Procedures in Epilepsy Patients

defining the risks of the procedure for the patient with epilepsy
steps to be taken before the procedure to reduce the risk of seizures
educating health care providers about a patient’s seizures and medications and first aid for seizures
defining the effects of anesthetics or analgesics used for the procedure on seizure threshold and the potential for interaction with antiepileptic drugs (AEDs). (This is the topic of the following pages.)
differential diagnosis of paroxysmal behavioral events that occur around the time of procedures

Defining the risks

Epileptic seizures during procedures can be dangerous—think of the onset of uncontrolled movements in an extremity in which a microsurgical procedure is being performed under local anesthesia. (On the other hand, the onset of status epilepticus is less dangerous when it occurs in a physician's office than when it occurs in a patient who is at home alone.) Patients with epilepsy are often considered at high risk during routine procedures, based primarily on the risk of seizures occurring during or shortly after the procedure, and, to a lesser degree, on the potential interaction between drugs for the procedure and for seizure control. Increased risks among patients with epilepsy have been documented for few medical or dental procedures, however.

Most general and local anesthetics have proconvulsant and anticonvulsant properties. Except for enflurane, which has been associated with a higher risk for seizures, all of the anesthetics in use may be safely administered to epilepsy patients if the proper approach in epilepsy patient care is observed. The risk of seizures during or after a surgical or dental procedure is minimal when routine precautions and guidelines are followed.

Steps to reduce risk

Some simple precautions should be taken before a person with epilepsy undergoes a procedure. Proper history taking with attention to the patient's seizure type and frequency as well as medication compliance and response is of basic importance. Blood levels of AEDs should be measured before and after a procedure and adjusted individually (if needed) to minimize the risk of seizures or side effects. Drug interactions should be considered in adjusting maintenance doses.

Factors that can precipitate seizures should be avoided. Because missed medications are a common cause of breakthrough seizures,1 emphasize compliance and ensure that patients continue taking medication up until shortly before the procedure. Although patients are instructed not to eat or drink for at least 8 hours before surgery, medications are often administered with sips of water within a few hours of surgery. AEDs also should be given at this time.

Sleep deprivation, common before many procedures, should be avoided. When needed, low doses of chloral hydrate or benzodiazepines can be safely used for insomnia the night before a procedure.

Patients with epilepsy, who should always avoid excessive alcohol intake (i.e., greater than two beverages per day), should avoid alcohol for a week before surgery.2

Educating health care providers

Much of the concern regarding patients with epilepsy results from perceived as well as real risks associated with seizures. Health care workers often receive little education concerning seizure classification, phenomenology, duration, and first aid. This lack of understanding fosters fear and conservatism that can lead to excessive precautions and restrictions and management errors.

For example, induced labor and cesarean section are examples of interventions and procedures that may be undertaken more often in women with epilepsy than medical reasons alone would justify—two to four times more often than in other pregnancies.3 Epilepsy alone is not an indication for either of these interventions. In selected cases, however, labor should be induced or a cesarean section should be performed. These interventions may be on an elective basis, such as when weekly tonic-clonic seizures occur during the last trimester, or on an emergency basis, when a tonic-clonic seizure occurs during labor or when active maternal contribution is lacking.4

Physicians, nurses, dentists, technicians, and other health care workers involved with procedures in patients with epilepsy should have a basic understanding of the patient’s seizure types, medications, and first aid for the seizures. A complex partial seizure during a routine dental procedure can frighten the dentist and the technologist. If previously informed of the possibility and educated about the need for calm observation as opposed to intervention, fears and chances of inappropriate responses can be reduced. For example, restraint during a complex partial seizure or after a tonic-clonic seizure can provoke an aggressive reaction, which leads to a dangerous cycle that requires greater restraint. In such cases, restraint should be removed, and the patient should be reassured in a comforting manner.

Differential diagnosis of events

Paroxysmal behavioral events that occur during or after procedures have a differential diagnosis that extends well beyond epileptic seizures.5 Occasionally, a patient with psychogenic seizures has events mainly around the time of medical procedures. More commonly, patients with convulsive syncope develop symptoms during painful or emotional procedures. In such cases, which can occur in procedures such as venipuncture, excision of moles under local anesthesia, and electromyography, the patient experiences a tonic-clonic seizure secondary to a fall in heart rate or blood pressure.6 These seizures are typically brief, lasting less than 2 minutes, but they may be followed by prominent postictal confusion. No specific therapy is required, and AEDs should not be prescribed. In selected cases of recurrent convulsive syncope associated with medical procedures, an anticholinergic agent may be beneficial.

