Recurrent or continuous seizures occur with all seizure type. Commonly used categories of status include generalized convulsive status (GCSE); simple partial status; myoclonic SE; and NCSE. Nonconvulsive status encompasses absence, complex partial, and atonic seizures. Kaplan suggests classifying NCSE into three types: NCSE of generalized epilepsies; NCSE of localization-related epilepsies [subclassified by electroencephalographic (EEG) features]; and an indeterminate form of NCSE not fitting the prior categories (5).

Debate persists regarding the duration of seizure activity constituting status. At the 1962 Marseilles conference, status was defined as an “enduring epileptic state” (6). The International League against Epilepsy defined it as a seizure persisting for sufficient length of time to produce such an enduring state, or repeated seizures occurring frequently without recovery between attacks (7). Subsequent attempts to define status as 30 minutes of continuous or recurrent seizure activity reflected experimental and epidemiologic evidence of the approximate time needed to produce cerebral injury (8). However, this definition interferes with management, because aggressive treatment to status should not be delayed to achieve success and prevent brain injury. A typical secondarily generalized tonic-clonic seizure generally stops by 3 minutes and almost always by 5 min (6,9). Seizures may last somewhat longer in children and still remit spontaneously, but a seizure in a child that has lasted 12 minutes is unlikely to do so within the next 30 minutes (10). Whether one chooses to define status based on such operational definitions (11), or maintains the older definition but begins treatment earlier in order to stop seizure activity before it lasts 30 minutes is a point of intellectual but not clinical relevance.

The brain has intrinsic inhibitory mechanisms that serve to prevent seizures, and to terminate those that do occur. However, these mechanisms fail in status, either because of
increased neuronal excitability or loss of normal inhibitory pathways (12). Receptors for the major inhibitory transmitter, γ-amino butyric acid (GABA), are the site of most effective antistatus agents (e.g., the benzodiazepines). Conversely, proconvulsant agents such as penicillin can precipitate status by antagonizing the inhibitory neurotransmitter. However, the GABA agonists lose efficacy over many minutes, perhaps because GABA receptors undergo rapid changes in subunit composition, which decreases their affinity for these substances (13). Excitatory neurotransmitters are considered to be important in the maintenance of status, including glutamate, aspartate, and acetylcholine. N-methyl-D-aspartate (NMDA)-linked calcium channels appear to be particularly involved in the pathogenesis of status (14), and NMDA antagonists are promising agents for the control of refractory status (15).

Cerebral injury occurs from status independent of the systemic metabolic disturbances it produces (16), although the latter undoubtedly contribute to neuronal damage in many cases (17). Primary neuronal injury appears to be a consequence of calcium-mediated excitotoxicity and increased metabolic demands from excessive neuronal activity. The upregulation of glial metabotropic glutamate receptors has been proposed as a mechanism in the epileptogenesis induced by status (18). Recently, nerve growth factor and other neurotrophins were suggested to have specific protective roles against excitotoxic cell stress (19), but many of these notions currently are speculative.

During the first several minutes of GCSE, recurrent isolated or continuous clinical convulsions are manifestations of discrete electrographically recordable seizures. There is sympathetic overactivity with hypertension and tachycardia. Blood lactate and glucose levels increase, with reduced pH secondary to metabolic acidosis, and respiratory acidosis as well when there is airway compromise. Cerebral glucose metabolism, oxygen use, and blood flow increase acutely, and brain lactate levels are also increased.

With persistence of status beyond 30 to 60 minutes, visible seizures become more subtle, seen only as focal myoclonic twitches, followed by complete disappearance of motor manifestations despite persistence of ongoing electrographic seizures. Discrete seizures are initially seen on the EEG, corresponding to the clinical events. Subsequently, waxing and waning electrographic seizures develop, followed by continuous ictal activity. With time, the pattern degenerates into continuous epileptiform activity interrupted by flat periods, and eventually into periodic lateralizing epileptiform discharges (PLEDs) (20). Hypotension develops, along with persistently increased lactate, hypoglycemia, hyperthermia, and respiratory compromise. Cerebral autoregulation is impaired with decreased cerebral blood flow related to systemic hypotension. Cerebral glucose and oxygenation are also reduced (18). Vasogenic cerebral edema occurs with prolonged seizures.

