PBLD: Anesthesia for Epilepsy Surgery

Authors: Ankur Dhanda MD [Senior Resident]¹

Ashish Bindra MD, DM [Associate Professor]¹

Gyaninder Pal Singh MD, DM [Associate Professor]¹

Shaun Gruenbaum, MD, PhD [Senior Associate Consultant]²

Girija Prasad Rath MD, DM [Professor]¹

Affiliation:       1. Department of Neuroanaesthesiology and Critical Care, Neurosciences Centre
All India Institute of Medical Sciences (AIIMS), New Delhi, India
2. Department of Anesthesiology and Perioperative Medicine
May Clinic, Jacksonville, Florida

CASE: A 26-year-old female presents with complaints of recurrent abnormal movements on her right side for the previous 10 years. She described feelings of fear that are followed by right sided upper limb posturing and secondary generalization. She has experienced 3 to 4 seizures per week, and each seizure has lasted approximately 1 minute in duration. The patient was started on multiple anti-epileptic drugs (AEDs) with no resolution of the seizure frequency or duration. She was diagnosed with left sided mesial temporal sclerosis and was scheduled for Electrocorticography (ECoG)-guided temporal lobe resection.

Past medical history: no co-morbidities.

Medications: Valproic acid, lamotrigine and clobazam.

Physical examination: 45 kg, conscious and oriented. No pallor, icterus, cyanosis and clubbing.

Neurological examination: Normal higher cognitive function, no neurological deficits.

Vital signs: Pulse 86/min, blood pressure 119/76 mmHg, respiratory rate 16/min, SpO₂ 99% on room air.

Magnetic Resonance Imaging (MRI): left hippocampal hyperintensity and volume loss.

Electrophysiological studies: Electroencephalography (EEG) and video EEG demonstrated left temporal onset.

Labs: Hb 13.3 gm/dl, total leukocyte count 6050/mm³, platelet count 193,000/mm³, blood urea nitrogen 24 mg/dl, creatinine 0.6 mg/dl, INR 1.11, AST 33 IU/L, ALT 28 IU/L, ALP 80 IU/L, total bilirubin 0.7 mg /dl, serum valproic acid 95.35 µg/ml, chest x-ray (CXR) normal, electrocardiography (ECG) normal.

KEY QUESTIONS AND DISCUSSION:

1. What defines a seizure? How would you define epilepsy and drug resistant epilepsy (DRE)?

In 2005 the International League Against Epilepsy (ILAE) formulated a conceptual definition of a “seizure”, which was defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activities in the brain [1]. In 2014, the ILAE conceived an operational clinical definition [2], and epilepsy was defined as a disease of the brain with any of the following conditions:

1. At least two unprovoked (or reflex) seizures occurring more than 24 hours apart.
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general risk of recurrence (at least 60%) after two unprovoked seizures, occurring over the next 10 years.
3. A diagnosis of an epilepsy syndrome.

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age, or those who have remained seizure-free for the previous 10 years without any anti-seizure medications for the previous 5 years.

DRE is defined as seizures that persist despite treatment with antiepileptic drugs (AEDs), as monotherapy or in combination, in adequate dosages and for the appropriate indications [3].

2. What are some side effects and drug interactions on commonly used AEDs?

Patients with DRE are commonly on multiple AEDs. First-generation AEDs like phenytoin, carbamazepine, and valproate are efficacious and cost-effective, and are still widely used in many countries. They require frequent monitoring of serum levels, however, and their well-known effects on liver enzyme metabolism result in multiple drug interactions. The favorable pharmacokinetics of the newer AEDs result fewer drug interactions, and do not require frequent monitoring of serum drug levels. These drugs are not free of side effects, however. Adverse effects and interactions of commonly-used AEDS are listed in the table below (Table 1):

Table 1.

