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Anesthesia for Epilepsy Surgery
Introduction
Epilepsy is a clinical brain disorder characterized predominantly by paroxysmal recurring seizures. The International League Against Epilepsy (ILAE) proposed the definition as a “disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.”
With an estimated incidence of 34–76 per 100,000 new cases per year (median incidence of 50.4/100,000 per year), epilepsy affects about 70 million people worldwide. The median incidence of epilepsy in developed countries is around 45.0/100,000 per year [interquartile range (IQR) 30.3–66.7] while for low- and middle-income countries it is almost double with an incidence of 81.7/100,000 per year (IQR 28.0–239.5). The higher incidence of head trauma and of infections and infestations of the central nervous system (CNS) such as malaria, neurocysticercosis, and invasive bacterial infections may be important causes for this disparity. There are very few incidence studies from India, and the one reported in 2010, suggests an age-standardized incidence rate of 27.3/100,000 per year.
Surgical Management of Epilepsy
In 2001, Wiebe et al. demonstrated the effectiveness of surgical treatment over continued pharmacotherapy in patients with long-standing pharmacoresistant temporal lobe epilepsy (TLE) with an absolute risk reduction for seizure recurrence with surgery being 50% by intention-to-treat and 56% by efficacy analysis. As a result of this study and a literature review, the American Academy of Neurology Practice Parameter concluded that surgery is the treatment of choice for medically intractable TLE (Class I Evidence).
Nonetheless, over the past decades indications for epilepsy surgery (ES) have varied considerably. The published literature is plagued with inconsistencies about ES indications and acceptable seizure outcomes, and there are no internationally accepted indications for an ES referral. Seizure severity, type, and frequency are no longer appropriate indications for ES. The ultimate goal of epilepsy treatment is now no seizures and no side effects. Curative surgical resection is a consideration in patients with drug-resistant, uncontrolled, disabling focal epilepsy (FE) if the seizures originate from a region that can be removed with minimal risk of disabling neurologic or cognitive dysfunction. ILAE has defined drug resistant epilepsy (DRE) as “failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drugs (AEDs) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.” Sustained seizure control refers to an interseizure interval of either 1 year or three times the longest preintervention interseizure interval, whichever is longer. In appropriately selected patients with drug-resistant TLE, the combination of ES with medical treatment is four times as likely as medical treatment alone to achieve freedom from seizures.
Patients with chronic, intractable epilepsy due to discrete lesions such as mesial temporal sclerosis; low-grade neoplasms such as meningiomas, gangliogliomas, dysplastic neuroepithelial tumors, astrocytomas, and oligodendrogliomas; vascular malformations; encephalomalacia from stroke or trauma; and focal cortical dysplasias are common surgical candidates. Good surgical outcomes are also possible in patients with normal magnetic resonance imaging (MRI) if the seizures are electrographically well localized to the temporal lobe.
In tuberous sclerosis complex, resection of an epileptogenic tuber may sometimes palliate seizures. Similarly in patients with Sturge–Weber syndrome, resection of brain affected by the leptomeningeal venous angioma may control seizures. The most effective treatment is, however, hemispherectomy in patients who have developed severe hemiparesis. Hypothalamic hamartomas are rare developmental lesions attached to the tuber cinereum or the mammillary bodies, sometimes resulting in intractable epilepsy with gelastic (laughing) seizures. Complete microdissection by an endoscopic technique, or radiosurgery, can be effective.
Indications for ES differ in children from those in adults. In children, the goal of ES is to stop seizures as soon as possible to prevent epilepsy-induced encephalopathy and associated declines in cognition and neurodevelopment. Many children with early-onset epilepsy have lesions that are very large, often occupying an entire cerebral hemisphere, such as Rasmussen syndrome or hemimegalencephaly. Thus, children undergoing ES have or are at risk for neurological deficits from their etiology and the surgical procedure. Nonetheless, an early surgery can take advantage of developmental brain plasticity, which helps mitigate some of the existing and imposed neurological deficits associated with surgery.
Types of Surgical Treatment
ES usually consists of ablation of an epileptogenic zone, defined as the cortical area necessary for the generation of clinical epileptic seizures, in an attempt to achieve a seizure-free outcome. Surgical resection has been categorized into two broad categories, anatomical standardized resection and tailored resection ( Table 16.1 ). The anatomically standardized resections rely on the concept that resection of classic mesial pathology seen on imaging studies will include the epileptogenic zone, and that resection of eloquent areas will be avoided by conforming to certain anatomical boundaries. In contrast, tailored resections emphasize altering the degree of resection based on individual pathophysiology, functional mapping of eloquent cortex, and intraoperative electrocorticography (ECoG).