Status occurs either because of an overwhelming acute insult to the brain or in situations in which acute processes are superimposed on prior brain injury. It may be precipitated de novo in patients with no prior history of seizures owing to acute metabolic or structural injury to the brain. Anticonvulsant noncompliance or withdrawal from other hypnosedative agents, including ethanol, is the commonest precipitating cause of status in our practices. Acute electrolyte disturbances (especially acute hypoosmolar states), renal failure, sepsis, nervous system infections, stroke, toxicity from medications, hypoxia, and head trauma are also among the common causes of status (3). These latter acute derangements are associated with poorer outcome and are more refractory to treatment (21). Conversely, status in patients with pre-existing epilepsy usually follows poor compliance or tapering of medications. There is frequently good response to treatment in this situation and other etiologies (including
ethanol abuse, cerebral tumors, and late epilepsy following prior strokes).

The following discussion of management applies to status of generalized tonic-clonic seizure type and is based on our general experience, drawn in part from the experiences of others of course. The management of complex partial NCSE is similar; however, absence NCSE is usually approached less aggressively than the generalized variety because there are no data suggesting that simple partial status causes significant injury. Less vigorous efforts are also recommended because these seizures are remarkably resistant to treatment and efforts to completely abolish them generally result in medicationinduced side effects.

There are five aspects to the management of status: general supportive care, termination of status, prevention of seizure recurrence, correction of precipitating causes, and prevention and treatment of complications. The aggressiveness of treatment reflects the likelihood of brain injury and systemic complications with prolonged convulsive status. Early initiation of treatment appears to be critical to a favorable outcome.

Initial therapy follows the general principles of any emergency medical condition regarding the basics of airway, breathing, and circulation. However, there are some precautions and difficulties specific to status. Airway management is critical to avoid exacerbating status through hypoxia. In those patients with spontaneous adequate breathing, airway patency should be maintained by either oral or nasopharyngeal devices supplemented by 100% oxygen. Intubation with mechanical ventilation is required in those with evidence of respiratory compromise. This should be considered prior to respiratory compromise once the decision is made to treat with agents that tend to cause respiratory suppression. Patients with status frequently need neuromuscular blocking agents to facilitate intubation. It is important to use short-acting neuromuscular blocker (e.g., vecuronium, 0.1 mg/kg), because the cessation of muscle activity makes diagnosing seizure activity clinically difficult. Neostigmine (50 to 70 µg/kg) reverses the neuromuscular blockade once it begins to wear off. Use of succinylcholine should be discouraged because of the potential for severe hyperkalemia associated with this drug in neurological patients.

Secure intravenous access is essential for blood samples, management of fluid and electrolytes, and administration of medications. Cardiac monitoring allows recognition and treatment of potentially life-threatening arrhythmias, which occasionally develop in these patients. If a patient is hypotensive, one should begin volume replacement and consider the use of vasoactive agents. Conversely, if a patient is hypertensive, delay treating the blood pressure primarily, because the drugs used to terminate status tend to cause hypotension. With prolonged status, intensive care unit (ICU) admission is essential. If the blood glucose concentration is low, 50 mL of 50% dextrose (or 1 mL/kg) along with 100 mg thiamine should be administered intravenously, because hypoglycemia commonly presents with seizures, which may be partial. Hypoglycemia also can occur as a complication of prolonged status. If one contemplates the use of phenytoin, at least one line containing normal saline as the infusion fluid is required.

Routine laboratory analysis should include complete blood count, serum glucose, electrolytes, liver enzymes, and renal function tests; arterial blood gas, anticonvulsant levels, urinalysis, and blood and urine screening for psychotropic agents as appropriate.

The role of the EEG in the management of status cannot be overestimated. Patients without improving responsiveness, in whom neuromuscular blocking has been used, or patients with refractory status, require some form of EEG monitoring. Persistent electrographic seizures after control of visible seizures were seen in 20% of the patients in the Department of Veterans Affairs (DVA) cooperative study (22) and in about 15% in the study by DeLorenzo and coworkers (23).

Early initiation of treatment is crucial in these patients. Animal and human experiments indicate that status becomes progressively refractory to anticonvulsants with increasing duration (24). In experimental status induced by lithium and pilocarpine, the total dose of diazepam required to control seizures more than doubled if therapy was delayed until the second seizure compared to the dose required following the first (25). Lowenstein and Alldredge (3) showed that status was terminated in 80% of patients when treated within 30 minutes of onset, but was less than 40% successful if delayed for 2 hours or more.