Epilepsy is one of the major neurological disorders, affecting roughly 1-2% of the world's population, of which approximately 20–25% of patients are drug resistant. A variety of drugs have been used to activate and identify the epileptic area in patients during presurgical evaluation. We studied the cerebral blood flow (CBF) by single photon-emission computed tomography (SPECT) and bioelectrical brain activity responses to etomidate in 11 patients. Etomidate (0.1 mg/kg) was administered while patients were monitored by video-electroencephalography with foramen ovale electrodes (FOEs). After etomidate administration, a brief period of high-frequency activity was observed, followed by a generalized, high-voltage delta pattern. Increased regional CBF was observed bilaterally in thalamus, putamen, and posterior hippocampus. Besides, the only interhemispheric difference was observed in the posterior hippocampus, where CBF decreased in the epileptic temporal lobe. Activation by etomidate induces a specific and repetitive response in the bioelectrical activity. In addition, CBF changes induced by etomidate may serve as a diagnostic tool in the near future.
Epilepsy affects 1–2% of the population worldwide and can be considered one of the most prevalent neurological illnesses [
SPECT is a technique that measure the regional cerebral blood flow (CBF) using radio-tracers [
Alternatively, a pharmacological approach can be taken to identify the EZ. For this purpose, several different drugs have been used, including methohexytal [
An ideal drug for EEG activation should have the following features: (1) it should be well tolerated by the patient, with a fast onset and rapid decline of activity, as well as a low level of side-effects, (2) it should produce selectively increased activity in the epileptic zone, implying no new interictal epileptiform discharges (IEDs) emerging, and (3) it should specifically distinguish between the interictal zone (IZ, the area showing interictal epileptiform discharges or IED) and ictal onset zone (IOZ, where seizures in fact start) [
Etomidate is a rapidly-inactivating imidazol derivative [sulphate-R-(+)-ethyl-1-(-1-phenylethyl)-1-H-imidazol-5-carboxylate] with a peak effect at 1 min and a duration of 3–5 min. It is a nonbarbiturate hypnotic agent without analgesic properties but does activate gamma-aminobutyric acid A (
The central aims of this study were to analyze changes in regional CBF in patients with TLE in response to administration of etomidate and to examine its possible utility for diagnosis during presurgical evaluation.
The present study included 11 patients (5 women, 6 men) who were diagnosed with intractable epilepsy of the mesial temporal lobe. Informed consent was obtained from all patients and were studied according to an approved protocol used by the Epilepsy Surgery Unit at La Princesa Hospital [
Clinical features of patients.
Patient | Sex | Age (years) | History (years) | Basal SPECT | Seizure type | MRi | v- | Surgery/Engel’s grade |
---|---|---|---|---|---|---|---|---|
1 | F | 38 | 18 | Left mes temporal | Partial complex | Normal | Left- Mesial Temporal | L AMTR/ I |
2 | F | 39 | 34 | Bi-T (L > R) | Partial complex | Right MS | Right mesial | R AMTR/ I |
3 | F | 35 | 33 | Left mes temporal | Partial complex | Left MS | Left mesial | L AMTR/ I |
4 | M | 25 | 9 | Left mes temporal | Partial simple & complex | Left parasellar cyst | Left mesial | L AMTR/ I |
5 | F | 22 | 5 | Left temporal Left F-P | Secondary Generalized | Normal | Left mesial | L AMTR/ I |
6 | M | 38 | 37 | Bi-T mes (Left > Right) | Partial complex | Left MS | Left mesial | L AMTR/ I |
7 | M | 21 | 5 | Right mes temporal | Partial complex | Normal | Right mesial | R AMTR/ I |
8 | M | 30 | 11 | Right mes | Partial complex | Left MS | Bi-T (Left > Right) | #L AMTR/ IV |
9 | M | 36 | 13 | Left mes temporal | Partial complex | Normal | Left mesial | L AMTR/ II |
10 | F | 34 | 26 | Left Mesial temporal | Partial complex | Normal | Left mesial | No surgery |
11 | M | 23 | 11 | Left Mesial temporal | Partial complex | Normal | Left mesial | L AMTR/ I |
AMTR: anterior medial temporal resection; Bi-T, Bi-temporal; F: female; F-P: fronto-parietal; L: left; M: male; mes: mesial; MS: mesial sclerosis; R: right. Engel’s grade [
Patients were evaluated presurgically using the following: (1) 19-channel scalp EEG according to the 10–20 international system, (2) interictal SPECT using
The EZ includes the IZ, where IEDs appear, and IOZ. The IOZ was defined as the region where the seizures originated according to the v-
During the v-EEG recording, antiepileptic drugs were removed from the second to the fourth day of the test. To evaluate etomidate, the drug was administered intravenously ( i.v.) between the second to the third day in the v-EEG unit.