Perioperative epileptic seizures have numerous potential etiologies. They usually are not the result of anesthetics. Seizures are a frequent occurrence after operation and irradiation for supratentorial gliomas, and anticonvulsants may be effective in reducing the incidence of those seizures.7

Cardiac surgery is also associated with a higher incidence of perioperative epileptic paroxysms owing to the complex and sometimes severe metabolic, hemodynamic, or blood modifications that are induced by cardiopulmonary bypass and may alter cerebral electrogenesis.8 It seems that normothermic light hemodilution and elimination of neuroleptic drugs for analgesia prevent preoperative and postoperative epileptic paroxysms.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Premedication

Author: S Najjar, O Devinsky, and AD Rosenberg

During the preoperative interview, the anesthesiologist determines and prescribes premedication for the patient. The choice of premedication can have major implications for the patient with epilepsy.

Administering antiepileptic drugs (AEDs)

Administering the patient's daily medications orally with a sip of water or via an alternate route (intravenously, intramuscularly, or rectally) can avoid decreasing serum levels into the subtherapeutic range. Not only AEDs but also antihypertensives and cardiac, diabetic, and asthma medications should be given in this way.

In non per os patients, AEDs may be given parenterally or rectally. If AEDs cannot be administered orally or parenterally (e.g., hyperemesis, gastrointestinal procedures, AEDs without parenteral forms), rectal administration is possible for some types see Table: Antiepileptic Drugs Available for Rectal Administration). (Although clonazepam has an intermediate absorption rate,10 the injectable forms of diazepam and lorazepam are rapidly absorbed rectally.11,12 A gel formulation of diazepam (Diastat) is rapidly absorbed rectally, with an absolute bioavailability of 90% relative to injectable diazepam. Diazepam rectal gel is an effective and safe treatment that is used to abort an episode of acute repetitive seizures in children.13 Carbamazepine can be given rectally with 80% absorption.14 When the liquid parenteral form of phenobarbital is administered rectally, 90% is absorbed in 4.4 hours.11 Phenytoin (liquid parenteral form) given rectally is slowly absorbed in dogs.15 Rectal absorption of oral forms of sodium valproate is complete, with peak concentrations occurring approximately 2 hours after administration.16

There is a need for close clinical monitoring during parenteral administration of AEDs in patients with renal, hepatic, or cardiac diseases. To minimize the incidence of adverse effects in this population, AEDs need to be administered at lower doses or infused more slowly. Monitoring therapeutic levels is essential to prevent postoperative seizures. Patients dying as a direct result of their epilepsy show a significantly greater incidence of subtherapeutic anticonvulsants than those dying of unrelated causes.17

Sedatives and analgesics

To calm the patient for transport to the operating room and to smooth induction, benzodiazepines (e.g., diazepam, midazolam, lorazepam), antihistamines (e.g., hydroxyzine), barbiturates, and opioids (e.g., meperidine, morphine) may be administered. The proconvulsant and anticonvulsant considerations of these medications are addressed on their individual pages.

Diminishing risks of complications

Careful choice of preoperative medications can diminish the risks of perioperative problems such as aspiration, hemorrhages, or postoperative nausea and vomiting.

Complications associated with aspiration are related to the volume (greater than 25–30 mL) and acidity (pH of less than 2.5) of the aspirated gastric fluid. Medications are administered based on their ability to increase gastric pH or decrease gastric volume. Histamine 2 antagonists (e.g., cimetidine, ranitidine, and nizatidine) increase gastric pH and are often administered to patients who are at high risk for aspiration (e.g., obesity, hiatal hernia). Although histamine 2 antagonists do not have proconvulsant activity, cimetidine can increase phenytoin plasma levels, and serum phenytoin blood levels should be monitored.

Metoclopramide is also prescribed for patients at risk for aspiration, because it increases low esophageal sphincter tone, facilitates gastric emptying, and has an antiemetic effect. This medication works both centrally and peripherally as a dopaminergic antagonist. Metoclopramide should be used cautiously in epilepsy patients because it may increase the frequency and severity of seizures.18

