoint of the intensivist, three channels are particularly important, because their activation may raise intracellular free calcium to toxic concentrations: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and metabotropic channels. These excitatory amino acid systems are crucial for learning and memory. Many drugs that block these systems are available but are too toxic for chronic use. Counter-regulatory ionic events are triggered by the epileptiform discharge as well, such as the activation of inhibitory interneurons which suppress excited neurons via GABA_A synapses.

The cellular effects of excessive excitatory amino acid channel activity include (1) generation of toxic concentrations of intracellular free calcium; (2) activation of autolytic enzyme systems; (3) production of oxygen free radicals; (4) generation of nitric oxide, which both enhances subsequent excitation and serves as a toxin; (5) phosphorylation of enzyme and receptor systems, making seizures more likely; and (6) an increase in intracellular osmolality, which produces neuronal swelling. If adenosine triphosphate production fails, membrane ion exchange ceases, and neurons swell further. These events produce the neuronal damage associated with status epilepticus. Longer status epilepticus duration produces more profound alterations and an increasing likelihood of permanence and of becoming refractory to treatment.²⁷ The processes involved in a single seizure and the transition to status epilepticus have been reviewed.²⁸

Many other biophysical and biochemical alterations occur during and after status epilepticus. The intense neuronal activity activates immediate-early genes and produces heat shock proteins, providing indications of the deleterious effects of status epilepticus and insight into the mechanisms of neuronal protection.²⁹ The mechanisms by which status epilepticus damages the nervous system have been reviewed.³⁰ Absence status epilepticus is an exception among these conditions; it consists of rhythmically increased inhibition and does not produce clinical or pathologic abnormalities.

The electrical phenomena of status epilepticus at the whole brain level, as seen in the scalp electroencephalogram (EEG), reflect the seizure type that initiates status epilepticus (e.g., absence status epilepticus begins with a 3-Hz wave-and-spike pattern). During status epilepticus, this rhythm slows, but the wave-and-spike characteristic remains. Generalized convulsive status epilepticus goes through a sequence of electrographic changes (Table 36-2).³¹ The initial discharge becomes less well formed, implying that neuronal firing loses synchrony. The sustained depolarizations that characterize status epilepticus alter the extracellular milieu, most importantly by raising extracellular potassium. The excess potassium ejected during status epilepticus exceeds the buffering ability of astrocytes.

TABLE36-2 Electrographic-Clinical Correlations in Generalized Convulsive Status Epilepticus

^* 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.

Data from Treiman DM. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34: S2-11.

The increased cellular activity of status epilepticus elevates demand for oxygen and glucose, and cerebral blood flow initially increases. After approximately 20 minutes, however, energy supplies are exhausted, causing local catabolism to support ion pumps (in an attempt to restore the internal milieu); this is a major cause of epileptic brain damage. In addition to damaging the CNS, generalized convulsive status epilepticus produces life-threatening systemic effects.³² Excess secretion of epinephrine and cortisol cause systemic and pulmonary arterial pressures to rise dramatically at seizure onset and also produce hyperglycemia. Muscular work raises blood lactate levels. Both airway obstruction and abnormal diaphragmatic contractions impair respiration. Carbon dioxide excretion falls while its production increases markedly. Muscular work accelerates heat production, raising core body temperature.

The combined respiratory and metabolic acidoses frequently reduce the arterial blood pH to 6.9 or lower. The acidemia may produce hyperkalemia; in addition to its deleterious effects on cardiac electrophysiology, the elevated extracellular potassium level helps propagate seizure activity. Coupled with hypoxemia and the elevation of circulating catecholamine concentrations, these conditions rarely can produce cardiac arrest. This sequence probably accounts for some cases of epileptic sudden death; neurogenic pulmonary edema is the likely cause of many others. The severity of the acidosis may prompt consideration of bicarbonate administration. When this is attempted, however, the likelihood of the occurrence of pulmonary edema is inordinately high. Rapid termination of seizure activity is the most appropriate treatment; the restitution of ventilation and the metabolism of lactate quickly restore a normal pH.

After approximately 30 minutes of continuous convulsions, motor activity may diminish while electrographic seizures persist. Hypotension and hyperthermia ensue, and gluconeogenesis can fail, resulting in hypoglycemia. Generalized convulsive status epilepticus patients often aspirate oral or gastric contents, producing chemical pneumonitis or bacterial pneumonia. Rhabdomyolysis is common and may lead to renal failure. Compression fractures, joint dislocations, and tendon avulsions are other serious sequelae.

The mechanisms that terminate seizure activity are poorly understood. The leading candidates are inhibitory mechanisms, primarily GABA-ergic interneurons and inhibitory thalamic neurons.

Clinical Manifestations

Three problems complicate seizure recognition: (1) the occurrence of complex partial seizures in the setting of impaired awareness, (2) the occurrence of seizures in patients receiving pharmacologically induced paralysis and/or sedation, and (3) misinterpretation of other abnormal movements as seizures. ICU patients often have depressed consciousness in the absence of seizures owing to their disease, its complications (such as hepatic³³ or septic³⁴ encephalopathy), or drug administration. A further decline in alertness may reflect a seizure; an EEG is required to confirm that one has occurred.

Patients receiving neuromuscular junction blocking agents do not manifest the usual signs of seizures. Patients with increased intracranial pressure (ICP) from primary brain injury, hepatic encephalopathy, or other critical illnesses may be both paralyzed and sedated, making identification of seizures particularly challenging. Tachycardia, tachypnea, 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.