DRUG	ADVERSE EFFECTS	INTERACTIONS
Phenytoin	Gum hyperplasia, lymphadenopathy, hirsutism, osteomalacia, facial coarsening, skin rash, ataxia, diplopia	Levels increased by isoniazid, fluoxetine, sulfonamides; levels decreased by enzyme-inducing drugs
Carbamazepine	Aplastic anemia, leukopenia, hepatotoxicity, ataxia, diplopia, sedation	Levels increased by erythromycin, isoniazid, cimetidine, fluoxetine; levels decreased by enzyme-inducing drugs
Valproic acid	Hepatotoxicity, thrombocytopenia, weight gain, hyperammonemia, tremors, ataxia	Levels decreased by enzyme-inducing drugs
Lamotrigine	Skin rash, Stevens-Johnson syndrome, sedation, ataxia, diplopia	Levels increased by valproic acid; levels decreased by enzyme-inducing drugs and oral contraceptives
Topiramate	Psychomotor slowing, paresthesias, speech or language difficulties, kidney stones, glaucoma, hypohidrosis	Levels decreased by enzyme-inducing drugs
Levetiracetam	Anemia, leukopenia, sedation, mood changes	No known significant interactions
Clonazepam	Anorexia, sedation, ataxia	Levels decreased by enzyme-inducing drugs
Zonisamide	Psychosis, aphasia, anorexia, kidney stones, psychosis	Levels decreased by enzyme-inducing drugs

Long-term AED therapy with phenytoin and carbamazepine results in increased resistance to nondepolarizing muscle relaxants such as vecuronium and rocuronium [4,5], and less commonly atracurium [6]. The likely mechanisms that account for this effect include hepatic enzyme induction and upregulation of Ach receptors [4]. Anticonvulsant therapy predisposes to opioid resistance, which seems to have a dose-effect relationship with the number of anticonvulsants administered [7]. Patients on enzyme-inducing AEDs can also have increased plasma clearance of dexmedetomidine [8]. AEDs are further known to potentiate the central nervous system (CNS) depressant effects of general anesthetics, as both classes of agents interact with sodium channels and GABA(A) receptors with little selectivity [9].

3. What type of surgery will be required for this patient? What other causes of epilepsy are commonly treated with surgery?

Mesial temporal lobe epilepsy (MTLE) is the most common cause of medically-intractable focal epilepsy. Most patients with MTLE present with complex partial seizures. Surgery consists of anterior temporal resection or selective amygdalohippocampectomy. The procedure can be modified according to the extent of the focal lesion [10], and can be done with or without intraoperative ECoG to help guide the extent of resection.

Other causes of surgically-remediable epilepsy include:

• Focal lesions: Focal cortical dysplasia, dysembryoplastic neuroepithelial tumor (DNET), hypothalamic hamartoma, vascular lesions/cavernoma, gliosis (traumatic).
• Multifocal lesions: Lennox Gastaut syndrome, West Syndrome, bi-hemispheric sequelae of infectious, traumatic or vascular pathology, gliosis.
• Hemispheric lesions: Rasmussen’s encephalitis, Struge Weber syndrome, tuberous sclerosis, infantile hemiplegic syndrome, hemimegancephaly.

Focal lesions typically require lesionectomy, and patients generally experience favorable outcomes with minimal morbidity. In hemispheric lesions, disconnective surgeries such as functional or anatomical hemispherotomies are performed, which carry a significantly higher rate of morbidity. Multifocal lesions and lesions near the eloquent cortex may require palliative procedures such as subpial transection, corpus callosotomy or vagal nerve stimulation.

4. Why might it important to localize the seizure focus prior to surgery? What investigations should be carried out to define the seizure focus before proceeding to surgery?

A thorough preoperative evaluation is required to identify the epileptogenic foci, which includes clinical, radiological and electrophysiological investigations. ILAE recommended a set of diagnostic tests prior to resective epilepsy surgery [11]. Interictal EEG and MRI are the only mandatory tests among the various clinical cohorts, and are sufficient for identifying the seizure focus in approximately 75% of patients with temporal lobe epilepsy. However, discordance between the clinical and radiographic results requires further investigations.