The role of valproate in inducing hemorrhage or exacerbating surgical blood loss is not clearly defined, but it has been suspected in the pathogenesis of hemorrhagic complications of surgery. Sodium valproate can cause thrombocytopenia and platelet dysfunction. The mechanism that underlies these effects is unknown. The presurgical evaluation of patients taking sodium valproate must include bleeding time and platelet count. Specific platelet function tests, such as platelet adhesiveness or aggregation, may also be helpful. There was a significant increase in the number of patients with abnormal bleeding times and a significant difference (p <.001) in blood loss during spine surgery in patients who took valproic acid as monotherapy.19 Other studies showed that valproic acid apparently did not increase complications of hemostasis during therapeutic surgical resections for epilepsy, and these studies did not recommend routinely discontinuing valproic acid before craniotomy.20 For major surgical procedures, another AED should be substituted, if possible. When valproate is used, dosages over 40 mg/kg per day should be avoided, because the hematologic effects of sodium valproate may be dose-related.21

Topiramate has several mechanisms of action, including inhibition of carbonic anhydrase, which may result in a normal anion-gap metabolic acidosis. This side effect can become clinically significant during surgery, especially with concomitant use of another carbonic inhibitor.22

Adapted from: Najjar S, Devinsky O, Rosenberg AD, et al. Procedures in epilepsy patients. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;499–513.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Anesthesia

Author: S Najjar, O Devinsky, AD Rosenberg

In general, when seizures occur during surgery, their onset often coincides with the introduction of a specific anesthetic or analgesic drug. However, there have been reports of postoperative convulsions that appeared to be caused by anesthetic or analgesic drugs administered intraoperatively via injection or inhalation.

Some anesthetics may possess proconvulsant properties, anticonvulsant properties, or both. One possible factor is an inherent pharmacodynamic variability in the responsiveness of inhibitory and excitatory target tissues in the central nervous system.23

The effects of general and local anesthetics on seizure threshold have been examined to determine intrinsic pharmacologic properties and mechanisms of action; interictal and ictal effects on surface, depth, or cortical electroencephalogram (EEG) recordings; and behavioral effects in animals and humans.

The following pages discuss specific types of anesthetics:

General anesthetics

Local anesthetics

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

General anesthetics

Author: S Najjar, O Devinsky, AD Rosenberg

Inhalation and intravenous anesthetics possess both proconvulsant and anticonvulsant properties. The mechanisms of these contrasting neural effects are not fully understood. Biological differences in responses, bioavailability, effect on excitatory and inhibitory neurons, and these neurons’ responses to the agents may result from delivery of varying concentrations or doses. With deepening levels of anesthesia, characteristic EEG changes occur (see Table: Anesthetic Drugs and the EEG):

increased beta activity
progressive slowing of the background
a flat-line or burst-suppression record

Postoperatively, EEG slowing often persists for several days or, occasionally, for several weeks.

As general anesthetics, all halogenated inhalational agents have anticonvulsant properties and can terminate status epilepticus.24 Among the volatile anesthetics, methoxyflurane and halothane produce the least CNS irritability; enflurane produces the most irritability, and isoflurane and desflurane produce intermediate levels of irritability.25,26 Changes in the basicity of these compounds, which depends on the degree of fluorination of the carbon atoms adjacent to the ether oxygen, may parallel effects on cortical excitability. Isoflurane, the least fluorinated and most basic of these ethers, produces the least amount of cortical reactivity.25

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Enflurane

Author: S Najjar, O Devinsky, and AD Rosenberg

Enflurane is the inhalation agent that anesthesiologists most often avoid when caring for patients with epilepsy, because it lowers seizure threshold. In children and adults with no history of epilepsy, enflurane can cause epileptiform activity with concomitant facial or appendicular myoclonus or generalized tonic-clonic movements.28–30 In epilepsy patients, the extent but not the frequency of spike activity on the electrocorticogram is increased.29 Epileptogenic foci may be activated during epilepsy surgery.23,31 As the depth of anesthesia is increased with enflurane, the EEG demonstrates high-voltage spikes and spike and slow-wave complexes, the spikes with burst suppression.

The mechanism of enflurane-induced hyperexcitability in humans is unclear. In animals, enflurane inhibits synapses and stimulates excitatory neuronal transmission in cortical and subcortical areas.27

Although low enflurane concentrations (1.0–1.5%) administered to a normocarbic patient (arterial partial pressure of carbon dioxide [PaCO2] equals 40 mm Hg) are not frequently associated with seizure activity,32 increasing enflurane concentrations (2–3%) or hyperventilating an anesthetized patient enhances seizure activity. Hyperventilation to a PaCO2 of 20 mm Hg from 40 mm Hg is associated with seizure activity at a 1% lower enflurane concentration. Because hyperventilation is frequently used by neuroanesthesiologists to decrease cerebral blood flow and intracranial pressure, enflurane is avoided when hyperventilation is indicated. An increase in PaCO2 from 40 mm Hg to 60 mm Hg increases the minimum enflurane concentration at which seizures occur by 1%.27

