Procedures and Anesthesia in Patients with Epilepsy

Orrin Devinsky

Douglas R. Nordli Jr.

Introduction

Patients with epilepsy are often considered to be at high risk for routine medical and dental procedures. This designation is 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 those for seizure control. Although few procedures have been documented to have increased risks among patients with epilepsy, an increased level of concern is often present. Procedures in children and adults with epilepsy raise the following issues: (a) steps that can be taken before the procedure to reduce the risk of seizures associated with it, (b) education of health care workers involved in a procedure about a patient’s seizures and medications and first aid for seizures, (c) defining the risks of the procedure for patients with epilepsy, (d) defining the effects of anesthetics or analgesics used for the procedure on seizure threshold and potential for interaction with antiepileptic drugs, which is the focus of this chapter, and (e) differential diagnosis of paroxysmal behavioral events occurring around the time of procedures.

Epileptic seizures during medical and dental procedures can be more dangerous (e.g., onset of uncontrolled clonic movements in an extremity in which a microsurgical procedure is being performed under local anesthesia) or less dangerous (e.g., onset of status epilepticus in a physician’s office) than seizures occurring at other times (e.g., while sleeping alone in bed).

Some simple precautions should be employed before a person with epilepsy undergoes a procedure. First, factors that can precipitate seizures should be avoided. Because missed medications are a common cause of breakthrough seizures, the physician should emphasize compliance and ensure that patients continue taking medication up until shortly before the procedure (see later discussion). 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. Antiepileptic drugs should be given at this time as well. 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., more than two beverages per day), should avoid alcohol for 3 to 4 days before surgery to reduce the potential for withdrawal effects.

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 and phenomenology, duration, and first aid. This lack of understanding fosters fear and conservatism that can lead to excessive precautions and restrictions and to management errors. Induced labor and cesarean section are examples in which interventions and procedures may be undertaken more often in women with epilepsy—two to four times more often than in other pregnancies—than medical reasons alone would justify.¹¹⁵ Epilepsy alone is not an indication for either of these interventions. However, in selected cases, labor should be induced and cesarean section should be done on an elective (e.g., weekly tonic–clonic seizures during the last trimester) or emergency (e.g., tonic–clonic seizure during labor or lack of active maternal contribution) basis.⁴⁴

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 both the dentist and technologist. If these professionals are informed of the possibility ahead of time and educated about the need for calm observation as opposed to intervention, fears and chances of inappropriate responses will be reduced. For example, restraint during a complex partial seizure or after a tonic–clonic seizure can provoke an aggressive reaction leading to a dangerous cycle requiring greater restraint. In such cases, restraint should be removed and the patient reassured in a comforting manner.

Paroxysmal behavioral events occurring during or after procedures have a differential diagnosis extending well beyond epileptic seizures.⁷⁵ An occasional 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 include such procedures as venipuncture, excision of moles under local anesthesia, and electromyography, the patient suffers a tonic–clonic seizure secondary to a fall in heart rate or blood pressure.⁶⁴ These seizures are typically brief, lasting <2 minutes, but may be followed by prominent postictal confusion. No specific therapy is required, and antiepileptic drugs should not be prescribed. In selected cases of recurrent convulsive syncope associated with medical procedures, anticholinergic agents may be beneficial.

Premedication and Assessment

During the preoperative interview, the anesthesiologist determines and prescribes premedication for the patient. Choice of premedication can have major implications for the patient with epilepsy. Considerations include the following:

Continuing the patient’s prescribed daily medications. Administering medications either orally with a sip of water or via an acceptable alternate route (intravenous, intramuscular, or rectally) can avoid decreasing serum levels into the subtherapeutic range. Antiepileptic drugs (AEDs) are included in this category as well as antihypertensives and cardiac, diabetic, and asthma
medications. When oral or parenteral administration of AEDs cannot be done (e.g., because of hyperemesis, gastrointestinal procedures, AEDs without parenteral forms), some may be given rectally (Table 1). Although clonazepam has an intermediate absorption rate,⁵³ the injectable forms of diazepam and lorazepam are rapidly absorbed rectally.³⁹^,⁷⁵ Carbamazepine can be given rectally with 80% absorption.³⁸ Ninety percent of rectal phenobarbital (liquid parenteral form) is absorbed in 4.4 hours.³⁹ Phenytoin (liquid parenteral form) given rectally is slowly absorbed in dogs.³⁵ Rectal absorption of oral forms of sodium valproate is complete, with peak concentrations occurring approximately 2 hours after administration.⁴⁷

