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Convulsive status epilepticus in adults: Treatment and prognosis

Author: Frank W Drislane, MD


Section Editor: Paul Garcia, MD
Deputy Editor: Janet L Wilterdink, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Jul 19, 2017.

INTRODUCTION — Status epilepticus is a relatively common medical and neurologic emergency that requires prompt
evaluation and treatment. Status epilepticus manifests as many different syndromes, each defined by distinctive clinical features
and EEG findings. Causes, prognoses, and treatments differ, and optimal evaluation and treatment requires an understanding of
both the type of status epilepticus and the underlying cause. Some forms of status epilepticus have an excellent prognosis,
whereas others are associated with major morbidity or even mortality.

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".)

Treatment and prognosis of convulsive status epilepticus is discussed below. Nonconvulsive status epilepticus and the diagnosis
and management of status epilepticus in children are discussed separately. (See "Nonconvulsive status epilepticus" and
"Clinical features and complications of status epilepticus in children" and "Management of convulsive status epilepticus in
children".)

INITIAL TREATMENT — All patients with generalized convulsive status epilepticus (GCSE) require rapid evaluation and
treatment. GCSE is operationally defined as ≥5 minutes of continuous seizure activity, or more than one seizure without
recovery in between [1,2]. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section
on 'Definition'.)

Many possible pharmacologic approaches have been developed empirically, but there are few controlled trials comparing
different regimens [3-6]. The approach outlined below is generally consistent with consensus-based guidelines published by the
Neurocritical Care Society [1].

Initial management is divided into three phases: assessment and supportive treatment; initial pharmacologic therapy with a
benzodiazepine; and urgent therapy that achieves long-term control using a nonbenzodiazepine antiseizure drug such as
fosphenytoin (algorithm 1). Despite initial treatment, about 20 percent of patients develop refractory status epilepticus and
require additional therapy.

Rapid assessment and support — A rapid neurologic examination should be performed to determine of the type of status
epilepticus and, if possible, its etiology. A focused general medical evaluation should assess respiratory and circulatory status.
Attention to airway, breathing, and circulation is urgent, as in other medical emergencies. Supportive therapy (eg, oxygen,
mechanical ventilation) should be instituted as necessary. Measurement of arterial blood gases is often valuable, as most
patients with GCSE who do not respond rapidly to initial treatment require intubation and mechanical ventilation.

Intravenous (IV) catheters should be placed and blood obtained for electrolytes including calcium, phosphorus, and magnesium,
serum glucose, liver function tests, a complete blood count, toxicology studies, and antiseizure drug levels, as appropriate. A
rapid fingerstick glucose should also be obtained. Cardiac monitoring, frequent measurement of blood pressure, and pulse
oximetry should be instituted. Thiamine (100 mg) and dextrose (50 mL of 50 percent dextrose solution) should be considered.
These tasks require at least one to five minutes and should overlap with the next phase of treatment (algorithm 1).

Neuromuscular blocking agents are often used to facilitate rapid intubation, but they can abolish the motor manifestations of
seizures and thus mask ongoing status epilepticus. They are not a treatment for status epilepticus. Alternative agents, such as
midazolam or thiopental, are therefore preferred to facilitate rapid intubation. When neuromuscular blocking agents are used,
EEG monitoring is mandatory in order to know whether status epilepticus has resolved or is continuing and needs further

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treatment. (See "Induction agents for rapid sequence intubation in adults outside the operating room", section on 'Status
epilepticus'.)

Initial pharmacologic therapy

When IV access is available — Benzodiazepines are the first-line treatment for GCSE. In addition, treatment with a
nonbenzodiazepine antiseizure drug is recommended to prevent recurrence, even if convulsions have ceased following
benzodiazepine treatment [1]. Among the antiseizure drugs that can be loaded intravenously, fosphenytoin or valproate have
been preferred for most patients [1]. Small randomized trials also support the use of intravenous levetiracetam, but these trials
are limited by modest power to detect differences between the drugs. To address the question of which drug, if any, should be
preferred, the National Institutes of Health has funded an adequately-powered, randomized controlled trial (ESETT) comparing
fosphenytoin, valproate, and levetiracetam [7-10]. (See 'Efficacy and dosing of specific drugs' below.)

● Lorazepam 0.1 mg/kg should be administered intravenously at a maximum rate of 2 mg/minute, allowing one minute to
assess its effect before deciding whether additional doses are necessary [1]. An alternative to a weight-based initial loading
dose of lorazepam is a 4 mg fixed dose, repeated if still seizing. Diazepam 0.15 mg/kg IV, up to 10 mg per dose, may be
substituted if lorazepam is not available. (See 'Benzodiazepines' below.)

● If seizures continue at this point, additional doses of lorazepam can be infused at a maximum rate of 2 mg/minute, and a
second intravenous catheter placed. There is no definite maximum 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 drug should follow in order to
maintain seizure control.

● A fosphenytoin infusion of 20 mg/kg phenytoin equivalents (PE) (or 20 mg/kg for phenytoin) should be started at 100 to 150
mg PE/min (or 25 to 50 mg/minute for phenytoin), but the infusion rate should be reduced if significant adverse effects
occur. Phenytoin (but not fosphenytoin) and any of the benzodiazepines are incompatible and will precipitate if infused
through the same intravenous line; the same applies to phenytoin and any fluid with glucose/dextrose. An additional dose (5
mg PE/kg fosphenytoin or 5 mg/kg phenytoin) can be given 10 minutes after the loading infusion if seizures persist. Valproic
acid 20 to 40 mg/kg and levetiracetam 40 to 60 mg/kg (maximum 4500 mg) are reasonable alternatives to fosphenytoin as
initial nonbenzodiazepine therapy in patients with hypersensitivities. Further dosing and administration details are provided
below. (See 'Fosphenytoin and phenytoin' below and 'Valproic acid' below and 'Levetiracetam' below.)

Optimally, this phase of treatment is completed within 10 to 20 minutes (algorithm 1). In patients who are actively seizing despite
two initial doses of lorazepam or other benzodiazepine, preparation for a continuous midazolam or propofol infusion should
occur simultaneously with administration of fosphenytoin, valproic acid, or levetiracetam, since the primary role of the
nonbenzodiazepine antiseizure drug is to prevent recurrence rather than break the seizures. (See 'Refractory status epilepticus'
below.)

When IV access is not available — If IV access is not available, intramuscular (IM) midazolam is a safe and effective
alternative for initial benzodiazepine therapy [11-13]. Midazolam can be given at a dose of 10 mg IM, nasally or buccally, for
patients with a body weight >40 kg and 5 mg for patients with a body weight of 13 to 40 kg [12,14].

