Convulsive status epilepticus in adults: Management

INTRODUCTION — Status epilepticus is a medical and neurologic emergency that requires prompt evaluation and treatment. The rapid evaluation and treatment of convulsive status epilepticus is discussed below.

The definition, classification, clinical features, and diagnosis of convulsive status epilepticus in adults are reviewed separately. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".)

Nonconvulsive status epilepticus and the diagnosis and management of status epilepticus in children are discussed elsewhere. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis" and "Clinical features and complications of status epilepticus in children" and "Management of convulsive status epilepticus in children".)

RAPID RECOGNITION OF STATUS EPILEPTICUS

●Diagnosis – The diagnosis of convulsive status is clinical and is confirmed by verifying the presence of either an unremitting generalized convulsive seizure lasting longer than five minutes or multiple bilateral convulsive seizures without an interictal return to the baseline level of consciousness.

Patients with generalized convulsive seizures that are frequent or separated by a period of significantly impaired consciousness (ie, status epilepticus) or who are medically unstable require immediate assessment and treatment in an acute care setting (emergency department or intensive care unit). (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Definition of status epilepticus'.)

●Differential diagnosis – Few other conditions appear similar to generalized convulsive status epilepticus. Focal motor and myoclonic status epilepticus may be more difficult to distinguish from other conditions. The main considerations in the differential are:

•Psychogenic status epilepticus

•Encephalopathies with unresponsiveness and myoclonus

•Movement disorders, such as tremors and dystonias

The differential diagnosis of convulsive status epilepticus is reviewed in greater detail separately. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Differential diagnosis'.)

●Speed – Treatment of status epilepticus is time sensitive. One small study found that creating and implementing a "status epilepticus alert" (similar in concept to a "code stroke" or "code ST-elevation myocardial infarction") reduced the time to administration of a nonbenzodiazepine antiseizure medication from 58 minutes to 22 minutes [1].

Initial management involves rapid assessment and supportive treatment; urgent pharmacologic therapy with a benzodiazepine; and urgent therapy that achieves long-term control using a nonbenzodiazepine antiseizure medication (algorithm 1).

URGENT FOCUSED EVALUATION — During early treatment, the clinician should obtain a focused history from a family member or caregiver to determine:

●Prehospital administration of benzodiazepines and any antiseizure medications

●Patient history of epilepsy

●Precipitating factors prior to seizure (eg, acute illness, possible toxic exposure, trauma, recent heavy alcohol intake or cessation of chronic drinking, change in antiseizure medications)

●Current medications, including prior or current use of antiseizure medications

●For patients with prior status epilepticus, history of treatment response

●Other active medical diagnoses

In patients with status epilepticus, the initial physical examination is limited:

●A focused general medical evaluation should assess respiratory and circulatory status. Attention to airway, breathing, and circulation is urgent, as in other medical emergencies. The examiner should also look for signs of head trauma, sepsis, anisocoria or meningitis.

●A rapid neurologic examination should be performed to determine the type of status epilepticus and, if possible, its etiology.

IMMEDIATE SUPPORTIVE CARE

Approach — In patients with convulsive status epilepticus, immediate supportive care must occur simultaneously with prompt administration of antiseizure medications (algorithm 1).

The main goals of care are:

●Establish and maintain adequate airway, breathing, and circulation

●Stop the seizure and thereby prevent brain injury

●Identify and treat life-threatening causes of status epilepticus, such as trauma, sepsis, meningitis, encephalitis, or structural brain lesion

Monitoring — All patients with generalized convulsions should have continuous monitoring of heart rate and rhythm, breathing, pulse oximetry, and periodic measurement of blood pressure and temperature. However, continuous motor activity may interfere with the ability of electronic monitors to detect abnormalities. Thus, frequent clinical assessment of breathing, pulse, and color must supplement monitor readings to ensure rapid detection of apnea, cyanosis, or shock.

Measurement of arterial blood gases is often valuable, as most patients with generalized convulsive status epilepticus (GCSE) who do not respond rapidly to initial treatment require intubation and mechanical ventilation. However, in general, one should use clinical findings when deciding whether to perform endotracheal intubation rather than rely exclusively on blood gas findings, as the combined metabolic and respiratory acidosis can result in overestimation of respiratory compromise by blood gas monitoring. (See "The decision to intubate".)

Airway and breathing — Important airway interventions in include:

●Maintaining an open airway through positioning maneuvers and airway devices as needed. Some authors recommend against insertion of an oropharyngeal airway due in part to the difficulty in placement, the associated risk of upper airway obstruction, and the potential for injury to medical personnel placing the airway [2]. Nasopharyngeal airways can be placed more easily and with less potential trauma to patient and medical personnel. (See "Basic airway management in adults", section on 'Airway adjuncts'.)

●Administering 100 percent oxygen and assessing for cyanosis by visual appearance and pulse oximetry.

For patients with transient apnea or hypoxemia, the clinician may use bag-mask ventilation as long as the airway can be maintained and spontaneous breathing with adequate oxygenation resumes within a short period of time. (See "Basic airway management in adults", section on 'Bag-mask ventilation'.)

Patients with any one of the following should undergo rapid sequence endotracheal intubation (RSI) and mechanical ventilation:

●Unprotected or unmaintainable airway

●Apnea or inadequate ventilation

●Hypoxemia

●Status epilepticus lasting ≥30 minutes

●Need to protect airway for urgent brain imaging (eg, in a patient with preceding trauma or signs of basilar territory stroke)

When performing RSI in this setting, using an induction agent that has antiseizure activity such as propofol (see "Refractory status epilepticus in adults", section on 'Propofol') makes theoretical sense. Propofol is an excellent choice for induction if the provider is familiar with its use in this setting. Alternatives are etomidate and midazolam. Etomidate is associated with a slightly increased risk of seizure activity, but in this setting, securing the airway safely takes precedence; patients require antiseizure therapy and electroencephalographic (EEG) monitoring after intubation regardless of the induction agent used.

