Approach

Treatment of generalized convulsive SE, the most common type of SE, should be initiated immediately to prevent neurologic damage and death. Achieving seizure control within the first 1 to 2 hours of onset is a significant determinant of outcome.[41] Generalized convulsive SE is considered a neurologic emergency because it carries a high risk of mortality and morbidity. Increased duration of generalized convulsive SE also correlates with greater refractoriness to therapy, implying a poorer outcome. The earlier that treatment of SE is instituted, the more likely it is to be successful.[32] The main objectives of acute treatment include termination of seizure activity and airway protection; complications should be prevented and treated. Underlying conditions should be treated concurrently, particularly if they contribute to SE. Treatment of other forms of SE depends on the subtype diagnosed.

Supportive measures

Treatment must be concurrent with clinical evaluation and investigations. Management of generalized convulsive and nonconvulsive SE should start with basic life-support measures (airway, breathing, circulation, disability, and neurologic assessment), as in any other acute medical emergency.[34]

The patient's airway should be secured.[2] Despite brief hypoxia, most patients breathe efficiently during SE if the airway is clear.[20] Securing the airway may be challenging during ongoing convulsions. Many patients will require a nasopharyngeal airway with oxygen therapy to maintain adequate saturations.[32] Neuromuscular blockade is an option in extreme cases. A short-acting medication such as vecuronium should be used. Short-acting neuromuscular blockers are favored because they allow assessment of persistent seizures immediately after intubation.[34]

100% oxygen should be delivered by nasal cannula or a nonrebreathing mask.[37]

Vital signs should be checked:

  • Passive cooling should be used if body temperature exceeds 104°F (40°C).[42] In SE, hyperthermia most commonly results from seizure activity rather than being secondary to underlying infections.

  • Hydration and vasopressors should be used if there is hypotension.

Intravenous access should be established and blood sent for laboratory studies (liver function, renal function, electrolytes, calcium, phosphorus, magnesium, complete blood count, toxicology, and serum anticonvulsant medication levels).[43]

Serum glucose level should be measured and thiamine administered followed by dextrose if there is a concern about thiamine deficiency and hypoglycemia (e.g., suspected alcohol misuse).[34][44]

In extreme cases of acidosis, bicarbonate should be used.[43] ECG monitoring should be instituted.[34] Cardiac complications are not infrequent and some of the drugs used, particularly phenytoin, can also have cardiac side effects.[19][32]

Generalized convulsive SE

The treatment cascade aims to abort the clinical and electrographic seizures.

  • Initial therapy should be administered when SE is recognized (i.e., after 5 minutes of seizure activity or as soon as possible).[34]

  • In hospital settings, intravenous lorazepam is the most commonly used initial therapy.[45] [ Cochrane Clinical Answers logo ] [Evidence B] Intravenous diazepam and intramuscular midazolam are also acceptable first-line treatment options.[34]

  • In prehospital settings, or where intravenous access or intramuscular midazolam may not be available, rectal diazepam, or buccal or intranasal midazolam, are recommended.[34] Rectal diazepam is commonly given for home use in pediatric epilepsies.[46]

  • Dose-dependent depression of consciousness and respiratory drive may result from benzodiazepines. Higher doses of benzodiazepines may be needed to abort SE in patients who take benzodiazepines or barbiturates chronically (because of possible cross-tolerance), with a warning that central nervous system depression may be exacerbated.

  • Intravenous lorazepam or diazepam may be repeated once within the first 5 to 20 minutes.[34] Patients should receive a maximum of two doses (including prehospital treatment).[32]

  • One prospective cohort study of children with refractory convulsive SE showed that delaying benzodiazepine administration beyond 10 minutes after the onset of seizure was associated with an increased risk of morbidity and mortality.[47]

  • If the patient is already taking anticonvulsants, the typical therapy should be given at full dose in addition to the emergency treatment.[37] If the dose of anticonvulsants was recently reduced, the changes should be reversed if that is thought to be the cause of SE, as long as it is safe to do so.

  • If benzodiazepines do not stop the seizures, the next step is phenytoin, fosphenytoin, valproic acid, levetiracetam, or phenobarbital.[34][48] While there are no studies to guide the timing of second-line therapy, experts advocate second-line therapy following 15 to 20 minutes of seizure activity.[2][34] A phenytoin infusion may result in venous irritation and tissue damage if the undiluted drug is administered through a small-bore venous catheter. In addition, a rare complication of intravenous phenytoin use is purple glove syndrome: a dark discoloration that extends from the injection site to the distal limb, and is associated with pain and swelling. Fosphenytoin is a water-soluble prodrug of phenytoin that has fewer infusion-related complications but is significantly more expensive.[20] Hypotension and arrhythmias may result from phenytoin and fosphenytoin at high infusion rates.[8]

    • One randomized double-blinded trial in children and adults with convulsive SE who were unresponsive to treatment with benzodiazepines found that levetiracetam, fosphenytoin, and valproic acid each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients. The three drugs were associated with similar incidences of adverse events.[49] The efficacy within age groups did not differ by drug.[50] Subsequent analysis found that endotracheal intubation in children occurred most commonly with fosphenytoin treatment, but other secondary safety outcomes were similar across treatments.[50] Therefore, levetiracetam, fosphenytoin, and valproic acid are all acceptable second-line treatments for benzodiazepine-refractory SE.

