What medication may be administered IV to assist in reducing status epilepticus seizure activity?

Journal Article Editor's Choice

• The authors have reviewed the mechanism of action of old and new antiepileptic drugs.

• Awareness is required regarding seizure-provoking properties of certain anaesthetic drugs.

• Status epilepticus, refractory to two antiepileptic drugs carries a high morbidity and requires general anaesthesia.

• For uncontrolled seizures, treatment with midazolam, thiopental, or propofol is acceptable; opioids should be avoided.

Epilepsy is a tendency to have recurrent unprovoked seizures. It is the most common serious neurological disorder with a prevalence of 0.5–1% of the population. The highest incidence is at the extremes of age and in those with structural or developmental brain abnormalities. The International League against Epilepsy (ILAE) has classified seizures into focal (or partial) seizures which arise from one hemisphere and generalized seizures which show electrographic seizure onset over both hemispheres.1,2 Lamotrigine and carbamazepine are considered drugs of choice in focal epilepsies, while valproate is probably the most effective drug for primary generalized seizures.3,4 If the initial antiepileptic drug (AED) results in adverse effects, an alternative AED is tried as monotherapy. If, on the other hand, seizures continue in spite of adequate doses, combination therapy is often necessary.

In the last 20 yr, there has been an influx of a new generation of AEDs.5 Many of these are the products of rational drug development programmes, while others are modifications of previously existing molecules that result in improved pharmacokinetic properties. The newer AEDs are generally associated with fewer adverse effects and drug interactions. Many anaesthetic agents affect the propensity to seizures, both in patients with epilepsy and in those with no prior history of seizures. In patients taking AEDs, drug interactions and maintenance dosing of AEDs during periods of starvation are important considerations in the perioperative period.

Patients with epilepsy often require anaesthesia for elective and emergency surgery. Appropriate perioperative management of AED therapy is vital in maintaining seizure control in these patients. Anaesthetists need to be aware of the pharmacological properties of commonly used AEDs. Patients with epilepsy may also require anaesthetic care during treatment of status epilepticus, either for airway management or induction of general anaesthesia for refractory status epilepticus. This article aims to examine the current treatment of epilepsy, the mode of action of antiepileptics, the effect of AEDs on anaesthesia, and the effect of anaesthesia on epilepsy in adults. The use of anaesthetic agents in the management of refractory status epilepticus is also discussed.

Mechanisms of action of AEDs

In simple terms, a seizure can be seen as the result of imbalance between excitatory and inhibitory neuronal activity. This leads to the generation of hyper-synchronous firing of a large number of cortical neurones. Traditional AEDs exert antiseizure activity by the following mechanisms: The effects are summarized in Table 1. In addition, many new AEDs possess novel mechanisms of action. Novel sites of drug binding include synaptic vesicle (SV2) protein (levetiracetam), steroid binding sites on GABAA receptors (ganaxolone), and voltage-gated potassium channel (retigabine).6,7

• reduce the inward voltage-gated positive currents (Na+, Ca2+),

• increase inhibitory neurotransmitter activity (GABA),

• decrease excitatory neurotransmitter activity (glutamate, aspartate).

Table 1

Main modes of action of commonly used AEDs.6,7 *From the evidence, it is not clear which of the actions of valproate is responsible for its actions. Lamotrigine is primarily a sodium channel blocker with some effects on T-type calcium channels

Effect of antiepileptics on anaesthesia

There are important pharmacokinetic and pharmacodynamic interactions between AEDs and drugs commonly used in anaesthesia. These affect both drug efficacy and the risk of seizure activity intraoperatively.8

