Presurgical Focus Localization in Epilepsy: PET and SPECT

Presurgical Focus Localization in Epilepsy: PET and SPECT William H. Theodore, MD Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be used to assist localization of seizure foci in patients with drug-resistant epilepsy. Both should be interpreted in the context of clinical, electrographic, and magnetic resonance imaging data. PET has wider research applications, particularity when used with ligands for neurotransmitter receptors or inflammatory processes. Semin Nucl Med ]:]]]-]]] C 2016 Published by Elsevier Inc.

Drug-resistant epilepsy is a serious medical problem, associated with neuropsychiatric and neuropsychological comorbidities, social and economic disability, diminished quality of life, and increased mortality compared to the general population. Surgery may be beneficial in carefully selected patients. Postoperative seizure control depends on accurate localization of epileptogenic zones. Comprehensive neuropsychological evaluation and appropriate imaging studies must be performed as well to assess the risks of resection. Positron emission tomography (PET) using [18F]-fluorodeoxyglucose (FDG) and single-photon emission computed tomography (SPECT) using either 99mTc-ethyl cysteinate dimer (ECD) or 99mTc-hexamethyl propylene amine oxime (HMPAO) are now standard procedures for preoperative evaluation of patients with epilepsy. PET cameras generally have somewhat better resolution than SPECT, although recent advances have reduced the difference.1 Both modalities suffer from the risk of “partial volume effects” due to which the camera may not be able to resolve small lesions, or be affected by the volume loss that can occur in lesions such as mesial temporal sclerosis (MTS). Magnetic resonance imaging (MRI)–based partial volume correction routines can obviate much of this problem, and the advent of combined scanners, for example PET/MR, should improve coregistration of structural and functional images.2 Advances in MRI, may reduce the importance of PET and SPECT for preoperative evaluation. Functional MRI, for example, has ended the temporary use of [15O]H2O PET for presurgical functional mapping. However, PET and SPECT National Institute of Neurological Disorders and Stroke, Bethesda, MD. Address reprint requests to William H. Theodore, MD, National Institute of Neurological Disorders and Stroke, NIH Building 10, Room 7D-43, Bethesda, MD 20892. E-mail: [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2016.09.008 0001-2998/& 2016 Published by Elsevier Inc.

have been used to investigate epilepsy comorbidities, particularly psychiatric disorders, and pathophysiology, through neurotransmitter receptor binding (the latter approach has been used (less frequently) to support focus localization as well). These applications should become increasingly valuable with the development of new ligands than can image important systems such as excitatory amino acids and immunomodulation. PET’s role in particular in helping to elucidate the pathophysiology of epilepsy may become more important than its clinical value for seizure focus localization.

FDG-PET Seizure Focus Localization About 80% of patients with temporal lobe epileptic foci have hypometabolism on [18F]FDG-PET scans.3-6 Some more recent studies have found that up to 100% of patients have hypometabolism.7 Others found only 60%-70% positive PET scans.8 The difference depends in part on analytic technique, but the proportion of patients with abnormal MRI probably is more important. In a meta-analysis of 46 studies from 1992-2006, study design heterogeneity made overall assessment difficult.9 PET hypometabolism alone was thought to have a predictive value of 80% for “good” outcome (not always equivalent to being seizure-free) in patients with normal MRI, and 72% in patients with nonlocalized ictal scalp electroencephalographic (EEG) discharges, but not to improve accuracy for seizure focus localization or surgery outcome in patients with congruent ictal scalp EEG and MRI localization. In a study of [18F]FDG-PET in 194 adults including 64 with temporal lobe epilepsy (TLE), 66 with frontal lobe epilepsy (FLE), 38 with seizure foci in other extratemporal regions, and 1

W.H. Theodore

2

Figure 1 Left temporal focal hypometabolism in a patient with Normal MRI scan and left temporal seizure onset on ictal video-EEG monitoring. Focal cortical dysplasia was found at surgery.

26 with a focus including temporal lobe and additional regions, 158 had normal MRI.8 PET scans were normal in 37%, showed unifocal hypometabolism in 50.5% (67% in TLE vs 52% in FLE) and bilateral hypometabolism in 12% of patients. PET was thought to provide useful information in 53%, leading directly to surgery in only 6%, but helping in planning intracranial EEG 35%. Patients with focal hypometabolism were five times more likely to be selected for surgery than those without hypometabolism.8 Several studies have shown that patients with normal MRI but anterior temporal hypometabolism are good surgical candidates (Fig. 1).10-12 Two large series showed similar results. Of 193 patients, 46 had negative MRI but positive PET; there was no difference in surgical outcome.13 Overall, 79% of MRI-negative PET-positive TLE patients were seizurefree 2 years after surgery, compared to 82% of with MTS on MRI as well as hypometabolism.14 In a recent study, FDG-PET performed better than either MRI diffusion tensor imaging or cortical thickness measurement for identifying temporal lobe foci.15 The authors used a stepwise logistic regression model that showed the two MRI modalities combined did not add localizing value to [18F]FDG-PET alone. Bitemporal hypometabolism is associated with less-well localized ictal epileptiform onsets and may be a negative surgical prognostic indicator.16-18 For FLE patients who showed good outcome after surgical resection, 73% of patients with, and 36% without MRI structural lesions had focal hypometabolism.19 Patients with extratemporal seizure foci were more likely to be seizure-free if there was no hypometabolism either contralateral to the lesion, or if ipsilateral, in a different lobe.20 Hypometabolism that is not contiguous with, or distant from the seizure focus, as opposed to perifocal hypometabolism, may be a negative prognostic factor in patients with both mesial temporal and neocortical electrographic seizure onsets.20,21