Interictal EEG: Scalp EEG recordings have limited spatial resolution. The reliability of localizing the seizure focus is higher for convexity foci than basal, mesial temporal or interhemispheric foci. A dense array EEG has a higher localization value than conventional electrode placement [12].

Ictal EEG with video: Ictal video EEG is particularly useful for confirming the seizure semiology, identifying multiple seizure types, and for differentiating epileptic from non-epileptic events.

Extra operative invasive EEG monitoring (IEM): IEM is considered the gold standard for the localization of epileptogenic foci. Subdural or depth electrodes (alone or in combination) can be inserted in discrete brain areas under general anesthesia. Depth electrodes are typically placed with stereotactic guidance. IEM is generally done in cases with discordant lesions, in which the seizure focus cannot be localized by interictal EEG and MRI alone. Potential complications of IEM include hemorrhage, infection, misplacement and increased intracranial pressure in the subdural grid electrodes [13,14].

MRI and functional MRI (fMRI): A high resolution MRI acquisition protocol is required for the detection of specific brain abnormalities.

FLAIR and special imaging protocols are particularly high yield. fMRI can be used to reliably lateralize language function and can also be used to facilitate the localization of seizure foci by detecting the cerebral hemodynamic changes produced by epileptiform discharges. Post-ictal states, vascular malformations with vascular steal, and large mass lesions with edema can reduce its reliability. Obtaining an MRI in non-cooperative patients, children, and patients with status epilepticus typically requires general anesthesia.

Magnetoencephalography (MEG): MEG aids in the 3-D localization of inter-ictal spikes, and can define foci as small as 4-8 cm², compared with EEG which by contrast detects larger foci that measure 10-15 cm². Major limitations for this modality include limited access and high costs.

Ictal Single-photon emission computerized tomography (SPECT): SPECT is a useful non-invasive method that is commonly used for seizure focus localization. Following an intravenous injection of an ictal tracer, hyperperfusion in the seizure focus is observed during the ictal period and hypoperfusion is observed during the inter-ictal period. The timing of SPECT injection for seizure focus localization is especially critical, as late injections may provide false localization or even lateralization.

Interictal 18-Fluoro-deoxyglucose positron emission tomography (FDGPET): FDGPET can be very useful for defining foci lateralization, and to a lesser extent, localization. FDGPET demonstrates hypometabolism in the seizure focus during the inter-ictal period.

5. Are there any other preoperative tests that can be performed to help assist in language and memory lateralization? How are these tests conducted?

The Wada Test is the gold standard against which novel language lateralization techniques are measured. The Wada test is not a routine screening test for epilepsy surgery and is performed only in select centers. Lesser invasive modalities such as fMRI and intraoperative neurophysiological monitoring are currently more commonly used than the Wada test.

To conduct Wada test, Amobarbital (75- 125 mg) is selectively injected over 4 sec into the internal carotid artery either via direct puncture or through a cannulated femoral artery. The test is conducted on both sides in sequence, with at least 30 minutes between injections to ensure a return to baseline. Language testing is done immediately after the injection. Within three minutes of injection, language and memory functions are assessed during the phase of drug-induced EEG slowing and associated hemiparesis. If speech persists in the phase of hemiparesis, language is presumed non-dominant in that hemisphere. Memory function testing is less reliable because mesial temporal structures are primarily perfused via the posterior circulation. Etomidate (2 mg bolus followed by 6 ml/hr infusion) [15] and propofol (10 mg diluted as 2mg/ml given over 5 sec up to 20 mg) have been used as an alternatives to Amobarbital [16].

The Superselective Wada test inhibits the arterial territory that supplies a specific brain region and avoids the confounding effects of inhibiting a large hemisphere area. To perform this test, the drug is injected selectively into the P2 segment of the posterior cerebral artery via a micro-catheter or superselective injection into the anterior choroidal artery (via the internal carotid artery, after occluding the vessel distal to the origin of the anterior choroidal artery), or injecting selectively into the M1 segment of the middle cerebral artery [17]. Brain stem inactivation may occur during selective posterior cerebral artery testing. Of note, this test requires patient cooperation and therefore cannot be performed in uncooperative adults or small children.