Induction and inhibition of the cytochrome P450 isoenzymes in hepatic metabolism constitutes the most significant mechanism of drug interactions involving AEDs. Many of the older-generation AEDs, such as carbamazepine, phenytoin, phenobarbital, and primidone, have potent enzyme-inducing properties. This leads to a decreased plasma concentration of many medications including immunosuppressants, antibacterials, and cardiovascular drugs, particularly amiodarone, β-blockers (propranolol, metoprolol), and calcium channel antagonists (nifedipine, felodipine, nimodipine, and verapamil).9 In patients taking warfarin, introduction or withdrawal of enzyme-inducing AEDs requires close monitoring of the international normalized ratio. Oxcarbazepine and eslicarbazepine are weaker inducers of hepatic microsomal enzymes compared with carbamazepine, but the effects may be clinically significant.10 Topiramate also induces hepatic microsomal enzymes in a dose-dependent manner. Valproate is an inhibitor of hepatic microsomal enzyme systems and may reduce the clearance of many concurrently administered medications, including other AEDs. Gabapentin, lamotrigine, levetiracetam, tiagabine, and vigabatrin do not induce hepatic enzymes.11

Macrolide antibiotics, particularly erythromycin, are potent inhibitors of CYP3A4, which is involved in carbamazepine metabolism and can lead to carbamazepine toxicity. Concomitant use of carbapenem antibiotics can lead to a significant decrease in serum valproate concentrations.12,13

Effect of anaesthetic agents on epilepsy

Many of the agents used possess both pro-convulsant and anticonvulsant properties, which could impact on the choice of anaesthetic.14

Inhalational anaesthetics

Nitrous oxide (N2O) provokes seizures in animal models (cats), but this has not been replicated in humans. In mice, withdrawal seizures have been seen after short exposures to N2O.15 During a case of electrocorticographic monitoring for epilepsy surgery, N2O visibly suppressed epileptiform activity, which manifested again on N2O withdrawal.16 Myoclonus has been observed in volunteers exposed to hyperbaric (1.5 atm) N2O17 and when used in combination with isoflurane or halothane.18

There are multiple case reports of sevoflurane-provoking seizure-like activity, particularly in children19 and where high concentrations are used in conjunction with hypocapnea.20 In high concentration, enflurane exhibits periods of suppression with paroxysmal epileptiform discharges in cats and rats.21 There have been multiple reports of seizure activity in humans after enflurane anaesthesia.18,22 Isoflurane has well-characterized anticonvulsant properties. Both isoflurane and desflurane can be used in refractory status epilepticus, described in a later section.23

Opioids

Meperidine is the opioid with the strongest association with myoclonus and tonic-clonic seizure activity.24 However, fentanyl, alfentanil, sufentanil, and morphine have been reported to cause generalized seizure patients after low-to-moderate dose,25,26 particularly after intrathecal use.27–29 Fentanyl and its analogues have not been shown to possess any anticonvulsant properties.

Opioid anaesthetic agents are used to enhance EEG activity in patients with focal epilepsy. Both remifentanil and alfentanil have been used to induce spike activity in localizing epileptogenic zones intraoperatively during epilepsy surgery,30 although alfentanil appears to be the more potent activator.31 The addition of alfentanil to propofol anaesthesia for electroconvulsive therapy (ECT) also increases seizure duration.32

I.V. anaesthetic agents

The barbiturates (thiopental, methohexital, and pentobarbital) and propofol are well established as agents for the treatment of refractory status epilepticus.33–35 All agents have been reported to produce excitatory activity, such as myoclonus, opisthotonus, and rarely generalized seizures on induction of anaesthesia. The highest incidence appears to be with etomidate,36 followed by thiopental, methohexital, and propofol. Etomidate has been shown to increase seizure duration in ECT when compared with thiopental.37 At higher doses, all agents act as anticonvulsants.38,39

Ketamine is a non-competitive glutamate antagonist acting at N-methyl-d-aspartate receptors, a property which could be beneficial in management of status epilepticus refractory to other agents (see below). As with the other i.v. agents, low doses may facilitate seizures, but at doses that produce sedative or anaesthetic effects, ketamine shows anticonvulsant properties.40

Benzodiazepines

All benzodiazepines in clinical practice possess potent anticonvulsant properties.41 Diazepam, midazolam, and lorazepam are widely used to terminate episodes of status epilepticus (see below).