While neuromuscular blocking agents block the motor manifestations, they do not treat the underlying seizure activity; therefore, EEG monitoring is mandatory in order to know whether GCSE has resolved or is continuing and needs further treatment. Some experts advise against depolarizing blocking agents such as succinylcholine due to the risk of exacerbating hyperkalemia in patients with recent seizures or those found down with prolonged immobilization. While succinylcholine (duration of action four to six minutes) is shorter-acting than rocuronium and vecuronium (duration of action 30 to 40 minutes), the latter drugs can be easily reversed with sugammadex if necessary.

EEG monitoring is especially important when a second dose of a longer-acting paralytic is given to facilitate diagnostic studies such as computed tomography (CT) scanning or lumbar puncture. If longer-acting paralytics are used without EEG monitoring, it would not be clear if or when the GCSE had stopped.

RSI and the use of induction agents and neuromuscular blocking agents are reviewed in detail separately. (See "Rapid sequence intubation in adults for emergency medicine and critical care" and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Status epilepticus' and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)

Circulation and vascular access

●Establish venous access – Patients with status epilepticus require timely vascular access for sampling of blood and administration of medications and fluids. Peripheral intravenous (IV) access with at least two catheters should be established as soon as possible. Alternative routes of antiseizure medication administration (eg, rectal, intramuscular [IM], buccal, or intranasal) should be used if IV administration is not possible within the first five minutes. IM (or nasal or buccal) midazolam is first choice if no IV access; there should be no delay in treatment awaiting IV access. Although not required for the most urgent treatments (benzodiazepines), an intraosseous (IO) line should be placed if IV access is further delayed. Many antiseizure medications can be given via the IO route if IV access is not available, including all benzodiazepines, phenytoin, and levetiracetam [3]. However, IO administration in adults is not as well studied as IM or IV administration.

●Hemodynamic support – Status epilepticus does not independently cause hypotension, at least early in its course; the presence of hypotension in patients presenting with status epilepticus should prompt consideration of an underlying systemic condition, cardiogenic cause, traumatic hemorrhage, or sepsis. In addition, the presence of oliguria, tachypnea, poor perfusion (eg, cool, clammy skin), and metabolic acidosis are warning signs that point to shock and tissue hypoxia.

Hypotension may also result from benzodiazepines, barbiturates, and sedative/anesthetic agents used to treat status epilepticus.

Patients with suspected shock should receive hemodynamic support with IV fluids (usually crystalloids in boluses of 500 to 1000 mL), followed by vasopressors (table 1) if IV fluids fail to restore adequate tissue perfusion.

Initial studies — Initial blood and urine studies should be obtained for rapid determination of:

●Serum glucose and a rapid "finger-stick" or point-of-care glucose

●Serum electrolytes

●Calcium, phosphorus, and magnesium

●Liver function tests

●Complete blood count

●Serum antiseizure medication levels, if applicable

●Urine and blood toxicology

●Qualitative pregnancy test (urine or blood) in women of childbearing age

Cardiac troponin and pyridoxine levels may be considered based on evidence that cardiac injury may be under-recognized in refractory status epilepticus [4], and low or low-normal pyridoxine levels are common in patients presenting with status epilepticus [5].

Other studies may also be indicated based upon the most likely underlying cause. Serum lactate is often checked, as elevated or increasing levels may suggest hypoperfusion or underlying infection.

These tasks require at least one to five minutes and should overlap with the next phase of treatment (algorithm 1).

Correct hypoglycemia and metabolic derangements — Hypoglycemia should be treated with 100 mg of thiamine and 50 mL of 50 percent dextrose solution. If IV access is not available, IM glucagon or IO 50 percent dextrose can be given.

Hypoglycemia may provoke seizures and convulsive status epilepticus. Although uncommon, either severe hyponatremia or hypocalcemia may cause status epilepticus that is refractory to antiseizure medication and requires timely correction. Metabolic acidosis is often present in patients with status epilepticus and can be severe, but it usually resolves without treatment once seizures are controlled.

Suspicion for isoniazid poisoning — Pyridoxine (vitamin B6) treatment is required for all patients with seizures or GCSE from acute isoniazid (INH) poisoning and should be considered in all patients with refractory GCSE (see "Refractory status epilepticus in adults"). Clinicians should suspect INH as a possible cause of seizures when the patient or a patient's family member is being treated with INH or has emigrated from an area where tuberculosis infection is endemic or when seizures fail to respond to appropriate benzodiazepine therapy. (See "Isoniazid (INH) poisoning", section on 'Seizure management'.)

EMERGENCY ANTISEIZURE TREATMENT — Many possible pharmacologic approaches to status epilepticus have been developed empirically, but there are few controlled trials comparing different regimens. The approach outlined below is generally consistent with consensus-based guidelines published by the Neurocritical Care Society and the American Epilepsy Society [6,7].

Generalized convulsive status epilepticus (GCSE) — Clinically obvious GCSE should be treated immediately with a benzodiazepine and a long-acting antiseizure medication, without waiting for an EEG or other studies (algorithm 1). Treatment delay is associated with increased morbidity and mortality.