6. The presence of epilepsy and epilepsy-associated syndromes is associated with an increased risk of perioperative complications. How will you assess the patient with DRE scheduled for epilepsy surgery?

A detailed history and thorough examination should be performed in each patient. Patients should be asked about seizure onset, duration, frequency, and its semiology, which will be helpful for differentiating a seizure from psychomotor behavior during the perioperative period. While MTLE is typically a non-syndromic condition, patients with refractory seizures should be screened for associated syndromes such as tuberous sclerosis and neurofibromatosis, as well as signs of multisystem involvement. Patients with neurofibromatosis can have respiratory tract tumors or cranial nerve involvement that result in airway compromise [18]. The respiratory system can also be compromised by chronic aspiration syndrome, pulmonary fibrosing alveolitis, pulmonary hypertension and cor pulmonale. Pheochromocytoma or renal artery stenosis can present as episodic hypertension. Patients with tuberous sclerosis can have cardiac dysrhythmias, intracardiac tumors, renal dysfunction, and aneurysms. A detailed cardiac examination should be done in these patients, including a preoperative echocardiography. Adequate precautions should be taken when anesthetizing syndromic patients.

7. The patient is on three AEDs. Would you order for any preoperative laboratory studies? Is it safe for patients on the ketogenic diet for DRE to undergo general anesthesia?

A complete medication history including use of AEDs and other medications should be obtained. Drug interactions and adverse effects of AEDs should be considered when planning preoperative studies. Liver enzymes can be elevated in patients receiving anticonvulsant therapy (γ-glutamyl transpeptidase is elevated in 75% of patients and alanine aminotransferase in 25%) [19]; surgery should not be postponed in the setting of an otherwise asymptomatic elevation of liver enzymes. Topiramate has been associated with intraoperative metabolic acidosis [20]. Carbamazepine can cause a severe depression of the hemopoietic system and cardiac toxicity. Valproic acid results in a dose-related platelet dysfunction and thrombocytopenia [21]. Clobazam contributes to perioperative drowsiness and sedation. After discussion with the neurologist and neurosurgeon, AEDs should be continued or withheld on the morning of the surgery to facilitate EEG monitoring and localization. Patients on the ketogenic diet can safely undergo surgery under general anesthesia [22]. These patients can develop a metabolic acidosis in the perioperative period [23]. Intraoperative acid-base status and plasma glucose levels should be evaluated frequently in such cases. Preoperative studies should include a complete blood count, liver function tests, coagulation profile, kidney function tests, ECG, chest x-ray, and serum AED levels. The possibility of intraoperative awareness should be discussed with the patient, as there is a significant reduction in the sedative hypnotic drugs during ECoG monitoring. 

8. What perioperative concerns do you have for the patient with MTLE?

MTLE surgery is generally performed under general anesthesia, and has a fairly predictable intraoperative course. Most patients are extubated at the end of surgery, and postoperative ventilation is rarely required. The intraoperative anesthetic goals include tailoring the anesthetic agents during neurophysiological monitoring to facilitate the localization of the epileptogenic foci and eloquent areas, and to optimize cerebral perfusion pressures. Brain bulging is rarely encountered except in cases that require the placement of large surface grid ECoG electrodes. Smooth and rapid emergence from anesthesia facilitates early neurologic assessment and is strongly desired. Patients undergoing complex resections and those on multiple AEDs can experience delayed awakening or perioperative drowsiness.

9. What monitors will you plan to use during surgery?

Standard ASA monitoring should be utilized for these procedures, which includes ECG, pulse oximetry, end tidal carbon dioxide, temperature, non-invasive/invasive arterial blood pressure and minimum alveolar concentration (MAC). Normocapnia and normothermia should be maintained. ECoG is utilized for defining the extent of surgical resection. Careful selection of anesthetic agents during electrophysiological monitoring is of paramount importance.