As nasal and buccal midazolam are absorbed more rapidly than IM midazolam, it is possible, perhaps likely, that this route is
superior [15], but these routes are not as well studied as IM midazolam in adults.

Out-of-hospital/prehospital treatment — Treatment of status epilepticus out-of-hospital by paramedics appears to be safe


and effective. Lorazepam 4 mg IV and midazolam 10 mg intramuscular (IM) are the best studied drugs in this setting.
Clonazepam (1 mg IV) is also an option in Europe and elsewhere but is not available in IV form in the United States.

● 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 lorazepam or diazepam than placebo (59, 43, and 21 percent,
respectively) [16]. Active treatment also reduced the rates of respiratory or circulatory complications (10.6, 10.3, and 22.5
percent, respectively), lessening concern for the respiratory side effects of benzodiazepines.

● In another randomized study of 898 patients with status epilepticus in the prehospital setting, 10 mg IM midazolam was
superior to 4 mg IV lorazepam in adults [12]. On arrival to hospital, patients receiving IM midazolam had a higher rate of
seizure control (73 percent vs 63 percent) than patients receiving IV lorazepam. The superiority of IM administration arose
from the time required to insert an IV; the treatment response for IV lorazepam was faster than IM midazolam (1.6 versus

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3.3 minutes) if counted from the time of medication administration, while time to treatment administration was shorter for
midazolam compared with lorazepam-treated patients (1.2 versus 4.8 minutes). Adverse reactions were similar for both
treatments.

● A smaller 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
[17]. 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 US but is
commonly used in Europe as a first-line agent. (See 'Benzodiazepines' below.)

● In a randomized trial in children, IM midazolam was more effective than IV diazepam for the treatment of prolonged seizures
[18].

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]. In one randomized trial, buccal midazolam was more effective than
rectal diazepam in children with repetitive seizures [19]. The typical dose is 0.2 mg/kg, or 10 mg in adolescents and adults.
Intranasal midazolam can be given as a metered spray of 0.1 ml containing 0.5 mg (a solution of 5 mg/mL), three to five times,
per nostril, and repeated if necessary, to a total dose of 10 mg for adults. This was more effective than IV diazepam in one trial
for febrile seizures in children [20].

Rectal diazepam is also available for outpatient seizure treatment [21], given in doses of 0.2-0.5 mg/kg, or 20 mg for an adult.

Efficacy and dosing of specific drugs

Benzodiazepines — Benzodiazepines are the first-line treatment for convulsive status epilepticus because they control
seizures rapidly [3,6,12,16,22]. Several studies have addressed the different uses and pharmacology of the three most
commonly used benzodiazepines for status epilepticus: diazepam, lorazepam, and midazolam. For IV therapy, lorazepam is
preferred in adults [6]; midazolam is preferred for intramuscular (IM), intranasal or buccal therapy; and diazepam is preferred for
rectal administration.

● Lorazepam – Use of lorazepam as a first-line agent is supported by the Veterans Affairs (VA) comparative trial, a study that
randomized 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) [3]. 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). 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 [3]. Success with any
regimen was much lower for "subtle" GCSE compared with "overt" GCSE. Almost half of the patients required additional
treatment with a second antiseizure drug, but when the first medication failed, only 7 percent of patients responded
successfully to a second antiseizure drug.

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 [23]. (See "Management of convulsive status epilepticus in children", section on
'Benzodiazepines'.)

● Diazepam – Diazepam has high lipid solubility and can therefore rapidly cross the blood-brain barrier. It is highly effective in
terminating seizures rapidly when administered at doses of 0.1 to 0.3 mg/kg intravenously. An effect upon seizure activity
can be seen as early as 10 to 20 seconds after administration, and cerebrospinal fluid (CSF) concentrations reach half of

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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
intravenous diazepam is seen in 50 to 80 percent of patients [3], but if no other medication is provided, there is a 50 percent
chance of seizure recurrence within the next two hours [24,25].

Nonetheless, 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 [26] and phenytoin
are not. A rectal gel formulation of diazepam is also marketed and provides rapid delivery when intravenous access is
difficult, or for at home use for patients who have frequent repetitive or prolonged seizures [27].

● 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 [26]. Intramuscular, nasal, and buccal administration of midazolam (0.2 mg/kg, maximum 10
mg) are effective alternatives to IV lorazepam when IV access is difficult [13,19,28,29]. Continuous infusion of IV midazolam
is also used in the management of refractory status epilepticus. (See 'Out-of-hospital/prehospital treatment' above and
'Refractory status epilepticus' below.)

● Clonazepam – Outside the US, IV clonazepam (0.015 mg/kg) is commonly used as a first-line therapy for status epilepticus
[17,30]. 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 [31]. The study also raised concern that lorazepam was given in inadequate doses more often than
clonazepam, perhaps explaining some of the difference in efficacy.

Fosphenytoin and phenytoin — Support for the use of phenytoin/fosphenytoin as urgent control therapy in adults with
GCSE is drawn primarily from observational studies and a small number of randomized trials, which have reported rates of
seizure control ranging from 56 to 84 percent when phenytoin is used as initial therapy in combination with benzodiazepines
[3,32,33].

● Fosphenytoin – Fosphenytoin is the generally preferred formulation of phenytoin for rapid intravenous dosing. The loading
dose is 20 mg/kg phenytoin equivalents (PE), 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 intravenous 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/minute versus 50 mg/minute with phenytoin). In addition, the increased water solubility of fosphenytoin makes
intramuscular (IM) administration possible if intravenous (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 convulsive SE.

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. At least two studies have suggested that
the incidence of adverse hemodynamic effects with fosphenytoin and phenytoin infusions is similar [34,35].

Phenytoin and fosphenytoin are reported to intensify seizures caused by cocaine, other local anesthetics, theophylline, or
lindane [36-38].

● Phenytoin – Phenytoin is generally infused at a rate of up to 50 mg/minute to a total dose of 20 mg/kg. 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.

Valproic acid — Intravenous valproic acid 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 non-sedating option in patients with focal or myoclonic status epilepticus.

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Accumulating evidence suggests that loading doses of 20 to 40 mg/kg can be infused safely at a rate of 5 mg/kg per minute in
adults without adverse effects on blood pressure or heart rate [39-43]. Loading doses in this range yield concentrations in typical
therapeutic ranges and without significant sedation. Patients who are already on enzyme-inducing antiseizure drugs may need
higher doses, and the free phenytoin level may rise with concurrent administration. (See "Antiseizure drugs: Mechanism of
action, pharmacology, and adverse effects", section on 'Valproate'.)