Generalized tonic-clonic and myoclonic seizures can occur within the immediate postoperative period and, potentially, for a few days after enflurane anesthesia. The role of other CNS-active drugs remains uncertain in these cases.33 The convulsant effects may result from enflurane’s organic and inorganic nonvolatile fluorinated metabolites.34

Although anesthesiologists consider diazepam and thiopental to be anticonvulsants and use them extensively to treat seizure activity, there is some evidence that these drugs may potentiate enflurane-related epileptiform activity in humans.35 Nitrous oxide (N2O) does not alter epileptiform activity induced by enflurane.32

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Other inhalational agents

Author: S Najjar, O Devinsky, and AD Rosenberg

Halothane

Halothane has anticonvulsant properties and can terminate status epilepticus. When used alone, halothane does not cause CNS irritability.36 In the few reports of halothane-related seizures, N2O was also administered.37

Rarely, sharp waves that are maximal over the vertex can appear during the first postoperative week, usually during the first 2 postoperative days. Persistence of an epileptogenic halothane metabolite (e.g., trifluoroacetic acid) may contribute to this sharp activity.36

Isoflurane

Isoflurane, a commonly used inhalation agent, is an isomer of enflurane and contains little or no epileptogenicity.26 In the few cases of isoflurane-related seizures, N2O was also administered.38 Isoflurane has anticonvulsant properties; it suppresses drug-induced convulsions in animals39 and terminates status epilepticus in patients at inspired concentrations from 0.5% to 3.0%.40,41

Isoflurane reduces the frequency and field of spikes on the electrocorticogram of people with epilepsy.29,40

Desflurane

Desflurane is structurally similar to isoflurane. Compared to isoflurane, it has a more rapid onset of action and recovery.

The EEG patterns for desflurane are similar to those seen with equipotent doses of isoflurane. Burst suppression is easily achieved. There was some concern that EEG tolerance may develop to desflurane, but this has not been demonstrated in humans.42,43

Sevoflurane

Sevoflurane is an inhalation agent currently in use in Japan. Small studies have shown EEG but no clinical evidence of seizure activity with sevoflurane induction in patients with epilepsy. This effect was suppressed by giving nitrous oxide.44,54

Nitrous oxide

N2O has very low epileptogenic potential and has been used extensively in patients with and without epilepsy.23,45 N2O does not significantly affect neuronal firing in the human limbic areas.46

Among 11 epilepsy patients who underwent dental procedures, there were no EEG changes during anesthesia in 9 patients, and there was a decreased frequency of paroxysmal discharges in 2 patients.45

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Barbiturates

Author: S Najjar, O Devinsky, and AD Rosenberg

Barbiturates are anticonvulsants that can also have proconvulsant actions. Slight structural changes of a barbiturate (e.g., sulfuration or methylation of the 1 position) can convert it from an anticonvulsant to a convulsant.47 Depending on the dose used, some barbiturates can have both proconvulsant and anticonvulsant properties, with low doses associated with seizure activity in epilepsy patients48 and higher doses leading to burst suppression.

Thiopental (Pentothal) and ultra–short-acting barbiturates

Thiopental is used to stop seizures, including those due to overdose of local anesthesia. Thiopental may be a safer induction agent than methohexital for patients with epilepsy.50 The proconvulsant action of thiopental is lower than that of methohexital.49 It is less effective than methohexital in activating existing epileptogenic activity on the electrocorticogram in epilepsy patients.

Other ultra–short-acting thiobarbiturates, such as thiamylal sodium, buthalitone, and thialbarbitone, have the same pharmacologic properties as thiopental.

Methohexital

Methohexital is an ultra short–acting methyl barbiturate that does not cause seizure activity in patients without epilepsy. It can be associated with some excitatory phenomena, however, such as hiccoughing, tremors, and abnormal muscle movements.23

In patients with epilepsy, electrographic and clinical seizures can occur after intravenous (0.5–1.0 mg/kg), intramuscular (10 mg/kg), and rectal (25 mg/kg) administrations.50,51 Low-dose methohexital (less than 0.5 mg/kg) can activate interictal and ictal discharges among epilepsy patients during electrocorticography.49 The activating effect of methohexital may be largely restricted to patients with partial epilepsy, occurring in up to 72% of such patients.52 Methohexital does not appear to cause seizures during anesthetic induction of patients with generalized epilepsy.50,52