10. What are the effects of inhalational anesthetics on epileptic activity?

The inhalation anesthetics cause a shift of occipital α-waves to the frontal region followed by progression to θ- and δ-waves. Burst suppression with inhalation agents can occur at MAC doses that exceed 1.5. Desflurane has not shown any evidence of activation of inter ictal activity (IEA) [24]. Isoflurane has also not shown any evidence of IEA activation but may suppress IEAs when used with nitrous oxide (N₂O). Sevoflurane is considered to be epileptogenic and produces dose-dependent, nonspecific activation of epileptiform discharges [25]. Enflurane can cause nonspecific spikes activation, and seizures can be triggered when the patient is hypocarbic. At concentrations less than 50%, N₂O may suppress spikes and has a synergistic suppressive effect when used in combination with other inhalational agents [26,27].

Opioids have no effect on background ECoG when administered as a low-dose bolus or continuous infusion; however, activation of spikes is possible with a large bolus [28]. The effect of opioids is attenuated by the prior administration of a benzodiazepine. Dexmedetomidine has a minimal effect on background IEAs and do not cause any activation or suppression [29]. Benzodiazepines cause a marked reduction in IEAs and can make it difficult to record the ECoG.

Propofol can cause variable responses at all dose ranges and may activate or suppress IEAs [30,31]. Thiopental can activate spikes when administered as a bolus. Methohexital is a potent activator of spikes, but its effects are often nonspecific [32]. Etomidate causes the activation of nonspecific spikes and can induce seizures. Ketamine causes nonspecific IEA activation, especially in the limbic structures.

11. Suppression of IEA is common under anesthesia. How would you optimize the ECoG recordings in this patient?

The use of benzodiazepines for premedication should be avoided, as as they are known to suppress the IEA. Intravenous induction of general anesthesia should be done with propofol or short-acting barbiturates in combination with opioids. For maintenance of anesthesia, low dose inhalational agents or total intravenous anesthesia (TIVA) can be used. Inhalational agents can be used at concentrations <0.5 MAC and can be discontinued before ECoG recording. Infusion of propofol should be stopped 15-20 minutes prior to ECoG recordings, as it elicits high-frequency beta EEG activity for as long as 30 minutes after its discontinuation [33]. Opioids such as sufentanil (0.3-1 mcg/kg/hr), remifentanil (0.1-0.5 mcg/kg/min), or fentanyl may be used as infusions, and higher doses can be used during ECoG if the other anesthetic agents are discontinued. Dexmedetomidine (0.2-0.7 mcg/kg/hr) has minimal effect on ECoG and IEA recordings, and can be a useful anesthetic adjunct when other anesthetic agents are discontinued. If motor mapping is implemented, neuromuscular blocking agents should not be used and volatile agents even at low concentrations (0.2-0.4 MAC) can attenuate cortical MEPs. If remifentanil is used, a longer-acting analgesic and multimodal analgesia should be considered for postoperative pain management. Since this patient will have intraoperative ECoG monitoring, which is based on recording interictal activity, anesthetic agents which have minimal interference with IEA should be used. Low concentrations of isoflurane and desflurane can be used in this case, and dexmedetomidine is a reasonable alternative during ECoG monitoring.

12. During the case, you observe an absence of inter-ictal activity on ECoG. What are you considerations and next steps in management?

If spontaneous interictal signals are not being recorded during intraoperative ECoG, it might be necessary to activate interictal epileptiform spikes. Before pharmacological activation is considered, ice-cold saline and AEDs should be readily available. The basic principle here is to selectively increase the cortical excitability by increasing the IEA. Only a few centers practice pharmacological activation.  Pharmacological activation might result in one of three responses: a run of IEA, electrographic seizures, and electroclinical seizures. Alfentanil (20-100mcg/kg), Etomidate (0.2 mg/kg) and Methohexital (25-100mg) are most widely used for this purpose [28], but ketamine has also been used. Successful activation is defined as an increase in the frequency of spikes, an increase in the spike distribution, or both. Hyperventilation and cortical stimulation are other methods of activation. However, when pharmacological activation is used, one should consider that the activation is non-specific, can over-estimate the seizure foci, and can result in onset of frank seizures. Due to these reasons, many centers prefer other methods of defining focus over induced activation of IEA.