First therapy: Benzodiazepines — Benzodiazepines are the first-line treatment for convulsive status epilepticus because they control seizures rapidly [8-13]. The three most commonly used benzodiazepines for status epilepticus are diazepam, lorazepam, and midazolam. In adults, choice of benzodiazepine medication varies by route of administration [9]:

●For the intravenous (IV) route, lorazepam is preferred

●Midazolam is preferred for intramuscular (IM), intranasal, or buccal administration

●Diazepam is preferred for rectal administration

In addition to benzodiazepines, treatment with an intravenous nonbenzodiazepine antiseizure medication (eg, levetiracetam, fosphenytoin, or valproate preferred; or lacosamide or phenobarbital as alternatives) is given to prevent recurrence, even if convulsions have ceased following benzodiazepine treatment [6,7]. (See 'Second therapy: Antiseizure medications' below.)

Prehospital treatment — Benzodiazepine treatment of status epilepticus out of hospital appears to be safe and effective using the following medications [10,11,14-17].

●Midazolam 10 mg IM and lorazepam 4 mg IV and are the best-studied drugs in this setting.

●Clonazepam 1 mg IV is an option in Europe and elsewhere but is not available in IV form in the United States.

●Rectal diazepam is given in doses of 0.2 mg/kg up to 20 mg for an adult [17]. Intranasal diazepam given at 0.2 mg/kg is an alternative.

●Buccal and nasal midazolam are also promising for outpatient interruption of seizures or status epilepticus and can be administered without IV access or medical personnel [14]. The typical dose of buccal midazolam is 0.2 mg/kg, or 10 mg in adolescents and adults. The dose of intranasal midazolam using the nasal spray formulation (5 mg/0.1 mL) is one spray (5 mg) in each nostril to give 10 mg. If the spray formulation is not available, midazolam can also be given intranasally using the injectable solution of 5 mg/mL as a metered spray of 0.1 mL containing 0.5 mg, three to five times per nostril, and repeated if necessary, to a total dose of 10 mg for adults.

In-hospital treatment — Pharmacologic therapy begins with a benzodiazepine and a nonbenzodiazepine antiseizure medication (algorithm 1). Despite initial treatment, approximately 20 percent of patients develop refractory status epilepticus and require additional therapy [18]. (See "Refractory status epilepticus in adults".)

Inadequate dosing of benzodiazepine is a common problem leading to prolongation of status epilepticus [19].

●When IV access is available – Lorazepam 0.1 mg/kg should be administered intravenously at a maximum rate of 2 mg/minute, allowing a few minutes (eg, three to five minutes) to assess its effect before deciding whether additional doses are necessary [6]. An alternative to a weight-based initial loading dose of lorazepam is a 4 mg fixed dose, repeated if still seizing.

If seizures continue at this point, additional doses of lorazepam can be infused at a maximum rate of 2 mg/minute. There is no definite maximum cumulative dose of lorazepam; clinicians must be guided by the clinical effect (including on blood pressure) and seizure control, both clinically and by EEG, once available. Even if seizure activity stops following lorazepam, a loading dose of a nonbenzodiazepine antiseizure medication should follow in order to maintain seizure control.

Diazepam 0.15 mg/kg IV, up to 10 mg per dose, may be substituted if lorazepam is not available.

●When IV access is not available – Placement of an access catheter may be difficult in some patients. When IV access is not immediately available, IM midazolam is a safe and effective alternative for initial benzodiazepine therapy [10,20,21]. As nasal and buccal midazolam are absorbed more rapidly than IM midazolam, it is possible or even likely that these routes are superior [22], but they are not as well studied as IM midazolam in adults.

For patients with a body weight >40 kg, midazolam can be given at a dose of 10 mg by IM, nasal, or buccal administration [10,14]. With buccal administration of midazolam, one report suggests that a dose of 15 to 20 mg for adults may be effective (when necessary) and well tolerated [23].

Benzodiazepine efficacy — In a randomized, double-blind study of 205 patients with status epilepticus, status epilepticus was terminated by arrival at the emergency department in more patients treated with IV lorazepam or diazepam than placebo (59, 43, and 21 percent, respectively) [11]. Of note, either benzodiazepine treatment also reduced the rates of respiratory or circulatory complications compared with placebo (10.6, 10.3, and 22.5 percent, respectively), lessening concern for the respiratory side effects of benzodiazepines.

●Lorazepam – Use of lorazepam as a first-line agent is supported by the Veterans Affairs (VA) comparative trial that randomly assigned 570 patients with a confirmed diagnosis of status epilepticus to one of four initial regimens: lorazepam (0.1 mg/kg), phenytoin (18 mg/kg), diazepam (0.15 mg/kg) plus phenytoin (18 mg/kg), or phenobarbital (15 mg/kg) [8]. Status epilepticus was diagnosed after 10 minutes of seizure activity, clinically or on EEG. In the subgroup of 384 patients with "overt" (clinically evident) GCSE, treatment with lorazepam alone was most effective in terminating seizures within 20 minutes and in maintaining seizure freedom for the first 60 minutes after treatment (65 percent versus 58 percent with phenobarbital, 56 percent with diazepam plus phenytoin, and 44 percent with phenytoin alone), although the only statistically significant difference was between lorazepam alone and phenytoin alone.

No significant differences in the success rates of the different regimens were observed in the 134 patients with "subtle" GCSE (ie, status epilepticus evident on EEG after convulsions had ceased, with some residual myoclonic jerking or eye movements as the only clinical signs of ongoing seizures), and overall there were no significant differences in seizure recurrence during the 12-hour study period, outcome at 30 days, or in the incidence of adverse events [8]. Success with any regimen was much lower for "subtle" GCSE compared with "overt" GCSE. Almost half of the patients with "overt" GCSE required additional treatment with a second antiseizure medication, but when the first medication failed, only 7 percent of patients responded successfully to a second antiseizure medication.