At higher doses, methohexital can suppress epileptogenic foci and cause electrical silence. This suppressive effect is used in the methohexital suppression test, which has been recommended as an adjunctive tool to distinguish the primary focus in patients with secondary bilateral synchrony or multifocal discharges.53 This is most valuable in the investigation of temporal lobe epilepsy. Methohexital is administered in incremental doses of 0.5–1.0 mg/kg until EEG silence is obtained or only a single focus remains. If total EEG silence is obtained, it is hoped that a single focus becomes evident as the EEG returns.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Etomidate

Author: S Najjar, O Devinsky, AD Rosenberg

Etomidate is a hypnotic nonbarbiturate, ultra–short-acting anesthetic agent associated with involuntary muscle movements in 10–70% of patients. These movements can be violent and mimic seizure activity. Etomidate is often administered because of its cardiovascular stabilizing effect. In patients without epilepsy, surface electrode recordings during the myoclonic movements are not associated with epileptiform activity.54

In epilepsy patients, etomidate (0.2 mg/kg) can activate seizure foci within 30 seconds55 and has been used intraoperatively for this purpose.

Despite the lack of evidence that etomidate causes seizures in nonepileptic patients, epileptiform activity occurred in 6 of 30 nonepileptic patients who were induced with etomidate for heart valve replacement.54

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Benzodiazepines

Author: S Najjar, O Devinsky, and AD Rosenberg

Benzodiazepines are potent anticonvulsants that are commonly used intravenously and occasionally rectally to treat status epilepticus.23 Diazepam, midazolam, clonazepam, and lorazepam are all used as AEDs.48 Diazepam rectal gel is effective in controlling acute repetitive seizures (clusters). Intravenous midazolam drip may be more effective for refractory status than other benzodiazepines56 and may represent a substantial improvement over other therapeutic approaches, such as pentobarbital anesthesia.57

Paradoxically, diazepam may induce seizures in patients with Lennox-Gastaut syndrome and lower the seizure threshold in epilepsy patients receiving enflurane.58

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Opioids

Author: S Najjar, O Devinsky, and AD Rosenberg

Patients without epilepsy are not at risk for seizures when administered typical anesthetic doses of opioids, but high doses can elicit seizures. What appears to be seizure activity may actually be myoclonic jerks, rigidity, and other nonepileptic drug-induced movements.23 Simultaneous scalp EEG and electromyography recordings do not reveal epileptiform activity during abnormal movements.

In epilepsy patients, high-dose opioids may elicit seizure activity in isolated cases (see Fentanyl below). However, scalp EEG recordings may not be adequate to determine this, and electrocorticographic recordings may be required to detect narcotic-induced seizure activity in epilepsy patients.59

Morphine

In humans, routine oral or intravenous morphine doses have little or no effect on seizure threshold.23 Seizures have occurred after epidural administration of morphine in an epilepsy patient60 and after inadvertent intrathecal administration of a high dose to a cancer patient without prior seizures.61 In animals, high doses of intravenous morphine can cause epileptic seizures.59

Meperidine

Myoclonus, seizures, jitteriness, and tremors are neurotoxic effects of meperidine. Myoclonus generally precedes seizures, but both resolve over several days with discontinuation of meperidine administration.62 These neurotoxic effects are directly related to blood levels of normeperidine, the N-demethylated active metabolite of meperidine.62,63 Because the half-life of normeperidine (14 to 21 hours) is longer than that of meperidine (3 to 4 hours), continued use can result in high systemic normeperidine levels.62,63 In patients receiving oral meperidine, normeperidine levels may increase at a faster rate owing to hepatic metabolism.64 AEDs that induce microsomal hydroxylation (e.g., phenytoin, phenobarbital) increase the conversion of meperidine to normeperidine.

Patients with renal disease have decreased normeperidine clearance and an increased risk of toxicity.63 Patients with sickle cell anemia and malignancy also are at increased risk.62,63 Seizures have been reported in patients who receive long-term or high-dose meperidine via patient-controlled analgesia pumps.66

If meperidine causes significant neurotoxicity, it should be discontinued. A short course of a benzodiazepine may help to control jitteriness and tremors, although myoclonus can be refractory.65

Seizurelike movements have not been reported in patients with epilepsy during acute or chronic meperidine administration. It is unknown whether acute or chronic meperidine use activates epileptogenic EEG foci in epilepsy patients. Neither meperidine nor its metabolites have anticonvulsant properties.23

EEG changes in otherwise healthy individuals in whom seizures have occurred after repeated meperidine administration include diffuse slow activity and epileptiform discharges.2,67

Fentanyl, sufentanil, and alfentanil

Myoclonic movements and rigidity occurring with fentanyl, sufentanil, and alfentanil prompted reports that high doses of narcotics can cause seizures. These reports have not been substantiated with EEG documentation of seizure activity, however.68,69 Simultaneous EEG and electromyography recordings during fentanyl, sufentanil, and alfentanil induction did not reveal epileptiform activity during intense rigidity and associated movements that might be interpreted as seizures.