At present there is little evidence to suggest that quantitative approaches such as statistical parametric mapping are more accurate for localization of seizure foci than “expert” visual analysis.22-24 However, it is important for neurologists treating patients with epilepsy to review [18F]FDG-PET (as well as MRI) images themselves, as they are able to make important clinical and electrographic correlations with the imaging data. For example, re-examination of MRI images in patients with hypometabolism and “normal” MRI, particularly with neocortical or extratemporal or foci, may show initially undetected subtle lesions such as focal cortical dysplasia (FCD). Some investigators suggest that when temporal hypometabolism extends beyond the limits of an MRI lesion such as MTS, wider resection may improve outcome.25 However, in another study, the volume of [18F]FDG- as well as [11]C-FMZ PET abnormality resected were not significantly related to outcome.26 The correlation between the degree of mesial temporal neuronal loss and hypometabolism is inexact, and hypometabolism extends beyond the epileptogenic zone defined by pathology and electrophysiology to include, in mesial TLE, ipsilateral frontal cortex, thalamus, and insula.27-29 The physiologic basis for hypometabolism in the absence of MRI lesions is uncertain, but may be related to decreased synaptic activity, impaired maintenance of membrane potentials, differences in hippocampal surface anatomy, or alterations in adjacent white matter tracts on diffusion tensor imaging.30-33 The extent of epileptic networks determined by seizure spread on ictal EEG recordings correlated strongly with patterns of hypometabolism in 114 patients with mesial TLE.29 Data from studies of FCD suggest that hypometabolism is associated with reduced mitochondrial complex IV function, but not the extent of the structural abnormality.34 However, there was no difference in mean hippocampal hilar neuron and dentate

Presurgical focus localization in epilepsy gyrus granule cell densities between patients who all had focal hypometablism, but with and without observable MRI evidence of MTS.13 The clinical role of FDG-PET in nonfocal epilepsy syndromes is less certain. Children with infantile spasms and normal structural MRI have hypometabolism in parieto-temporo-occipital cortex, associated with “occult” malformations of cortical development; FDG-PET imaging may help guide resection strategy.35

Clinical Applications of Other PET Ligands Several other PET ligands, particularly [11C]flumazenil (FMZ) may have localizing potential for patients with focal epilepsy syndromes. Reduced benzodiazepine receptor binding on [11C]FMZ PET ipsilateral to temporal lobe foci occasionally may detect abnormal regions not seen on [18F]FDG-PET.36-39 In a study of 100 patients, about 98% had focal reduced GABA-benzodiazepine receptor binding, compared to about 90% with regional hypometabolism and 85% with abnormal MRI,38 suggesting that [11C]FMZ PET could detect focal abnormalities in a very high proportion of MRI-negative focal epilepsy patients. In another study only about 40% of patients with normal MRI had reduced [11C]FMZ binding, a proportion similar to [18F]FDG-PET.40 [11C]FMZ PET at least partially detected seizure onset zones in 10 children with neocortical epilepsy, while [18F]FDG-PET showed congruent hypometabolism in only eight.41 Neither PET study was able to delineate regions of rapid seizure spread. FMZ PET was more sensitive than FDG-PET for detection of neocortical seizure onset in children with extraTLE.41 [18F]Flumazenil has been suggested as an alternative, and more practical ligand to [11C]FMZ due to its longer ligand half-life.42 Some [11C]FMZ PET studies found binding increases and decreases in periventricular white matter in patients with both temporal and extratemporal foci and normal MRI that were presumed to identify periventricular nodular heterotopiae.43,44 Detection of these regions of increased periventricular [11C] FMZ binding was associated with poor outcome after temporal lobectomy. In a subsequent study, 16 patients with MTS had [18F]FDG and [11C]FMZ PET. On a group level, non–seizure free vs SF patients had greater periventricular increases with both tracers, but individually FMZ-PET was more sensitive. Against controls, non–seizure free patients showed more prominent periventricular [11C]FMZ and [18F]FDG signal increases than SF patients. However FMZ had greater sensitivity for FDG and correlation with outcome.45 [11C] α-methyl-l-tryptophan (AMT) may be able to differentiate epileptogenic from “silent” tubers in children with tuberous Sclerosis.46 Overall, 58% of patients with nonlocalized EEG had localized AMT-PET. In another study, only 2 of 12 patients showed clearly increased uptake; although sensitivity was low, specificity was 100%.47 Increased binding has been reported in patients with FCD, particularly type IIB, may have increased [11]C-AMT binding.48

3

Clinical Applications of SPECT Imaging Subtraction of interictal from ictal SPECT images, with coregistration to MRI, has been reported to predict outcome after both temporal and extratemporal epilepsy surgery49,50 (Fig. 2). Injection as soon as possible (preferably within 15 seconds) after seizure onset is crucial for accurate localization. Combining “hyperperfusion” with “hypoperfusion” images may increase seizure focus detection. Overall, 63% of patients with TLE, and 58% with extratemporal lobe epilepsy (ETLE), have seizure-free surgical outcome if ictal SPECT cerebral blood flow (CBF) abnormalities are concordant with the resected region, but only 20% when concordance is absent.51 In a study comparing ictal and interictal SPECT with EEG-fMRI, there were significant positive correlations between ictal hemodynamic changes and spikes in 96% of patients.52 Hyperperfusion was generally associated with ictal activity and hypoperfusion with interictal deactivation. SPECT CBF changes congruent with EEG discharges occurred in regions distant from presumed foci, such as cerebellum and basal ganglia. Not all studies suggest ictal SPECT adds to preoperative evaluation; it has the added disadvantage of being an inpatient procedure. A comparison of 124 patients who had SPECT as part of their evaluation with 116 who did not showed no difference in the proportion offered surgery or invasive monitoring.53 Mean duration of hospital stay was longer, secondary generalized tonic-clonic seizure more frequent, and the cost of evaluation 35% higher for the SPECT group. No difference in surgical outcome was found. In children being evaluated for epilepsy surgery, mean length of hospital stay was 5.1 days when SPECT was performed, compared with 3.5 days when it was not.54 Although 68% of patients with extratemporal epilepsy had localization on subtraction ictal SPECT coregistered to MRI (SISCOM), interictal and ictal EEG but not SPECT results were significant predictors of surgery outcome even when MRI was normal.55 A total of 58 patients, including both TLE and ETLE had structural magnetic resonance imaging (MRI), highdensity electric source imaging (HD-ESI), and metabolic imaging (positron emission tomography [PET]; singlephoton emission computed tomography [SPECT]); only MRI and HD-ESI significantly predicted seizure-free outcome after surgery.56 Just as for [18F]FDG-PET, most studies suggest that the role of ictal SPECT when MRI shows hippocampal sclerosis is uncertain.51 One study found SPECT most valuable in confirming focus localization and helping to avoid invasive studies in patients with lesional mesial TLE but nonlocalizing ictal EEG or dual pathology but SPECT not in patients having either TLE or ETLE with normal MRI, since those patients needed depth or subdural investigation.57 statistical parametric mapping–based analytic approaches increased the sensitivity of ictal-interictal SPECT from about 40%-70% for TLE, and 35%-55% for ETLE in patients with normal MRI.58

W.H. Theodore

4

Figure 2 Left: Interictal SPECT showing possible right posterior quadrant hypoperfusion. Center: Ictal injection showing relative right hyperperfusion. Right: ictal-interictal subtraction coregistered to MRI. Ictal scalp EEG showed seizure onset in the right parieto-occipital junction region. (Courtesy: Dr Kirk Frey.) (Color version of figure is available online.)

There have been a series of comparisons between [18F]FDGPET and ictal-interictal SPECT, usually showing comparable results for seizure focus localization and surgical outcome prediction.56,59-65 Combining modalities may improve results. A coregistration study found that combined PET, MRI, and SISCOM helped detect epileptogenic zones in 35 patients, particularly with normal MRI; SISCOM showed ictal hyperperfusion less frequently than PET hypometabolism.66 A total of 58 patients, including both TLE and ETLE had structural MRI, HD-ESI, and FDG-PET; single-photon emission computed tomography (SPECT); only MRI and HD-ESI significantly predicted seizure-free outcome after surgery.56 When both FDG-PET and ictal SPECT were concordant with each other and with MRI and vEEG defined focus in a study of 123 patients, 62% were seizure-fee at 5 years for extratemporal epilepsies, significantly more than if the studies were not concordant.65 However, for TLE, SPECT-PET concordance did not improve outcome. Several studies suggest that [18F]FDG-PET may be more sensitive for TLE, and SPECT for ETLE.7,51,63 Fewer SPECT studies have been performed in patients with presumed nonfocal epilepsy syndromes than in patients being considered for surgery for focal epilepsy. In 10 patients with Lennox-Gastaut syndrome, isotope injections during tonic seizures and within 10 seconds of onset, found hyperperfusion in pons and cerebellar hemispheres and bilateral pericentral hypoperfusion.67 Later injection led to midline and lateral cerebellar hyperperfusion, and widespread bilateral frontal hypoperfusion. The findings suggested involvement of frontal attentional regions with pontine reticular formation.

Research Applications of PET Neurotransmitter Receptor Imaging The serotonin (5HT)-1A receptor has been implicated in the pathophysiology of epilepsy as well as depression. 5HT1A

receptor postsynaptic terminals are abundant in limbic regions, and their activation reduces glutamate release and hyperpolarizes hippocampal membranes. Several investigators found reduced binding in mesial temporal foci (Fig. 3).68-71 The reduction was present even after partial volume correction to account for volume loss in limbic structures such as hippocampus and amygdala. In combination with FDG-PET, 5HT1A receptor imaging may help predict outcome after temporal lobectomy.72 In patients with depression, one of the most common epilepsy comorbidities, there was a significant relation between increasing scores on the Beck Depression inventory and the Montgomery-Asberg inventory and reduced 5HT1A receptor binding.70,73 Compared with healthy controls and patients who did not have a diagnosis of major depressive disorder on the structured clinical interview for DSM IV, depressed patients had lower 5HT1A binding.74 Since the structured clinical interview for DSM IV is designed to diagnose major depressive disorder even when overt symptoms, or an acute episode, are not present, the results suggest that patients with depression as

Figure 3 [18F]-FCWAY PET scan showing reduced left temporal 5HT1A receptor binding in a patient with a left temporal focus on ictal video-EEG monitoring. (Color version of figure is available online.)

Presurgical focus localization in epilepsy well as epilepsy, have additive reductions of 5HT1A receptor binding as a trait-related phenomenon, persisting even when symptoms are not clinically evident. These results extend previous FDG-PET studies that showed ipsilateral or bifrontal hypometabolism in patients with both depression and epilepsy.75-77 Altered serotonergic neurotransmission forms a particularly strong link between epilepsy and depression. Reduced 5HT1A receptor binding had an effect on verbal memory scores (after correction for partial volume effects) that was additive to the influence of hippocampal atrophy, and independent of depression scales.78 PET studies using a ligand for the serotonin transporter activity was reduced in patients with both TLE and depression, as compared to subjects with TLE alone; both groups had reduced 5HT1A receptor binding.79 The transporter facilitates reuptake of serotonin into the presynaptic axon terminals after its release and interaction with postsynaptic receptors. It is possible that reduced transport, leading to reduced reuptake and thus increased synaptic 5HT availability, might represent a compensatory mechanism for 5HT1A receptor loss a clinical implication of the PET data is that selective serotonin reuptake blockers should be used in patients with epilepsy and comorbid depression. Mu opiate-receptors were increased ipsilateral to epileptic foci in lateral, but not mesial, temporal structures; kappa receptors may be reduced.80-82 Increased H1 histamine and MAO-B binding potential, and decreased regional binding of [76Br]4-bromodexetimide, a muscarinic acetylcholine receptor antagonist, in the anterior hippocampus ipsilateral to epileptic foci could be explained by focal gliosis and neuronal loss.83-85 In patients with autosomal dominant nocturnal FLE, who have mutations in the nAChR alpha4 or beta2 subunit, PET using [18F]-F-A-85380, a high-affinity agonist at the alpha4beta2 nAChRs, showed increased binding in mesencephalon, pons, and cerebellum, and decreases in the dorsolateral prefrontal region when compared to control subjects.86 Several studies have shown alterations of dopamine receptor binding, with decreases in ipislateral temporal lobe in TLE.87 Results varied depending on the ligand and analysis technique.88 Patients with MTS had reduced [18F]fallypride dopamine D2/D3 receptor binding potential significantly reduced in temporal lobe ipsilateral to seizure foci and bilateral putamen. There was a positive correlation between age at onset of epilepsy and [18F]FP BPnd In the ipsilateral temporal lobe and a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole, suggesting progressive receptor loss with increasing length of seizure history.89 The N-methyl-Daspartate (NMDA) receptor ligand [11C]-(S)-[N-methyl]ketamine, showed reduction of tracer radioactivity in epileptogenic temporal lobes, also possibly due to focal atrophy).90 A recent study showed increased availability of the neurokinin-1 receptor in TLE, mirroring studies in experimental models that have suggest a role for substance P in epileptogeneiss.91 Several variables, in addition to structural atrophy, might affect PET neuroreceptor imaging in epilepsy. The length of the seizure-free interval correlated with [11C]FMZ hippocampal binding; the shorter the interval, the lower Bmax.92 In several cases, scans performed at different intervals after seizures

