Michael L. McGarvey and Danielle A. Becker

Epidemiology

The incidence of SE is 10–41/100,000/year in Europe and the United States. SE of focal onset (often followed by secondary generalization) is the most common SE. The major causes of SE in adults are stroke, hypoxia, metabolic derangements, alcohol intoxication, and drug withdrawal. In patients with epilepsy, nonadherence with antiepileptic drug (AED) therapy is the most likely cause. Men are more affected than woman. The estimated direct costs for SE admissions in the United States may be as high as $4 billion per year.

The most common causes of CSE are AED withdrawal or nonadherence to AED therapy in epileptic patients and cerebral vascular disease, whereas alcohol withdrawal, cancer, metabolic disorders, anoxia, poisoning, central nervous system (CNS) infections, and traumatic brain injury (TBI) also contribute. NCSE is likely 25% to 50% of the total incidence of SE although it has been as high as 81% in some series. In critical care patients, 75% to 92% of patients diagnosed with SE are found to be in NCSE as opposed to CSE. In a study of 570 ICU patients with altered mental status who were placed on continuous EEG monitoring (cEEG), 19% had NCSE. The increased availability and utilization of cEEG have undoubtedly increased the clinical team’s ability to identify NCSE in patients. The incidences for both CSE and NCSE are considerably higher in those older than 60 years of age.

As noted earlier, the first and most important distinction is whether the patient has convulsive (CSE) or nonconvulsive SE (NCSE). However, there is an overlap between these two basic classifications as patients may transition between them during their course. For example, in a study of 164 patients treated for CSE with standard therapy and then placed on EEG monitoring, 14.5% of them were found to be in NCSE despite resolution of their convulsions.

CSE by definition requires convulsive movements, defined as rhythmic movements or posturing of the extremities. These movements can be further classified into tonic-clonic, clonic, tonic, and myoclonic CSE. These subtypes are associated with specific EEG correlates at their onset. CSE can then be further subdivided into convulsions consisting of bilateral extremity movement (generalized) versus unilateral extremity or facial movement (partial/focal). Further differentiation is made depending on the patient’s level of awareness. In simple CSE, consciousness remains intact, whereas in complex CSE, consciousness is altered. Simple focal CSE and complex focal CSE may also have secondary generalization. If CSE is allowed to persist in any of these subtypes, it is possible that there will be attenuation of the motor symptoms and patients will transition into NCSE (Figure 70.E1).

NCSE is defined as a change in mental status or behavior of at least 30 minutes in duration, without rhythmic motor activity in the extremities, along with an EEG consistent with epileptiform activity. The clinical presentation of NCSE varies extensively among patients and may range from mild confusion to coma. These patients may present with changes in their behavior manifested by increased aggression, crying, inappropriate laughter, or psychosis. When comatose, there may be subtle motor signs such as facial twitching, blinking, nystagmus, eye deviation, or hippus (a rhythmic dilation and contraction of the pupil), which, when present, may be a diagnostic clue.

The diagnosis of NCSE requires the use of EEG, but, even with EEG, it may be difficult to distinguish the subtypes. It is often the case that NCSE goes undiagnosed if EEG monitoring is not employed, particularly in the critical care setting where consciousness is variable due to illness and sedation. Hirsch and colleagues have devised criteria for defining and diagnosing NCSE. These criteria include any pattern lasting greater than 10 seconds (sec) along with the primary criteria of either repetitive generalized focal spikes, sharp waves, spikes and slow waves, or sharp and slow waves at > 3/sec or sequential rhythmic, periodic, or quasi-periodic waves at > 1/sec that gradually increase or decrease in frequency by at least 1/sec. Alternatively, the definition of repetitive generalized focal spikes, sharp waves, spikes and slow waves, or sharp and slow waves < 3/sec with an improvement in clinical state or “normalization” of the EEG pattern acutely following the use of rapidly acting antiepileptic drugs (AEDs) has also been used. Experts in the field still believe there may be scenarios where clinical judgment will take precedent over these criteria in the diagnosis of NCSE but that meeting these criteria is adequate.