Table 16.1
Types of Epilepsy Surgical Treatment
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Most commonly performed curative surgical procedures include lesionectomy, anterior temporal lobectomy, corticectomy, multiple subpial transections, corpus callosotomy, and various combinations of these procedures. In addition, various other surgical alternatives have been proposed for FE, which involve selective disconnection of the epileptic foci instead of removing it. These include comissurotomies, hemispherotomy in its different varieties, temporal lobotomy and amygdalohippocampotomy. The most common surgical procedures performed in children are focal resection, hemispherectomy, and vagal nerve stimulator placement.
Presurgical Evaluation
An epileptogenic focus has been described to consist of several different zones based on the generation of the seizures and the electrophysiologic manifestations of epilepsy. The success of ES depends upon accurate localization of the epileptogenic zone, assessments of the functional deficit zone, as well as the localization of eloquent regions of brain during presurgical evaluation. Thus, an accurate prognosis for postoperative seizure control as well as functional capacities for individual patients can be achieved.
Presurgical evaluation begins with a complete history of the patient’s epilepsy, physical and neurologic examination, imaging of the brain to assess structural abnormalities, and neuropsychological testing. The structural neuroimaging techniques include MRI, diffusion-weighted imaging, tractography, electroencephalography (EEG), and magnetoencephalography (MEG).
Functional MRI, magnetic resonance spectroscopy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) scans are common functional neuroimaging methods that are currently used to evaluate patients with TLE, either through routine application or through investigational use. These tools aid the clinician in accurately assessing the lateralization of memory and language, to identify the epileptogenic region, and to predict and prevent postoperative complications. The intracarotid amobarbital (or Wada) test was initially used to localize the lateralization of language and memory functions across the left and right hemispheres. However, this test does not provide specific information for surgical guidance, depends highly on the symmetric arterial supply of the two hemispheres, and is invasive. Formal neuropsychological testing is mandatory in all patients for detection of subtle neurological alterations that are typical to each patient, tailoring of intraoperative testing according to the patient, and to assess the neuropsychological risks of surgery.
The reliability and spatial resolution of noninvasive means are generally considered too low to be the sole basis of surgical resection. Invasive monitoring by ECoG may still be needed in patients with refractory FE to better define the cortical areas to be resected and/or to minimize the risks of postoperative unacceptable deficits by cortical mapping of functional cortex. Continuous ECoG recordings also monitor for the occurrence of electrical seizures, or even clinical seizures during the resection. Despite its benefits, ECoG has certain limitations. The main shortcomings of intraoperative ECoG are the short duration of its recordings, the poorly defined influence of anesthetics, its inability to seldom capture the seizures, and the localization usually relying on interictal abnormal activity. Therefore, intraoperative ECoG is restricted to the definition of the irritative zone and has limitations for sufficiently delineating the seizure-onset zone or eloquent cortex.
Anesthesia for Epilepsy Surgery
Patients with epilepsy often require anesthesia for particular diagnostic and therapeutic procedures. In addition, certain anesthetic drugs are often employed during ES to assist in the localization of the seizure focus and in functional mapping of the brain. A continuum of critical care is thus required throughout the perioperative period, keeping in mind the unique patient characteristics and requirements of surgical procedures.
Potential concerns associated with the use of anesthesia include:
- 1.
potential proconvulsant and anticonvulsant properties of various anesthetics;
- 2.
pharmacokinetic and pharmacodynamic interactions between AEDs and anesthetic medications;
- 3.
the adverse effect profile of various AEDs;
- 4.
the presence of concomitant medical problems occasionally associated with epilepsy;
- 5.
effect of general anesthetics on intraoperative electrophysiological mapping procedures;
- 6.
delayed emergence from anesthesia (i.e., difficulty awakening) following surgery; and
- 7.
risk of perioperative seizures.
Effect of Anesthetic Agents in Patients With Epilepsy
Depending on clinical situation, many anesthetic drugs have both pro- and anticonvulsant properties. The true incidence of clinical seizure activity in individuals without epilepsy in response to general anesthetic drugs is largely unknown. In patients with a seizure disorder undergoing general anesthesia (GA) for diagnostic studies or nonneurosurgical procedures, seizures were observed in 2% anesthetic procedures during intubation or after the procedure prior to recovery from GA. Seizures associated with anesthesia occurred in 0.8% of adult procedures and 3% of pediatric procedures. In general, there is a greater propensity for anesthetics to induce epileptiform activity in patients with epilepsy than in normal controls.