5 show contradictory focus localization. Antiepileptic drugs (AEDs) or other agents affecting brain blood flow or metabolism, or receptor binding itself, might be important. Using [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, eight patients not taking antidepressants had globally increased binding compared to controls, while three taking antidepressant drugs had decreased binding.93 No focal abnormalities clearly associated with MRI or EEG discharges were seen. These studies show the importance of controlled clinical conditions for interpretation of neurotransmitter receptor PET in epilepsy. Several genetic epilepsy syndromes have been investigated using PET neuroreceptor imaging. Patients with ring chromosome 20 epilepsy have was decreased bilateral [18F]fluoro-lDOPA uptake in putamen and caudate nucleus.94 Impaired dopamine uptake was reported in the midbrain of patients with juvenile myoclonic epilepsy.95 In patients with succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of GABA metabolism associated with cognitive impairment, ataxia, and seizures, PET using [11C]flumazenil detected reduced postsynaptic benzodiazepine receptor binding, probably due to down-regulation related to increased synaptic GABA levels.96

Research in PET Imaging of Inflammation in Epilepsy Inflammation has been shown to play a role in a wide range of neuropsychiatric disorders, including epilepsy.97 [18F]FDG-PET may show focal increased metabolism in patients with anti-NMDA receptor encephalitis.98,99 Several PET ligands can be used to image the translocator protein 18 kDa (also known as the “peripheral benzodiazepine receptor”), a marker of activated microglia and reactive astrocytes. Studies using [11C]-PK-11195 had shown increased binding in a patient with Rasmussen’s encephalitis.100 Several case reports have suggested potential value in localizing seizure foci. A 5-year old with intractable epilepsy and normal [18F]FDG-PET had an area of increased [11C]-PK-11195 binding co-localized with epileptiform discharges on EEG; resection led to seizure control and microglial activation was found on pathological examination.101 A patient with FCD had increased binding co-localized with EEG, MR, and [18F]FDG-PET seizure focus localization.102 Patients with TLE did not show increased binding in studies using [11C]PK-11195. However, with two newer ligands, [11C]PBR28 and l11C]DPA 714, increased brain uptake was present in a bilateral distribution compared with healthy volunteers, but significantly higher ipsilateral to the seizure focus in hippocampus, amygdala, and temporal neocortex in patients both with and without MTS, although the asymmetry was more pronounced in patients with hippocampal sclerosis than in those without (Fig. 4).103,104 Patients with FCD also had increased binding using these 2 new ligands. The results parallel studies in experimental epilepsy models including the kainic acid rat model.105 Using PK-11195, rats with spontaneous seizure after electrically kindled status epilepticus who

W.H. Theodore

6

Figure 4 [11C]-PBR PET scan in a patient with mesial temporal sclerosis and a right temporal seizure focus. The scan showed greater hippocampal binding of the ligand for the TSPO receptor complex in the right than the left hippocampus. (Reproduced with permission from Gershen et al.104) (Color version of figure is available online.)

were responsive to phenobarbital, did not show greater binding than sham-control animals, while drug-resistant animals did.106 a possible link between inflammation and drug resistance is provided by P-glycoprotein (P-gP) transporters, which are upregulated in some patients with epilepsy. In a comparison of 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls, pharmacoresistant patients had higher P-glycoprotein activity than seizure-free patients in several temporal regions both ipsilateral and contralateral to seizure foci.107 Higher P-gp activity was associated with higher seizure frequency. Seven patients with drug-resistant TLE (R)-[11C]verapamil (VPM) PET before and after temporal lobectomy.108 Patients who became seizure-free off AEDs after surgery had higher preoperative ligand binding, and temporal lobe P-gP function before surgery, and reduced global P-gP function postoperatively, than those who did not become seizure-free off AEDs.

SPECT Neuroreceptor Imaging SPECT has been used for neuroreceptor mapping studies much less frequently than PET, due to disadvantages in resolution and quantitation. The benzodiazepine receptor ligand [123I]-iomazenil was superior to interictal SPECT CBF studies for localizing seizure foci in TLE patients.109 In four patients with tuberous sclerosis complex, reduced [123I]iomazenil binding was found in all tubers seen on MRI, but epileptogenic lesions were not distinguished.110 Seizure frequency was positively correlated with postsynaptic putamen and caudate D2 density measured with [123I]IBZM in ring chromosome 20 epilepsy patients; presynaptic transporter activity measured with [123I]ioflupane showed negative correlation with seizure activity.111 A SPECT ligand for translocator protein has not been used in epilepsy.

PET and SPECT in Epilepsy Evaluation: Problems and Pitfalls Unfortunately the number of patients in most epilepsy nuclear imaging studies has been too small for definitive results.

Prospective multicenter studies would have a much better chance of determining their optimal use, and preventing not only waste of resources but also unneeded radioactivity exposure. Clear guidelines have been developed that allow imaging studies to provide reasonably reliable evidence.112 These include clearly defining study populations and controls, prospective data collection, applying tests to all patients uniformly, data analysis blinded to patient identity and clinical characteristics, discussion of limitations and study power, and if surgical outcome is a study end point, objective assessment of postoperative seizure control. FDG-PET is a more forgiving technique than ictal-interictal SPECT. However, interpretation may be made more difficult by seizures occurring during, or even immediately before tracer administration and the 30-40 minute uptake period. Unrecognized seizures may lead to false lateralization as hypermetabolism ipsilateral to the true seizure focus may make the contralateral cortex appear relatively hypometabolic. Recent seizure activity may produce altered patterns of metabolism on FDG-PET persisting for several days.113,114 Prior depth electrode implantation may cause hypometabolism.115 Large cortical malformations may have increased metabolism.116 Bilateral temporal hypometabolism may be more common on scans performed within 2 days of a seizure.117 If EEG monitoring cannot be performed, patients should be attended by an observer able to recognize seizure activity. Ictal SPECT requires constant video-EEG monitoring, as well as the ability to inject the tracer within 15-30 seconds after seizure onset. It is likely that neither technique adds much to concurrent MRI and EEG seizure focus localization. The main pitfall in interpreting ictal-interictal SPECT studies is the effect of interval between seizure onset and injection. Longer intervals, depending on seizure type and duration, may lead to apparent ipsilateral hypometabolism, as well as more extensive CBF alterations associated with seizure spread. It is also crucial in planning epilepsy surgery to make sure that the seizure studied with SPECT is in fact a patient’s habitual event. If seizures are very short, it may be difficult to perform a true ictal injection. Hypermotor seizures may require measures to prevent patient injury that make injection difficult or impossible.