Eight of nine patients with complex partial epilepsy had fentanyl-induced epileptiform activity on the electrocorticogram.59 In four of these patients, epileptiform activity was recorded beyond the seizure focus.

Alfentanil increases the mean temporal lobe spike frequency during temporal lobe electrocorticography.70

Fentanyl plus droperidol

Among 104 patients receiving opioid and neuroleptic anesthesia for various neurodiagnostic procedures using metrizamide, there was no clinical or EEG evidence of seizures.71

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Ketamine

Author: S Najjar, O Devinsky, and AD Rosenberg

Ketamine hydrochloride, a dissociative anesthetic, has proconvulsant and anticonvulsant properties. It should be used with caution in epilepsy patients. Of eight epilepsy patients who underwent dental work with ketamine, two had focal motor seizures and another had a generalized tonic-clonic seizure. In some patients with epileptiform activity on their baseline EEGs, particularly those receiving 2–4 mg/kg intravenous doses, the activity progressed to electrical seizure.72 EEG recordings in all of these patients returned to their preanesthetic baseline within a week.73

If a clinical seizure occurs during ketamine use, further administration of ketamine to deepen anesthesia should be avoided. Instead, a CNS depressant, such as a barbiturate or benzodiazepine, should be used.3

In other studies, ketamine did not increase epileptiform or seizure activity in epilepsy subjects.74,75 Owing to the mixed depressant-stimulant effects of ketamine, epilepsy patients should be adequately premedicated with anticonvulsants and sedatives.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Propofol

Author: S Najjar, O Devinsky, and AD Rosenberg

During induction with propofol, spontaneous movements can occur without associated epileptiform abnormalities. These movements may include:

dystonia
chorea
athetosis
twitches
opisthotonus

Abnormal movements may mimic tonic and clonic movements during seizures, especially during the postoperative period.76 In several cases, cortical epilepsy was activated during electrocorticography, with epileptiform activity beginning 20–30 seconds after a bolus of intravenous propofol.77 Seizures may recur for 7 to 23 days after propofol anesthesia, suggesting a proconvulsant metabolite.78,79

Propofol also has anticonvulsant properties in animals80 and humans.81 Continuous propofol infusion can terminate status epilepticus refractory to other therapies.82

In epilepsy patients who underwent dental procedures, administration of propofol in subanesthetic doses to achieve conscious sedation did not provoke seizures or enhance any interictal epileptiform activity.45

One study showed that administration of calcium chloride minimizes the hemodynamic effects of propofol in patients who undergo coronary artery bypass grafting, and thereafter it may potentially reduce postoperative epileptic paroxysms in these patients.9 Recent studies indicate that the synergetic sedation with propofol and midazolam in intensive care patients after coronary artery bypass grafting reduces hemodynamic impairment, which is implicated in the pathogenesis of postoperative seizures.83

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Local anesthesia

Author: S Najjar, O Devinsky, and AD Rosenberg

Differences in CNS effects of local anesthetics are attributable to several factors 84:

potency
systemic rate of absorption from the site of injection
speed of passage through the blood-brain barrier
rate of biotransformation
speed of intravascular injection of the anesthetic

CNS stimulation with some local anesthetics may result from selective depression of inhibitory neurons. Rapid administration or large doses can depress all neuronal activity with no CNS signs of stimulation or only transient signs.85

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Lidocaine

Lidocaine hydrochloride has proconvulsant and anticonvulsant effects, with CNS effects related to blood concentrations. Low doses (2–3 mg/kg) can terminate status epilepticus.

With increasing blood levels, CNS symptoms and signs of toxicity occur, from perioral numbness, lightheadedness, dizziness, tinnitus, and fine tremors to generalized seizures and coma. In animals, lidocaine produces epileptiform activity that is limited to the amygdala and hippocampus.86

Lidocaine doses that are commonly used for local anesthesia can cause CNS toxicity if they are inadvertently administered intravenously. For example, when administering epidural anesthesia, total doses of 5–8 mg/kg are commonly injected into the epidural space.84 Accidental intravascular injection of this dose can cause epileptic seizures.

