34
CHAPTER
Status Epilepticus and Frequent Nonconvulsive Seizures
Keith E. Dombrowski
Status epilepticus (SE), particularly generalized convulsive status epilepticus (GCSE), is a common problem encountered in the United States and worldwide. In the simplest terms, SE is defined as the occurrence of incessant seizures without recovery in between. The International League Against Epilepsy (ILAE) defines SE as “a seizure which shows no clinical signs of arresting after a duration encompassing the great majority of seizures of the type in most patients or recurrent seizures without resumption of baseline central nervous system function interictally.” There are as many forms of SE as there are types of epilepsy. Of the various types of SE that are known, GCSE is the most common with an annual incidence of approximately 150,000. When considering the other forms of SE, the true incidence of SE is significantly higher. Though morbidity and mortality depend on the form of SE, current mortality estimates of GCSE are approximately 35%, with an additional 13% left with severe neurologic deficits (1). SE has been a known entity for much of human history but only in the past century have effective treatments been developed. EEG and now continuous EEG (cEEG) monitoring has helped define and shape diagnostic and treatment algorithms (2). Similarly, the development of emergency medical services and critical care has also played a significant role in effectively treating SE.
NOMENCLATURE
The impact of SE on the patient depends on the type and etiology of SE. GCSE carries the greatest risk for death and disability. Morbidity and mortality in nonconvulsive status epilepticus (NCSE) differs significantly based on the underlying etiology. NCSE is a broad term that encompasses absence SE, forms of simple and complex partial SE (CPSE), as well as NCSE in the critically ill. Absence or atypical absence status epilepticus appears to be a benign diagnosis that can be treated with oral medications in most cases. By contrast, focal status epilepticus or epilepsia partialis continua (EPC) that is caused by a brain tumor or abscess probably has a worse prognosis. NCSE in the critically ill is associated with worse neurologic outcome and is probably associated with neuronal injury.
ABSENCE STATUS EPILEPTICUS
Absence SE (ASE) is generally associated with idiopathic generalized epilepsy, including typical absence epilepsy and juvenile myoclonic epilepsy (JME). Other forms of ASE include atypical absence SE as seen in symptomatic, generalized epilepsy such as Lennox-Gastaut syndrome. Semilogically, ASE or atypical ASE is a subtype of NCSE, but there appears to be no association with resultant neuronal damage or increase in death or disability as a result of its occurrence. ASE has been defined as a state of altered consciousness, often with brief eyelid or limb jerking, that occurs in those with idiopathic or symptomatic generalized epilepsy and is associated with generalized spike and wave (GSW) EEG activity. Typical ASE is associated with 3 Hz or faster GSW, whereas atypical ASE is associated with slower GSW (less than 2.5 Hz). There are numerous reports of de novo ASE that can occur in the elderly and other cases that are situational or are provoked, such as in cases of benzodiazepine withdrawal (3). Treatments can be specific to the disorder in certain cases, but the first-line treatment for most cases of ASE will consist of intravenous benzodiazepines followed by phenytoin or valproic acid (VPA). Ethosuximide or VPA would both be reasonable choices for typical ASE, as either would likely be the maintenance drug of choice. VPA would be a reasonable choice in a patient with JME. The utility of new anticonvulsants is unknown and would be determined by the responsiveness of individual patients.
FOCAL STATUS EPILEPTICUS
Focal SE (FSE) can include a wide variety of prolonged (greater than 30 minutes) clinical manifestations, including repetitive focal motor, sensory, and myoclonic activity as well as uncommon cases of aphasia and visual loss. EPC is a type of motor FSE that consists of recurrent focal motor seizures that are often myoclonic but can consist of repetitive dystonic movements that can continue for days, week, or even years. In less common circumstances, FSE can be associated with an alteration in mental status, which is sometimes seen in patients with subdural hematomas and rarely in those with an orbitofrontal focus. The etiology of these conditions is typically from focal cerebral pathology, including tumor, trauma, and particularly stroke in the elderly. In children and young adults, Rasmussen’s encephalitis should certainly be considered as a cause (4). However, some diffuse conditions like nonketotic hyperglycemic hyperosmolar state and mitochondrial encephalopathies can be associated with FSE. These conditions can be difficult to diagnose depending on the presentation and are often frustrating to treat due to a variable pharmacologic response. cEEG monitoring is often helpful in confirming the diagnosis, but electrographic seizures often do not have a scalp EEG correlate due to very restricted foci of seizure activity. The utility of intracranial EEG monitoring is unknown but may be helpful in some circumstances. In many cases, the diagnosis of FSE may be entirely clinical or substantiated by functional imaging such as PET or SPECT to identify hypermetabolic areas of the brain. Pharmacologic control of FSE, particularly EPC, can be difficult and frequently require multiple medications. Little is known about the individual efficacy of different anticonvulsants, but topiramate and levetiracetam may be effective (5). Complete resolution of the seizures may not be possible in some circumstances or may require aggressive treatment such as hemispherectomy in Rasmussen’s encephalitis to prevent seizures and progression of the underlying disease. Surgical options should also be considered in other patients who have had refractory seizures caused by a focal lesion such as an abscess, tumor, or hematoma. The outcome of patients with FSE is variable and depends on the underlying condition that is associated with the FSE. Although focal sensory symptoms may not lead to further neuronal damage, focal motor SE in Rasmussen’s encephalitis is strongly correlated with outcome.
