epilepsy is one of the most common neurological disorders , affecting almost 0.5%1.0% of the general population ( theodore et al 2006 ) . patients usually respond well to pharmacological treatment
however , approximately , 25%30% of patients are drug - resistant ( engel 1996a ) . for this group
, surgery can be a suitable therapeutic option ( engel 1992 , 1996b ; wiebe et al 2001 ) .
surgical treatment requires an exhaustive presurgical evaluation in order to identify the epileptogenic area and minimize the side effects of the operation .
presurgical evaluation usually includes , among others ( pastor et al 2005 ; sola et al 2005 ) , electroencephalography ( eeg ) , video - electroencephalography ( v - eeg ) , magnetic resonance imaging ( mri ) and single photon emission computerized tomography ( spect ) . interictal or basal spect is a presurgical study not performed systematically in the majority of epilepsy - surgery units because it is affected by a number of drawbacks that limits its results ( henry and heertum 2003 ) . in order to overcome these problems , some epilepsy - surgery units perform ictal spect , in which a radiotracer is intravenously administered after a seizure onset is identified ( spencer et al 2000 ; van paessen et al 2000 ; henry and heertum 2003 ; cascino et al 2004 ) .
ictal spect has been shown to be an accurate means of localization of temporal lobe seizures when the tracer is injected immediately after the seizure ( catafau 2001 ; van paessen 2004 ) .
the localizing information was better when the injection was given soon after seizure onset ( newton et al 1992 ; avery et al 1999 ; van paessen et al 2000 ) .
sometimes , during v - eeg recording and in order to increase the probability of seizures , pharmacologically induced stimulation has been performed using different drugs ; ie , clonidine , metohexital , etc ( kofke et al 1993 ; brockhaus et al 1997 ; schmitt et al 1999 ) . among these
, the use of etomidate , a nonbarbiturate hypnotic , short - lived imidazol derivate , has been rare ( ebrahim et al 1986 ; modica et al 1990 ) . in the hospital
la princesa , currently , we are characterizing the response to etomidate in patients with mesial temporal lobe epilepsy ( mtle ) and undergoing evaluation for surgery while they are monitored with v - eeg using foramen ovale electrodes ( foe ) .
it is not our objective to describe this method in detail ( see dominguez - gadea et al 2006 ) , but to show a fortunate result obtained in the context of that study , describing the case of a patient that suffered a seizure during etomidate infusion after the radiotracer injection for activated spect .
this allowed us to obtain that which is , to our knowledge , the first true initial ictal spect ( recorded during the true beginning of the seizure and not during the propagated ictal activity ) described in the literature .
we have implemented a numerical model previously published ( andersen 1989 ) for the analysis and discussion .
a 14-year - old , right handed girl with a diagnosis of refractory temporal lobe epilepsy ( tle ) was referred to the epilepsy unit , hospital universitario 
previously tried anti - epileptic drugs ( aed ) included phenitoin , carbamacepine , etosuximide , zonisapride , and levetiracetam . at the present time
pharmacological treatment included ( mg / d ) : topiramate 300 ; oxcarbamazepine 1500 ; valproate 600 ; and clobazam 10 .
presurgical evaluation , following the previously described la princesa hospital protocol ( pastor et al 2005 ; sola et al 2005 ) , included neurological and neuropsychological examinations , scalp eeg ( nihon kohden ) with 19 electrodes according the 1020 international system , 1.5 t magnetic resonance imaging ( mri ; general electric ) and interictal single photon emission computerized tomography ( spect , general electric ) with tc - d , l - hexamethylene - propyleneamine oxime ( tc - hmpao ) and video - electroencephalography ( v - eeg ; easy ii cadwell ) using 19 scalp electrodes and foramen ovale electrodes ( pastor et al 2006 ) removing aed from the second to day of recording .
this research was approved by the ethical committee of the hospital la princesa and informed consent was obtained from the parents because the patient was under 18 years .
spect imaging studies were performed using 740 mbq of tc - hmpao , with a low - energy high - resolution collimator , simple - head camera ( starcam 3200 , general electric ) and 96 projections of 22 s each using a 64  64 matrix .
slices were reconstructed by filtered back projection using a butterworth filter ( order 10 with a 0.6 cut - off ) .
v - eeg recording was performed with a bandwidth of 170 hz for scalp electrodes and 1100 hz for foe recording , with a sampling rate of 200 hz .