In addition to direct intravascular injection and immediate toxicity, systemic lidocaine levels can rise to toxic levels by rapid systemic absorption from the area of injection. This can occur 10 to 20 minutes after injection. Anesthesiologists often add 5 mg/mL of epinephrine to the local anesthetic to decrease systemic absorption and peak serum lidocaine levels. When a regional anesthesia block is successful, early reinjection of local anesthesia can cause toxicity (including seizures), because peak absorption of the first injection occurs while additional medication is injected.

Efforts should be made to deliver minimum amounts of lidocaine to the lower respiratory tract in airway anesthesia (e.g., for bronchoscopy), because its pharmacokinetics at that site are similar to those with intravenous administration.87

High doses of lidocaine cause sedation. Increasing the arterial partial pressure of carbon dioxide (PaCO2) decreases the dose of lidocaine needed to produce a generalized electrical seizure.88 Higher PaCO2 levels increase cerebral blood flow, thus increasing the amount of anesthetic reaching the brain, and may directly excite the amygdala. In contrast to the usual pattern, in which hyperventilation activates seizure activity, hyperventilation may prevent seizures from occurring in patients with lidocaine overdose by decreasing cerebral blood flow.

Lidocaine is injected intravenously to provide local anesthesia (intravenous regional anesthesia or Bier blocks). In this technique, after an extremity is exsanguinated, and the blood supply is arrested by a tourniquet, lidocaine is injected into a vein to provide anesthesia. Doses of lidocaine up to 3 mg/kg of 0.5% solution without preservatives or epinephrine are used. Premature tourniquet release (less than 20 minutes) can result in high systemic lidocaine levels and possible seizure activity. Release after 20 minutes can also be associated with toxicity. Some physicians cycle the deflation of the tourniquet with an intermittent inflation-deflation-inflation cycle in an attempt to decrease rapid absorption of lidocaine from the extremity.

Seizures induced by lidocaine can be terminated with barbiturates.

Etidocaine hydrochloride, a long-acting derivative of lidocaine, as well as mepivacaine and prilocaine hydrochloride, share common pharmacologic properties with lidocaine hydrochloride.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Other local anesthetics

Author: S Najjar, O Devinsky, and AD Rosenberg

Bupivacaine

Bupivacaine causes CNS toxicity at plasma levels greater than 4 mg/mL. Seizures can occur with lower plasma levels after accidental intravenous injection during obstetric epidural anesthesia.89 A more dangerous concern with bupivacaine toxicity is intractable ventricular fibrillation.

Cocaine

Cocaine produces electrical and clinical seizure activity in animals. Electrographic discharges arise in the amygdala. Protection against such cocaine-induced seizures is afforded by dibenamine, chlorpromazine, reserpine, pyridoxine, and hydroxylamine, but not with traditional anticonvulsants. Thus, cocaine may cause seizures by potentiating noradrenergic or dopaminergic activity in the amygdala.90

Seizures occurred in an 11-week-old infant who received intranasal installation of a 4% cocaine solution91 and in a child who received topical cocaine solution through a bronchoscope.92 Edematous and inflamed mucosa may absorb excessive amounts of anesthetic. In these settings, recommended ways of managing cocaine-induced seizures in children include:91

administering benzodiazepines or short-acting barbiturates
using local vasoconstrictors
rinsing the mucosal surface with water or normal saline to prevent further drug absorption

Procaine

At low doses, procaine has anticonvulsant properties.93 Given at 18–29 mg/kg, it causes generalized tonic-clonic seizures.

In one study, thiopental pretreatment failed to prevent procaine-induced seizures, but it increased the dose of procaine necessary to produce seizures. Thiopental given during a procaine-induced seizure stopped the seizure.84

Para-aminobenzoic acid (PABA) is a procaine metabolite that can prevent seizures induced by local anesthetics.94 This metabolite might explain the low incidence of generalized convulsions reported during the continuous infusion of intravenous procaine.

Chloroprocaine, a halogenated derivative of procaine, shares the same pharmacologic properties as procaine.

Tetracaine hydrochloride, a derivative of PABA, is 10 times more active and potent than procaine after intravenous injection.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Anesthetic adjuvants

Author: S Najjar, O Devinsky, and AD Rosenberg

Muscle relaxants

None of the muscle relaxants used in clinical anesthesia has been reported to cause epileptiform activity or seizures, nor have anticonvulsant properties been reported in humans. Accumulation of laudanosine, a metabolite of atracurium, may slightly decrease the seizure threshold.95

Resistance to metocurine96 and atracurium or vecuronium-induced97 neuromuscular blockade has been demonstrated in patients who chronically receive phenytoin. Patients treated with chronic anticonvulsant therapy recovered from pipecuronium more rapidly than nonmedicated patients. Furthermore, there seems to be a dose-effect relationship between the number of anticonvulsants received and a decreased time to recovery from pipecuronium neuromuscular blockade.98

Anticholinesterases

Anticholinesterases used in clinical anesthetic practice have not been reported to cause or stop seizures.