Presurgical focus localization in epilepsy

7

Imaging Drug-Resistant Epilepsy MRI lesion matches ictal EEG, semiology

Normal MRI

Focal

FDG PET OR ictal SPECT ? FMZ PET

FDG PET, ictal SPECT ? FMZ PET

Non-focal

Focal

Cognitive evaluation (NP tests, fMRI, IAP, ECOG)

Discordant or mulfocal MRI

Invasive EEG

Non-focal

Focal Non-focal

resection

Other treatment options: experimental drugs; Non-resective surgery; brain stimulation

Figure 5 Flow chart showing how PET and SPECT may contribute to evaluation of patients with drug-resistant epilepsy for possible surgery.

The choice of which study to use depends mainly on facilities and experience; imaging evaluation strategy for patients with epilepsy should be based on electroclinical classification.118 As long as patients are seizure-free on AEDs, there is no reason to perform clinical [18F]-FDG-PET or SPECT; there are only indicated when surgery is considered. Patients with clearly defined generalized, presumably genetic epilepsy syndromes such as childhood absence, juvenile absence or juvenile myoclonic epilepsy do not need imaging studies. For patients with presumed focal epilepsy syndromes, or those who do not have definite evidence of a genetic epilepsy syndrome, MRI is the first step. Identification of a seizure disorder depends on clinical and EEG data, and imaging, including PET and SPECT, should not be used as a diagnostic tool.

PET and SPECT in Comprehensive Evaluation of Drug-Resistant Epilepsy Brain surgery has irrevocable effects, and should only be performed after careful discussion and consideration of all available data. PET and SPECT should be integrated into the overall patient evaluation (Fig. 5). Only limited data suggest that patients with focal MRI matching ictal EEG seizure focus localization and consistent clinical semiology may benefit from PET or SPECT. If MRI is normal, but PET or ictal SPECT clearly focal and consistent with clinical and EEG localization, surgery can be considered with or without invasive electrode studies (which may in any case be indicated for language and memory mapping. [11C]FMZ-PET may be considered as an additional potential localizing procedure. If MRI is multifocal, or discordant with EEG and clinical localization, PET, SPECT, or even both may be performed in an attempt to form a plan for invasive EEG evaluation. If these studies are unrevealing, the chance of finding a resectable focus may be very low, and other treatment options should be pursued.

References 1. Slomka PJ, Pan T, Berman DS, et al: Advances in SPECT and PET hardware. Prog Cardiovasc Dis 2015;57:566-578 2. Ding YS, Chen BB, Glielmi C, et al: A pilot study in epilepsy patients using simultaneous PET/MR. Am J Nucl Med Mol Imaging 2014;4: 459-470 3. Engel J Jr, Kuhl DE, Phelps ME, et al: Interictal cerebral glucose metabolism in partial epilepsy and its relation to EEG changes. Ann Neurol 1982;12:510-517 4. Engel J Jr, Henry TR, Risinger MW, et al: Presurgical evaluation for partial epilepsy: Relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG. Neurology 1990;40:1670-1677 5. O’Brien TJ, Hicks RJ, Ware R, et al: The utility of a 3-dimensional, largefield-of-view, sodium iodide crystal–based PET scanner in the presurgical evaluation of partial epilepsy. J Nucl Med 2001;42:1158-1165 6. Theodore WH, Newmark ME, Sato S, et al: [18F]fluorodeoxyglucose positron emission tomography in refractory complex partial seizures. Ann Neurol 1983;14:429-437 7. Joo EY, Seo DW, Honh S-C, et al: Functional neuroimaging findings in patients with lateral and mesio-lateral temporal lobe epilepsy; FDG-PET and ictal SPECT studies. J Neurol 2015;262:1120-1129 8. Rathore C, Dickson JC, Teotónio R, et al: The utility of 18Ffluorodeoxyglucose PET (FDG PET) in epilepsy surgery. Epilepsy Res 2014;108:1306-1314 9. Willmann O, Wennberg R, May T, et al: The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy. A meta-analysis. Seizure 2007;16:509-520 10. Carne RP, O’Brien TJ, Kilpatrick CJ, et al: MRI-negative PET-positive temporal lobe epilepsy: A distinct surgically remediable syndrome. Brain 2004;127:2276-2285 11. Gok B, Jallo G, Hayeri R, et al: The evaluation of FDG-PET imaging for epileptogenic focus localization in patients with MRI positive and MRI negative temporal lobe epilepsy. Neuroradiology 2013;55:541-550 12. Yang PF, Pei JS, Zhang HJ, et al: Long-term epilepsy surgery outcomes in patients with PET-positive, MRI-negative temporal lobe epilepsy. Epilepsy Behav 2014;41:91-97 13. LoPinto-Khoury C, Sperling MR, Skidmore C, et al: Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy. Epilepsia 2012;53:342-348 14. Capraz I, Gökhan Kurt G, Akdemir O, et al: Surgical outcome in patients with MRI-negative, PET-positive temporal lobe epilepsy. Seizure 2015; 29:63-68