The purported clinical advantage of lorazepam over diazepam is that the effective duration of action against seizures is as long as four to twelve hours because of its less pronounced redistribution into adipose tissue. The time from its injection to its maximum effect against seizures is as long as two minutes. Nevertheless, a randomized clinical trial in children with status epilepticus found that lorazepam and diazepam were similarly effective in terminating seizures, with no difference in the rate of assisted ventilation [24]. (See "Management of convulsive status epilepticus in children", section on 'Benzodiazepine efficacy and pharmacokinetics'.)

●Diazepam – Diazepam has high lipid solubility and can therefore cross the blood-brain barrier rapidly. It is highly effective in terminating seizures rapidly when administered intravenously at doses of 0.1 to 0.15 mg/kg, up to 10 mg per dose. An effect upon seizure activity can be seen as early as 10 to 20 seconds after administration, and cerebrospinal fluid concentrations reach half of their maximum value in three minutes. Because of subsequent redistribution of the drug into adipose tissue, however, the duration of diazepam's acute anticonvulsant effect is typically <20 minutes. Initial termination of seizure activity with IV diazepam is seen in 50 to 80 percent of patients [8], but if no other medication is provided, there is a 50 percent chance of seizure recurrence within the next two hours [25,26].

Nonetheless, IV diazepam remains the drug of first choice in some settings because it is stable in liquid form for long periods at room temperature. Thus, diazepam is available in resuscitation kits in premixed form, while lorazepam [27] and phenytoin are not. Midazolam is also stable at room temperature, as discussed below.

A rectal gel formulation of diazepam provides rapid delivery when IV access is difficult, or for at-home use for patients who have frequent repetitive or prolonged seizures [28]. A nasal spray formulation of diazepam (and midazolam, see below) is also available [29]; it is approved by the US Food and Drug Administration (FDA) for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients age six years and older [30].

●Midazolam – Like lorazepam and diazepam, midazolam is very effective in terminating seizures rapidly (frequently in less than one minute), but it has a short half-life in the central nervous system. Midazolam appears to be quite stable at ambient temperatures in ambulances [27]. IM, nasal, and buccal administration of midazolam (0.2 mg/kg, maximum 10 mg) are effective alternatives to IV lorazepam when IV access is not already established [21,23,31,32]. In a randomized trial of 898 patients with status epilepticus in the prehospital setting, 10 mg IM midazolam was superior to 4 mg IV lorazepam in adults [10]. On arrival to hospital, patients receiving IM midazolam had a higher rate of seizure control (73 versus 63 percent) than patients receiving IV lorazepam. The superiority of IM administration arose from the time required to insert an IV; the treatment response with IV lorazepam was faster compared with IM midazolam (1.6 versus 3.3 minutes) if counted from the time of medication administration, while time to treatment administration was shorter with midazolam compared with lorazepam-treated patients (1.2 versus 4.8 minutes). Adverse reactions were similar for both treatments.

Continuous infusion of IV midazolam is used in the management of refractory status epilepticus. (See "Refractory status epilepticus in adults", section on 'Midazolam'.)

●Clonazepam – Outside the United States, IV clonazepam (0.015 mg/kg) is commonly used as a first-line therapy for status epilepticus [15,33]. Although comparative data are relatively limited, one observational study found that first-line therapy with clonazepam was associated with a lower risk for refractory status epilepticus compared with lorazepam, even after adjusting for relevant confounders [19]. The study also raised concern that lorazepam was given in inadequate doses more often than clonazepam, perhaps explaining some of the difference in efficacy. A randomized trial in 107 adults with status epilepticus found that prehospital administration of levetiracetam (2.5 grams IV) plus clonazepam (1 mg IV, repeated at 5 minutes for ongoing seizures) offered no benefit over clonazepam alone [15]. Rates of seizure cessation at 15 minutes were similar for combined treatment compared with clonazepam alone (74 versus 84 percent, 95% CI for percentage difference -24 to 3), as were all secondary endpoints, including rates of recurrent seizure activity, need for intubation, and length of hospital stay. Of note, IV clonazepam is not available in the United States but is commonly used in Europe as a first-line agent.

Second therapy: Antiseizure medications — As noted above, treatment with a nonbenzodiazepine antiseizure medication is given to prevent recurrence, even if convulsions have ceased following benzodiazepine treatment [6]. This is especially important if diazepam or midazolam was used to stop seizures, as they have a short duration of action. With initial therapy given alone, the recurrence rate of status epilepticus is unacceptably high [8,10]. Exceptions to the need for a nonbenzodiazepine antiseizure medication may include patients who have seizures that stop with lorazepam treatment and have a rapidly reversible cause of GCSE that has been definitively corrected, such as severe hypoglycemia [6].

It is important to calculate the weight-based dose; underdosing of antiseizure medication should be avoided.

Choosing an agent — We suggest treatment with either levetiracetam, fosphenytoin, or valproate, rather than alternative antiseizure medications.

●Levetiracetam – Levetiracetam is given at a loading dose of 60 mg/kg (maximum 4500 mg) infused over 15 minutes. (See 'Levetiracetam' below.)

