The clinical presentation is most consistent with secondary generalized convulsive status epilepticus (GCSE). Current opinion holds that any convulsive seizure lasting greater than > 5 minutes or 2 or more convulsions in a 5-minute period without a return to preconvulsive neurological baseline is defined as status epilepticus (SE).^1-6 This definition is based on animal and human data suggesting irreversible neuronal injury and pharmacoresistance^7-9 after 5 minutes of prolonged seizures. Furthermore, observations have shown that most isolated clinical and electrographic seizures last less than 5 minutes, and prolonged seizures beyond this time typically are not self-resolving.^10-12

SE is a relatively common neurologic emergency with an overall estimated incidence of 41 to 61 cases per 100 000 patients per year.¹³ Despite its prevalence, it continues to be associated with significant morbidity and mortality because of previously discussed associations with irreversible neuronal injury and treatment pharmacoresistance. Subsequently, rapid recognition, diagnosis, and treatment are crucial, and these multidisciplinary efforts begin in the prehospital setting to optimize the management of SE. Classic clinical features can range from obvious positive signs of rhythmic jerking and posturing, to more subtle positive symptoms of twitching, nystagmus, automatisms, and eye deviation. Focal weakness may occur in the setting of Todd’s paralysis. Negative symptoms of seizures include staring, coma, lethargy, confusion, and aphasia. Negative symptoms may be confused with a postictal state; however, a high suspicion must be maintained that these negative symptoms represent the presence of nonconvulsive SE (NCSE) as nearly half of GCSE patients will continue to have electrographic seizures after the clinical manifestations resolve.¹⁴

The most important factor in the successful treatment of SE is initiating treatment as early as possible.^15,16 In one study, therapy given within 30 minutes of onset resulted in an 80% response to the first-line antiepileptic drug (AED), whereas a 40% response was seen if the therapy started beyond 2 hours.¹⁵ Follow-up studies were then performed to evaluate the potential of expanding treatment even earlier to the prehospital management of SE. Patients treated with lorazepam by EMS prior to reaching the hospital had better acute seizure control than those who received diazepam or placebo. Importantly, these authors found that respiratory compromise was more commonly seen in the placebo group, suggesting that prompt and targeted dosing administration of AEDs in the prehospital setting was both efficacious and safe. However, the ability of EMS to establish venous access, as well as the storage of intravenous (IV) lorazepam in ambulances provides limitations to their use. As a result, intramuscular (IM) midazolam (10 mg) has been used increasingly in the prehospital setting, and a study has revealed its efficacy and efficiency as an alternative treatment to IV lorazepam.¹⁷

Treatment of these patients should be guided by an institutional protocol to allow multiple team members to simultaneously initiate a series of steps including assessment of airway, breathing, and circulation (ABCs); administration of antiepileptic medications; addressing the underlying cause of seizures; and obtaining IV access. Initiation of treatment should begin immediately, and the situation should be managed as a neurologic emergency. In most patients with GCSE, their airway will not be safely protected, either because of the seizures or the escalation of seizure treatment. Therefore, intubation should be performed early if it is deemed necessary. Hemodynamic monitoring is mandatory because SE as well as the AEDs used to treat SE have been associated with arrhythmias and hypotension. Hypoglycemia should be recognized early because hypoglycemic seizures will respond only to glucose administration and permanent damage will result if not corrected rapidly (Table 3-1).

In accordance with evidence from prospective randomized controlled trials, lorazepam (see Table 3-2 for dosing and pharmacokinetic information) should be given as the initial AED, with a success rate between 59% and 65%. However, as will be discussed in the next section, the treatment paradigm should involve benzodiazepine treatment in conjunction with a second-line AED. If IV access cannot be established rapidly, midazolam, 10 mg IM, buccal, or intranasal¹⁸ are established safe alternatives. Additionally, diazepam, 20 mg rectally (or IV solution; diastat may be used) may be used. It is important to provide an adequate first-line benzodiazepine dose because patients are frequently underdosed in the field and also in the ED because of the fear of causing respiratory depression. However, as stated earlier, previous trials have established the safety of therapeutic doses of benzodiazepines.

All patients with GCSE require a second-line antiepileptic medication because the initial benzodiazepine is not a long-term therapy to prevent recurrence of SE. Rather than administering the first- and second-line antiepileptic medications in sequential order, second-line AEDs should ideally be given concurrently with the benzodiazepine agents. Do not delay the use of second-line AEDs to assess whether the patient responds to the initial benzodiazepine.