8 15. Pustina D, Avants B, Sperling M, et al: Predicting the laterality of temporal lobe epilepsy from PET, MRI, and DTI: A multimodal study. Neuroimage Clin 2015;9:20-31 16. Koutroumanidis M, Hennessy MJ, Seed PT, et al: Significance of interictal bilateral temporal hypometabolism in temporal lobe epilepsy. Neurology 2000;54:1811-1821 17. Joo EY, Lee EK, Tae WS, et al: Unitemporal vs bitemporal hypometabolism in mesial temporal lobe epilepsy. Arch Neurol 2004;61:1074-1078 18. Kim MA, Heo K, Choo MK, et al: Relationship between bilateral temporal hypometabolism and EEG findings for mesial temporal lobe epilepsy: Analysis of 18F-FDG PET using SPM. Seizure 2006;15:56-63 19. Kim YK, Lee DS, Lee SK, et al: 18F-FDG PET in localization of frontal lobe epilepsy: Comparison of visual and SPM analysis. J Nucl Med 2002; 43:1167-1174 20. Wong CH, Bleasel A, Wen L, et al: Relationship between preoperative hypometabolism and surgical outcome in neocortical epilepsy surgery. Epilepsia 2012;53:1333-1340 21. Wong CH, Bleasel A, Wen L, et al: The topography and significance of extratemporal hypometabolism in refractory mesial temporal lobe epilepsy examined by FDG-PET. Epilepsia 2010;51:1365-1373 22. Theodore WH, Sato S, Kufta C, et al: Temporal lobectomy for uncontrolled seizures: The role of positron emission tomography. Ann Neurol 1992;32:789-794 23. Kim YK, Lee DS, Lee SK, et al: Differential features of metabolic abnormalities between medial and lateral temporal lobe epilepsy: Quantitative analysis of 18F-FDG PET using SPM. J Nucl Med 2003;44:1006-1012 24. van’t Klooster MA, Huiskamp G, Zijlmans M, et al: Can we increase the yield of FDG-PET in the preoperative work-up for epilepsy surgery? Epilepsy Res 2014;108:1095-1105 25. Vinton AB, Carne R, Hicks RJ, et al: The extent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy. Brain 2007;130:548-560 26. Stanišić M, Coello C, Ivanović J, et al: Seizure outcomes in relation to the extent of resection of the perifocal fluorodeoxyglucose and flumazenil PET abnormalities in anteromedial temporal lobectomy. Acta Neurochir (Wien) 2015;157:1905-1916 27. Henry TR, Babb TL, Engel J Jr, et al: Hippocampal neuronal loss and regional hypometabolism in temporal lobe epilepsy. Ann Neurol 1994;36:925-927 28. Foldvary N, Lee N, Hanson MW, et al: Correlation of hippocampal neuronal density and FDG-PET in mesial temporal lobe epilepsy. Epilepsia 1999;40:26-29 29. Chassoux F, Artiges E, Semah F, et al: Determinants of brain metabolism changes in mesial temporal lobe epilepsy. Epilepsia 2016. http://dx.doi. org/10.1111/epi.13377. [Epub ahead of print] 30. O’Brien TJ, Newton MR, Cook MJ, et al: Hippocampal atrophy is not a major determinant of regional hypometabolism in temporal lobe epilepsy. Epilepsia 1997;38:74-80 31. Theodore WH, Gaillard WD, De Carli C, et al: Hippocampal volume and glucose metabolism in temporal lobe epileptic foci. Epilepsia 2001;42: 130-132 32. Hogan RE, Carne RP, Kilpatrick CJ, et al: Hippocampal deformation mapping in MRI negative PET positive temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2008;79:636-640 33. Lippé S, Poupon C, Cachia A, et al: White matter abnormalities revealed by DTI correlate with interictal grey matter FDG-PET metabolism in focal childhood epilepsies. Epileptic Disord 2012;14:404-413 34. Tenney JR, Rozhkov L, Horn P, et al: Cerebral glucose hypometabolism is associated with mitochondrial dysfunction in patients with intractable epilepsy and cortical dysplasia. Epilepsia 2014;55:1415-1422 35. Chugani HT, Asano E, Juhász C, et al: Subtotal hemispherectomy in children with intractable focal epilepsy. Epilepsia 2014;2015(56):49-57 36. Burdette DE, Sakurai SY, Henry TR, et al: Temporal lobe central benzodiazepine binding in unilateral mesial temporal lobe epilepsy. Neurology 1995;45:934-941 37. Henry TR, Frey KA, Sackellares JC, et al: In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy. Neurology 1993;43:1998-2006

W.H. Theodore 38. Savic I, Persson A, Roland P, et al: In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 1988;2:863-866 39. Ryvlin P, Bouvard S, Le Bars D, et al: Clinical utility of flumazenil-PET versus [18F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy. A prospective study in 100 patients. Brain 1998;121: 2067-2081 40. Lamusuo S, Pitkanen A, Jutila L, et al: [11C]flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: Correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology. Neurology 2000;54:2252-2260 41. Muzik O, da Silva EA, Juhasz C, et al: Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy. Neurology 2000;54:171-179 42. Vivash L, Gregoire MC, Lau EW, et al: 18F-flumazenil: A γ-aminobutyric acid A-specific PET for the localization of drug-resistant temporal lobe epilepsy. Radiotracer. J Nucl Med 2013;54:1270-1277 43. Koepp MJ, Hammers A, Labbe C, et al: 11C-flumazenil PET in patients with refractory temporal lobe epilepsy and normal MRI. Neurology 2000;54:332-339 44. Hammers A, Koepp MJ, Richardson MP, et al: Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients. Brain 2003;126:1300-1318 45. Yankam Njiwa J, Gray KR, Costes N, et al: Advanced [18F]FDG and [11C] flumazenil PET analysis for individual outcome prediction after temporal lobe epilepsy surgery for hippocampal sclerosis. Neuroimage Clin 2014;7:122-131 46. Chugani HT, Luat AF, Kumar A, et al: α-[11C]-Methyl-L-tryptophan— PET in 191 patients with tuberous sclerosis complex. Neurology 2013;81:674-680 47. Rubí S, Costes N, Heckemann RA, et al: Positron emission tomography with α-[11C]methyl-L-tryptophan in tuberous sclerosis complex-related epilepsy. Epilepsia 2013;54:2143-2150 48. Chugani HT, Kumar A, Kupsky W, et al: Clinical and histopathologic correlates of 11C-alpha-methyl-L-tryptophan (AMT) PET abnormalities in children with intractable epilepsy. Epilepsia 2011;52:1692-1698 49. O’Brien TJ, So EL, Mullan BP, et al: Subtraction SPECT co-registered to MRI improves postictal SPECT localization of seizure foci. Neurology 1999;52:137-146 50. O’Brien TJ, So EL, Mullan BP, et al: Subtraction periictal SPECT is predictive of extratemporal epilepsy surgery outcome. Neurology 2000;55:1668-1677 51. So EL, O’Brien TJ: Peri-ictal single photon emission computed tomography: Principles and applications in epilepsy evaluation. In: Stefan H, Theodore WH, (eds): Handbook of Clinical Neurology. Epilepsy Part II. Amsterdam: Elsevier; 2012. pp. 425-436 52. Tousseyn S, Dupont P, Goffin K, et al: Correspondence between largescale ictal and interictal epileptic networks revealed by single photon emission computed tomography (SPECT) and electroencephalography (EEG)-functional magnetic resonance imaging (fMRI). Epilepsia 2015;56(3):382-392 53. Velasco TR, Wichert-Ana L, Mathern GW, et al: Utility of ictal single photon emission computed tomography in mesial temporal lobe epilepsy with hippocampal atrophy: A randomized trial. Neurosurgery 2011;68:431-436 54. Sun PY, Wyatt K, Nickels KC, et al: Predictors of length of stay in children admitted for presurgical evaluation for epilepsy surgery. Pediatr Neurol 2015;53:207-210 55. Noe K, Sulc V, Wong-Kisiel L, et al: Long-term outcomes after nonlesional extratemporal lobe epilepsy surgery. JAMA Neurol 2013;70: 1003-1008 56. Lascano AM, Perneger T, Vulliemoz S, et al: Yield of MRI, high-density electric source imaging (HD-ESI), SPECT and PET in epilepsy surgery candidates. Clin Neurophysiol 2016;127:150-155 57. Rathore C, Kesavadas C, Ajith J, et al: Cost-effective utilization of single photon emission computed tomography (SPECT) in decision making for epilepsy surgery. Seizure 2011;20:107-114 58. Sulc V, Stykel S, Hanson DP, et al: Statistical SPECT processing in MRInegative epilepsy surgery. Neurology 2014;82:932-939