The available data suggest that valproate is at least as effective as phenytoin, and possibly superior to phenytoin, in the
treatment of status epilepticus [32,39-48]. A 2014 systematic review included six open-label randomized trials of valproate
versus phenytoin, diazepam, or phenobarbital; all but one were single-center trials, the maximum sample size was 100, and
most included a mix of children and adults [48]. In trials using valproate as a second-line drug (after benzodiazepines), status
epilepticus was controlled in 50 to 90 percent of patients [48].

● In the largest comparative trial, valproate and phenytoin infusions were similarly effective, but valproate was better tolerated
[32].

● In the second largest trial, valproate was more effective than phenytoin as first-line treatment (without benzodiazepines),
and much more effective when used after failing the other medication [46].

The risk of hepatic toxicity and hyperammonemic encephalopathy due to valproate may pose diagnostic challenges in postictal
settings [49], particularly in children with some aminoacidopathies. Risks of hepatic dysfunction and coagulopathy are important
considerations in patients with active bleeding. (See "Valproic acid poisoning".)

Levetiracetam — Support for the use of intravenous levetiracetam in patients with status epilepticus is drawn primarily from
observational trials in patients with refractory status epilepticus [50-56] as well as two small randomized trials as first-line therapy
[7-10].

Status epilepticus guidelines differ in the ranges provided for a single dose of levetiracetam IV; one suggests 1000 to 3000 mg
IV in adults [1] and the other suggests 60 mg/kg up to a maximum of 4500 mg [57]. Doses are typically infused over 15 minutes
[58].

A meta-analysis of 8 small observational studies examining levetiracetam as a first-line long-acting antiseizure drug in
benzodiazepine-refractory status epilepticus reported a mean efficacy of 68 percent [56]. The efficacy of levetiracetam relative to
other agents has not been well studied prospectively, and the available data are somewhat mixed.

● A randomized trial with 50 patients in each arm found that seizure control was similar when comparing levetiracetam (25
mg/kg), valproate (30 mg/kg), and phenytoin (20 mg/kg) given as first-line agents for GCSE in combination with IV
lorazepam [7].

● In a separate nonblinded trial, 44 consecutive adults with status epilepticus and persistent seizure activity after one dose of
lorazepam (0.1 mg.kg) were randomized to receive either phenytoin (20 mg/kg) or levetiracetam (20 mg/kg) [8]. Rates of
seizure resolution within 30 minutes of the start of the infusion were similar in both groups (68 versus 59 percent, p = 0.53).

● By contrast, a retrospective study found that levetiracetam was associated with a higher rate of failure to control seizures
compared to valproate (48 versus 25 percent) when used as a second-line treatment for status epilepticus [33].

One small randomized trial found no benefit of levetiracetam when given in combination with IV clonazepam in the prehospital
setting, compared with clonazepam alone [17]. (See 'Out-of-hospital/prehospital treatment' above.)

Other second or third line drugs — There are several other antiseizure drugs that can be useful in the management of
status epilepticus but are not preferred as initial drugs in most cases due to side effect profile or lack of sufficient data on
efficacy [1,57].

Phenobarbital and lacosamide 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 when preservation of a higher level of
consciousness is desired.

Phenobarbital — Phenobarbital is a very effective anticonvulsant, especially in the acute management of seizures, but it
was not the best initial treatment in the VA comparative trial [3]. 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 [3,59]. High doses of phenobarbital will control almost any seizure [60], but at the cost of substantial

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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 administration is slow, it causes prolonged sedation, and it may involve a higher risk of
hypoventilation and hypotension than either benzodiazepines, phenytoin, valproate, or levetiracetam.

Initial doses of 20 mg/kg infused at a rate of 30 to 50 mg/minute are generally used; slower infusion rates should be used in
elderly 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 drugs because of its half-life of 87 to 100 hours.

Lacosamide — Accumulating data indicate that intravenous 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 [61-68]; rare serious
adverse events include second degree and complete atrioventricular block [61]. 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.

Others — Topiramate is a broad spectrum antiseizure drug. When administered via nasogastric tube in doses of up to
1600 mg/day, it appears to have some efficacy in refractory status epilepticus, as reported in small case series [69-71].
Topiramate can cause a metabolic acidosis, which is of particular concern in patients also receiving propofol. It is not available in
an intravenous form.

Clobazam may be useful as adjunctive treatment for refractory status epilepticus when given enterally by nasogastric tube [72].
It has effects similar to those of other benzodiazepines, with a rapidity of onset that is intermediate between that of lorazepam
and that of diazepam. Its duration of action is more prolonged than that of diazepam. (See 'Benzodiazepines' above.)

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

When focal motor status is caused by nonketotic hyperglycemia, seizures are usually controlled easily with correction of the
metabolic derangements [73]. Benzodiazepines can be used if seizures persist despite correction. Antiseizure drugs are often
unnecessary after resolution of the acute illness. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment".)

For the more prolonged episodes of epilepsia partialis continua (EPC), antiseizure drugs, including benzodiazepines, may be
helpful and necessary in preventing secondarily generalized seizures but they often do not stop the continued focal jerking, even
with multiple antiseizure drugs. 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 [74].

Myoclonic status epilepticus — Initial treatment of myoclonic status epilepticus (MSE) is heavily dependent upon the form of
MSE and the underlying etiology.

The relatively benign syndromes such as juvenile myoclonic epilepsy (JME) are usually recognizable readily by the history,
seizure types, and normal neurologic and cognitive function before the onset of MSE. Initial treatment is similar to that of GCSE,
except that certain antiseizure drugs (eg, phenytoin and carbamazepine) should be avoided [75]. Benzodiazepines and valproic
acid are the most effective drugs [76,77]. Patients often return to normal condition rapidly after initiation of treatment, with no
morbidity or residual effects. (See "Juvenile myoclonic epilepsy".)

Secondary forms of MSE that occur in other epilepsy syndromes in which myoclonus is not a prominent feature interictally are
more refractory to antiseizure drugs. In MSE associated with progressive myoclonic epilepsy syndromes, seizures and status
epilepticus are intermediate in their response to treatment, and patients often have abnormal baseline neurologic function.
Treatment is similar to that of GCSE.

Symptomatic MSE is frequently much more refractory to antiseizure drugs and often has a grave prognosis, especially after
anoxia [78-80]. Benzodiazepines, valproic acid and levetiracetam can diminish the myoclonic jerking, but they seldom alter the
long-term outcome.