etomidate ( janssen - cilag ) was intravenously applied in the resting condition , with the patient resting in bed , face up , under continuous supervision of an expert anesthesiologist at a dose of 0.1 mg / kg .
electrocardiogram and capillary oxygen saturation ( pulsioximetry ) were continuously monitored throughout the process . immediately after the etomidate infusion ,
brain spect was acquired in the 30 min after the complete recovery of the patient . to analyze the theoretical kinetic behavior of tc - hmpao
, we used a numerical model including four compartments ( see figure 2b ) and four parameters ( andersen 1989 ) .
it is important to keep in mind that the kinetic parameters are taken from biological data , but not adjusted for our patient .
the basic assumption was that tc - hmpao behaves according to the microsphere model and exhibits high rate extraction ( 76% ) by the brain tissue during the first microcirculatory pass ( lassen et al 1988 ) .
numerical solutions of the model were obtained by developing a home - made program using the runge - kutta method for solving differential equations , implemented in matlab r2007a ( mathworks , natic , usa ) and running on a personal computer ( pentium iv , 1 gb ram ) .
a ) basal ( left ) and etomidate - activated ( right ) spect recordings .
the arrow shows the hyperperfusion on the right temporo - occipital area ( around fusiform and lingual gyri ) that corresponds to the most occipital fo electrodes .
b ) kinetic model for numerical solution of distribution for lipophilic and hydrophilic tc - hmpao in blood and brain , according to a four - compartment model .
the first - order rate constants are ( min ) k1 = 0.81 ; k2 = 0.35 ; k3 = 0.92 and k4 = 0.25 -andersen 1989 ; c ) kinetic evolution of the model during the first 3.5 min after tc - hmpao iv perfusion that shows the distribution in the different compartments ; the broken - blue line represents the evolution of intracellular hydrophilic radio - tracer .
the first arrow ( from left ) marks the start of seizure and the second one indicates the end .
to analyze the theoretical kinetic behavior of tc - hmpao , we used a numerical model including four compartments ( see figure 2b ) and four parameters ( andersen 1989 ) .
it is important to keep in mind that the kinetic parameters are taken from biological data , but not adjusted for our patient .
the basic assumption was that tc - hmpao behaves according to the microsphere model and exhibits high rate extraction ( 76% ) by the brain tissue during the first microcirculatory pass ( lassen et al 1988 ) .
numerical solutions of the model were obtained by developing a home - made program using the runge - kutta method for solving differential equations , implemented in matlab r2007a ( mathworks , natic , usa ) and running on a personal computer ( pentium iv , 1 gb ram ) .
spect results and mathematical model of blood - brain tc - hmpao distribution . a ) basal ( left ) and etomidate - activated ( right ) spect recordings .
the arrow shows the hyperperfusion on the right temporo - occipital area ( around fusiform and lingual gyri ) that corresponds to the most occipital fo electrodes .
b ) kinetic model for numerical solution of distribution for lipophilic and hydrophilic tc - hmpao in blood and brain , according to a four - compartment model .
the first - order rate constants are ( min ) k1 = 0.81 ; k2 = 0.35 ; k3 = 0.92 and k4 = 0.25 -andersen 1989 ; c ) kinetic evolution of the model during the first 3.5 min after tc - hmpao iv perfusion that shows the distribution in the different compartments ; the broken - blue line represents the evolution of intracellular hydrophilic radio - tracer .
the first arrow ( from left ) marks the start of seizure and the second one indicates the end .
the scalp eeg showed the presence of frequent right temporal sharp waves , usually grouped in patterns , intermingled with irregular slow waves .
mri was normal and interictal spect showed inconclusive results , with left temporal antero - mesial hypoperfusion doubtful .
etomidate was intravenously applied by an anesthesiologist ( mlm ) whereas the patient stayed in the v - eeg monitoring unit .
ten seconds later , tc - hmpao was iv perfused ( ld - g ) in order to obtain a pharmacologically activated spect .
fifty two seconds after tc - hmpao injection , a seizure begun with head version to left , followed by left arm hypertony , oral automatisms and mild disconnection .
fifty - two seconds thereafter , the seizure finished and the patient recovered consciousness . no stupor or paralysis was observed , but a mild disorientation and agitation persisted for 25 seconds .
v - eeg recording showed a beta / gamma low voltage pattern in the right posterior mesial area ( right fo electrodes # 1 to # 3 ) , as we can observe in figure 1 .