Local anaesthetics

Local anaesthetic agents readily cross the blood–brain barrier, causing sedation and analgesia followed by generalized convulsions at higher doses.42,43 High blood levels result from an accidental i.v. administration or rapid systemic absorption from a highly vascular area.44

I.V. lidocaine has been used to treat status epilepticus in several small series, mainly in children.45–47 It was not associated with any major adverse events in these reports, but its efficacy and role in management of status epilepticus in adults remain to be proven.

Neuromuscular blocking agents

None of the neuromuscular blocking agents appear to have any pro-convulsant or anticonvulsant effects. Laudanosine, the primary metabolite of atracurium, has been known to cause EEG and clinical evidence of seizures in animals.48 This has not been replicated in humans, but the possibility should be considered in patients with hepatic failure in whom the half-life of laudanosine is significantly prolonged. Succinylcholine produces EEG activation related to an increase in cerebral blood flow afferent muscle spindle activity; an effect blunted by prior administration of non-depolarizing neuromuscular blocking agents. It has not been associated with seizure activity.49

Anticholinergics and anticholinesterases

The increase in acetylcholine via administration of atropine or scopolamine can produce central cholinergic blockade (or central anticholinergic syndrome). This manifests as agitation with seizures, hallucinations, and restlessness or stupor, coma, and apnoea. The most effective treatment for this is physostigmine.50 Glycopyrrolate does not cross the blood–brain barrier, so does not produce these effects.

Perioperative management of AEDs

In patients with a history of well-controlled epilepsy, it is vital that efforts are made to avoid disruption of antiepileptic medication perioperatively. Patients should be advised to take their regular medications on the morning of surgery and regular dosing should be re-established as early as practicable after surgery. If a single dose is missed (such as that might occur with day-case surgery), it should be taken as soon as possible after surgery. Where multiple doses are likely to be missed, AEDs should be administered parenterally where possible. I.V. forms of phenytoin, sodium valproate, and levetiracetam are available (where i.v. doses are equivalent to oral doses) and carbamazepine is available as a suppository. If the patient's regular AED is not available in parenteral formulation, advice should be sought from a neurologist regarding alternatives that may be used to cover the perioperative period.

In general, routine drug level monitoring is not required perioperatively as anaesthetic agents do not significantly alter the pharmacokinetics of AEDs. However, prolonged intensive care unit (ICU) stay, with attendant changes in serum pH and albumin levels and also the use of drugs that interact with AEDs, can affect their serum concentrations. Of the commonly used AEDs, phenytoin presents the greatest challenge because of its unique pharmacokinetic properties. In patients admitted to ICU, it is necessary to check serum concentrations of phenytoin daily to guide dosing.

Status epilepticus

Status epilepticus is a common medical emergency. The traditional definition of status epilepticus as a seizure lasting or recurring without regaining of consciousness over a 30 min period is primarily useful for epidemiological purposes. In clinical practice, most convulsive seizures abate within 2–3 min and a seizure that continues for more than 5 min has a low chance of terminating spontaneously, so should be treated with emergency antiepileptic medications.51

Physiological changes seen in status epilepticus

During the first stage of convulsive status epilepticus (CSE), there is an increase in cerebral metabolism, increased blood flow, and increased glucose and lactate concentration. This is associated with massive catecholamine release, raised cardiac output, hypertension, tachycardia, and increased central venous pressure. These compensatory mechanisms prevent cerebral damage in the first 30–60 min.52

Beyond this time, if seizures are not controlled, the compensatory mechanisms start to fail and cerebral damage may occur. Cerebral auto-regulation fails, leading to hypoxia, hypoglycaemia, an increase in intracranial pressure, and cerebral oedema. The net result is of hyponatraemia, potassium imbalance, and an evolving metabolic acidosis, which will lead to a consumptive coagulopathy, rhabdomyolysis, and multi-organ failure. These changes are represented in Figure 1. It should be noted that these changes occur more rapidly in CSE, but can also occur in non-CSE (NCSE).52

Open in new tabDownload slide

Physiological changes occurring during prolonged status epilepticus. Adapted from Shorvon.106 PED, periodic epileptic discharge; CBF, cerebral blood flow. 1, Loss of reactivity of brain oxygen tension; 2, mismatch between the sustained increase in oxygen and glucose utilization and a decrease in cerebral blood flow; 3, a depletion of cerebral glucose and glycogen concentrations; 4, a decline in cerebral energy state.