●Fosphenytoin and phenytoin – Fosphenytoin is started with a loading dose of 20 mg phenytoin equivalents (PE)/kg infused at 100 to 150 mg PE/min; phenytoin is started with a loading dose of 20 mg/kg and infused at 25 to 50 mg/minute. The infusion rate should be reduced if significant adverse effects occur. An additional dose of fosphenytoin 5 to 10 mg PE/kg (or phenytoin 5 to 10 mg/kg) can be given 10 minutes after the loading infusion if seizures persist, up to a maximum cumulative dose of 30 mg/kg.

Phenytoin (but not fosphenytoin) is incompatible with any of the benzodiazepines and will precipitate if infused through the same IV line; the same applies to phenytoin and any fluid with glucose/dextrose. (See 'Fosphenytoin and phenytoin' below.)

●Valproate – Valproate is given with a loading dose of 40 mg/kg and infused at a rate of 10 mg/kg per minute in adults (maximum dose 3000 mg); thus, the full dose can be given in four minutes, with no significant risk of acute adverse effects.

Factors influencing choice — The choice among antiseizure medications can be made according to individual patient factors such as comorbid conditions and potential adverse effects, as well as local availability and clinician experience.

For patients already on chronic therapy with one of the preferred agents prior to the onset of status epilepticus, clinical judgement is required to determine nonbenzodiazepine antiseizure medication selection and dosing for GCSE. As examples:

●For a patient on phenytoin treatment prior to the onset of GCSE who is known to have a recent therapeutic phenytoin dose or level, it is reasonable to use valproate or levetiracetam (rather than phenytoin or fosphenytoin) as the second agent for GCSE.

●For a patient on chronic valproate who is known to have a recent therapeutic dose or level, it is reasonable to use fosphenytoin/phenytoin or levetiracetam (rather than valproate) as the second agent for GCSE.

●For a patient on chronic phenytoin or valproate who is thought to have a low drug level, an additional, proportionate loading dose of that drug would be worthwhile.

●For a patient on chronic levetiracetam, it takes too long to obtain levetiracetam levels at most centers in the urgent setting of GCSE. Accordingly, it is reasonable to use fosphenytoin/phenytoin or valproate as the second agent for GCSE if the recent dosing or level of levetiracetam is unknown. An alternative is to reload with levetiracetam, as there is no serious risk to transient supratherapeutic levetiracetam levels.

Antiseizure medication efficacy

Comparative efficacy — Among the antiseizure medications that can be loaded intravenously, there is high-quality evidence from the Established Status Epilepticus Treatment Trial (ESETT) trial that fosphenytoin, valproate, and levetiracetam are equally effective and have similar rates of adverse effects [34]. The trial enrolled 384 pediatric and adult patients with convulsive status epilepticus refractory to benzodiazepines. The patients were randomly assigned to receive levetiracetam (n = 145 patients), fosphenytoin (n = 118), or valproate (n = 121). The trial was stopped early when an interim analysis met criteria for futility. The composite outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes was achieved in the levetiracetam group by 47 percent (95% credible interval 39-55), in the fosphenytoin group by 45 percent (95% credible interval 36-54), and in the valproate group by 46 percent of patients (95% credible interval 38-55). Although not statistically significant, there were numerically more episodes of hypotension and intubation in the fosphenytoin group and more deaths in the levetiracetam group compared with the other groups. Limitations to the ESETT include a substantial rate (approximately 50 percent) of unblinding of investigators and clinicians to permit choosing a second antiseizure medication for ongoing seizures; inadvertent enrollment of patients without status epilepticus, including patients with psychogenic nonepileptic seizures (approximately 10 percent of the study population, likely unavoidable); capping of weight-based dosing at 75 kg (such that heavier patients received a lower mg/kg dose); and absence of confirmatory EEG.

Prior to the ESETT, there were few high-quality data to guide the choice among the antiseizure medications for treating status epilepticus. The earlier evidence came from observational studies and a few smaller randomized trials; most of these reports suggested that phenytoin, valproate, and levetiracetam had similar efficacy for treating status epilepticus, but the findings for phenytoin were inconsistent [35-37].

Levetiracetam — We start levetiracetam using a loading dose of 60 mg/kg IV in adults (maximum 4500 mg) infused over 5 to 15 minutes [34,38]. Status epilepticus guidelines differ in the ranges provided for a single dose of levetiracetam IV; one suggests 1000 to 3000 mg IV in adults [6], and the other suggests 60 mg/kg up to a maximum of 4500 mg [7]. Doses are typically infused over 15 minutes [39]. Retrospective data suggest that rapid intravenous infusion (over 5 minutes) of levetiracetam in doses up to 4500 mg is safe and well-tolerated [38].

Although high-quality evidence to guide individual patient therapy is lacking, levetiracetam may be preferred for patients with status epilepticus who are already receiving levetiracetam at baseline and for those with liver failure. Levetiracetam is increasingly commonly used as the second treatment for GCSE (after the benzodiazepine) in part for its lack of interactions with other drugs and overall excellent tolerability, an advantage when transitioning to longer-term medication regimens.

Fosphenytoin and phenytoin

●Fosphenytoin – Fosphenytoin is the generally preferred formulation of phenytoin for rapid intravenous dosing. The loading dose is 20 mg PE/kg, infused at a rate of 100 to 150 mg PE/minute. Cardiac monitoring and frequent vital signs are required during the infusion of fosphenytoin or phenytoin and for at least 15 minutes after the end of a fosphenytoin infusion while it continues to be dephosphorylated into phenytoin (conversion half-life is 15 minutes).