GENERALIZED CONVULSIVE STATUS EPILEPTICUS
Epidemiology
GCSE is the most common form of status epilepticus with 150,000 reported cases per year. The estimated financial cost of GCSE is nearly $4 billion per year. The human cost is hard to define, but the mortality is approximately 25% to 30% with estimates as high as 60% in refractory (RSE) or super refractory SE (SRSE) cases. RSE has been defined as SE requiring initiation of anesthetic medications and SRSE is persistent status epileptic after 24 hours of anesthetic administration. SE is most common at the extremes of age, with the highest incidence in children less than 1 year and adults over 60. Age is also a significant predictor of mortality with highest reported number of deaths in the elderly (1).
Etiology
Most patients who develop status epilepticus have a history of epilepsy and the most common reason to develop SE is medication nonadherence. The majority of patients with epilepsy will not experience SE during their lifetime but many others will have SE as their presenting symptom of epilepsy. Other common causes of SE include cerebrovascular disease, other forms of remote brain injury, anoxic injury, alcohol, and drug withdrawal as well as metabolic dyscrasias. In the hospital, toxic-metabolic causes of SE are common and are associated with the administration of medications that lower seizure threshold (ie, certain antibiotics, antipyschotics, and anesthestics), systemic infection, and electrolyte disorders like severe hyponatremia and hypoglycemia. Drug or alcohol withdrawal seizures are especially common in the hospital including SE from benzodiazepine withdrawal. The etiology of the GCSE is significantly associated with outcome. Those with a history of epilepsy, seizures as a result of drug or alcohol withdrawal, and those with a chronic stroke have the best prognosis. Those with the worst prognosis include the critically ill patients especially those with sepsis, acute brain injury, anoxic–hypoxic injury, the elderly and those with multiple medical comorbidities. Those with refractory or super refractory SE also experience significant morbidity and mortality. The most common cause of refractory SE is likely anoxic–ischemic encephalopathy or CNS infection. In recent years, new-onset refractory and super refractory cases of SE (NORSE) have been reported in patients without a prior diagnosis of epilepsy. These patients may have a viral prodrome before the onset of seizures or in some cases prominent psychiatric symptoms before seizures begin. New-onset refractory cases are thought to be related to a viral encephalitis or autoimmune encephalitis. Unlike the more common causes of SE, it is very difficult to control seizures even with numerous anticonvulsants and anesthetic agents. As a result, the morbidity and mortality of NORSE cases is high (6).
Definition and Stages
Traditionally, GCSE has been defined as the occurrence of continuous seizure activity for 30 or more minutes, or more than two generalized seizures within a 30-minute period without recovery in between. However, a more practical definition is of continuous seizure activity lasting greater than 5 minutes or frequent clinical seizures without evidence of recovery in between. GCSE can consist of different types of generalized activity including tonic–clonic, tonic, clonic, or myoclonic seizure activity. Bilateral motor activity is common, but in many cases, motor activity can be seen predominantly on one side or the other. Generalized myoclonic SE is another form of GCSE and it has particular implications in postcardiac arrest patients. In most patients, particularly those who have not undergone therapeutic hypothermia, it is associated with a dismal prognosis. As a result, treatment is often directed at symptom management rather than suppression of electrographic seizures.
Though convulsive activity defines GCSE, these movements frequently terminate or degenerate after several minutes regardless of whether treatment is initiated or not. Due to responsive emergency medical services who administer benzodiazepines in the field, many cases of status epilepticus will be treated before arrival to the hospital. In cases where SE has not been adequately treated, generalized convulsions give way to subtle status epilepticus or nonconvulsive status epilepticus after several minutes. In these cases, the patient remains obtunded or comatose and may only have evidence of subtle limb jerking or eye movements even while electrographic seizure activity continues unabated. Without cEEG monitoring, it will be nearly impossible to tell whether the patient is continuing to have electrographic seizures or this activity has stopped. Urgent treatment remains a priority for these patients as the duration of SE is linked to the outcome of the patient. Diagnosis and treatment of nonconvulsive seizures is critical to prevent further neuronal injury (7).
Though some variation is expected, animal models and an increasing amount of human data accurately describe the natural history of SE physiologically, clinically, and electrographically. Physiologically, SE is initially characterized by an increased cerebral metabolic rate that is coupled with increased cerebral blood flow (CBF). Increased CBF is met by increased cardiovascular parameters and increased anaerobic respiration. However, metabolic decoupling rapidly occurs after several minutes as cerebral autoregulation fails and cardiovascular and autonomic collapse ensue. Hypoxemia, hypotension, and cerebral edema develop, which only worsen neuronal and organ damage (8). Clinically and electrographically, GCSE begins with discrete electroclinical seizures that quickly evolve into continuous seizure activity. After several minutes, motor activity will abate but persistent electrographic seizures will continue. Frequent well-developed or continuous electrographic seizures then degenerate into a waxing–waning pattern of ictal discharges. The EEG further devolves into continuous epileptiform discharges with brief periods of background suppression. As the periods of background suppression increase in length, continuous epileptiform activity gives way to periodic discharges on a very low amplitude background (9).