There continues to be a paucity of data and randomized controlled trials comparing AEDs among each other in order to determine a clear, efficacious, second-line agent. Despite this, phenytoin/fosphenytoin (Table 3-2) is recommended by most neurologists.¹⁹ However, evidence has emerged from several prospective, randomized, open-label trials to suggest that IV valproate is an efficacious and safe first- or second-line agent (66% and 88% response rate, respectively). Additionally, it is perhaps superior to phenytoin (66% response vs 42%, respectively) without the caveats of phenytoin’s side effects.²⁰ Other alternatives frequently used include levetiracetam, lacosamide, and phenobarbital. A recent meta-analysis has suggested that agents such as levetiracetam and valproate are more efficacious than the historically preferred phenytoin.²¹ However, these data have been based on a heterogeneous sample with inadequate numbers and differing SE definitions. An additional retrospective comparative review of phenytoin, valproate, and levetiracetam has also revealed the efficacy of valproate over phenytoin; however, it has also revealed that levetiracetam may be the least efficacious of these three.²² These differing results again point to the necessity of future studies to elucidate preferred second-line agents.

While rapid first- and second-line AED treatments are being given, management should be focused concurrently on three aspects: (1) making sure that the patient is medically stable, (2) diagnosing and addressing the underlying cause of GCSE, and (3) determining if electrographic seizures (ie, NCSE) are present.

1. 
   

   Medical stability: Hypotension and arrhythmias may be seen during loading with phenytoin or fosphenytoin. Hemodynamic monitoring may require the placement of an arterial line or central line if not done already.

   
   
2. 
   

   Diagnostic work up: The underlying differential is wide (Tables 3-3 and 3-4), and the diagnostic workup should be individualized depending on the clinical scenario (Table 3-5). In a general population-based study, the most common causes of SE were low levels of AEDs (34% of the cases), remote symptomatic etiologies (history of neurologic insults prior to the unprovoked seizures), and cerebrovascular disease.^23,24 Nevertheless, the causes of SE in critically ill patients may be different from those in the general population. In general ICUs, metabolic abnormalities and drug withdrawal represent 66% of the SE admissions.²⁵ In comatose patients admitted to general ICUs, anoxia-hypoxia followed by stroke and infection are the two most common causes of NCSE and refractory status ellipticus (RSE).^26-28.Basic diagnostic testing should be initiated in the ED, with a more thorough evaluation to be completed once the patient is admitted to the medical unit or to the NeuroICU. Basic blood and urine tests (including complete blood count, comprehensive metabolic panel, Ca and Mg levels, and toxicology screens) and relevant AED levels (ie, phenytoin, valproate, carbamazepine) should be routinely ordered. Neuroimaging should also be considered (noncontrast head CT) in the majority of cases. The presence of fever, leukocytosis, and nuchal rigidity at presentation should raise the suspicion for central nervous system (CNS) infection, and a timely lumbar puncture evaluation is imperative. Empiric treatment with bacterial and viral coverage should be started until the lumbar puncture and additional imaging results are available.

   
   
3. 
   

   Persistent electrographic seizures: The patient should be connected to continuous encephaographic monitoring (cEEG) as soon as possible because electrographic seizures persist in 20% to 48% of clinically apparently successfully treated GCSE, and 14% are in NCSE without any clinical signs of seizure activity.²⁴ These electrographic seizures in the aftermath of convulsive seizures are clearly associated with a worse prognosis. Although no study has investigated whether treatment of NCSE results in a better outcome, treatment for electrographic seizures should be the same as for clinical seizures.

Our patient has RSE, a neurological emergency that should be managed in the ICU setting and requires cEEG monitoring. Although some controversy regarding the exact definition persists, most experts classify RSE as continuous seizure activity that persists despite first- and second-line antiepileptic medication regardless of the elapsed time. Most patients with RSE appear comatose and have subtle or no clinical manifestations of seizures.²⁸ Prior to the widespread use of cEEG, the incidence of RSE was estimated at 2000 to 6000 cases per year. It can occur at any age, and both genders are equally at risk.²⁹ Overall, the exact incidence and prevalence are readily underestimated because of an absence of population-based studies with cEEG monitoring. For instance, in the Department of Veterans Affairs cooperative study, 38% of patients with “overt” SE and 82% with “subtle” SE continued seizing after receiving full doses of two AEDs. Moreover, depending on sampling bias and utilization of cEEG monitoring after GCSE, 9% to 48% of patients continued to seize after initial therapy.

The mortality rate at hospital discharge and 30 days are 9% to 21%.^30,31 and 19% to 27%.³² respectively, in adults with SE. Among SE survivors, disability, particularly cognitive impairment, is a common sequelae.^33,34 Factors associated with poor outcome include older age, impairment of consciousness, duration of seizures, and the presence of medical complications.^35,36 RSE may occur in up to one-third of patients with SE.³⁷

RSE carries a dismal outcome, with mortality rates close to 23% to 61%^38-43 and appears to be independent of the chosen therapeutic strategy.