Fosphenytoin is a pro-drug of phenytoin that is hydrolyzed to phenytoin by serum phosphatases. It is highly water soluble and therefore unlikely to precipitate during IV administration. The risk of local irritation at the site of infusion is significantly reduced compared with phenytoin; fosphenytoin can therefore be infused much more rapidly (up to 150 mg PE/minute versus 50 mg/minute with phenytoin). In addition, the increased water solubility of fosphenytoin makes IM administration possible if IV access cannot be obtained. IM administration, however, yields less predictable levels and a longer time to onset of effect than IV administration and should not be used for GCSE.

Because propylene glycol is not required to solubilize fosphenytoin, the cardiovascular side effects of fosphenytoin, especially hypotension, may be less frequent and severe than those of phenytoin, but at least two studies have suggested that the incidence of adverse hemodynamic effects with fosphenytoin and phenytoin infusions is similar [40,41].

Phenytoin and fosphenytoin are reported to intensify seizures caused by cocaine, other local anesthetics, theophylline, or lindane [42-44].

●Phenytoin – Phenytoin is generally started with a loading dose of 20 mg/kg, infused at a rate of up to 50 mg/minute. A common error is giving a "standard" dose of 1 gram, which is inadequate dosing for most patients weighing more than 50 kg (110 pounds), ie, most adults. It is critical to modify the infusion rate if hypotension or other adverse cardiovascular events occur. The risks of hypotension and cardiac arrhythmias increase with higher infusion rates, partly due to the propylene glycol used to solubilize phenytoin. In addition, the risks of local pain and injury (including venous thrombosis and the rare purple glove syndrome) increase with more rapid infusions. Cardiac monitoring during the initial infusion is mandatory because cardiac arrhythmias may occur.

Valproate — Intravenous valproate is increasingly used in the treatment of status epilepticus. It is preferred over phenytoin in patients with primary generalized epilepsies, although these patients represent a relatively small proportion of those with GCSE. It can also be particularly useful as a nonsedating option in patients with focal or myoclonic status epilepticus (MSE).

Accumulating evidence suggests that a loading dose of 40 mg/kg can be infused safely at a rate of 10 mg/kg per minute (maximum dose 3000 mg) in adults without adverse effects on blood pressure or heart rate [7,34]. Loading doses in this range yield concentrations in typical therapeutic ranges and without significant sedation. Patients who are already on enzyme-inducing antiseizure medications may need higher maintenance doses or shorter intervals between doses, and the free phenytoin level often rises markedly with concurrent administration, as both agents are highly protein-bound. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

The risk of hepatic toxicity and hyperammonemic encephalopathy due to valproate may pose diagnostic challenges in postictal settings [45], particularly in children with some aminoacidopathies or mitochondrial disorders. Risks of hepatic dysfunction and coagulopathy (independent of hepatic dysfunction) are important considerations in patients with active bleeding or recent neurosurgical procedures. (See "Valproic acid poisoning".)

Second- or third-line medications — There are several antiseizure medications that can be useful in the management of status epilepticus but are not preferred as initial drugs in most cases due to adverse effect profile or lack of sufficient data on efficacy [6,7].

Phenobarbital and lacosamide can be given intravenously and may be particularly useful as adjunctive agents in patients with focal or nonconvulsive status epilepticus, as an additional treatment in patients with refractory status epilepticus, and (for lacosamide) when preservation of a higher level of consciousness is desired.

●Phenobarbital – Phenobarbital is a very effective antiseizure medication, especially in the acute management of seizures, but it was not the best initial treatment in the VA comparative trial [8]. Various studies have shown a rate of seizure control of approximately 60 percent when phenobarbital is used alone, similar to that with lorazepam alone or the combination of phenytoin and diazepam [8,46]. High doses of phenobarbital will control almost any seizure [47] but at the cost of substantial sedation and potential reduction of blood pressure and respiration. Despite its efficacy, phenobarbital is generally not used as a first-line treatment in adults because it is slow to administer, causes prolonged sedation, and may involve a higher risk of hypoventilation and hypotension than benzodiazepines, phenytoin, valproate, or levetiracetam.

Initial doses of phenobarbital 20 mg/kg infused at a rate of 30 to 50 mg/minute are generally used; slower infusion rates should be used in older adult patients, although phenobarbital may have fewer cardiac side effects than phenytoin in these patients. Careful monitoring of respiratory and cardiac status is mandatory. Intubation is often necessary in order to provide a secure airway and minimize the risk of aspiration if phenobarbital is administered following benzodiazepines. The risk of prolonged sedation with phenobarbital is greater than with the other antiseizure medications, in part because of its half-life of 87 to 100 hours.

●Lacosamide – Accumulating data indicate that IV lacosamide (200 to 400 mg IV bolus) is usually well tolerated and may have similar efficacy compared with other agents used to treat refractory status epilepticus [48-56]; rare serious adverse events include second-degree and complete atrioventricular block [48]. An electrocardiogram should be performed before use of lacosamide and during maintenance to monitor for PR prolongation. Additional caution is warranted in patients with comorbid heart disease and with concurrent use of other drugs that may prolong the PR interval. A prospective randomized blinded trial showed that lacosamide was noninferior to fosphenytoin for the treatment of refractory nonconvulsive seizures [57]; however, there is a lack of similar high-quality data for convulsive status epilepticus to date.

Refractory GCSE — Optimally, treatment of GCSE with benzodiazepines and antiseizure medications is completed within 10 to 20 minutes (algorithm 1). In patients with GCSE who are actively seizing at 30 minutes despite two initial doses of a benzodiazepine and administration of one or two other antiseizure medication loads, preparation for a continuous infusion of midazolam, propofol, or pentobarbital should begin. At this stage, the patient will require endotracheal intubation and mechanical ventilation (if not already performed), neurologic consultation, and transfer to an intensive care unit with continuous EEG (cEEG) monitoring capability, as reviewed separately. (See "Refractory status epilepticus in adults".)