Anesthetic-related seizures are caused by excitation applied to a mass of neurons, which are primed to react to the excitation by going into an oscillatory seizure state. Increased GABAergic inhibition can sensitize the cortex so that only a small amount of excitation is required to cause seizures. In addition, the ratio of affected inhibitory or excitatory neurons in both the cortical and subcortical brain structures changes with depth of sedation. Without EEG monitoring, a number of nonseizure-related movements (e.g., myoclonus, dystonic reactions, extreme shivering) could mimic seizures. EEG-identified epileptiform activity occurs most commonly with anesthetic medications during induction or emergence from anesthesia, when the anesthetic drug concentration is relatively low.
Excitatory movements including myoclonus, tremor, and dystonic posturing have been observed during induction and emergence of anesthesia with etomidate, thiopental, methohexital, propofol, enflurane, and sevoflurane.
Nitrous Oxide (N 2 O)
In humans, 70% N 2 O alone in oxygen was found to produce characteristic fast oscillatory EEG activity in a predictable fashion, persisting for up to 1 h after discontinuation, but there was no evidence of seizure activity. Nevertheless, N 2 O has been observed to cause myoclonus in volunteers exposed to hyperbaric oxygen therapy (1.5 atm) and convulsions with spike and wave activity in EEG when used in combination with isoflurane.
N 2 O either alone or in combination with other anesthetics, has been shown to have a suppressive effect on the interictal spike activity, and hence it is recommended that N 2 O should be avoided during ECoG. On the contrary, Hosain et al. and Fiol et al. did not observe any effect on interictal spikes with the use of N 2 O in doses employed routinely during ES. The authors thus recommend its use during ES without concerns about suppression of epileptiform activity. N 2 O alone has never been demonstrated to possess anticonvulsant properties in humans. In one patient with refractory convulsions, 60% N 2 O alone slowed but did not eliminate tonic-clonic or EEG seizure activity.
Inhalational Anesthetics
Sevoflurane and enflurane enhances nonspecific spike activities, while the epileptogenic potential of isoflurane, desflurane, and halothane appears low. Inhaled drugs have also been shown to affect the background ECoG by suppressing the spontaneous interictal spikes even at 1 minimum alveolar concentration (MAC) levels. Accounting for their anticonvulsant property, both isoflurane and desflurane have been used in treatment of refractory status epilepticus (RSE).
Neuroexcitatory effects of isoflurane during or following anesthesia are controversial, particularly in epileptic patients. In children undergoing intraoperative and chronic invasive ECoG, isoflurane (0.5–1%, FiO 2 0.5) decreased the spike frequency under GA but it reliably reflected the awake interictal spiking pattern when spike frequency was >1 spike/min. Among the inhaled drugs, enflurane has maximum epileptogenecity and has been shown to activate both interictal spikes and ECoG seizures. With an alveolar enflurane concentration between 2.5% and 3%, hyperventilation produces an increase in the frequency, magnitude, and synchrony of the spiking activity in epileptics. This technique has been used for pharmacoactivation of silent epileptogenic foci intraoperatively to delineate the site of seizure activity before discrete surgical excision.
Sevoflurane has a stronger epileptogenic property than isoflurane. Sevoflurane provoked seizure-like activity is seen particularly in children and where high concentrations are used, even in normal brains. Sevoflurane mask induction elicits epileptiform EEG patterns both in patients with controlled hyperventilation and also during spontaneous breathing of sevoflurane. The effect of hyperventilation on epileptogenicity of sevoflurane is, however, variable. Iijima et al. demonstrated suppression of spike activity during hyperventilation. In contrast, multiple studies report an increase in the epileptogenicity of sevoflurane when high concentrations are used in conjunction with hyperventilation regardless of its timings. Sevoflurane causes widespread nonspecific neuroexcitatory activity, and thus do not facilitate seizure focus localization in patients with TLE. Hyperventilation further exaggerates this nonspecific activation and decreases the prediction specificity of leads with ictal spikes. With balanced anesthesia technique using fentanyl-based anesthesia, sevoflurane (1.5 MAC) suppresses ECoG activities. Hence, when used for ES, careful attention should be paid to the concomitantly administered anesthetic, concentration of sevoflurane used, and ventilatory status during intraoperative ECoG.