POSTICTAL RECOVERY — Most patients 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

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prolonged postictal recovery are sedation due to medications and the continuation of (nonconvulsive) seizures; these can be
impossible to distinguish clinically. All patients with seizures or status epilepticus who do not return to a normal level of
consciousness after initial treatment should therefore be monitored by EEG to determine whether treatment was adequate or if
the patient is still seizing.

In a prospective study of 164 patients presenting with GCSE in which continuous EEG monitoring was performed postictally
(beginning within 30 minutes of control of clinical seizures), the following findings were described [81]:

● Fifty-two percent of patients had no evidence of ongoing ictal discharges or seizures. The most common EEG patterns in
these patients were generalized slowing, attenuation, lateralizing periodic discharges (LPDs, previously known as PLEDS),
focal slowing, and/or burst suppression. Mortality in this subgroup was 13 percent.

● Fourteen percent of patients had evidence of nonconvulsive status epilepticus (NCSE). 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, and
mortality was 32 percent.

Secondary assessment — During the postictal recovery period it is also important to repeat a full neurologic examination,
looking for asymmetric or focal findings that may suggest clues to the underlying etiology. A head CT or MRI should be obtained
once seizures are controlled. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis",
section on 'Neuroimaging'.)

A lumbar puncture (LP) is warranted if the clinical presentation is suggestive of an acute infectious process 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, since a prolonged seizure itself can cause
cerebrospinal fluid pleocytosis (although usually only minor). Lumbar puncture should only be performed after a space-
occupying brain lesion has been excluded by appropriate imaging studies.

REFRACTORY STATUS EPILEPTICUS — Refractory status epilepticus is defined as ongoing convulsive or nonconvulsive
seizures following administration of an initial benzodiazepine and a nonbenzodiazepine antiseizure drug, given in appropriate
doses [82]. Refractory status occurs in approximately 20 percent of patients with status epilepticus [1,82-85]. Longer seizures
are less likely to stop spontaneously and are also less responsive to antiseizure drugs [3,86].

Whereas there is reasonable agreement upon the initial treatment of generalized convulsive status epilepticus (GCSE), the
optimal treatment of refractory status epilepticus is more controversial; there are no randomized trials comparing various
treatments. Regardless of the specifics of pharmacologic therapy, it is critical to provide adequate ventilatory and hemodynamic
support. Patients with refractory status epilepticus should be intubated and monitored with continuous electroencephalogram
(EEG) [1].

The primary drugs used for refractory status epilepticus are midazolam, propofol, and pentobarbital (or thiopental in some
countries). A systematic review of drug therapy for refractory status epilepticus assessed data on 193 patients from 28 trials in
an attempt to compare efficacy [87]. Pentobarbital was much more effective than either propofol or midazolam in preventing
breakthrough seizures (12 versus 42 percent), but was associated with a significantly increased incidence of hypotension,
defined as a systolic blood pressure below 100 mmHg (77 versus 34 percent). Overall mortality was 48 percent, but there was
no association between drug selection and the risk of death. Another study of 107 patients failed to show an influence of the
therapy used on the outcome of refractory status [88]. In a small randomized study that was stopped early due to slow accrual,
barbiturates and propofol were associated with similar rates of seizure control and hypotension, but patients receiving
barbiturates had significantly longer mechanical ventilation times [89].

It should be noted that most pentobarbital trials were before 1995, usually included only intermittent EEG recordings, and
typically aimed for a burst suppression or more suppressed EEG background as the goal of treatment. Most midazolam and
propofol studies published subsequently have used continuous EEG monitoring and aimed for seizure suppression rather than
burst suppression on the EEG. Consequently, the available data are probably not comparing equally effective doses of these
drugs. It is possible that pentobarbital would cause less hypotension if not titrated to such a suppressed EEG, while propofol and
midazolam might lead to fewer relapses if used more aggressively, although possibly causing more hypotension.

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General approach — Factors to consider when selecting pharmacologic therapy for refractory status epilepticus include the
urgency of seizure control (based on the underlying illness and the type and duration of seizure activity), the pharmacokinetics
of various drugs (especially the rapidity of anticonvulsant effect), drugs already used and failed, and potential complications of
treatment, especially hypotension and the risk for prolonged mechanical ventilation (algorithm 1). Clinicians should generally use
medications they and the care team are familiar with, in order to avoid unintended complications of therapy.

Continuous EEG monitoring should be instituted as soon as possible, along with continuous pulse oximetry and blood pressure
monitoring, often with an arterial catheter. Vasopressors should be available at the bedside. (See "Use of vasopressors and
inotropes".)

Treatment with high-dose pentobarbital (or thiopental, used more in Europe) remains common because of the greatest
experience with its use, and because it appears to offer greater effectiveness in seizure control than alternative drugs [87]. Many
experts prefer to start with midazolam or propofol, however, because these drugs offer the possibility of a quick resolution of the
status epilepticus and shorter duration of sedation. This can be particularly advantageous for patients who are at risk for
ventilator dependence with prolonged therapy (eg, those with severe pulmonary disease, severe debilitation, or malignancy). On
the other hand, longer infusions and higher doses of propofol may precipitate the propofol infusion syndrome (see 'Propofol'
below). Both barbiturates and propofol may exacerbate hemodynamic problems in unstable patients; the primary alternative,
midazolam infusion, is usually well-tolerated in this setting.

In addition to drugs administered by continuous intravenous infusion, one or more longer-acting antiseizure drugs are typically
administered in an effort to achieve and maintain seizure control and increase the likelihood of eventual tapering of the
continuously infused drug. In addition to phenytoin/fosphenytoin, drugs commonly used in this setting include valproic acid,
phenobarbital, levetiracetam, and lacosamide. (See 'Other second or third line drugs' above.)

Specific drugs

Midazolam — Midazolam is a water-soluble, rapidly-acting benzodiazepine that can control seizures within minutes [90,91].
It is generally initiated with a 0.2 mg/kg bolus given at a rate of 2 mg/min. Additional boluses should be given every five minutes
until seizures stop (up to a maximum of 2 mg/kg), followed by a continuous infusion of 0.1 mg/kg/hour, which can be titrated
upwards to as high as 3 mg/kg/hour. If this is unsuccessful within 45 to 60 minutes, a propofol or pentobarbital infusion should
be started. (See 'Propofol' below and 'Pentobarbital' below.)

Hypotension may be less common than with pentobarbital or thiopental [92] but commonly occurs at higher doses. The short
half-life of midazolam (one to four hours) can increase markedly after days of use [93]. Tachyphylaxis is common, and the
anticonvulsant effects of midazolam can cease rapidly when it is stopped. Withdrawal seizures and recurrent status epilepticus
are therefore an important concern. Relapses of status epilepticus may be less frequent and outcome may be better when
higher doses of midazolam are used [94].