Focal motor status epilepticus — Most focal status epilepticus is treated with the same antiseizure medications as for GCSE, but with somewhat less urgency and with higher priority given to the avoidance of oversedation and intubation. (See 'Generalized convulsive status epilepticus (GCSE)' above.)

●Nonketotic hyperglycemia – When focal motor status is caused by nonketotic hyperglycemia, seizures are usually controlled readily with correction of the metabolic derangements [58]. Benzodiazepines can be used if seizures persist despite correction. Antiseizure medications are often unnecessary after resolution of the acute illness. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".)

●Epilepsia partialis continua – For the more prolonged episodes of epilepsia partialis continua, antiseizure medications including benzodiazepines may be helpful and necessary in preventing bilateral tonic-clonic seizures, but they often do not stop the continued focal jerking, even with multiple antiseizure medications. Overall, treatment is seldom very effective. Surgical treatment can be pursued if the responsible lesion is clearly identified and small enough, but it is not always successful [59].

Myoclonic status epilepticus — Initial treatment of MSE is heavily dependent upon the form of MSE and the underlying etiology. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Myoclonic status epilepticus'.)

●Relatively benign MSE – MSE in the relatively benign epilepsy syndromes such as juvenile myoclonic epilepsy (JME) is often recognized readily and treated relatively easily with benzodiazepines; valproate and levetiracetam may also be helpful [60,61]. A primary consideration in the treatment of these (presumed) genetic generalized epilepsies is the avoidance of inappropriate use of sodium channel-based antiseizure medications such as carbamazepine, phenytoin, oxcarbazepine [62], and lacosamide, which may exacerbate seizures. Patients usually return to their baseline conditions relatively rapidly with treatment, without residual morbidity. (See "Juvenile myoclonic epilepsy".)

●More severe MSE – The more severe forms of MSE that occur in (usually childhood-onset) epilepsy syndromes, such as Dravet or Lennox-Gastaut syndrome, can be much more difficult to interrupt. Initial treatment is often with the antiseizure medications noted above but also with those used for GCSE. Many of these MSE cases include nonconvulsive seizures (sometimes difficult to distinguish from the baseline impaired cognition). Also, it can be difficult to recognize when seizures have ceased, so cEEG monitoring is usually necessary in both diagnosis and management. In the MSE associated with progressive myoclonic epilepsy syndromes, treatment is similar to that for GCSE. Seizures may come under control, but the underlying encephalopathy often progresses despite seizure cessation.

MSE due to medical illnesses causing encephalopathy (eg, uremia or sepsis) may be refractory. The antiseizure medications used for convulsive status epilepticus may interrupt the seizures, but the outcome depends primarily on treatment or management of the underlying medical illness.

●Anoxic MSE – Anoxic MSE is completely different [63-65]. Benzodiazepines, valproic acid, and levetiracetam can help control epileptiform discharges and clinical myoclonus, but the underlying encephalopathy usually determines the outcome, which is very often poor, although there are exceptions. (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis".)

POSTICTAL RECOVERY AND FURTHER EVALUATION

Expected pace of recovery — Most generalized CSE patients with generalized convulsive status epilepticus (GCSE) begin to recover responsiveness within 10 to 20 minutes after generalized convulsions, but there is a broad range. Close monitoring during this period is important.

The two most common reasons for prolonged postictal recovery are sedation due to medications and the continuation of (nonconvulsive) seizures; these can be impossible to distinguish clinically. Note that benzodiazepine reversal with flumazenil should be avoided in this setting, as reversal can precipitate seizures. Patients with seizures or status epilepticus who do not return to a normal level of consciousness after initial treatment should be monitored by EEG to determine if the patient is still seizing. (See 'EEG monitoring' below.)

Neurologic assessment — During the postictal recovery period, it is important to repeat a full neurologic examination, looking for asymmetric or focal findings that may suggest clues to the underlying etiology.

EEG monitoring — For patients with status epilepticus as the first presentation of seizures or epilepsy, an EEG should be done to evaluate background activity as soon as possible after the seizure stops. An EEG may not be necessary for patients with known epilepsy who are recovering as expected (ie, rapidly improving in alertness) from status epilepticus if the clinicians are confident the clinical seizures have stopped and there is no other independent reason that the patient would benefit from ongoing continuous EEG (cEEG) monitoring.

All patients with seizures or status epilepticus who do not return to a normal level of consciousness after initial treatment should be monitored by cEEG to determine whether seizures have stopped. In a prospective study of 164 patients presenting with generalized convulsive status epilepticus in which cEEG monitoring was performed postictally (beginning within 30 minutes of control of clinical seizures), the following findings were described [66]:

●Fifty-two percent of patients had no evidence of ongoing epileptic discharges or seizures. The most common EEG patterns in these patients were generalized slowing, background voltage attenuation, lateralized periodic discharges (LPDs; previously known as periodic lateralized epileptiform discharges [PLEDS]), focal slowing, or burst suppression. Mortality in this subgroup was 13 percent.

●Fourteen percent of patients had evidence of nonconvulsive status epilepticus. All of these patients were comatose and had no overt clinical signs of convulsive activity. The EEG pattern was focal or focal with secondary generalization in most patients. Mortality in this subgroup was 51 percent.