The epileptogenic potential of desflurane is low. Compared with sevoflurane, a rapid increase in the concentration of desflurane induces tachycardia but is not associated with epileptiform EEG.
Intravenous Anesthetics
Barbiturates : EEG or clinical seizure activity has not been reported in nonepileptic patients treated with ultrashort-acting barbiturates including thiopental and methohexital. However, excitatory phenomena such as abnormal muscle movements, hiccoughing, and tremor may occur with both these drugs, more commonly with methohexital. Generalized tonic-clonic seizures (GTCS) have been reported immediately following administration of methohexital. Low-dose (<0.5 mg/kg) methohexital causes a high percentage of spike activation (50–85%) in patients with psychomotor TLE. This technique has been used during intraoperative ECoG to activate epileptic foci during temporal lobectomy. In humans, barbiturates (thiopental and phenobarbital) have well-known anticonvulsant properties and are found effective in the treatment of RSE.
Etomidate : Involuntary myoclonic movements seen during induction of anesthesia with etomidate possibly represent subcortical seizure activity. Etomidate (0.2 mg/kg) has shown up to 95% successful spike activation in patients with intracranial electrodes. During electroconvulsive therapy, etomidate is preferred over thiopental for producing seizures of adequate duration in patients who have very high seizure thresholds. At high doses, etomidate produces burst suppression patterns analogous to the barbiturate compounds. Successful termination of EEG-documented status epilepticus (SE) has been demonstrated after etomidate administration.
Ketamine : EEG seizure activity has not been reported in nonepileptic patients during ketamine administration. However, the occurrence of myoclonic and seizure-like motor activity, representing subcortical seizure activity, has been observed clinically in patients given low doses [0.5–2 mg/kg intravenous (IV)] of ketamine. Ketamine at doses ≥2 mg/kg activates epileptogenic foci in patients with known seizure disorders, but lacks specificity with ECoG. In humans, ketamine has been used successfully in the management of RSE owing to its N -methyl- d -aspartate receptor antagonist property.
Propofol : Seizures or seizure-like phenomena, which are mostly convulsive, have been observed during the induction, maintenance, and withdrawal phases of propofol administration. In a systematic review, GTCS were observed in 43%, events presenting as increased tone with twitching and rhythmic movements in 36% and involuntary movements in 16% of nonepileptic patients during and after propofol anesthesia. In patients with epilepsy, 64% had GTCS during emergence. Studies have demonstrated that sedative doses of propofol have minimal effect on intraoperative ECoG recordings. Despite the claims that propofol has proconvulsant activity, there is significant evidence to the contrary. Continuous propofol infusion is an effective treatment for RSE.
Benzodiazepines : Midazolam has been shown to induce nonepileptic abnormal movements and a dystonic posture within seconds after administration and to induce choreoathetosis following prolonged IV administration. All benzodiazepines in clinical practice (diazepam, midazolam, and lorazepam) possess potent anticonvulsant properties and are widely used to terminate episodes of SE.
Dexmedetomidine : Since locus coeruleus plays a role in dexmedetomidine-induced modulation of mesolimbic dopamine pathways, it has been postulated that the large dose and extended use of dexmedetomidine leads to a reduction in the anticonvulsant activity of the locus coeruleus due to altered noradrenergic systems. Dexmedetomidine sedation elicits an EEG pattern similar to that of stage II sleep and does not hinder EEG interpretation suggesting that it may be a uniquely useful agent for EEG recording in children. Dexmedetomidine is useful during intraoperative ECoG recording in ES as it enhances or does not alter spike rate in most of the cases, without any major adverse effects.
Opioids : Fentanyl, alfentanil, sufentanil, remifentanil, and morphine have been reported to cause seizure-like movements. Synthetic opioids can be used safely during AC without a significant increase in the risk of perioperative seizures or changes in ECoG activities. Remifentanil administered at sedation doses does not adversely affect intraoperatively recorded interictal spike activity. However, high bolus doses of all the synthetic opioids can result in their increase.
The high effectiveness (ranging from 67.4% to 100%) and specificity of μ-agonists has led to their routine use in pharmacoactivation of potential epileptiform activity during intraoperative ECoG at the time of focal cortical resection. During ECoG, alfentanil produces spike activation at wide clinical doses (20–100 μg/kg) and has been shown to be most effective and specific when compared with remifentanil and fentanyl. Alfentanil as such is the preferred opioid for intraoperative activation of the ECoG in neurosurgical patients undergoing resection of a TLE focus. Remifentanil, however, may supplant alfentanil owing to its short elimination half-life, thereby facilitating neurologic function testing immediately after surgery. Fentanyl and its analogs have not been shown to possess any anticonvulsant properties.
