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Evidence on Use of Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy A Systematic Review Amy L. Jones, MD; Gregory D. Cascino, MD
IMPORTANCE Surgery is an effective treatment for drug-resistant focal epilepsy.
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Neuroimaging studies are considered essential in the diagnostic evaluation of individuals with medically refractory focal seizures being considered for surgical treatment. OBJECTIVES To review the evidence for the use of neuroimaging studies in the selection of patients with drug-resistant temporal lobe epilepsy for focal cortical resection and discuss the prognostic importance of selected techniques. EVIDENCE REVIEW Randomized clinical trials, meta-analyses, and clinical retrospective case studies (ⱖ20 patients with ⱖ1 year of follow-up) were identified using Medical Subject Headings and indexed text terms in EMBASE (1988-November 29, 2014); MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005-October 31, 2014). Twenty-seven articles describing 3163 patients were included. Neuroimaging techniques analyzed included magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Subpopulations and prognostic factors were identified. FINDINGS Of the 27 studies evaluated (3163 patients), 7 showed the outcome was more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis. Five additional studies indicated that the outcome was less favorable in patients with unremarkable MRI studies. There are conflicting findings regarding the prognostic importance of PET-identified focal hypometabolism; however, 2 investigations indicated that the presence of a PET imaging study demonstrating abnormalities in individuals with unremarkable MRI results showed an operative outcome similar to that in patients with mesial temporal sclerosis. The studies assessing SPECT use in temporal lobe epilepsy did not reveal a correlation with outcome. CONCLUSIONS AND RELEVANCE There is strong evidence that preoperative MRI-identified hippocampal atrophy consistent with mesial temporal sclerosis concordant with the seizure origin in the temporal lobe is a significant factor associated with a favorable outcome. PET studies may be valuable in individuals with unremarkable MRI findings. The current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery.
Author Affiliations: Division of Epilepsy, Department of Neurology, Mayo Clinic, Rochester, Minnesota. Corresponding Author: Gregory D. Cascino, MD, Division of Epilepsy, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). JAMA Neurol. doi:10.1001/jamaneurol.2015.4996 Published online February 29, 2016.
Section Editor: David E. Pleasure, MD.
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Clinical Review & Education Review
Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
E
pilepsy is one of the most common chronic neurologic disorders. An estimated 3 million individuals in the United States and 50 million people worldwide have epilepsy.1 The 2012 Institute of Medicine2 report indicated that 1 in 26 persons in the United States will develop a seizure disorder during their lifetime. Approximately one-third of individuals with epilepsy will have drugresistant seizures that are refractory to antiepileptic drug therapy.3 Pharmacoresistantepilepsymaybedefinedasfailureofadequatedrug trials of 2 tolerated, appropriately chosen, and correctly used antiepileptic drug regimens (monotherapy or combination therapy) to achieve seizure freedom.4 Individuals with disabling focal seizures may be considered candidates for an epilepsy surgical procedure to reduce seizure tendency and improve quality of life.5 The most effective operative management involves a focal cortical resection with excision of the epileptogenic cortex and the underlying pathologic findings.6 The most common operative procedure is an anterior temporal lobectomy that includes the lateral temporal neocortex and the amygdalohippocampal structures.5,7 There is level 1 evidence5,6 that surgical treatment is effective in the management of individuals with drug-resistant epilepsy of temporal lobe origin providing a grade A recommendation for epilepsy surgery. The evaluation of drug-resistant focal epilepsy is predicated on the localization of seizure onset and the identification of the pathologic findings underlying the epileptic brain tissue. Magnetic resonance imaging (MRI) has been shown8-10 to be the structural neuroimaging procedure of choice to identify the common pathologies associated with focal seizure disorders. The structural intracranial abnormalities commonly associated with chronic focal epilepsy include mesial temporal sclerosis (MTS), focal cortical dysplasia, ganglioglioma or dysembryoplastic neuroepithelial tumor, cavernous hemangioma, remote cerebral infarction, and posttraumatic encephalomalacia. With varying degrees of sensitivity and specificity, MRI has a high diagnostic yield for indicating the specific pathologic findings in these patients.9-11 The most common underlying pathology in individuals with temporal lobe epilepsy is MTS associated with medial temporal neuronal loss and gliosis (Figure 1).12 Patients with MTS often have medial temporal lobe epilepsy with
Key Points Question: What neuroimaging studies are of prognostic importance in patients with drug-resistant temporal lobe epilepsy undergoing surgical treatment? Findings: In this systematic review, the diagnostic yield of magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were evaluated in patients with drug-resistant focal seizures who had a surgically remediable epileptic syndrome. Hippocampal formation atrophy identified on MRI was a strong predictor of a seizure-free outcome; there were conflicting results regarding the importance of PET and SPECT. Meaning: Preoperative MRI-identified mesial temporal sclerosis concordant with the temporal lobe of seizure origin correlates with an excellent operative outcome in patients with temporal lobe epilepsy.