Traditionally, NCSE has been initially broken down by age with classifications for the neonatal period, childhood, and adult populations. Discussion of neonatal and childhood NSCE is beyond the scope of this chapter. NCSE in adult patients can be further divided into the following two categories: patients with preexisting epilepsy or patients with acute cerebral injury. There can be overlap between these groups. The group of patients with epilepsy comprises two groups: those with severe epileptic syndromes such as Lennox-Gastaut and other severely disabling childhood epilepsies where the patients have survived into adulthood and those patients with epilepsy but without preexisting childhood encephalopathies. The latter group includes patients with simple partial NCSE (spNCSE), complex partial NCSE (cpNCSE), absence status epilepticus (ASE) in generalized epilepsies, myoclonic status epilepticus in the idiopathic generalized epilepsies, and NCSE following CSE. The spNCSE is an NCSE without loss of consciousness but encompasses a wide spectrum of focal behavioral abnormalities, psychoses, and clinical signs including hallucinations, emotions, and laughter. The cpNCSE is defined as localization-related epilepsy with prolonged continuous or repetitive seizures and alteration of consciousness. The ASE is defined as a sudden but prolonged loss of consciousness without aura, and an EEG that has bilateral synchronous spike and wave discharges at 3/sec. Myoclonic status epilepticus in the idiopathic generalized epilepsies is extremely rare and must be differentiated from myoclonic SE associated with cerebral injury (cMSE). Myoclonic status epilepticus in the idiopathic generalized epilepsies is the nonconvulsive SE associated with patients who are nonencephalopathic but have juvenile absence epilepsy, awakening grand mal epilepsy, or juvenile myoclonic epilepsy.

NCSE in patients with acute cerebral injury can be further subdivided into patients who are comatose (cNCSE) or those who are noncomatose but in acute confusional states (ncNCSE). The comatose NCSE group includes a further subdivision differentiating those patients with cMSE or without myoclonus. All these subdivisions of NCSE can be divided into either generalized nonconvulsive SE, focal nonconvulsive SE, or focal secondarily generalized NCSE based on their clinical and electroencephalographic picture (see Figure 70.E1). Different classification symptoms do exist, and it should be noted that the term proper NCSE (pNCSE) denotes all patients who are in NCSE but are noncomatose and does not take into account the presence of acute cerebral injury.

Approximately 12% to 43% of SE cases fail to respond to first- and second-line therapies. The term refractory SE (RSE) is used commonly to describe SE that does not respond to initial dosing with benzodiazepines and at least one antiepileptic drug (Figure 70.1). Half of all patients with RSE have a prior history of epilepsy, but other causes are diverse and include hypoxic-ischemic injury, immune-mediated diseases, infections, toxic-metabolic syndromes, trauma, degenerative disorders, neoplasms, and endocrine disorders.

The term super-refractory SE (SRSE) is reserved for patients who continue to have seizures despite the use of general anesthetic agents (see Figure 70.1) to treat their SE or for whom seizures reoccur when therapy is tapered or withdrawn. SRSE may account for up 15% of SE cases. The most common cause of SRSE is acute severe brain injury, but other causes include immunologic, mitochondrial, infectious, toxic, and genetic disorders.

Pathophysiology

Seizures are the result of abnormal electrical discharges of cortical neurons and can arise because of abnormalities at any level in the central nervous system (CNS), from ions, receptors, cells, and networks, to the brain as a whole. Given that an overwhelming majority of seizures end spontaneously, it is hypothesized that an endogenous seizure terminating process must exist in the CNS or all seizures would be persistent. SE is attributed to a theoretic failure of the CNS’s innate ability to terminate an isolated seizure. This failure may occur through two mechanisms: persistence of excessive excitation or loss of normal inhibition. The mechanisms involved may include constant activation of the hippocampus, loss of inhibition by GABAergic interneurons on neurons in the hippocampus with intrinsic pacemaker capability, and increased glutamatergic excitatory synaptic transmission. All of these proposed mechanisms play a central role in epileptogenesis, leading to synchronous, repetitive firing of large populations of neurons. A genetic predisposition may also be involved in SE, shown by a higher incidence of SE in monozygotic than in dizygotic twins.

Neuronal damage is felt to be largely due to excitotoxicity-driven glutamatergic receptor overactivity leading to calcium influx followed by necrosis, apoptosis, and cellular dysfunction, which typically occur after a few hours of SE. Changes in the cellular microenvironment, including hypoxia, acidosis, elevated extracellular potassium levels, and breakdown of the blood-brain barrier, also contribute to neuronal death.

SE leads to widespread systemic effects that occur early and late (> 60 minutes) in its course as a result of its motor and its electrical manifestations. Many of these systemic effects are a result of the catecholamine surge that accompanies SE. Heart rate and blood pressure rise initially, and hypotension develops later. Although there may be increased cerebral blood flow initially in SE, this also declines late in the course, whereas metabolic demands persist, leading to anoxia. Hyperthermia results from tonic muscle contraction and failure of central regulatory mechanisms. A systemic leukocytosis and cerebral spinal fluid pleocytosis occur and sometimes lead to confusion with respect to whether an infectious etiology is causal. Patients can have both a respiratory acidosis and a lactic acidosis, which typically clear once motor seizures are controlled. Electrolyte disturbances, including hyperglycemia, hypoglycemia, hyperkalemia, and hyperphosphatemia, may occur. Aspiration pneumonia and renal failure caused by rhabdomyolysis may also occur.