13. Had the epileptic focus been close to the language cortex, would this change your anesthetic approach?

Epilepsy surgeries with lesion near the eloquent cortex are typically performed with an awake and cooperative patient, which allows for intraoperative speech and motor testing. Preoperative mapping of the eloquent cortex can be performed with the use of fMRI, magnetoencephalogram and diffusion tensor imaging (DTI). Motor and sensory mapping can also be done under general anesthesia by monitoring motor and somatosensory evoked potentials, but awake surgery is essential for intraoperative language mapping. Direct cortical stimulation in an awake patient remains the gold standard technique for defining the eloquent cortex. [34].

A cooperative patient is vital to the success of an awake craniotomy. The patient should be calm and conscious patient during cortical mapping, with minimal interference of sedative and anesthetic drugs on neurophysiological monitoring. Stable cerebral and systemic hemodynamic parameters should be maintained. Several approaches have been described for awake craniotomy procedures, and the selection of specific anesthetic agents as well as the airway management should be made in accordance with the individual expertise and preference of the attending neuroanesthesiologist, the patient’s needs, and institutional protocols. Local anesthetic infiltration of the scalp in combination with monitored anesthesia care (MAC) as well as asleep-awake-asleep techniques have been used for awake craniotomy. Conscious sedation with propofol and remifentanil or dexmedetomidine has been successfully described for epilepsy surgery in the awake patient [35].

14. During cortical stimulation the patient develops a seizure. What is your next step in management?

Intraoperative seizures during cortical stimulation are typically focal in nature, and most resolve spontaneously when the stimulation is ceased. The first line treatment includes irrigation of the cortex with cold saline, which has minimal effects on subsequent ECoG recordings. Generalized tonic-clonic seizures might require a bolus of propofol (10-50 mg), midazolam (1-5 mg), or thiopentone sodium (25-50 mg). However, benzodiazepines can interfere with subsequent recordings and should be avoided. A loading dose of AEDs such as phenytoin can be administered to patients with substantial background IEA after the recording to minimize subsequent stimulation triggered seizures.

15. In the postoperative period the patient continues to experience seizures. What are the likely causes and how would you manage this?

After surgery for mesial temporal sclerosis, patients can experience a varying degree of seizure control [36]. Postoperative seizures can be attributed to altered serum levels of AEDs, brain inflammation, incomplete removal of the epileptogenic focus (surgical failure) or the development of a new seizure focus. Approximately 30-50% of patients continue to experience some seizure activity after epilepsy surgery. A workup for postoperative seizure should include monitoring of serum AED levels, re-evaluation with EEG to investigate any residual or new seizure focus, monitoring of serum electrolyte concentrations, and a workup for possible CNS infection. The management of seizures should be tailored to the underlying etiology and can include a titration of AEDs and repeat surgery if necessary. Psychogenic non-epileptic seizures can pose a diagnostic dilemma, and psychiatric evaluation is often required for their management.

16. What other complications can be observed in the postoperative period?

Patient can experience a delayed emergence from anesthesia, as most AEDs cause sedation and somnolence. This can result in the need for postoperative ventilation, although most patients are successfully extubated after completion of the surgery. Postoperative nausea and vomiting occurs in up to 30-50% of intracranial neurosurgery cases [37]. Neurological deficits can be observed in 5- 19% of patients, with permanent deficits present in 0.8-3%. The most common neurologic deficit observed after temporal lobe epilepsy is visual field deficits. Perioperative mortality is rare after epilepsy surgery, and can occur in 0.4 and 1.2% patients with temporal and extra-temporal lobe epilepsy, respectively [38]. Perioperative complications have reduced significantly during the last few decades, and morbidity associated with refractory repetitive seizures far exceeds the morbidity associated with epilepsy surgery.

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