Table 1 Antiepileptic drugs available for rectal adminisration

Drug	Treatment usefulness	Dose (mg/kg per dose)	Preparation	Pharmacokinetics	Comments
Carbamazepine (CBZ)	Maintenance	Same as oral	Oral suspension (dilute with equal volume of water) Suppository gel (CBZ powder dissolved in 20% alcohol and methylhydroxy cellulose)^a	Peak concentration 4–8 hr; 80% absorbed	Cathartic effect
Clonazepam	?Acute	0.02–0.1 mg	Suspension	Peak concentration 0.1–2 hr	Onset may be too slow for acute use
Diazepam	Acute	0.2–0.5 mg	Parenteral solution	Effect in 2–10 min; peak concentration 2–30 min	Well tolerated nordiazepam accumulates with repeated doses
Lorazepam	Acute	0.05–0.1 mg	Parenteral solution	Peak concentration 0.5–2 hr	Well tolerated
Paraldehyde	Acute	0.3 mL	Oral solution (dilute with equal volume of mineral oil)	Effect in 20 min; peak concentration 2.5 hr	Moderate cathartic effect; use glass syringe
Phenobarbital	?Acute	10–20 mg	Parenteral solution	Peak concentration 4–5 hr; 90% absorbed	Onset may be too slow for acute use
Secobarbital	Acute	5 mg	Parenteral solution	Peak concentration 0.5–1.5 hr
Secobarbital	Maintenance	Same as oral	Same as acute	Same as acute
Valproic acid (VPA)	Acute	5–25 mg	Oral solution (dilute with equal volume of water)	Peak concentration 1–3 hr	Cathartic effect
Valproic acid (VPA)	Maintenance	Same as oral	VPA liquid from capsules mixed into Supocire C lipid base	Peak concentration 2–4 hr; 80% absorbed	Well tolerated
These data are based largely on pediatric studies. ^aExtemporaneously prepared using commercial products; all other preparations are commercial products given rectally. Source: Adapted from Graves NM, Kriel RL. Biovailability of rectally administered lorazepam. Clin Neuropharmacol. 1987;10:555–559; with permission.

Premedication for sedative or analgesic purposes. To calm the patient for transport to the operating room and smooth induction, benzodiazepines (diazepam, midazolam, lorazepam), antihistamines (hydroxyzine), barbiturates, and narcotics (meperidine, morphine) may be administered. Pro- and anticonvulsant considerations of these medications are addressed later.
Diminishing risks of perioperative problems or complications such as aspiration, hemorrhage, or postoperative nausea and vomiting. Complications associated with aspiration are related to both the volume (>25–30 mL) and the acidity (pH <2.5) of the aspirated gastric fluid. Medications are administered based on their ability to increase gastric pH or decrease gastric volume. H2 antagonists (cimetidine, ranitidine, and nizatidine) increase gastric pH and are often administered to patients at high risk for aspiration (e.g., obesity, hiatal hernia). Although H2 antagonists do not have proconvulsant activity, cimetidine can increase phenytoin plasma levels, and these should be monitored. Metoclopromide is also prescribed for patients at risk of aspiration because it increases lower esophageal sphincter tone, facilitates gastric emptying, and has an antiemetic effect. This medication works both centrally and peripherally as a dopaminergic antagonist. Metoclopromide should be used cautiously in epilepsy patients because it may increase the frequency and severity of seizures.¹¹

Sodium valproate can cause thrombocytopenia and platelet dysfunction. The mechanism underlying these effects is unknown. Bleeding time and platelet count are essential in the presurgical evaluation of patients on sodium valproate.
Specific platelet function tests such as platelet adhesiveness or aggregation may also be helpful. The role of valproate-induced hemorrhage or exacerbation of surgically induced blood loss is not clearly defined. However, valproate has been suspected in the pathogenesis of hemorrhagic complications of surgery. In one study of 29 children with cerebral palsy who underwent bilateral femoral osteomy, platelet counts were lower and the need for transfusion was higher (50% of cases) in those who were on antiepileptic drug regimens including valproic acid.¹⁷ For major surgical procedures, another AED should be substituted if possible. When valproate is used, doses of >40 mg/kg per day should be avoided because the hematologic effects of sodium valproate may be dose related.⁶⁵

Anesthesia

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

General Anesthetics

Inhalation and intravenous anesthetics possess proconvulsant and anticonvulsant properties. The mechanisms of these contrasting neural effects are not fully understood. Biologic differences in how patients respond may result from variations in bioavailability, relative effects on excitatory and inhibitory neurons, and the speed of delivery and changes in serum concentrations. With deepening levels of anesthesia, there are characteristic EEG changes, beginning with increased beta activity and followed by progressive slowing of the background until a flat line or burst suppression record is obtained (Table 2). Postoperatively, slowing often persists for several days, and occasionally for several weeks. As general anesthetics, all halogenated inhalational agents have anticonvulsant properties and can terminate status epilepticus.⁸²

Table 2 Anesthetic drugs and the electroencephalogram (EEG)

Drug	Effect on EEG frequency^a	Effect on EEG amplitude	Burst suppression?
Isoflurance			Yes, >1.5 MAC
Subanesthetic	Loss of alpha, ↑ frontal beta	↓
Anesthetic	Frontal 4–8 Hz activity	↑
Increasing dose >1.5 MAC	Diffuse theta and delta → burst suppression → silence	↑→0
Enflurane			Yes, >1.5 MAC
Subanesthetic	Loss of alpha, ↑ frontal beta	↓
Anesthetic	Frontal 7–12 Hz activity	↑
Increasing dose >1.5 MAC	Spikes/spike-and-slow-wave → burst suppression; hypocapnia → seizures	↑↑
Halothane
Low dose	↑ Frontal 10–20 Hz activity	↓	Not seen in clinically useful dose range
Moderate dose	Frontal 10–15 Hz activity	↑
Increasing dose >1.5 MAC	Diffuse theta, slowing with increasing dose	↑
Desflurane	Similar to equi-MAC dose of isoflurane	Similar to equi-MAC dose of isoflurane	Yes, >1.2 MAC
Nitrous oxide (alone)	Frontal fast oscillatory activity (>30 HZ)	↑, especially with inspired concentration >50%	No
Barbiturates			Yes, with high doses
Low dose	Fast frontal beta activity	Slight ↑
Moderate dose	Frontal alpha frequency spindles	↑
Increasing high dose	Diffuse delta → burst suppression → silence	↑↑↑→0
Etomidate			Yes, with high doses
Low dose	Fast frontal beta activity	↓
Moderate dose	Frontal alpha frequency	↑
Increasing high dose	Diffuse delta → burst suppression → silence	↑↑→0
Propofol			Yes, with high doses
Low dose	Loss of alpha, ↑ frontal beta	↓
Moderate dose	Frontal alpha waxing/waning alpha	↑
Increasing high dose	Diffuse delta → burst suppression → silence	↑↑→0
Ketamine			No
Low dose	Loss of alpha, ↑ variabillity	↑↓
Moderate dose	Frontal rhythmic theta	↑
High dose	Polymorphic delta, some beta	↑↑(beta is low amplitude)
Benzodiazepines			No
Low dose	Loss of alpha, increased frontal beta activity	↓
High dose	Frontally dominant delta and theta	↑
Opiates			No
Low dose	Loss of beta, alpha slows	↔↑
Moderate dose	Diffuse theta, some delta	↑
High dose	Delta, often synchronized	↑↑
MAC, minimum alveolar concentration. ^aDelta, <4 hz; theta, 4–7 Hz; alpha, 8–13 Hz; beta, >13 Hz. Source: Adapted from Black S, Mahla ME, Cucchiara RF. Neurologic monitoring. In: Miller RD, ed. Anesthesia. New York: Churchill Livingstone; 1994:1323.

Among the volatile anesthetics, methoxyflurane and halothane produce the least central nervous system (CNS) irritability and enflurane the most; isoflurane and desflurane are intermediate.²¹^,²² Changes in 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 cortical reactivity.²¹ 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.¹³

Patients on the ketogenic diet can safely receive general anesthesia.¹¹ Carbohydrate-free intravenous solutions should be used perioperatively. With more prolonged procedures, serum glucose and pH levels should be closely monitored. Although glucose levels are usually stable, metabolic acidosis can develop and patients may require intravenous bicarbonate.¹¹

Enflurane.

Enflurane is the major inhalation agent that anesthesiologists usually avoid when caring for epilepsy patients 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.¹⁵^,⁵¹^,⁶³ In epilepsy patients, the extent but not the frequency of spike activity on the electrocorticogram is increased.⁵¹ Epileptogenic foci may be activated during epilepsy surgery.³³^,⁷⁴ As the depth of anesthesia is increased with enflurane, the EEG demonstrates high-voltage spikes and spike-and-slow-wave complexes—spike with burst suppression. Although low enflurane concentrations (1%–1.5%) administered to a normocarbic patient (PaCO₂ = 40 torr) are not frequently associated with seizure activity,⁷⁸ increasing enflurane concentrations (2%–3%) or hyperventilating an anesthetized patient enhances seizure activity. Hyperventilation to a PaCO₂ of 20 torr from 40 torr is associated with seizure activity at a 1% lower enflurane concentration. Because hyperventilation is frequently employed by neuroanesthesiologists to decrease cerebral blood flow and intracranial pressure, enflurane is avoided when hyperventilation is indicated. An increase in PaCO₂ from 40 to 60 torr increases the minimum enflurane concentration at which seizures occur by 1%.¹³

Generalized tonic–clonic and myoclonic seizures can occur within the immediate postoperative period and potentially occur a few days after enflurane anesthesia. The role of other CNS-active drugs is uncertain in these cases.⁸¹ The convulsant effects may result from enflurane’s organic and inorganic nonvolatile fluorinated metabolites.²⁰

Although anesthesiologists consider diazepam and thiopental anticonvulsant agents and use them extensively to treat seizure activity, there is some evidence that both of these drugs may potentiate enflurane-related epileptiform activity in humans.²⁵ Nitrous oxide (N₂O) does not alter epileptiform activity induced by enflurane.⁷⁸

Halothane.

Halothane has anticonvulsant properties and can terminate status epilepticus. When used alone, halothane does not cause CNS irritability.¹² In the few reports of halothane-related seizures, N₂O was also administered.⁸⁷ Rarely, sharp waves maximal over the vertex can appear during the first postoperative week, usually on the first two postoperative days. Persistence of an epileptogenic halothane metabolite (i.e., trifluoroacetic acid) may contribute to this sharp activity.¹⁴

Isoflurane.

Isoflurane, a commonly used inhalation agent, is an isomer of enflurane containing little or no epileptogenicity.²¹ In the few cases of isoflurane-related seizures, N₂O was also administered.⁴³ Isoflurane has anticonvulsant properties, suppressing drug-induced convulsions in animals⁵⁶ and terminating status epilepticus in patients at inspired concentrations 0.5%–3%.⁵⁷^,⁹⁵ Isoflurane reduces both the frequency and field of spikes on the electrocorticogram of epilepsy patients.⁵¹^,⁵⁷

Desflurane.

Desflurane is an introduced inhalation agent structurally similar to isoflurane. Compared with 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. However, this has not been demonstrated in humans.⁹⁰^,¹¹⁶

Sevoflurane.

Sevoflurane is an inhalation agent. Sevoflurane produces dose-dependent epileptiform discharges at surgical levels of anesthesia⁵² and is more epileptogenic than isoflurane.⁵⁰ Sevoflurane induction can produce epileptiform activity without clinical evidence of seizure activity in children with or without a history of epilepsy.²³^,⁵⁹ In children of age 4 years and under without a history of seizures, sevoflurane induction has been rarely associated with convulsive seizures.¹ Patients with refractory epilepsy administered sevoflurane at a minimal alveolar concentration (MAC) of 0.5 had significantly fewer spikes than those with a MAC of 1.5.⁶¹ In healthy individuals, electrographic and clinical seizures can result from MAC of 2.0.⁵² The use of midazolam and thiopental, or nitrous oxide, prevents the appearance of epileptiform activity with sevoflurane induction.⁵¹^,⁷⁹

Nitrous oxide has very low epileptogenic potential and has been used extensively in both epilepsy and nonepilepsy patients.⁷⁴^,⁸⁰ It does not significantly affect neuronal firing in the human limbic areas.⁴ Among 11 epilepsy patients
undergoing dental procedures, there were no EEG changes during anesthesia in 9 patients and decreased frequency of paroxysmal discharges in 2 patients.⁸⁰

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