Propofol — Propofol is a highly lipophilic phenol derivative and GABA-A agonist with anticonvulsant properties. The drug is
unrelated to any of the currently used barbiturate, opioid, benzodiazepine, or imidazole intravenous anesthetic agents.
Hypotension and respiratory depression may complicate its use. (See "Sedative-analgesic medications in critically ill adults:
Properties, dosage regimens, and adverse effects", section on 'Propofol'.)

Experience with propofol in the treatment of status epilepticus has been reported in several small trials [89,90,95,96]. As an
example, one study compared the results of treatment with propofol or high dose barbiturates in 16 patients with refractory
status epilepticus [97]. Termination of seizures was significantly faster among successfully treated patients in the propofol group
(mean 3 versus 123 minutes), but there was a nonsignificant trend toward higher overall success rates in barbiturate-treated
patients (82 versus 63 percent). In a small retrospective study, propofol and midazolam had similar efficacy in controlling
seizures, but patients with substantial medical comorbidity were more likely to survive when midazolam was used [90].

Propofol infusion is initiated with a 1 to 2 mg/kg loading dose, administered over approximately five minutes and repeated until
seizures stop. A continuous infusion should be titrated over the next 20 to 60 minutes to maintain a seizure-free state; many aim
for a burst suppression pattern on the EEG. Infusion rates of up to 10 to 12 mg/kg/hour may be required but should not be
maintained for more than 48 hours because of the risk of the propofol infusion syndrome [97].

The propofol infusion syndrome consists of rhabdomyolysis, severe metabolic acidosis, and cardiac and renal failure [98]. It
appears to be more common with prolonged use (over 48 hours), in children, and with infusion rates of greater than 5 mg/kg/hr
[99,100]. To avoid this complication, some recommend keeping the dose below 5 mg/kg/hour, and for under 48 hours, especially

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in patients with acute neurologic insults such as head injury [98]. Others increase the dose to at least 15 mg/kg/hr as needed, at
least for shorter periods [97]. The risk of acidosis may be increased in patients receiving carbonic anhydrase inhibitors such as
acetazolamide, topiramate, or zonisamide. Arterial blood gases and serum levels of CPK, lactic acid, triglycerides, amylase, and
lipase should be followed and cardiovascular function monitored carefully during the continuous infusion. (See "Sedative-
analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects", section on 'Propofol infusion
syndrome'.)

If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of
5 percent per hour. This prevents rebound seizures that commonly occur with abrupt propofol discontinuation. It is critical that
high therapeutic levels of at least one longer-acting antiseizure drug are maintained prior to tapering the propofol in order to
reduce the risk of seizure recurrence. (See 'EEG monitoring and goals of treatment' below and 'Duration of continuous infusions'
below.)

Treatment with propofol should generally be considered unsuccessful if it does not terminate seizure activity within 45 to 60
minutes. In this case, switching to or adding a benzodiazepine drip or switching to a high dose barbiturate infusion may help.
(See 'Pentobarbital' below.)

Pentobarbital — An initial dose of 5 mg/kg of pentobarbital should be infused over approximately 10 minutes (maximum rate
50 mg/minute). If seizure activity continues, additional 5 mg/kg doses should be administered with careful attention to the EEG
and hemodynamic status. This is followed by a continuous infusion of 1 mg/kg/hour, titrated as needed up to 5 mg/kg/hour to
achieve seizure control or a burst suppression pattern on EEG.

Hypotension is common at this point, and many patients will require vasopressor support (typically phenylephrine or dopamine),
as well as crystalloid infusions. Hypotension severe enough to necessitate stopping pentobarbital is relatively uncommon. The
mortality rate associated with barbiturate coma is high, although not necessarily higher than with equipotent doses of propofol or
midazolam; contributing factors include the severity of the underlying illnesses causing refractory status epilepticus, adverse
hemodynamic effects (hypotension, cardiac depression), and possible immune dysfunction due to treatment [101]. The half-life
of pentobarbital is 15 to 60 hours and can increase with prolonged use, so there is always prolonged sedation and an inability to
assess the patient clinically.

If seizures are terminated with pentobarbital, the infusion is typically maintained for at least 24 hours before stopping. Many
clinicians continue pentobarbital (or other continuous infusions) for longer when prolonged rapid and rhythmic epileptiform
discharges suggest ongoing seizure activity, but continuing for frequent discharges alone is not advised.

Before tapering pentobarbital, high therapeutic concentrations of other antiseizure drugs (eg, phenytoin, phenobarbital, valproic
acid, or others) should be maintained. Phenobarbital may be particularly useful in patients who develop recurrent seizures as
pentobarbital is weaned [101]. Serum levels of pentobarbital are not particularly useful at this time, but they can be useful after
the medication is discontinued to show if there is still a high level of pentobarbital accounting for a patient’s unresponsiveness.
(See 'EEG monitoring and goals of treatment' below and 'Duration of continuous infusions' below.)

Immunomodulatory therapy — Although relatively rare, inflammatory or autoimmune etiologies such as anti-N-methyl-D-
aspartate (NMDA) receptor encephalitis are important to consider in patients with new-onset refractory status with no etiology
identified on the initial comprehensive evaluation, as early institution of immunomodulatory therapies (eg, glucocorticoids,
immune globulin) may improve outcomes [102-104]. The proportion of cases of GCSE that are ultimately identified as having an
autoimmune or paraneoplastic etiology ranges from 2 to 6 percent, with the higher estimate drawn from cases of refractory
status epilepticus [103,104]. The diagnosis and treatment of paraneoplastic and autoimmune encephalitis are discussed in detail
elsewhere. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic and autoimmune
encephalitis".)

Others — Ketamine is an N-methyl-D-aspartase (NMDA) antagonist that has promise as a treatment for refractory status
epilepticus [105-107]. Glutamate antagonists might be particularly helpful in the later phases of status epilepticus, when gamma-
aminobutyric (GABA) agonists or promoters (eg, benzodiazepines and barbiturates) have lost some effectiveness and excessive
glutamatergic activity may perpetuate seizures [108,109]. A typical loading dose of ketamine is 2 mg/kg, followed by an infusion
of 1.5 to 5 mg/kg/hr, but higher doses may have significant side effects, and optimal treatment has not yet been defined. (See
"Procedural sedation in adults outside the operating room", section on 'Ketamine'.)