a focal desynchronization was observed in the right temporo - occipital area of the scalp .
injection of the radiotracer began immediately after etomidate and 52 sec . before a seizure started .
a localized region of intense hyperperfusion was observed only in the right posterior mesial temporal lobe ( figure 2a , arrow ) .
this region fits well with right foe 13 , which were involved in the origin of the seizure .
no changes were observed in other regions compared with interictal spect performed after a 24-h seizure - free period .
the numeric simulation of the model ( see figure 2c ) showed that , in theory , at least , the hydrophilic brain concentration at the beginning of the seizure was approximately 18.9% of the total radiotracer injected , with only 36.6% remaining lipophilic in the blood . at the conclusion of the seizure ,
the theoretical brain hydrophilic concentration was 42.3% and only 15.3% of the radio - tracer persisted in its lipophilic form in the blood .
this implies that practically all the available tc - hmpao had been extracted by the end of seizure .
of course , we are conscious that these results only show the compatibility between the theoretical model and the time course of events observed in our patient .
this paper is the first report of an instance where the authors have knowledge of a true - early ictal spect , with the radiotracer injection performed at an adequate instant , demonstrated by means of bioelectrical recording .
an intense increase in regional cerebral blood flow is one of the hallmarks of partial - onset seizures .
this is probably due to an increase in regional synaptic activity and changes in neurotransmission .
usually , the tc - hmpao infusion is performed briefly after the seizure starts and , moreover , a delay must be overcome before the radiotracer gets to the brain .
so , ictal spect , although it is the most sensitive and reliable neuroimaging procedure for delineating the epileptogenic area in patients with medically intractable epilepsy ( bernal and altman 2003 ) , probably shows an increase in regional cerebral perfusion that is surely related to the seizure ( van paesschen 2004 ) , but is almost certainly indicating propagation from the area of ictal onset
. what is more important , if the delay between seizure onset and injection is big enough , a false lateralization or localization on ictal spect due to the  postictal switch 
thus , the early injection of radiotracer has been considered the most important factor for seizure localization .
taking into account that a majority of the radiotracer will be taken up in the first pass and that it takes around 30 seconds for the tracer to reach the brain , we can reasonably assume that a small amount of the ligand ( < 19% ) probably would be absorbed previous to the seizure onset ( pre - ictal state ) .
however , as we can observe from figure 2c , the most important amount of radiotracer will be taken up by the brain during the seizure ( period between both arrows ) .
the safest and most reproducible way to control the moment of injection could be through the use of a pharmacological activation of the seizures .
however , this possibility is far from being ready to use ( diekman et al 1998 ; kirchberger et al 1998 ) . in the model that we are developing in order to overcome that problem ,
the infusion of etomidate induces important changes in the cerebral regional perfusion , but usually with no associated seizures ( domnguez - gadea et al 2007 ) .
indeed , this case was the only one presenting a crisis out of 46 patients . in summary , we are conscious that the case reported here was a lucky occurrence , in which the correct order of events allowed to us to demonstrate that an increase in regional cerebral perfusion would be produced in the cerebral area that started the seizure .
the systematic methodology in pharmacological activated spect with etomidate could produce reproducible and consistent results even without pharmacologically activated seizures .
 drug - resistant epilepsy can sometimes be treated by surgery . in these cases , an accurate identification of the epileptogenic area 
 must be addressed before resection . 
 ictal spect is one of the presurgical evaluations that can be performed , but usually , the increase in the regional cerebral perfusion observed is produced by diffusion of ictal activity . 
 here we describe a patient studied with v - eeg and foramen ovale electrodes that suffered a seizure after intravenous infusion of etomidate . 
 the sequence of etomidate administration , followed by radiotracer and seizure was good enough for us to suspect that a true initial ictal spect was observed . 
 we have implemented a kinetic model with four compartments , previously described ( andersen 1989 ) , in order to estimate the fraction of hydrophilic radiotracer in the brain during the pre - ictal and ictal periods . 
 this model has shown that the fraction of hydrophilic radiotracer during the seizure into the brain would be between 18.9% and 42.3% of total infused . 
 we show the first true initial ictal spect demonstrated by bioelectrical recordings of the brain activity , obtained by a correct succession of events and compatible with theoretical data obtained from the kinetic model . 
Introduction
Case report
Methods
Kinetic model
Results
Discussion