An interesting aspect of the natural history of SE is the tendency for it to become self-sustaining. This is an important concept that is critical to understand, so that effective treatment is initiated rapidly. Though many cases of status epilepticus will self-terminate, the risk of self-perpetuating SE becomes more important when considering the pharmacoresistance that can develop. Many of the commonly used drugs to stop status will lose effectiveness rapidly, especially GABAergic agents like benzodiazepines and even some antiepileptic drugs (AEDs) such as phenytoin (7).
Systemic Complications
It is critical to understand that GCSE is a systemic process that can result in multiorgan failure. At the onset of SE, there is a massive surge of sympathetic activity originating from the brain. This wave of autonomic activity will drive extreme tachycardia and hypertension causing cardiac injury, arrhythmias, as well as neurogenic pulmonary edema and hypoxia. As a result of the convulsive activity, there is a risk of airway compromise and aspiration of gastric contents. Clinical seizure activity also results in massive muscle contraction with rhabdomyolysis, metabolic acidosis, and hyperpyrexia. Rhabdomyolysis results in renal injury or failure, which will further worsen the metabolic acidosis and increase the likelihood significant metabolic abnormalities. Hyperpyrexia can worsen neuronal injury and metabolic acidosis can further compromise the cardiovascular system. After several minutes of clinical seizure activity, the sympathetic surge will be give way to autonomic collapse with hypotension and loss of respiratory drive. If untreated, further organ damage or failure will ensure.
Neuronal Injury
Neuronal damage likely results from a combination of systemic complications as well as intrinsic injury produced by persistent neuronal hyperactivity. Animal and human studies show elevation in markers of neuronal injury after nonconvulsive seizures (NCS) and SE, including elevated neuronal-specific enolase levels and hippocampal atrophy (10,11). A small but increasing pool of evidence from critically ill populations has shown that electrographic seizure activity contributes to secondary brain injury or worsening neuronal damage (12).
Treatment
It is imperative that there be no delay in treating GCSE. In a landmark prehospital GCSE trial conducted by the VA Cooperative Study Group, 2 mg to 4 mg of intravenous (IV) lorazepam was found to be successful in terminating SE in 60% of patients when compared to diazepam or placebo (13). In a follow-up trial, lorazepam was found to be effective in stopping nearly 65% of GCSE cases when compared to diazepam, phenytoin, and phenobarbital (14). Because of this work, prehospital benzodiazepine administration is now the standard of care for patients with GCSE. A more recent and equally important trial has shown the effectiveness and superiority of 10 mg of intramuscular (IM) midazolam over IV lorazepam (15). Though the effect is likely due to the ease of administration of an IM injection, this trial provides additional therapeutic options. Other therapies that are available for patients in GCSE include intranasal and buccal midazolam and rectal diazepam. Though not all of these are approved in the United States, they are important therapeutic alternatives.
Similar to the prehospital setting, parenteral benzodiazepines remain the first-line drugs for treating GCSE emergently in the hospital (Table 34.1). Second-line therapy with AEDs is generally required after a benzodiazepine has been administered. Most hospitals have individual protocols for treating GCSE (Figure 34.1). Though protocols differ between institutions, phenytoin is probably used most often, followed by valproic acid. These drugs will likely remain AEDs of choice given IV formulation, physician comfort with dosing and side effects, and a belief in efficacy. However, there are little data regarding differential efficacy of phenytoin, valproic acid, and other AEDs. Fosphenytoin, a prodrug of phenytoin, can be an easily and rapidly administered IV with fewer of the side effects seen with intravenous phenytoin, namely, hypotension, and without the risk of soft tissue necrosis and “purple glove syndrome” in case of peripheral extravasation. Valproic acid is likely as effective as phenytoin and can be administered with minimal sedation, cardiac, and respiratory side effects. However, it should be avoided in those with known or suspected metabolic disorders and children under the age of 2 due to the risk of hepatotoxicity. Owing to uncommon instances of significant thrombocytopenia and rare bleeding complications, it may be wise to avoid in patients who have a bleeding diathesis or will require neurosurgery. Phenobarbital, once used quite often, has lost favor in recent years due to adverse effects, including prolonged sedation and hypotension, especially when administered in large doses. Its use is now limited to cases of refractory status epilepticus. Other agents such as levetiracetam and lacosamide will likely supplant older drugs in the future as they are now used frequently in the hospital and are gaining popularity due to their ease of administration, dosing, and benign side effect profiles. However, they are presently used as third- or fourth-line agents in most cases.