Inhalational anesthetics have been used for refractory SE [110]. Isoflurane and desflurane have been reported to be effective in
some highly refractory cases [111,112], but hypotension is a common problem, and relapses of seizures and status are relatively

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frequent upon medication withdrawal. They can provide definitive treatment but may be difficult to wean. Halothane has been
avoided because of possible organ toxicity, and there is concern that enflurane can precipitate seizures.

There are case reports and small case series describing a variety of other treatments for refractory status epilepticus, including
vagus nerve stimulation [113,114], surgical approaches [115-117], the ketogenic diet [118-120], and transcranial magnetic
stimulation [121]. In a randomized trial, induced hypothermia showed no evidence of benefit when added to standard therapies
for the initial treatment of convulsive status epilepticus [122].

EEG monitoring and goals of treatment — Continuous EEG monitoring is critical during the treatment of refractory status
epilepticus. Once continuous infusion of midazolam, pentobarbital or propofol has begun, continuous EEG monitoring is
necessary to confirm that seizures have been treated adequately; to guide use of antiseizure drugs and assess the level of
suppression achieved; and to monitor for relapse of seizures and status epilepticus, especially when infusions are tapered.

The optimal electroclinical endpoint of treatment has not been studied rigorously, and it is uncertain whether the goal should be
simple cessation of both clinical and electrographic seizures, or some degree of suppression of cerebral activity (eg, a burst
suppression pattern on EEG).

We generally aim for complete seizure control, both clinically and on the EEG, considering that there is no conclusive evidence
that a burst suppression pattern is necessary, and more suppression equates to more sedation and a longer intensive care unit
(ICU) course of treatment. Still, the EEG must be followed closely, as recurrent seizures often appear on the EEG before they
are evident clinically.

In one study of 35 patients on pentobarbital, three patients had EEGs showing simply freedom from seizures, and all survived
[123]. Of the others, the 20 patients suppressed to the point of a "flat" background did substantially better than the 12 patients
with a burst suppression pattern. This was not a prospective, randomized study, and it is possible that patients treated more
aggressively were those thought to have a better chance of survival. Another study found no clear benefit in outcome depending
on the depth of EEG suppression [88].

In a systematic review of drug therapy for refractory status epilepticus, patients treated with the goal of EEG background
suppression (mostly with pentobarbital) had a lower likelihood of breakthrough seizures (4 versus 53 percent) compared with
those with treatment sufficient to control clinical and electrographic seizures, mostly with midazolam or propofol [87].
Correspondingly, patients treated to EEG background suppression had a greater likelihood of significant hypotension compared
with those treated to suppress seizures without such suppressed EEGs (76 versus 29 percent). Mortality was high in both
groups (48 percent) but did not appear to differ based on the electroclinical endpoint of therapy.

Duration of continuous infusions — The duration of treatment is also inadequately studied. In general, infusions are typically
continued for 24 hours of clinical and electrographic seizure suppression and then gradually tapered over 12 to 24 hours.
Pentobarbital has a very long half-life and need not be tapered. One study of patients on pentobarbital raised the possibility that
a prolonged period of seizure and EEG suppression might be beneficial [123].

It is critical that high therapeutic levels of at least one longer-acting antiseizure drug be maintained before tapering continuous
infusions. Insufficient use of longer-acting antiseizure drugs likely increases the risk of relapse. Use of additional antiseizure
drugs at the time of tapering infusions is assumed in most trials, but this also has not been studied prospectively. In the study of
patients weaned from pentobarbital discussed above, all were maintained on phenytoin; those also on phenobarbital did
substantially better when levels were above 15 microgram/mL [123].

When electrographic seizures re-appear, they are generally not a benign finding, but rather predict a relapse of clinical seizures
and status epilepticus [124,125]. Breakthrough seizures usually warrant an increase in treatment. It is common practice to re-
treat with higher doses of the continuous infusional treatment, or for longer at doses that were successful earlier, and then have
additional antiseizure drugs (or higher levels of earlier antiseizure drugs) on board before the next attempt at tapering. Isolated
epileptiform discharges do not generally necessitate more treatment [123].

On the other hand, prolonged intensive care unit stays are of great concern, and a few seizures (especially if relatively short and
infrequent and without significant clinical manifestations) may have to be tolerated in order to wean the major sedating drugs.

EEG interpretation can also become difficult and controversial at this stage, and it is often hard to determine whether a given
electrographic pattern is indicative of ongoing seizures and contributing to the patient’s clinical deficit or more of an "interictal"
pattern and not necessary to suppress. The involvement of an experienced epileptologist and electroencephalographer is
crucial. (See "Nonconvulsive status epilepticus", section on 'Uncertain EEG patterns in critical illness'.)

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Of note, there is no particular duration of status epilepticus or number of failed trials after which further treatment is uniformly
futile, particularly in young patients and those without a severe underlying etiology. There are many reports of patients treated
for refractory status epilepticus for weeks to months with good recovery [126-130].

COMPLICATIONS AND OUTCOME

Generalized convulsive status epilepticus — The mortality rate for adults who present with a first episode of generalized
convulsive status epilepticus (GCSE) is roughly 20 percent [131,132]. Estimates vary widely, mainly as a function of the
underlying etiology and whether status epilepticus following cerebral anoxia is included in the study [133-136]. The mortality for
status epilepticus after anoxia ranges from 69 to 81 percent [86,131,137]. While etiology is the most important predictor of
outcome, older age, medical comorbidity, and high initial APACHE-II scores (a prognostic scoring system for ICU patients based
on underlying disease, chronic conditions, and physiologic variables) are also independent risk factors for mortality [90,136,138-
140].

Many of the underlying causes of GCSE (see "Convulsive status epilepticus in adults: Classification, clinical features, and
diagnosis", section on 'Etiology') are associated with significant morbidity and mortality, even in the absence of seizures. In one
series, 89 percent of deaths in patients with status epilepticus were attributed to the underlying etiology [141]. Another study
found that acute symptomatic status epilepticus is associated with a six-fold increased risk of mortality compared to status
epilepticus arising from chronic epilepsy [142]. Mortality is also lower in individuals who have previously survived an episode of
status epilepticus (4.8 versus 15.6 percent in one study), again suggesting that the underlying etiology is a major determinant of
outcome in status epilepticus [138]. In one report, patients who received mechanical ventilation had a three-fold increase in
mortality [136], likely due in large part to more refractory status epilepticus, underlying etiology, and medical comorbidity rather
than an independent effect of ventilatory support.

Systemic consequences of GCSE include cardiac arrhythmias, hypoventilation and hypoxia, fever, and leukocytosis [143].
Aspiration pneumonitis, neurogenic pulmonary edema, and respiratory failure may complicate status epilepticus. Cardiac injury
due to massive release of catecholamines may also contribute to morbidity [144,145]. (See "Cardiac complications of stroke",
section on 'Neurogenic cardiac damage'.)

Physiologically, there appear to be deleterious neurologic effects of status epilepticus that worsen after about 30 minutes in
humans, at least for GCSE, and similar derangements may occur after nonconvulsive status epilepticus [146]. In some series,
10 to 50 percent of survivors are left with disabling neurologic deficits [126,142,147]. Longer seizure duration and status
epilepticus in the setting of acute neurologic insult are risk factors for long-term neurologic disability.

Status epilepticus may also be epileptogenic. About 10 percent of chronic epilepsy presents with status epilepticus [148].
Conversely, about 40 percent of patients with a first episode of status epilepticus develop subsequent epilepsy [149], four times
the rate following a single acute symptomatic seizure. It could be, however, that patients more likely to have epilepsy in the
future may begin with more severe seizures at the onset, ie, status epilepticus may represent a marker for a more severe
epileptic process that has already begun [148].

Adult survivors of status epilepticus are at significant risk for recurrent seizures and status epilepticus [134]. In a population-
based study that followed patients for ten years, status epilepticus recurred in approximately one-third of patients [149]. When
patients with progressive neurologic disease were excluded, the risk was 25 percent and was similar among other etiologic
subgroups. Female gender and a failure to respond to the first drug administered for status epilepticus were risk factors for
recurrence.

Most studies of the cognitive consequences of status epilepticus have found minimal neuropsychologic morbidity [150,151], but
most of these studies were pediatric and retrospective. Comprehensive neuropsychologic evaluations before and after status
epilepticus are seldom available. It is difficult to control for many variables, and many neurologic deficits fluctuate. It is also
unclear whether the underlying illness or status epilepticus itself causes morbidity, and patients with progressive illnesses
worsen, whether or not related to the status epilepticus. It is also difficult to control for the influence of antiseizure drugs on
cognition. Medications, doses, serum levels, and drug interactions may change frequently in patients with refractory epilepsy,
including at the time of testing.

Pathologic studies of the effects of status epilepticus in humans are scarce, in part because fatal cases are often associated with
acute, severe brain-injuring illnesses such as ischemic stroke, hemorrhage, and encephalitis, all of which may cause damage
independently.

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Experimentally, neuronal death can occur under certain circumstances after as little as 30 to 60 minutes of continuous seizure
activity [152,153]. One pathologic correlate of this phenomenon, cortical laminar necrosis, may also be seen on brain MRI as a
persistent, high intensity lesion on T1 or diffusion-weighted images, which follows the gyral anatomy of the cerebral cortex
[154,155]. This may have a clinical correlate in the increased neurologic morbidity that follows status epilepticus of longer
duration, even after controlling for the effects of etiology [156].

Refractory status epilepticus — The outcome of refractory status epilepticus is often poor, with mortality rates ranging from 35
to 60 percent [84,85,126,157,158], essentially always attributed to the underlying cause of the status epilepticus [87,124]. As
with status epilepticus in general, the most important prognostic factors are age, etiology, and medical comorbidities. Seizure
duration may also impact prognosis, although it is difficult to determine whether this is a factor independent of underlying
etiology, particularly beyond the first few hours of status [137,157,159].

In a single-center retrospective study that included 111 patients with refractory status epilepticus treated over a six-year period,
the most common underlying etiologies were hypoxic encephalopathy (23 percent), brain tumor (14 percent), premorbid epilepsy
(10 percent), and ischemic stroke (8 percent) [84]. The mean duration of refractory status epilepticus was 101 hours, and the
overall in-hospital mortality rate was 38 percent. Patients with hypoxic encephalopathy and brain tumors had the highest risk of
in-hospital death (relative risk 2.4 and 2.8, respectively). Additional factors that were significantly associated with poor outcome
included longer seizure duration and presentation with nonconvulsive status in coma.

The prognosis for refractory status epilepticus patients treated with prolonged courses of pentobarbital, propofol or midazolam is
very poor. The high mortality is attributed almost invariably to the underlying etiology [87,90,125,160,161], although at least one
case control study has raised concern that the drugs themselves may also contribute to poor outcomes, independent of
confounding factors such as age, etiology, and seizure severity [162]. Nevertheless, there are several reports of status
epilepticus lasting over a month with reasonable recovery, depending mostly on etiology [125-127,130]. Treatment should not be
abandoned prematurely for young patients in prolonged status epilepticus, especially when no devastating cause has been
found; some recover.

The outcome of patients with new-onset refractory status epilepticus for which no etiology is identified on the initial
comprehensive evaluation may be more variable, and many surviving patients have at least partial recovery with longer term
follow up. A multicenter retrospective study identified 130 such cases admitted to 13 academic medical centers over a five-year
period [104]. With additional testing beyond the first 48 hours, approximately half of patients had an etiology identified and half
remained cryptogenic. The most common identified etiologies were autoimmune (19 percent) and paraneoplastic (18 percent).
The mortality rate was 22 percent, and 62 percent of patients had a poor functional outcome at discharge (defined as a modified
Rankin scale score >3). Among 63 surviving patients with post-discharge follow up available (median nine months), over half
had improved functional status, including 79 percent with good or fair outcome at last follow up. Over 90 percent of patients
remained on antiseizure drugs, including 37 percent with recurrent seizures.

Focal motor status epilepticus — The long-term prognosis of focal motor status epilepticus depends on the prognosis of the
underlying lesion. Long-term morbidity in terms of weakness, sensory, and visual loss, and language dysfunction can be
substantial, and many patients have severe cognitive problems [74]. In one series, nearly half the patients died over a follow-up
averaging three years, usually because of the underlying lesion [163].

Myoclonic status epilepticus — As with treatment, the prognosis of myoclonic status epilepticus (MSE) is strongly dependent
upon the form of MSE. The more benign primary epilepsy syndromes (such as juvenile myoclonic epilepsy) occasionally lead to
MSE that is usually successfully treated with no residual morbidity. In the secondary myoclonic epilepsy syndromes (in which
encephalopathy is more prominent than myoclonus interictally), status epilepticus is typically more refractory to antiseizure
drugs.

The prognosis is poorest for patients with MSE due to an acute new illness, particularly when there has been a period of anoxia
[78,164,165]. In such cases, the prognosis is determined by the anoxia, rather than by the seizures [79,80]. Rarely, patients
recover from multifocal and irregular myoclonus after anoxia [166,167]. In a review of several studies including 134 cases of
post-anoxic MSE, 89 percent of patients died, 8 percent remained in a vegetative condition and 3 percent survived; only two had
a good recovery [168]. The prognosis for MSE due to anoxia may be improved somewhat by therapeutic hypothermia [169].
Patients with MSE due to multiple medical problems, such as a combination of uremia and sepsis, also tend to have poor
outcomes. (See "Hypoxic-ischemic brain injury: Evaluation and prognosis".)

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".)
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SUMMARY AND RECOMMENDATIONS

● Generalized convulsive status epilepticus (GCSE) is a common medical emergency that requires prompt evaluation and
treatment.

● The initial assessment and treatment of a patient in status epilepticus should proceed simultaneously (algorithm 1).
Hemodynamic and respiratory monitoring are also required in order to avoid side effects of therapy. (See 'Rapid
assessment and support' above.)

● For patients presenting with convulsive status epilepticus, we recommend initial treatment with a benzodiazepine (Grade
1A). When intravenous (IV) access is readily available, lorazepam is preferred over other benzodiazepines based on
pharmacokinetic properties (Grade 2C). The typical loading dose of IV lorazepam for status epilepticus is 0.1 mg/kg IV,
infused at a maximum rate of 2 mg/min, allowing one minute to assess the effect before deciding whether additional doses
are necessary. An alternative to a weight-based initial loading dose of lorazepam is a 4 mg fixed dose, repeated if still
seizing.

In addition to benzodiazepines, we recommend a loading dose of a longer-acting antiseizure drug in order to maintain
seizure control (Grade 1B). We suggest fosphenytoin (20 mg/kg phenytoin equivalents [PE]) in most patients rather than
alternative antiseizure drugs (Grade 2C). Valproic acid (20 to 40 mg/kg IV) and levetiracetam (40 to 60 mg/kg, maximum
4500 mg) are reasonable alternatives, particularly in patients with phenytoin hypersensitivity or a history of primary
generalized epilepsy (algorithm 1). (See 'Initial pharmacologic therapy' above.)

In patients who are actively seizing despite two initial doses of lorazepam or other benzodiazepine, preparation for a
continuous midazolam or propofol infusion should occur simultaneously with administration of fosphenytoin, valproic acid, or
levetiracetam, since the primary role of the nonbenzodiazepine antiseizure drug is to prevent recurrence rather than to
break the seizures.

● In the prehospital setting or if IV access is delayed or impossible, intramuscular (IM) midazolam (10 mg for adults) is an
effective alternative to IV lorazepam. Nasal or buccal midazolam (0.2 mg/kg, maximum 10 mg) is also a reasonable,
although less well studied, option in adults. (See 'Out-of-hospital/prehospital treatment' above.)

● Most patients begin to recover responsiveness within 10 to 20 minutes after generalized convulsions, but there is a broad
range. 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. All patients with seizures or status
epilepticus who do not return to a normal level of consciousness after initial treatment should therefore be monitored by
EEG to determine whether treatment was adequate or if the patient is still seizing. (See 'Postictal recovery' above.)

● During the postictal recovery period it is also important to repeat a full neurologic examination, looking for asymmetric or
focal findings that may suggest clues to the underlying etiology. A head CT or MRI should be obtained once seizures are
controlled. A lumbar puncture (LP) is warranted if the clinical presentation is suggestive of an acute infectious process that
involves the central nervous system, or if the patient has a history of a malignancy and there is concern for metastasis to
the meninges. (See 'Secondary assessment' above.)

● There are many possible approaches to the treatment of refractory status epilepticus. Treatment typically includes a
continuous infusion of midazolam, propofol, or pentobarbital (algorithm 1). Factors to consider when selecting
pharmacologic therapy for refractory status epilepticus include the urgency of seizure control (based on the underlying
illness and the type and duration of seizure activity), the pharmacokinetics of various drugs (especially the rapidity of
anticonvulsant effect), drugs already used and failed, and potential complications of treatment, especially hypotension and
the risk of prolonged mechanical ventilation. (See 'Refractory status epilepticus' above.)

● EEG monitoring is critical during the treatment of refractory status epilepticus in order to confirm that seizures have been
treated adequately, guide use of antiseizure drugs and assess the level of suppression achieved, and monitor for relapse of
seizures as infusions are tapered. (See 'EEG monitoring and goals of treatment' above.)

● The optimal duration of treatment for refractory status epilepticus is not well established. In general, infusions are typically
continued for 24 hours of clinical and electrographic seizure suppression and then gradually tapered over 12 to 24 hours.
(See 'Duration of continuous infusions' above.)

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● The prognosis depends most strongly on the underlying etiology, but there is some evidence that status epilepticus is
independently associated with mortality and neurologic sequelae. (See 'Complications and outcome' above.)

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GRAPHICS

Treatment of convulsive status epilepticus in adults

Note that all infusion rates should be adjusted to individual patients; maximum doses listed are not always required.

ABG: arterial blood gas; AED: antiepileptic drug; CBC: complete blood count; IV: intravenous; LFTs: liver function tests; PE: phenytoin equivalent.
* There is no definite maximum dose of lorazepam; clinicians should be guided by the clinical effect (including on blood pressure) and seizure
control.
¶ Cardiac monitoring required. Phenytoin or fosphenytoin may be ineffective for toxin-induced seizures and may intensify seizures caused by cocaine
and other local anesthetics.
Δ In patients who are actively seizing despite two initial loading doses of lorazepam or other benzodiazepine, preparation for a continuous midazolam
or propofol infusion should occur simultaneously with administration of fosphenytoin, valproic acid, or levetiracetam, since the primary role of the
nonbenzodiazepine antiseizure drug is to prevent recurrence rather than break the seizures.
◊ Begin continuous infusion of one of the three drugs below. Selection of an agent depends upon the need for rapid seizure control, the patient's
respiratory and hemodynamic status, and medical comorbidities. Most neurologists start with midazolam or propofol. Clinicians should generally use
medications they and the care team are familiar with, in order to avoid unintended complications of therapy.
§ May substitute valproic acid, lacosamide, or levetiracetam if allergic to phenytoin or phenobarbital, or if they cause other serious side effects.

Graphic 74649 Version 10.0

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Contributor
Disclosures
Frank
W
Drislane,
MD Nothing to disclose Paul
Garcia,
MD Grant/Research/Clinical Trial Support: Medtronic, Inc. [Thalamic
stimulation (Deep brain stimulation therapy)]. Janet
L
Wilterdink,
MD Nothing to disclose

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