    • Two open-label randomized trials found no significant difference between levetiracetam and phenytoin, with respect to seizure control, when used as a second-line treatment for convulsive SE in pediatric patients.[51][52] However, the ease of administration and the good safety profile of levetiracetam make it a reasonable alternative to phenytoin as second-line treatment.[51]

  • Phenobarbital is another alternative second-line treatment, although it has potential for sedative effects.[53]

  • Additional doses of the selected intravenous anticonvulsant drug (i.e., phenytoin, fosphenytoin, valproic acid, levetiracetam, or phenobarbital) may be given if the agent does not abort SE.

  • It should be noted that dose-dependent depression of consciousness and respiratory drive may result from benzodiazepine and barbiturate use.

  • If SE persists despite the preceding measures, the next step is to intubate and start general anesthesia.[37] The patient should be ventilated and placed on continuous electroencephalographic (EEG) monitoring while general anesthesia is started. Maintenance doses of anticonvulsants should be continued. Midazolam and propofol are often used as initial agents for general anesthesia, but other agents may be used, including pentobarbital (note: pentobarbital is an active metabolite of thiopental).[54][55] There is little evidence to guide timing, but experts suggest that following 40 to 60 minutes of seizure activity, third-line therapy should be implemented.[2][34]

  • Super-refractory status epilepticus (SRSE) is defined as SE that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia.[56][57] At this time, there is insufficient evidence to suggest favoring the use of any particular anticonvulsants, inhalational agents, or adjunctive treatments over others in SRSE, as data is limited to case series and case reports with substantial confounding factors.[4]​ A specialist should be consulted for advice on management of SRSE.​​​

The American Clinical Neurophysiology Society (ACNS) recommends continuous EEG (cEEG) to exclude possible nonconvulsive SE after clinical seizures.[35]

The ACNS recommends cEEG for a minimum of 24 hours in critically sick patients with:[35]

  • Persistent abnormal mental status following generalized convulsive SE or other clinically evident seizures. This includes patients without clear signs of improvement of alertness within 10 minutes, or any impairment of consciousness more than 30 minutes after cessation of motor activity, or other clinical signs of seizure activity.

  • Acute supratentorial brain injury with altered mental status.

  • Fluctuating mental status or unexplained alteration of mental status without known acute brain injury.

  • Routine EEG that shows periodic discharges (generalized, lateralized, or bilateral independent) or lateralized rhythmic delta activity. These EEG patterns are more often seen in patients who develop nonconvulsive seizures.

  • Requirement for pharmacologic paralysis (e.g., therapeutic hypothermia protocols, extracorporeal membrane oxygenation), and risk for seizure.

  • Clinical paroxysmal events suspected to be seizures, to determine if they are ictal or nonictal.

If resources do not permit cEEG monitoring, frequent serial EEGs should be obtained to guide therapy, and physicians may consider transferring the patient to a facility with cEEG capabilities.

Most experts recommend that the general anesthetic agent should be tapered after 24 to 48 hours.[2]​ If electrographic or clinical seizures recur, the infusion should be reinstituted for another 24 hours.[2]

If hypotension develops, a vasoactive agent may be needed. Consult a specialist for guidance on suitable regimens. Selection of appropriate vasoactive agents should only take place under critical care supervision, and may vary according to the type of shock, physician preference, and local practice guidelines.

Nonconvulsive SE

Generalized or focal SE with impaired consciousness

  • There is a lack of clear, evidence-based guidance for the management of nonconvulsive SE.[20] In clinical practice, the treatment is similar to that for generalized convulsive SE, although the choice of agents and decision of when to escalate to the next level of treatment should be carefully considered by the treating physician within the clinical context.

Focal SE without impaired consciousness

  • Potential causes of focal SE without impaired consciousness (formerly simple partial SE) are numerous, and treatment should be guided by the underlying etiology. Use of anticonvulsants constitutes first-line intervention. These will either abort the focal seizures or, at least, help prevent their propagation. Some physicians prefer phenytoin and phenobarbital first, but another anticonvulsant may be used.

  • Focal SE without impaired consciousness is rarely considered a medical emergency. However, this form of SE may occasionally be severely disabling, in which case aggressive intervention is justified. Brain imaging may reveal a structural lesion explaining the origin of these seizures. If there is pharmacoresistance or there are structural lesions, a neurologic consultation is highly recommended.

Safety of anticonvulsants in pregnancy

Fosphenytoin, phenytoin, valproic acid (and its derivatives), and phenobarbital are associated with an increased risk of major congenital malformations and neurodevelopmental disorders when used in pregnancy.[58][59]​​​ However, this is a relative contraindication, and these drugs may be tried when a mother's life is at risk, after weighing the risk and benefits and specialist consult. Levetiracetam may be the safer option in pregnancy.[58][60][61]​​​​​​

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