Presurgical focus localization in epilepsy 59. Won HJ, Chang KH, Cheon JE, et al: Comparison of MR imaging with PET and ictal SPECT in 118 patients with intractable epilepsy. AJNR Am J Neuroradiol 1999;20:593-599 60. Hwang SI, Kim JH, Park SW, et al: Comparative analysis of MR imaging, positron emission tomography, and ictal single-photon emission CT in patients with neocortical epilepsy. AJNR Am J Neuroradiol 2001;22: 937-946 61. Seo JH, Holland K, Rose D, et al: Multimodality imaging in the surgical treatment of children with nonlesional epilepsy. Neurology 2011;76:41-48 62. von Oertzen TJ, Mormann F, Urbach H, et al: Prospective use of subtraction ictal SPECT coregistered to MRI (SISCOM) in presurgical evaluation of epilepsy. Epilepsia 2011;52:2239-2248 63. Desai A, Bekelis K, Thadani VM, et al: Interictal PET and ictal subtraction SPECT: Sensitivity in the detection of seizure foci in patients with medically intractable epilepsy. Epilepsia 2013;54:341-350 64. Kudr M, Krsek P, Marusic P, et al: SISCOM and FDG-PET in patients with non-lesional extratemporal epilepsy: Correlation with intracranial EEG, histology, and seizure outcome. Epileptic Disord 2013;15:3-13 65. Chandra PS, Vaghania G, Bal C, et al: Role of concordance between ictalsubtracted SPECT and PET in predicting long-term outcomes after epilepsy surgery. Epilepsy Res 2014;108:1782-1789 66. Fernández S, Donaire A, Serès E, et al: PET/MRI and PET/MRI/SISCOM coregistration in the presurgical evaluation of refractory focal epilepsy. Epilepsy Res 2015;111:1-9 67. Intusoma U, Abbott DF, Masterton RA, et al: Tonic seizures of LennoxGastaut syndrome: Periictal single-photon emission computed tomography suggests a corticopontine network. Epilepsia 2013;54:2151-2157 68. Toczek MT, Carson RE, Lang L, et al: PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 2003; 60:749-756 69. Merlet I, Ostrowsky K, Costes N, et al: 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: An [18F]MPPF-PET study. Brain 2004;127:900-913 70. Savic I, Lindstrom P, Gulyas B, et al: Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology 2004;62:1343-1351 71. Giovacchini G, Toczek MT, Bonwetsch R, et al: 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J Nucl Med 2005;46:1128-1135 72. Theodore WH, Martinez AR, Khan OI, et al: PET imaging of serotonin 1A receptors and cerebral glucose metabolism for temporal lobectomy. J Nucl Med 2012;53:1375-1382 74. Hasler G, Bonwetsch R, Giovacchini G, et al: 5-HT(1A) receptor binding in temporal lobe epilepsy patients with and without major depression. Biol Psychiatry 2007;62:1258-1264 73. Theodore WH, Hasler G, Giovacchini G, et al: Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia 2007;48:1526-1530 75. Bromfield EB, Altshuler L, Leiderman DB, et al: Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 1992;49:617-623 76. Victoroff JI, Benson F, Grafton ST, et al: Depression in complex partial seizures. Electroencephalography and cerebral metabolic correlates. Arch Neurol 1994;51:155-163 77. Salzberg M, Taher T, Davie M, et al: Depression in temporal lobe epilepsy surgery patients: An FDG-PET study. Epilepsia 2006;47:2125-2130 78. Theodore WH, Wiggs EA, Martinez AR, et al: Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy. Epilepsia 2012; 53:129-133 79. Martinez A, Finegersh A, Cannon DM, et al: The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy. Neurology 2013;80: 1465-1471 80. Frost JJ, Mayberg HS, Fisher RS, et al: Mu-opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy. Ann Neurol 1988;23:231-237 81. Mayberg HS, Sadzot B, Meltzer CC, et al: Quantification of mu and nonmu opiate receptors in temporal lobe epilepsy using positron emission tomography. Ann Neurol 1991;30:3-11