Stages of GCSE and drug treatment

Intervention is required for all convulsive seizures that have continued beyond 2 min longer than the patient's habitual seizures. In most cases, this means that treatment should be administered if the seizure is continuing at 5 min. Benzodiazepines are the first-line agents. There is evidence that the longer seizures continue, the less efficacious treatment becomes.53 This is related to altered localization of GABA receptors on neuronal membrane induced by seizures.54 Treatment with benzodiazepines should therefore be administered as soon as it is apparent that the seizure is not self-terminating. Patients who have suffered one episode of CSE, especially those with structural brain abnormalities and learning disability should be prescribed benzodiazepines to be used in the community to prevent the development of refractory CSE. Rectal diazepam has traditionally been used for this purpose, but buccal or nasal midazolam appears equally effective and is more acceptable to adult and paediatric patients (Table 2).55,56

Table 2

Drug administration details for CSE.102 Doses are i.v. unless stated otherwise

Emergency investigations should include arterial blood gas measurement, glucose, renal and liver function, calcium and magnesium, full blood count (including platelets), coagulation, and AED levels. Consider saving blood and urine samples for future analysis, including toxicology if cause is unclear. Chest radiograph can be used to exclude aspiration pneumonia. Other investigations will be directed at potential aetiology, such as brain imaging or lumbar puncture.52 During the management of CSE, due to the sedative nature of the drug treatments used, respiratory depression requiring intubation is not uncommon.

The underlying cause of CSE should be identified and treated wherever possible. Alcohol withdrawal and metabolic disturbances including hypoglycaemia and hyponatraemia can present with seizures. In patients with epilepsy, failure to adhere to prescribed medications and the resultant rapid decrease in serum levels can precipitate SE. Infective and inflammatory conditions of the brain can present with CSE, which can negatively affect the prognosis of these conditions. Failure to treat the underlying cause of CSE is a common cause of seizures remaining refractory to antiepileptic medication.

Pre-monitory stage (out of hospital or first 5 min)

Buccal midazolam or rectal diazepam can be administered by the patient's carers or emergency medical personnel.

Early stage (first 5–10 min)

Initial management of seizures is supportive with airway protection, supplemental oxygen, and assessment of cardiorespiratory function with establishment of i.v. access. If hypoglycaemic seizures are suspected, glucose (50 ml of 50% dextrose) should be administered immediately. In patients suspected of impaired nutrition or alcohol abuse, high-dose thiamine (250 mg), should be administered with glucose.57

Benzodiazepines are used as first line in early GCSE.58 While all benzodiazepines share the same receptor site on the GABA receptor α subunit, their pharmacokinetic properties vary.59 Lorazepam has been shown to result in higher rates of seizure control compared with phenytoin, phenobarbital, and phenytoin with diazepam, and is the agent of choice.60 If lorazepam is unavailable, diazepam may be used, but the risk of seizure relapse is higher owing to its rapid redistribution.61 Where i.v. access is delayed, further doses of rectal diazepam or buccal or nasal midazolam may be tried. I.M. midazolam may be an alternative, and a randomized controlled trial is currently underway comparing it with i.v. lorazepam, the current gold standard in the treatment of early CSE.62

Established CSE (5–30 min)

At present, four agents can be considered as options in the treatment of established CSE—phenytoin (or its prodrug, fosphenytoin), valproate, phenobarbital, and levetiracetam.63 There is little evidence regarding the relative efficacy of these agents and adequate trials are urgently needed.