●In the remaining 34 percent of patients, EEG demonstrated evidence of noncontinuous rhythmic discharges lasting 10 seconds to several minutes and considered to be electrographic seizures, mostly without clinical accompaniment; mortality in this subgroup was 32 percent.

A secondary analysis of the subsequent Established Status Epilepticus Treatment Trial (ESETT) evaluated patients who had EEG done within 24 hours of presentation (mainly in the emergency department) [67]. In the subgroup of patients who were intubated, the prevalence of electrographic seizures was 15 percent (95% CI 7 to 30 percent). Similarly, in the subgroup of patients who had resolution of clinically apparent seizures within 60 minutes and improving mental status, the prevalence of electrographic seizures was 13 percent (95% CI 7 to 21 percent). These findings suggest that electrographic seizures occur at a similar rate among patients with apparent treatment success and patients who are not improving, and support the early use of EEG monitoring in the emergency department, when feasible, if complete return to baseline is at all delayed.

Neuroimaging — For patients with status epilepticus as the first presentation of seizures or epilepsy, those with suspected focal onset of status epilepticus or those who are not recovering as expected, a head CT or magnetic resonance imaging (MRI) should be obtained once seizures are controlled. CT may be performed in the emergency department setting, but MRI has superior yield for determining the underlying etiology. Some experts obtain neuroimaging for everyone with status epilepticus. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Neuroimaging' and "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis", section on 'Neuroimaging'.)

Lumbar puncture — A lumbar puncture (LP) for cerebrospinal fluid analysis is warranted if the clinical presentation is suggestive of an acute infection that involves the central nervous system, or if the patient has a history of a malignancy and there is concern for leptomeningeal metastases. In other circumstances, LP is less likely to be helpful and may even be misleading, because a prolonged seizure itself can cause cerebrospinal fluid pleocytosis (although usually only minor). LP should only be performed after a space-occupying brain lesion has been excluded by appropriate brain imaging studies; blood cultures should be obtained and empiric antimicrobials should be started prior to brain imaging if there is concern for infection.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)

SUMMARY AND RECOMMENDATIONS

●Recognition and evaluation – Generalized convulsive status epilepticus (GCSE) is an unremitting generalized convulsive seizure lasting longer than five minutes or multiple motor seizures without an interictal return to the baseline level of consciousness. (See 'Rapid recognition of status epilepticus' above and 'Urgent focused evaluation' above.)

●Immediate supportive care – The initial assessment and treatment of a patient in status epilepticus should proceed in quick succession and include (algorithm 1):

•A focused history from a family member or caregiver, assessment of respiratory and circulatory status, and a rapid neurologic examination. (See 'Urgent focused evaluation' above.)

•Maintenance of an adequate airway, breathing, and circulation, and placement of cardiorespiratory monitoring. (See 'Airway and breathing' above and 'Monitoring' above.)

•Placement of two intravenous (IV) or intraosseous (IO) catheters and hemodynamic support as required. However, there should be no delay in initial benzodiazepine treatment while awaiting IV access. (See 'Circulation and vascular access' above.)

•Laboratory studies including serum glucose (rapid point-of-care), electrolytes, calcium, and magnesium; serum antiseizure medication levels (if applicable); and urine and blood toxicology. (See 'Initial studies' above.)

•Correction of hypoglycemia and metabolic abnormalities. (See 'Correct hypoglycemia and metabolic derangements' above.)

●Antiseizure treatment of GCSE – The pharmacologic management of GCSE is summarized in the algorithm (algorithm 1).

•Benzodiazepine – For patients presenting with GCSE, we recommend initial treatment with a benzodiazepine (Grade 1A). When IV or IO access is already established, lorazepam is preferred over other benzodiazepines based on pharmacokinetic properties (Grade 2C). The typical loading dose of lorazepam is 0.1 mg/kg IV, infused at a maximum rate of 2 mg/min, allowing three to five minutes to assess the effect before deciding whether additional doses are necessary. An alternative is a fixed dose of lorazepam (4 mg), repeated if the patient is still seizing. (See 'First therapy: Benzodiazepines' above.)

In the prehospital setting when there is no established IV access, intramuscular (IM) midazolam (10 mg) is superior to IV lorazepam due to more rapid delivery. Nasal or buccal midazolam (0.2 mg/kg, maximum 10 mg) is also a reasonable option.

•Antiseizure medication – For patients presenting with GCSE, in addition to benzodiazepines (algorithm 1), we suggest treatment with an IV loading dose of a longer-acting antiseizure medication in order to maintain seizure control (Grade 2C). Levetiracetam (60 mg/kg, maximum 4500 mg), fosphenytoin (20 mg phenytoin equivalents [PE]/kg), or valproate (40 mg/kg) are all effective antiseizure medications in this setting. (See 'Second therapy: Antiseizure medications' above.)

•Refractory GCSE – For patients with GCSE that is not controlled despite treatment with two appropriately dosed antiseizure medications (ie, a benzodiazepine and a longer-acting antiseizure medication), preparation for a continuous infusion of midazolam, propofol, or pentobarbital should begin. At this stage, the patient will require endotracheal intubation and mechanical ventilation, neurologic consultation, and transfer to an intensive care unit with continuous electroencephalography (cEEG) monitoring capability. (See "Refractory status epilepticus in adults".)

●Postictal recovery and assessment – The most common reasons for prolonged postictal recovery are sedation due to medications and the continuation of (nonconvulsive) seizures; these can be impossible to distinguish clinically. Patients who do not recover responsiveness within 10 to 20 minutes after generalized convulsions require further evaluation with cEEG. (See 'Postictal recovery and further evaluation' above.)