Anticholinergics

Atropine can reduce abnormal discharges on the EEGs of patients with epilepsy.99 It can also block spontaneous and hyperventilation-induced absence seizures.100 These effects are probably related to its central anticholinergic action.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Non-opioid analgesics

Author: S Najjar, O Devinsky, and AD Rosenberg

Acetaminophen

Phenytoin facilitates the elimination of acetaminophen by accelerating its biotransformation.57 Phenobarbital induces acetaminophen metabolism, which can result in an increase in toxic metabolites and may increase the risk of acetaminophen overdose.101

Salicylates

Salicylates compete with phenytoin for plasma protein–binding sites. One study showed an increase from 10% to 16% in the unbound fraction of phenytoin when acetylsalicylic acid (ASA) was taken. Changes were proportional to the ASA dose, which ranged from 900 mg to 3,600 mg per day.102 Although high and repeated doses of ASA may cause a slight increase in free phenytoin and a decrease in the total phenytoin level, there is usually no need to adjust the phenytoin dose.103

An increase of the free fraction but not the total valproate concentration can occur in patients who receive 15 to 30 mg/kg of ASA. This increase is not clinically significant in most cases.

Ibuprofen

Ibuprofen has not been reported to interact significantly with antiepileptic drugs or to affect the seizure threshold.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Preoperative planning and management

Author: S Najjar, O Devinsky, and AD Rosenberg

Neurologists may be asked to provide clearance for an epilepsy patient to have surgery. A good history with particular emphasis on seizures types and frequency is important. History of status epilepticus should be sought, as it may place the patient in a higher risk group. Seizure etiology should be identified, and progressive neurologic disorder should be excluded. Medication history, including reactions, tolerance, side effects, and efficacy, should be obtained. Current medical problems that require medications should be defined, anticipating possible interactions with antiepileptic drugs (AEDs) and anesthetics.

Serum drug levels should be checked before surgery, and additional doses should be given to attain desired and steady-state drug levels before the procedure. Oral doses can be administered the morning of surgery with a small sip of water. If the duration of the surgical procedure exceeds the half-life of the maintenance AED, some AEDs can be administered intravenously.

The decision to use an intravenous AED in patients maintained on AEDs that only can be given orally depends on several factors, including the degree of preoperative seizure control and the anticipated surgical time. The risk of seizures is minimal if adequate blood levels are attained before surgery. Intraoperative or postoperative seizures can occur in undiagnosed or undertreated epilepsy patients.104

Serum drug levels may be significantly altered by anesthetics and by the physiologic changes resulting from surgery. These changes include:

AED distribution
enzyme saturation and competition
binding competition at the neuroreceptor level and carrier substances
pharmacokinetics and pharmacodynamics
blood loss and volume changes

For example, carbamazepine levels can increase up to twofold after surgery and return to normal in 7 to 10 days. Phenytoin levels can also increase.

Serum drug levels should be obtained after surgery to see this pattern. Clinical toxicity from an AED can cause a significant delay in postoperative recovery, and seizures may occur as a result of a decrease in drug levels.48

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Dental Procedures

Author: S Najjar, O Devinsky, and AD Rosenberg

Before a dental procedure, levels of antiepileptic drugs (AEDs) should be measured and adjusted based on the individual patient’s history. The dental team should be informed about the patient’s seizure type and first aid.

Seizure-precipitating factors, such as sleep deprivation or alcohol intake, should be avoided before the procedure.

Methohexital was compared to local anesthetic in conservative dental procedures. Although a seizure occurred in only 1 out of 200 patients, the main disadvantage of its use over local anesthetic is side effects, including tongue movements, coughing, hiccoughs, and prolonged lethargy after the procedure.105

Seizures that occur during or after a dental procedure can occur with N2O104 and methohexital.51 In these studies, seizures most often occurred in patients with undiagnosed epilepsy or those who missed a dose of their antiepileptic medications on the day of the dental procedure.

Other studies demonstrate that N2O and propofol in subanesthetic doses for conscious sedation are safe for mentally handicapped epilepsy patients who undergo dental procedures.45 N2O and propofol are almost always safe in epilepsy patients who are adequately treated with AEDs.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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Author: S Najjar, O Devinsky, and AD Rosenberg

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Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.