Phenytoin is probably the most widely used drug in the UK for management of SE that continues after benzodiazepine administration. It is water insoluble and the vehicle for i.v. administration has a highly alkaline pH.64 Phenytoin should therefore only be administered via a large-bore i.v. cannula or a central line as extravasation can result in extensive tissue necrosis. Cardiac rhythm and arterial pressure should also be monitored as hypotension and bradycardia can occur, especially in the elderly. Fosphenytoin, a prodrug of phenytoin, is rapidly converted to phenytoin after i.v. administration.64 It can be administered more rapidly i.v. or as an i.m. injection and is generally associated with fewer injection site complications. It is, however, significantly more expensive than phenytoin and not widely available in UK hospitals.

Phenobarbital has been in use as an AED for nearly a century and remains the most commonly used AED worldwide. I.V. phenobarbital is an alternative to phenytoin as a second-line agent for management of status epilepticus. High doses are often required, with the attendant risk of sedation.65,66 It is not commonly used, for fear of provoking respiratory depression when administered to patients who have already received benzodiazepines.

Sodium valproate has been available as i.v. preparation since the late 1990s and is being used increasingly in the treatment of established CSE. In a randomized comparison of i.v. valproate and phenytoin as the first-line treatment for CSE in 68 patients, valproate had a better seizure cessation rate as the first-line treatment (66% vs 42%, P<0.05) and when crossed over as the second-line treatment (79% vs 25%, P<0.005), where the other drug had failed.67 Participants in this study did not receive benzodiazepines as the first-line therapy, which would be the accepted standard of care. The data regarding the relative efficacy of the study drugs should therefore be treated with caution. Moreover, another study comparing the two agents used as initial treatment for SE and acute repetitive seizures failed to find significant differences in efficacy, but valproate appeared to be better tolerated.68 Acute encephalopathy and hyperammonaemia remain potentially serious but fortunately rare complications of valproate therapy.69

The newer AED levetiracetam has been reported to be effective in several small case series of CSE.70–74 It has very favourable pharmacokinetic characteristics, with no clinically significant interactions or sedative properties.75 Its efficacy as a second-line agent for the treatment of CSE remains to be established. Prospective studies are lacking, but a retrospective analysis of 187 cases of CSE treated with levetiracetam, phenytoin, or valproate as second-line agents has been published recently. The authors reported that levetiracetam was more likely to fail (48.3%) than valproate (25.4%) (odds ratio 2.69, 95% confidence interval: 1.19–6.08). Phenytoin was not statistically different from the other two agents (41.4%).76

Of other AEDs, topiramate77–79 and lacosamide80–83 have been reported to be effective in controlling CSE in small retrospective case series. Their role in the management of status epilepticus remains uncertain.

Refractory status (30–60 min)

Refractory CSE (RSE), where SE continues in spite of administration of two AEDs (e.g. benzodiazepines and phenytoin), is associated with a high risk of complications. These include tachyarrhythmias, pulmonary oedema, hyperthermia, rhabdomyolysis, and aspiration pneumonia. RSE has a high mortality rate and less than one-third of patients recover to their pre-morbid level of functioning.84,85

In patients not responding to other measures, general anaesthesia should be induced and maintained with midazolam, propofol, or barbiturates (thiopental or pentobarbital).52 High-dose propofol infusion should be considered with caution due to the risk of propofol infusion syndrome, and for this reason is not recommended in children.86 EEG is needed to titrate doses and to ensure that electrographic seizures have been abolished. Maximal therapy should be maintained until 12–24 h after the last clinical or electrographic seizure, after which the dose should be tapered. If seizures recur, therapy can be re-instituted or altered.87

Both propofol and thiopental are effective treatments for RSE. Where one treatment has failed, another may be successful.88,89 Thiopental has a lower rate of treatment failure and breakthrough seizures, but a prolonged recovery, duration of ventilation, and hospital stay.90,91 There has been increasing concern relating to the prolonged use of high-dose propofol, due to the risk of propofol infusion syndrome. Cardiovascular collapse and mortality has been reported in patients with no prior history of cardiac disease.92,93

Ketamine can be effective in cases of status epilepticus refractory to other agents.94 There is also experimental evidence that neuronal loss induced by status epilepticus may be reduced by treatment with ketamine.95 However, these potential benefits have to be balanced against the risk of ketamine-related neurotoxicity which has been observed in some cases.96 In patients who do not respond to i.v. anaesthetics, inhalation anaesthetics, such as isoflurane and desflurane, have been shown to cause effective EEG burst suppression. In a case series of seven patients, concentrations of 1.2–5% isoflurane were used over a mean of 19 days, with some recurrence after cessation of treatment. The authors see this as a tool to control seizures while regular treatment is instituted.23 However, there are clearly technical difficulties with administration of volatile agents.

Non-convulsive status epilepticus

NCSE is the term applied to the finding of electrographic seizure patterns on EEG without clinically detectable seizure phenomena. In the intensive care setting, such patients are usually unconscious.97 Such cases may represent advanced CSE, where the motor activity has become attenuated over time. This is a grave situation with almost uniformly poor outcome. A variety of acute neurological insults (encephalitis, stroke, trauma, and post-cardiac arrest) may also present with coma and electrographic seizures on EEG.98–100 The finding of NCSE usually indicates a poorer prognosis for the underlying neurological condition. However, a proportion of these patients show improvement in consciousness level after treatment with AEDs. Therefore, treatment with i.v. AEDs should be mandatory in all patients in whom EEG diagnosis of status epilepticus is made. The EEG diagnosis of NCSE, however, is not straightforward and EEG patterns that require treatment can be difficult to determine.101

In the literature, the term NCSE is also used to describe absence or complex partial status epilepticus.102 Absence status occurs in a variety of idiopathic and symptomatic generalized epilepsies. Complex partial seizures are probably under recognized and may be more common in the elderly.103 The typical manifestations of impaired consciousness with automatisms may not always be present. This should be considered in the differential diagnosis of all confusional states, especially if there is a previous history of epilepsy or a structural brain abnormality. Absence and complex partial status are not associated with the same extent of cerebral damage as generalized tonic-clonic seizures. The risk-associated aggressive treatment with i.v. drugs is therefore thought not to be justifiable. Optimizing existing AED therapy and use of oral benzodiazepines is often sufficient to improve consciousness level. The EEG diagnosis may require administration of rapidly acting i.v. AEDs such as diazepam during EEG recording to observe clinical and EEG response.101

Non-epileptic attack disorder (psychogenic non-epileptic seizure)

It must be noted that in specialist centres, the number of psychogenic pseudo-status outnumber the number of status epilepticus episodes.104 Psychogenic non-epileptic attacks may also be particularly likely to occur in the perioperative period.105 There are a number of clinical features that can help distinguish this condition from epileptic seizures—careful clinical observation is key.

Conclusions

Anaesthetists encounter epilepsy commonly in the perioperative setting. They may also be involved in airway management and administration of general anaesthesia for treatment of status epilepticus. Awareness of pharmacological properties of AEDs and potential interactions with drugs used in anaesthesia is essential for adequate management of patients with epilepsy. While certain anaesthetic agents can provoke seizures, recovery from anaesthesia can be associated with shivering and myoclonus, which does not indicate epilepsy. Patients with epilepsy may experience breakthrough seizures in the perioperative period, but psychogenic non-epileptic attacks can also occur in this setting.

Status epilepticus is a common neurological emergency and requires urgent management. Loss of benzodiazepine responsiveness is a prominent feature in established CSE and prompt treatment is important for seizure termination, in addition to appropriate resuscitation. Second-line agents include phenytoin or fosphenytoin and valproate, with newer agents such as levetiracetam and lacosamide yet to demonstrate clear evidence of efficacy. For refractory status epilepticus, general anaesthesia with midazolam, propofol, or thiopental is the currently accepted treatment. Opioids should be avoided. Clinical seizures can become less prominent over time and electrographic monitoring is mandatory to ensure that seizure control is achieved. NCSE should be considered in the unconscious patient where the cause is unclear.

Declaration of interest

Speaker fee and conference hospitality given to R.M. from both UCB pharma (manufacturers of levetiracetam and lacosamide) and Eisai (manufacturers of zonisamide, rufinamide, and eslicarbazepine).

Funding

None.

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