Exact mechanisms underlying the development of RSE are to date not completely understood. Evidence has accumulated that prolonged seizure activity leads to an internalization of γ-aminobutyric acid (GABA) receptors^44,45 in addition to the upregulation of excitatory AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartate) receptors. These two processes appear to be interrelated, causing a hyperexcitable cascade, but their exact pathophysiologic mechanism has yet to be determined.

There is a lack of data related to the optimal treatment for RSE. Many neurologists choose an additional conventional AED as a third-line agent for RSE treatment. However, after standard treatment with two AEDs, the likelihood of response to a third conventional medication, regardless of the agent, is only 2% to 5%, depending on the type of SE. Subsequently, many experts propose a rapid and aggressive escalation with continuous IV (cIV) anesthetic agents with intubation (if not already performed). Frequently used agents include continuous drips of midazolam, propofol, or pentobarbital (Table 3-6). cEEG will be essential and necessary for seizure detection and treatment endpoints at this stage. In patients where intubation is not possible, valproic acid is a good alternative AED, if not already being employed as a second-line agent.

Traditionally, treatment algorithms of RSE have included phenobarbital loading with escalation to cIV pentobarbital.⁴⁶ However, owing to the caveats of barbiturate use, preference for the use of midazolam and propofol has emerged in the treatment practice of RSE. A number of studies have reported the effectiveness of continuous drips of propofol or midazolam as third-line agents for RSE. Also, mixed data regarding the safety of propofol has led to the use of midazolam as a frequently utilized treatment in RSE. Concerns over propofol infusion syndrome have been a long-standing concern. Although not statistically significant, some evidence in a small retrospective series has shown that propofol is associated with a higher mortality rate than midazolam. However, an additional retrospective single-center study has suggested the safety of cIV propofol infusions, with mean rates of 4.8 mg/kg/h for 3 days, and treatment success rates of approximately 77%.^47,48 Unlike the concerns over prolonged high doses of propofol, there is recent evidence that higher maintenance infusion rates of midazolam may be used with a good safety profile, lower rates of withdrawal seizures, and lower discharge mortality (Table 3-6).^49,50

Despite concerns for its safety, the barbiturates remain an effective treatment option in the treatment of patients with RSE. Pentobarbital infusions lower the cerebral oxygen demand, intracranial pressure (ICP), and lipid peroxidation. Similar to most anesthetic agents, adequate doses will invariably stop seizure activity; however, it is the dose-dependent side effects that limit adequate “therapeutic” dosing. Side effects include hypotension and refractory acidosis due to propylene glycol toxicity with subsequent multiorgan failure, along with its long half-life and sedating properties. In a systematic review of published cases and small series, pentobarbital was found to be more effective terminating seizures (acute treatment failure, breakthrough seizures, and post-treatment seizures) than midazolam or propofol. When comparing these 3 agents, there was no difference in mortality (approximately 50%). However, the pentobarbital-treated group experienced more frequent side effects (ie, hypotension requiring pressors). These results are to be interpreted with caution because of small sample size, lack of cEEG monitoring for the pentobarbital cases, and the heterogeneity of SE patients and treatment regimens compared with current practice. A more recent single-center retrospective review again revealed the efficacy of pentobarbital in seizure control along with its relative safety compared with prior reports. Although associated with 48% withdrawal seizure rates, the use of phenobarbital during the weaning process appears to be effective in preventing these relapses.⁵¹

All of these treatment decisions are controversial because there are little or no data to base them on. The most recent European Federation of Neurological Studies guidelines recommend treatment with cIV therapies, with the goal of burst suppression on EEG if propofol or barbiturates are used and seizure suppression if midazolam is used. Although no consensus is available on the preference between the two treatment titration regimens, many experts prefer seizure suppression as a goal. This is to be maintained for a minimum of 24 hours while conventional AEDs level are optimized. A small study of 49 patient with RSE treated with propofol or pentobarbital infusion (with or without additional midazolam) concluded that outcome was independent of the choice of agent and the EEG titration goal. In the literature, advocates have published varying treatment endpoints of nonconvulsive seizure cessation,^52-58 titration to diffuse beta activity, burst suppression, and complete suppression of EEG.^59-61 Most experts would recommend continuing cIV AEDs for at least 24 to 72 hours after cessation of electrographic status to prevent recurrence of seizures. The physician should target cEEG goals rather than serum levels of these medications, but should at the same time be wary of their potential side effects as the dosage is increased.