Etomidate (Janssen-Cilag, Spain) was administered i.v. at a dose of 0.1 mg/kg under quiescent conditions, with the patient resting supine in bed while under continuous supervision by an expert anaesthesiologist (MLM, JLM-Ch, ED). Supplementary oxygen was administered through nasal goggles at 5 L/ min rate. The electrocardiogram (EKG), capillary oxygen saturation (SaO2), and respiration rate (RR) were continuously monitored during the evaluation. Electrical brain activity was monitored by v-
Regional CBF was evaluated by SPECT imaging. A bolus of
Quantitative analysis of brain perfusion was performed using NeuroGam software (General Electric) to compare several areas of interest, including the frontal, temporal, parietal, and occipital lobes, the putamen, globus pallidus, and thalamus, as defined by default by the software. Moreover, we defined the following areas according to the Talairach-Tournoux atlas (1998): the latero-basal temporal cortex, amygdaloid body, anterior hippocampus, and posterior hippocampus.
To evaluate changes in CBF, we defined the
Statistical comparisons between groups were performed using the Student’s
Statistical analyses were performed with SigmaStat 3.5 software (Point Richmond, USA). The significance level was set at
Intravenous administration of etomidate to awake patients was performed over a period of 3
All patients recovered in less than 10 min and did not require any special care.
Administration of etomidate produced no changes in SaO2, heart rate measured by EKG, or RR.
Shortly after completion of etomidate administration, small increases in the amplitude and frequency were observed in the scalp EEG (stage 1), followed by generalized, large-amplitude delta activity (stage 2). This pattern was similar to that described previously for nonepileptic subjects [
Bioelectrical brain activity induced by etomidate. (a) Scalp and FOE recording in basal conditions, 1 minute previous to etomidate administration. (b) Activity recorded 1 minute after etomidate. Slow high-amplitude activity is observed widespread in scalp, specially in anterior regions. It is important to note that IEDs appear in the same region where the spontaneous seizure originated.
Taking into account the short latency of changes in EEG and the dynamics of brain activity after etomidate injection, we can assume that almost a 40% of
Therefore, etomidate induced a specific pattern of brain activity, which included nonirritative activity on the majority of scalp leads, in addition to irritative activity specifically over those areas where IEDs previously were observed.
We measured the changes in CBF induced by etomidate. We observed a significant increase in the regional CBF in the thalamus (
Effects of etomidate on CBF. (a) Graph showing the global pattern of changes induced by etomidate, considering cerebral regions from both hemispheres. (b) Graph summarizing the CBF changes by etomidate in regions pertaining to the epileptic hemisphere (black box) and nonepileptic hemisphere (empty box). (c) Ventral view of different brain SPECTs in the same patient, during basal condition (left) and when activated by etomidate (middle). The image on the right corresponds to the substraction of the two previous images. The circle shows the increase in regional CBF in the right posterior mesial area.
It is interesting to consider the activation mediated by etomidate in the mesial temporal region because we would expect to find an increase in CBF associated with increased interictal activity.
In this study, we have shown that administration of etomidate is a safe and efficient pharmacological method potentially useful in patients suffering from TLE during presurgical evaluation. However, the changes observed in regional CBF, specifically in areas associated with the EZ, have been unexpected.
Traditionally, several different drugs are used to induce brain activity. As stated previously, it is clinically important that side effects induced by a drug be well tolerated by the patient [
The appearance of myoclonus following etomidate perfusion has previously been described [
As previously reported [
Traditionally an intense increase in regional CBF is one of the hallmarks of partial-onset seizures. This is probably due to an increase in regional synaptic activity and changes in neurotransmission. During the ictal SPECT, the
The relative decrease in regional CBF observed in the posterior hippocampus of EZ was a surprising result. Instead, we expected an increase in regional CBF in the IOZ, taking into account the significant increase in the IED induced by etomidate. Recently, it has been demonstrated that in the sclerotic hippocampus there is a consistent and highly significant reduction of micro-blood vessels, particularly in the CA1 field [
In contrast to other anaesthetics, etomidate has a very specific target at clinical concentrations [
Theoretical mechanisms of etomidate effect on the epileptic activity. Astroc: astrocyte; pre-N: presinaptic neuron; post-N: postsinaptic neuron. (a) Reversal of Cl- potential. Here,
On the other hand, studies in cultured astrocytes have shown that etomidate can inhibit glutamate uptake, increasing the extracellular glutamate concentration to such a level that can spill out of the synaptic cleft and activate extra-synaptic receptors. As a consequence, irritative activity would be increased [
We conclude that activation of bioelectrical activity and measurement of regional CBF in patients during presurgical evaluation could be of great utility in epilepsy units as a complementary test to increase the accuracy of diagnosis in patients being evaluated for TLE.
video-Electroencephalography;
Foramen Ovale Electrodes;
Single Photon Emission Computed Tomography;
Cerebral Blood Flow;
Epileptogenic Zone;
Interictal Epileptiform Discharges;
Temporal Lobe Epilepsy.
This work was supported by a grant from the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (