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Epilepsy & Behavior 15 (2009) 5055

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Epilepsy & Behavior


journal homepage: www.elsevier.com/locate/yebeh

Review

PET and SPECT in epilepsy: A critical review


C. la Fougre *, A. Rominger, S. Frster, J. Geisler, P. Bartenstein
Department of Nuclear Medicine, Ludwig Maximilian University of Munich, Marchioninistrasse 15, D-81377 Munich, Germany

a r t i c l e

i n f o

Article history:
Received 18 February 2009
Accepted 19 February 2009
Available online 21 February 2009
Keywords:
Epilepsy
SPECT
PET

a b s t r a c t
Molecular imaging with ictal and interictal single-photon emission computed tomography (SPECT) as
well as positron emission tomography (PET) rank among the established functional imaging tests for
the presurgical evaluation of epileptic onset zone in patients with intractable partial epilepsy. In temporal
lobe epilepsy the sensitivity of these methods was shown to be excellent, in particular if a multimodal
platform is used, which combines the functional imaging with the additional morphological information
of magnetic resonance imaging (MRI), but was lower in extra temporal lobe epilepsy. Functional imaging
with SPECT and PET reects seizure related changes of cerebral perfusion, glucose-metabolism and neuroreceptor status. In this review the usefulness of SPECT and PET imaging in clinical routine in epilepsy as
well as the role of different neuroreceptor PET-tracer, which were used in epilepsy are discussed. The use
of perfusion SPECT tracer allows the investigation of ictal activations, but the low temporal resolution of
ictal perfusion SPECT often results in the detection of both the ictal onset zone as well as the propagation
pathways, an area that has not always need to be resected in order to render a patient seizure free. The
additional use of interictal PET with uorine-18 uorodeoxyglucose which measures regional cerebral
metabolism or interictal perfusion SPECT enhance the informational value of ictal SPECT and were shown
to be important tools to better dene the ictal onset and surround inhibition zones. In recent years PET
imaging of different cerebral neuroreceptor-systems inter alia GABAA receptors, serotonin receptors
(5-HT1A), opioid receptors as well as dopamine receptors was used to investigate the neurochemical basis
of epilepsy, the role of these neurotransmitters for the epileptogenesis as well as the spread of epileptic
activity during seizures and partially entered in clinical routine. Currently some of these radioligands are
also used to investigate new treatment approaches.
2009 Elsevier Inc. All rights reserved.

1. Introduction
Epilepsy is a chronic disorder characterized by repeated seizures caused by the excessive electrical ring of a number of neurons. Antiepileptic drugs are useful in controlling the seizures, but
20 to 30% of patients with epilepsy continue to have seizures despite treatment [1]. Surgical intervention is an important option
and has become an accepted treatment method in properly selected patients with intractable focal epilepsy, but accurate resection of epileptogenic areas is imperative for successful seizure
control. For the selection of patients eligible for surgery, as well
as for best treatment response, precise localization of the epileptogenic region in the brain is necessary to identify the epileptogenic
area and minimize the side effects of the operation. This localization should be done ideally using several methods based on different pathophysiological principles. To plan the optimal surgical
approach for the achievement of complete seizure control, an addi-

* Corresponding author. Fax: +49 89 7095 7646.


E-mail address: christian.lafougere@med.uni-muenchen.de (C. la Fougre).
1525-5050/$ - see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2009.02.025

tional important objective of presurgical investigation is denition


of the boundaries of the epileptogenic region.
Although long-term intracranial EEG evaluation remains the
gold standard here, the invasiveness of this approach requires careful patient preselection. Structural imaging with magnetic resonance imaging (MRI) is necessary for presurgical investigation to
identify morphological abnormalities such as hippocampal sclerosis and malformations of cortical development. In addition, MRI
can provide anatomical information for functional imaging modalities like single-photon emission computed tomography (SPECT)
and positron emission tomography (PET).
Functional neuroimaging by PET and SPECT has a role in the
presurgical evaluation of epilepsies, as these methods are able to
detect epileptogenic foci in morphologically inconspicuous areas
and because they are, in contrast to EEG-based methods, not primarily dependent on the electrical activity of the brain. State-ofthe-art imaging with PET and SPECT should be an integral part of
a multimodality imaging platform and can, if properly used, substantially reduce the number of invasive EEG recordings. In addition, these are important research tools to gain a better
understanding of the neurobiology of epilepsy.

C. la Fougre et al. / Epilepsy & Behavior 15 (2009) 5055

2. SPECT
Although brain perfusion SPECT allows only quantitative estimations through tracer uptake ratios, it is widely used to measure
regional cerebral blood ow (rCBF) and is an accepted adjunctive
technique in the presurgical evaluation of patients with refractory
partial epilepsy [2]. In epilepsy, its application is based on the
assumption that the increased ictal neuronal activity occurring
during epileptic seizures is associated with increased metabolism
and regional cerebral blood ow. For brain perfusion SPECT
investigations, iodine-123- and technetium-99m-labeled radiopharmaceuticals are commercially available that differ in pharmacokinetic behavior and physical characteristics [3]. However, these
radiopharmaceuticals have in common the ability to cross the intact bloodbrain barrier rapidly, because of their small molecular
size and their lipophilicity, to be distributed proportionally to the
blood ow in the cerebral tissue and to be retained in the brain
for a sufcient time to permit image acquisition (>30 min) [4].
Initially 123I-labeled amines were used for this purpose, but
these tracers reach peak brain activity as late as 20 min after injection and, additionally, show redistribution over time, resulting in
reuptake into the cerebral cortex that is not proportional to rCBF
[5]. Because of this, 99mTc-hexamethylpropyleneamine-oxime
(99mTc-HMPAO) and 99mTc-ethyl cysteinate dimer (99mTc-ECD),
which have several advantages over 123I-labeled amines, are currently the most frequently used tracers for investigating rCBF.
These tracers have a quicker initial uptake in brain and reach the
peak within 2 min of injection, without redistribution. Thus, the
initial tracer uptake and distribution correspond to rCBF at the
time of injection and remain unchanged up to at least 2 h, independent of rCBF variations occurring after the xation time. Consequently, the radiotracer can be injected into the patient outside
the nuclear medicine facility, for example, during an epileptic seizure in the epilepsy ward; rCBF images reecting the distribution
at the moment of seizure can be acquired later with a SPECT camera after recovery from the seizure. The appropriate half-time (6 h)
of technetium, as well as the stability of the tracer (particularly
ECD), renders this technique useful and affordable for clinical
routine.
The superiority of ictal SPECT compared with interictal SPECT
for identication of the location or the lateralization of epileptic
seizures has been demonstrated by several studies of patients with
temporal lobe epilepsy (TLE), indicating sensitivities between 73
and 97% for ictal SPECT and only 50% for interictal SPECT [69].
Although there are fewer studies dealing with the role of SPECT
in extra-TLE, data suggest lower sensitivity (66%) for ictal SPECT
compared with the results found in TLE [8,10].

51

Cortical and subcortical rCBF changes during seizures may begin with hyperperfusion in the epileptic zone followed by rapid
extension to other regions through seizure spread and generalization. However, because of its low temporal resolution, ictal
SPECT hyperperfusion patterns often contain both the ictal onset
zone and the propagation pathways; however, the latter region
does not need to be resected to render a patient seizure free
[11].
Ictal SPECT has been shown to be more accurate for localization
of temporal lobe seizures when the radiotracer is injected immediately after the seizure [12], but usually, tracer injection is performed briey after the seizure starts, and moreover, a delay
must be overcome before the radiotracer gets to the brain. Therefore, ictal SPECT shows an increase in rCBF that is related to the seizure, but that also might indicate propagation from the area of ictal
onset. Moreover, the so-called postictal switch phenomenon,
which results in false localization or lateralization of the ictal seizure, can be observed when the delay between seizure onset and
tracer application is too long [13].
The marksmanship of SPECT has been shown to be improved by
digital analysis of ictal and interictal examinations, that is, by subtraction of ictal and interictal scans, as shown in Fig. 1, which
should preferentially be co-registered to MRI (SISCOM) [1419].
This multimodality imaging, which combines the structural and
functional imaging information, improves the ability to detect
and dene the extent of epileptogenic lesions and to regionalize
potentially epileptogenic regions in patients who have normal
MRI scans. In addition, the remarkable predictive value of SISCOM
with respect to surgical outcome has been described, and could be
of help in the decision making for epilepsy surgery: among patients
whose SISCOM ndings fell within the margins of the resected tissue or in the disconnected hemisphere, 75% were rendered seizure
free; among those whose SISCOM ndings fell outside the margins
of the surgery, 100% continued to have seizures [19].
3. Glucose metabolism with [18F]FDG
Positron emission tomography with uorine-18 uorodeoxyglucose ([18F]FDG), as well as other receptor ligands, is an important tool to dene the ictal onset zone and to better understand
the neurobiology and functional alterations induced by various
forms of epilepsy.
The glucose analog [18F]FDG is an indirect marker of neuronal
activity and allows absolute quantication of cerebral glucose
metabolism when additional arterial (ideally) or venous blood
samples are taken. Interictal [18F]FDG-PET has an established role
in the noninvasive localization of epileptogenic foci and also re-

Fig. 1. Patient with focal epilepsy in the left frontal lobe left. Ictal 99mTc-ECD SPECT scan (A) shows a discrete hyperperfusion in the left frontal lobe (red arrow), but the
interictal 99mTc-ECD SPECT scan (B) reveals no signicant asymmetry. The result of subtraction of the ictal and interictal scans (blue area), which is superimposed on the
interictal scan (B), delineates ictal activation. In the corresponding interictal [18F]FDG-PET investigation (C), a discrete hypometabolism was observed in this area (red arrow).

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C. la Fougre et al. / Epilepsy & Behavior 15 (2009) 5055

ects dynamic seizure-related changes in cerebral cellular


functions.
The epileptogenic focus in the interictal phase usually appears
as a hypometabolic area on [18F]FDG-PET. In TLE, comparison with
the contralateral side has been shown to be useful for localization
of the epileptic zone. However, [18F]FDG uptake frequently extends
beyond the seizure onset zone, which makes precise focus localization difcult. For example, many patients with TLE present with an
additional pronounced hypometabolism of the frontal lobe, which
may represent inhibitory phenomena induced by the epileptogenic
focus.
Numerous studies, some of which consisted of large numbers of
patients, have reported a sensitivity of 7085% for [18F]FDG-PET in
patients with TLE. In patients with extra-TLE, however, the populations investigated were smaller, and the values for diagnostic sensitivity and accuracy reported for interictal studies were
signicantly lower: 3060% depending on the localization of the
focus [2025]. The highest clinical benet of [18F]FDG-PET can be
achieved in patients with suspected TLE and normal MRI ndings.
In this situation, PET correctly lateralizes the lesion in 80% of the
cases [25].
Ictal [18F]FDG-PET cannot be routinely performed because of logistic difculties due mainly to the short half-life of the 18F label
(110 min). In addition, interpretation is difcult because of the prolonged cerebral [18F]FDG uptake, which may lead to contamination
of the signal by seizure propagation [26].
4. Neuroreceptor PET
Neurotransmitters are directly responsible for modulating synaptic activity and PET also allows quantication of specic ligand
receptor relationships that seem to be important for epileptogenesis and spread of epileptic activity. Several PET receptor ligands

have been used to investigate the neurochemical basis of the epilepsies and have partially entered clinical routine.
4.1. GABAA receptors: [11C]Flumazenil
[11C]Flumazenil binds to the central benzodiazepine receptor
(cBZR)-c-aminobutyric acid (GABAA) receptor complex. Measurements of GABAA receptor density with PET and [11C]umazenil
have been demonstrated to be promising methods of identifying
and localizing epileptogenic regions. In this context, GABA receptor
binding was signicantly lower in the epileptic focus than in the
contralateral homotopic reference region and the remaining neocortex [27]. Reduced binding can be seen at the epileptogenic focus
and the seizure onset region, however, in a more restricted distribution than the corresponding area of [18F]FDG hypometabolism,
and sometimes also in projection areas [28]. In addition, the degree
of GABA receptor reduction showed a positive correlation with seizure frequency.
Furthermore, [11C]umazenil PET has been shown to distinguish patients with frequent seizures. Therefore, the method may
not only be suitable for noninvasive localization of the seizure focus, but may also provide a biochemical marker of epileptogenicity,
strengthening the hypothesis that inhibitory mechanisms are disturbed in the epileptic focus [29]. Moreover, [11C]umazenil PET
was shown to be more accurate than [18F]FDG-PET for the detection of cortical regions of seizure onset and frequent spiking in patients with extra-TLE, whereas both [18F]FDG and [11C]umazenil
PET showed low sensitivity in the detection of cortical areas of rapid seizure spread [30]. Even if [11C]umazenil PET did not prove
superior to [18F]FDG-PET in assessing the extent of the ictal onset
zone, as dened by intracranial EEG recordings, some authors stated that it may provide useful data complementary to those of MRI
and [18F]FDG PET [24], as shown in Fig. 2. However, the use of

Fig. 2. [18F]FDG (A: coronal, B: transversal) and [18F]ethylumazenil (C: coronal, D: transversal) PET scans of a patient with right TLE showing relatively decreased glucose
metabolism and reduced binding to the cBZR-GABAA receptor complex in the mesial temporal lobe (red arrows).

C. la Fougre et al. / Epilepsy & Behavior 15 (2009) 5055

interictal [11C]umazenil PET in patients with idiopathic generalized epilepsy has yielded nonuniform results: thus, a slight reduction in the neocortex of patients with idiopathic generalized
epilepsy has been reported in comparison with patients with partial seizures [31]; in another study, the authors reported a widespread increase in benzodiazepine receptors in cerebral
neocortex, thalamus, and cerebellar cortex [32]. Also observed
was increased benzodiazepine receptor density in the cerebellar
nuclei and decreased density in the thalamus [33].
In unilateral hippocampal sclerosis, reduction of binding of
[11C]umazenil has been shown to be conned to the hippocampus
and to be over and above that caused by neuron loss and hippocampal atrophy [34]. In malformations of cortical development,
abnormalities of benzodiazepine receptors, as demonstrated with
[11C]umazenil PET, were more extensive than the structural
abnormality revealed with MRI [35]. There often were areas of increased benzodiazepine receptors, a pattern that may reect both
functional and structural anomalies [36].
Currently, the clinical role of [11C]umazenil and its SPECT
derivative [123I]iomazenil for the detection of temporal and extratemporal foci is viewed controversially in the literature [37,38].
Even though [11C]umazenil binding has revealed focal abnormalities in 80% of patients with refractory TLE and normal high-quality
MRI [38], this method has not been considered consistently helpful
in localizing epileptic foci. In addition, the short half-time of 11C
(20 min) hampers the wide use of [11C]umazenil for clinical routine. The possible implementation of [18F]umazenil in clinical
routine will most probably provide a more denite answer about
the clinical benet of benzodiazepine receptor imaging [39]. This
radiopharmaceutical has ideal properties for PET imaging and will
allow with state-of-the-art equipment to image benzodiazepine
GABAA receptor binding with a spatial resolution of approximately
3 mm [40].
4.2. Serotonin receptors (5-HT1A): [18F]MPPF
Experimental data in animals indicate that 5-HT1A receptors are
located predominantly in limbic areas and that serotonin, via these
receptors, mediates an antiepileptic and anticonvulsant effect.
(20 -methoxyphenyl-(N-20 -pyridinyl)-p-[18F]uoro[18F]MPPF
benzamidoethylpiperazine), an antagonist of the 5-HT1A receptors,
was used to assess the extent of 5-HT1A receptor binding changes
in patients with TLE and hippocampal ictal onset. A signicantly
decreased binding potential (BPND) was detected ipsilateral to the
epileptogenic zone in the hippocampus, temporal pole, insula,
and temporal neocortex. In patients with normal hippocampus volume, the BP decrease was restricted to the temporal pole [41]. The
decrease was more pronounced in the seizure onset zone and in regions where the discharge propagated than in regions where only
interictal paroxysms or no epileptic activity was recorded [42].
Therefore, these results indicate that [18F]MPPF binding not only
reects structural changes or neuronal loss, but can also be considered a marker of the epileptogenic zone.
The reduction in 5-HT1a BPND in patients with mesial TLE may
be explained, on the one hand, by a decrease in receptor density
due to depletion of serotonin, which leads to downregulation
and hyperexcitability, or, on the other hand, by an increase in
endogenous serotonin as a reactional process to modulate
hyperexcitability.
A recent study showed that, in individual patients with TLE, visual analysis of [18F]MPPF PET data, blinded to clinical information
and data from other presurgical investigations, permits identication of the epileptogenic lobe with a sensitivity of 90% (38 of 42 patients), even in those without hippocampal sclerosis, and proved
usable in clinical practice for preoperative evaluation of patients
with TLE [43]. Comparison between [18F]FDG and [18F]MPPF PET

53

data showed the clear-cut superiority of the latter for localizing


visually the epileptogenic area in patients with mesial TLE. The
specicity of [18F]FDG PET was lower than that of [18F]MPPF PET,
with only 23% of patients showing hypometabolism restricted to
hippocampus, amygdala, and temporal pole, versus 38% demonstrating such abnormalities with [18F]MPPF PET [43].
4.3. Opioid receptors
PET studies using opioid receptor ligands with different selectivity support ndings from animal experiments suggesting a predominantly anticonvulsant effect of opioid peptides (for review see
Henriksen et al. [44]). The earliest human PET study indicating
selective modulation of the opiate system in partial epilepsy was
that of Frost et al. [45], who demonstrated, with the l-selective ligand [11C]carfentanyl, increased l-opioid receptor availability in
the areas of the epileptogenic temporal lobe exhibiting interictal
hypometabolism. In contrast to this nding no comparable asymmetry was detectable with the nonspecic opioid receptor ligand
[11C]diprenorphine and the l- and j-selective ligand [18F]cyclofoxy [4648]. A study with the d-selective opioid receptor ligand
[11C]methylnaltrindole also showed increased receptor availability
in the epileptogenic temporal lobe, but with a different regional
pattern [49]. The in vivo demonstration in humans of selective regional alterations of l- and j-receptor binding in TLE supports the
hypothesis derived from animal studies that endogenous ligand
binding to these receptor subtypes plays a role in the tonic anticonvulsive mechanism that limits the spread of seizure activity
from the epileptogenic focus [44].
The in vivo demonstration of a generalized displacement of opioid receptor ligands during absence seizures [50] and a focal displacement during seizures of reading epilepsy [51] provides
strong support for the prevailing opinion that endogenous opioids
are released following generalized and partial seizures [52]. Results
of a study with [11C]diprenorphine by Hammers et al. [53] suggest
a role for the opioid system in the postictal rise in seizure threshold. This study demonstrated a postictal increase in [11C]diprenorphine binding. The authors of the study suggested that synaptic
opioid levels increase at the time of seizures, leading to a reduction
in [11C]diprenorphine binding, and that this is followed by a gradual recovery of available surface receptors with an overshoot over
basal levels, which is detected by PET about 8 h after seizures, and
a gradual return to normal or low-normal levels during the interictal phase.
4.4. Dopamine receptors: [18F]Fallypride
The role of dopamine in the pathophysiology of focal epilepsy is
a matter of controversy. The dopaminergic inuence on epileptic
seizures arising from mesial temporal structures [54] might be
inhibitory (i.e., via dopaminergic hippocampal projections enhancing Ca2+-dependent K+ conductance) [55]. Data obtained in animals
suggest that activation of the dopaminergic D1- and D2-receptors
has diverging effects on the regulation of seizure threshold, D2
being anticonvulsant and D1 activation more proconvulsant
[54,56]. Further studies in animals suggest a neuroprotective role
of dopamine through the inhibitory control of glutamate neurotransmission and excitotoxicity in epilepsy [57].
The high-afnity dopamine D2/D3-receptor antagonist [18F]fallypride can be used to characterize striatal as well as extrastriatal D2/
D3-receptor binding. In patients with mesial TLE and hippocampal
sclerosis, D2/D3-receptor binding was reduced at the pole and the
lateral aspects of the epileptogenic temporal lobe, but there was
no change in hippocampal binding although all patients had hippocampal atrophy. This selective decrease in D2/D3-receptor binding in
the pole and lateral temporal lobe, which show hypometabolism on

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C. la Fougre et al. / Epilepsy & Behavior 15 (2009) 5055

[18F]FDG-PET, is an indication of a modulation of the dopaminergic


system in the irritative zone, indicating that the dopaminergic
system might also be part of the endogenous anticonvulsant mechanism that prevents seizure generalization [58].
In conclusion, SPECT and PET are useful and reliable tools for
imaging epilepsies in clinical routine as well as for research purposes. Their unique ability to image in vivo changes in brain biochemistry has provided valuable insights into the mechanisms of
epileptogenesis, seizure propagation, and termination. Progress in
the sensitivity and spatial resolution achieved by modern instrumentation will probably further increase the clinical role of functional imaging in the preoperative assessment of patients with
epilepsy.
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