Local anesthetics ( LAs ): LAs can possess both proconvulsant and anticonvulsant properties because of their membrane-stabilizing effects. At subtoxic doses, LAs can act as anticonvulsants, sedatives, and analgesics followed by generalized convulsions at higher doses. High blood levels result from an accidental IV administration, accumulation after repeated injections, or rapid systemic absorption from a highly vascular area. IV lidocaine has been used to treat SE, mainly in children.
Neuromuscular blocking agents : In humans, none of the nondepolarizing muscle relaxants (NDMRs) have been reported to have any proconvulsant or anticonvulsant effects. Laudanosine, the primary metabolite of atracurium, has been known to cause EEG and clinical evidence of seizures in animals. 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 with increases in cerebral blood flow and intracranial pressure (ICP) related to an increase in afferent muscle spindle activity and to increased muscle carbon dioxide (CO 2 ) production. It has not been associated with seizure activity.
Anticholinergics and anticholinesterase : In clinically relevant doses, neither atropine nor scopolamine would be expected to have a significant therapeutic effect on seizure activity in humans. Similarly, none of the cholinesterase inhibitors used in clinical anesthesia has been reported to have proconvulsant or anticonvulsant properties in humans.
Antiepileptic Drug Interactions
Awareness of pharmacological properties of AEDs and potential interactions with drugs used in perioperative period is essential for adequate management of patients undergoing ES. Most of the first-generation AEDs such as phenobarbital, primidone, phenytoin, and carbamazepine are inducers of cytochrome P450 isoenzymes involved in hepatic metabolism. Enzyme induction results in increased metabolism, decreased serum concentrations and pharmacological effect of the affected drug, and possibly loss of seizure control. The process is reversed when the inducer is withdrawn, resulting in increased serum concentrations and potential for toxic side effects of the affected drug. Hence, it is important to monitor the drug concentrations closely 2–4 weeks following addition or withdrawal of a drug. In addition, phenytoin, benzodiazepine, and valproic acid are highly protein bound. Other effects on free drug level may arise from competition for protein-binding sites.
Similarly, it is preferable to avoid enzyme-inducing AEDs in patients with chronic medical conditions other than epilepsy since two-thirds of drugs will undergo increased clearance as a result of enzyme induction, including the antiarrhythmic drugs particularly amiodarone, digoxin, calcium channel blockers (nifedipine, felodipine, nimodipine, and verapamil), β-blockers (propranolol, metoprolol), lipid-lowering agents, warfarin, antibacterial agents, antiretroviral agents, many antifungals, chemotherapeutic agents, immunosuppressives, and psychiatric medications, including some antidepressants and antipsychotics. An increase in warfarin dose is required to maintain the target international normalized ratio, with close monitoring during AED therapy in patients with epilepsy.
The net effect of AEDs (phenytoin, carbamazepine, or phenobarbital) on NDMRs is the result of several processes. At first, they inhibit the release of acetylcholine (Ach) quanta at the nerve terminal. Patients on AEDs, therefore, experience an acute increase in sensitivity to NDMRs. Over a few weeks, decreased ACh quanta results in an increase in ACh receptors. Along with induction of NDMR liver metabolism and increased release of acute-phase reactant proteins (which bind some NDMRs and change volume of distribution), this results in observed resistance to NDMRs, including pancuronium, vecuronium, rocuronium, and cisatracurium, but less so to atracurium. Moreover, epileptic patients receiving AEDs require higher doses of fentanyl to maintain a comparable depth of anesthesia. The cause or causes of this resistance to opioids is unknown. Possibilities include changes in the number of receptors and/or alterations in drug metabolism.
Macrolide antibiotics inhibit carbamazepine metabolism by inhibiting CYP3A4, giving rise to potential serious toxicity if antibiotics are administered. Valproate is an inhibitor of hepatic microsomal enzyme systems and may reduce the clearance of many concurrently administered medications, including other AEDs. Concomitant use of carbapenem antibiotics can lead to a significant decrease in serum valproate concentrations.
The newer AEDs are less interacting because their pharmacokinetics are more favorable. Gabapentin, lacosamide, levetiracetam, pregabalin, and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions. However, since the newer AEDs are often used as adjunctive therapy with older AEDs, they are susceptible to interactions by the addition of comedication.
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