9 82. Theodore WH, Carson RE, Andreasen P, et al: PET imaging of opiate receptor binding in human epilepsy using [18F]cyclofoxy. Epilepsy Res 1992;13:129-139 83. Iinuma K, Yokoyama H, Otsuki T, et al: Histamine H1 receptors in complex partial seizures. Lancet 1993;341:238 84. Muller-Gartner HW, Mayberg HS, Fisher RS, et al: Decreased hippocampal muscarinic cholinergic receptor binding measured by 123Iiododexetimide and single-photon emission computed tomography in epilepsy. Ann Neurol 1993;34:235-238 85. Kumlien E, Nilsson A, Hagberg G, et al: PET with 11C-deuteriumdeprenyl and 18F-FDG in focal epilepsy. Acta Neurol Scand 2001;103:360-366 86. Brodtkorb E, Zuberi S, Gambardella A, et al: Alteration of the in vivo nicotinic receptor density in ADNFLE patients: A PET study. Brain 2006;129:2047-2060 87. Werhahn KJ, Landvogt C, Klimpe S, et al: Decreased dopamine D2/D3receptor binding in temporal lobe epilepsy: An [18F]fallypride PET study. Epilepsia 2006;47(8):1392-1396 88. Bouilleret V, Semah F, Biraben A, et al: Involvement of the basal ganglia in refractory epilepsy: An 18F-fluoro-L-DOPA PET study using 2 methods of analysis. J Nucl Med 2005;46:540-547 89. Bernedo Paredes VE, Buchholz HG, Gartenschläger M, et al: Reduced D2/D3 receptor binding of extrastriatal and striatal regions in temporal lobe epilepsy. PLoS One 2015;10(11):e0141098 90. Kumlien E, Hartvig P, Valind S, et al: NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy. Epilepsia 1999;40:30-37 91. Danfors T, Åhs F, Appel L, et al: Increased neurokinin-1 receptor availability in temporal lobe epilepsy: A positron emission tomography study using [11C]GR205171. Epilepsy Res 2011;97:183-189 92. Bouvard S, Costes N, Bonnefoi F, et al: Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: A [11C] flumazenil-PET study. Brain 2005;128:1330-1343 93. McGinnity CJ, Koepp MJ, Hammers A, et al: NMDA receptor binding in focal epilepsies. J Neurol Neurosurg Psychiatry 2015;86(10): 1150-1157 94. Biraben A, Semah F, Ribeiro MJ, et al: PET evidence for a role of the basal ganglia in patients with ring chromosome 20 epilepsy. Neurology 2004;63(1):73-77 95. Odano I, Varrone A, Savic I, et al: Quantitative PET analyses of regional [11C]PE2I binding to the dopamine transporter—Application to juvenile myoclonic epilepsy. Neuroimage 2012;59:3582-3593 96. Pearl PL, Gibson KM, Quezado Z, et al: Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency. Neurology 2009;73:423-429 97. Vezzani A, Aronica E, Mazarati A, et al: Epilepsy and brain inflammation. Exp Neurol 2013;244:11-21 98. Chanson JB, Diaconu M, Honnorat J, et al: PET follow-up in a case of anti-NMDAR encephalitis: Arguments for cingulatelimbic encephalitis. Epileptic Disord 2012;14(1):90-93 99. Greiner H, Leach JL, Lee KH, et al: Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome. Seizure 2011;20(3):266-270 100. Banati RB, Goerres GW, Myers R, et al: [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology 1999;53:2199-2203 101. Kumar A1, Chugani HT, Luat A, et al: Epilepsy surgery in a case of encephalitis: Use of 11C-PK11195 positron emission tomography. Pediatr Neurol 2008;38(6):439-442 102. Butler T, Ichise M, Teich AF, et al: Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging 2013;23:129-131 103. Hirvonen J, Kreisl WC, Fujita M, et al: In vivo expression of an inflammatory marker in temporal lobe epilepsy. J Nucl Med 2012;53:234-240 104. Gershen LP, Zanotti-Fregonara P, Dustin IM, et al: Neuroinflammation in temporal lobe epilepsy measured using pet imaging of translocator protein. JAMA Neurol 2015;75:882-888

10 105. Harhausen D, Sudmann V, Khojasteh U, et al: Specific imaging of inflammation with the 18 kDa translocator protein ligand DPA-714 in animal models of epilepsy and stroke. PLoS One 2013;8(8):e69529 106. Bogdanović RM, Syvänen S, Michler C, et al: (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: Evaluation in a rat epilepsy model. Neuropharmacology 2014;85:104-112 107. Feldmann M, Asselin MC, Liu J, et al: P-glycoprotein expression and function in patients with temporal lobe epilepsy: A case-control study. Lancet Neurol 2013;12:777-785 108. Bauer M, Karch R, Zeitlinger M, et al: In vivo P-glycoprotein function before and after epilepsy surgery. Neurology 2014;83:1326-1331 109. Usui K, Matsuda K, Terada K: Epileptic negative myoclonus: A combined study of EEG and [123I]iomazenil (123I-IMZ) single photon emission computed tomography indicating involvement of medial frontal area. Epilepsy Res 2010;89:220-226 110. Mori K, Mori T, Toda Y, et al: Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex. Brain Dev 2012;34:478-486 111. Del Sole A, Chiesa V, Lucignani G, et al: Exploring dopaminergic activity in ring chromosome 20 syndrome: A SPECT study. Q J Nucl Med Mol Imaging 2010;54:564-569 112. Gaillard WD, Cross JH, Duncan JS, et al: Epilepsy imaging study guideline criteria: Commentary on diagnostic testing study guidelines and practice parameters. Epilepsia 2011;52:1750-1756

W.H. Theodore 113. Leiderman DB, Albert P, Balish M, et al: The dynamics of metabolic change following seizures as measured by positron emission tomography with fludeoxyglucose F 18. Arch Neurol 1994;51: 932-936 114. Savic I, Altshuler L, Baxter L, et al: Pattern of interictal hypometabolism in PET scans with fludeoxyglucose F 18 reflects prior seizure types in patients with mesial temporal lobe seizures. Arch Neurol 1997; 54:129-136 115. Sperling MR, Alavi A, Reivich M, et al: False lateralization of temporal lobe epilepsy with FDG positron emission tomography. Epilepsia 1995;36:722-727 116. Poduri A, Golja A, Takeoka M, et al: Focal cortical malformations can show asymmetrically higher uptake on interictal fluorine-18 fluorodeoxyglucose positron emission tomography (PET). J Child Neurol 2007; 22:232-237 117. Tepmongkol S, Srikijvilaikul T, Vasavid P, et al: Factors affecting bilateral temporal lobe hypometabolism on 18F-FDG PET brain scan in unilateral medial temporal lobe epilepsy. Epilepsy Behav 2013;29: 386-389 118. Berg AT, Berkovic SF, Brodie MJ, et al: Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-685