focal seizures arising from the amygdalohippocampal complex.13 The MRI findings in MTS include T1-weighted hippocampal atrophy and an increased T2-weighted and fluid-attenuated inversion recovery signal change.9-11 Studies11 on MRI volumetrics may reveal quantitative hippocampal volume loss. The diagnostic yield of MRI in patients with MTS is approximately 80% to 90%. Previous studies7 have indicated that identification of MTS in the excised hippocampus has correlated with an excellent operative outcome with nearly 90% of patients being rendered seizure free. Approximately 60% of individuals with unremarkable MRI findings who have temporal lobe epilepsy will be rendered seizure free after surgical treatment.14 The MRI changes of hippocampal atrophy and increased signal intensity have served as a surrogate for this focal pathology.8 Positron emission tomography (PET) is the most frequently performed functional neuroimaging technique in patients with drugresistant focal epilepsy being considered for surgical treatment.15-18 The role of PET, particularly using fludeoxyglucose F 18, is well established. In patients with temporal lobe epilepsy, the interictal
Figure 1. Coronal Magnetic Resonance Imaging in a Patient With Temporal Lobe Epilepsy A T1-weighted image
B
FLAIR sequence
A, T1-weighted volume image in the oblique-coronal plane (section thickness, 1.5 mm; the left temporal lobe is on the right side of the image). There is left hippocampal atrophy and volume loss (arrowhead) in this patient with pathologically verified mesial temporal sclerosis. B, Fluid-attenuated inversion recovery (FLAIR) sequence (section thickness, 1.5 mm; the left temporal lobe is on the right side of the image) in this patient reveals a prominent signal hyperintensity (arrowhead) in the left hippocampus. E2
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
PET study may reveal focal or regional hypometabolism in approximately 80% of patients (Figure 2).Of patients with medial temporal lobe epilepsy, 20% to 30% have no identifiable MRI abnormality.17,18 PET may correctly lateralize the seizure focus in 95% of patients with an abnormal MRI study and 84% of patients with an unremarkable MRI study.19 Individuals with focal PET hypometabolism and an unremarkable MRI study may have focal cortical dysplasia, gliosis, or no histopathologic alteration.20 Coregistration with MRI has become standard for PET studies in epilepsy. Simultaneous image acquisition using integrated PET/MRI scanners may facilitate comparison of structural and functional images.21 PET appears to have a higher diagnostic yield in patients with focal seizures of temporal lobe origin than for those with extratemporal seizures.15 The physiological basis for hypometabolism in the absence of MRI lesions is uncertain but may be related to a combination of factors including decreased synaptic activity or alterations in adjacent white matter tracts.15,19,22,23 Single-photon emission computed tomography (SPECT) may be used to identify focal or regional perfusion changes associated with focal seizures24-26 (eFigure in the Supplement). Seizure activity increases brain metabolism and cerebral blood flow in the epileptogenic zone during seizure initiation and propagation. Intravenous injection of a radiotracer makes it possible to measure local differences in cerebral blood flow. Subtraction-ictal SPECT coregistered with MRI (SISCOM) may increase the diagnostic yield of this neuroimaging study.25 These studies would be performed during long-term videoelectroencephalographic (EEG) monitoring while the patient is in an epilepsy monitoring unit. SISCOM may correctly indicate a localized focal hyperperfusion abnormality in 88% of patients with epilepsy. The rationale for the present evidence-based review is to analyze the prognostic importance of MRI, PET, and SPECT in patients with temporal lobe epilepsy undergoing surgical treatment for a drugresistant seizure disorder.
Data Sources and Extraction We searched the EMBASE (1988-November 29, 2014), MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005 to October 31, 2014) databases using the Medical Subject Headings and the indexed text terms temporal lobe epilepsy, surgery, and neuroimaging to identify randomized clinical trials, meta-analyses, and clinical retrospective case studies (ⱖ20 patients with ⱖ1 year of follow-up). Excluding nonhuman studies and those published in languages other than English, 72 unique articles were identified. Inclusion criteria required that the studies included more than 20 patients with temporal lobe epilepsy who underwent epilepsy surgery and had a minimum postsurgical follow-up of 1 year, and that the investigations related the outcome of surgery to the neuroimaging modalities. Forty-five articles were excluded (13 studied extratemporal lobe epilepsy, 10 had short follow-up, full text could not be accessed in 5, 5 did not relate the outcome of surgery to imaging, 5 included an insufficient number of patients, 3 focused on an intra-arterial amobarbital sodium [Wada] test, 3 were systematic reviews, and 1 did not include surgery). Twenty-seven studies met the criteria and included 3163 patients. The quality of the studies was graded jamaneurology.com
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Figure 2. Coronal Positron Emission Tomography in a Patient With Temporal Lobe Epilepsy
Focal hypometabolism (arrowhead) involving the left temporal lobe is shown on the right side of the image.
using the Quality Assessment Tool for Quantitative Studies from the Effective Public Health Practice Project.
Findings Twenty-four studies7,13-15,19,22,23,27-43 included details on MRI imaging and its association with surgical outcome (18 retrospective, singlecenter studies; 4 prospective, single-center studies; and 2 retrospective, multicenter studies). Eleven studies (References 13, 15, 19, 22, 23, 27, 35, 36, 40-42) evaluated the prognostic importance of FDG-PET imaging (1 prospective, single-center study; 2 retrospective, multicenter studies; and 8 retrospective, single-center studies). Seven studies13,27,36,42,44-46 involved SPECT imaging and its association with surgical outcome (2 retrospective, multicenter studies; 4 retrospective, single-center studies, and 1 single-center, randomized controlled trial). Twelve (References 13, 15, 19, 22, 27, 35, 36, 39-42, 44) of the 27 studies presented the evaluation of 1 or more neuroimaging technique in patients with drug-resistant focal epilepsy undergoing an anterior temporal lobectomy. The studies predominantly used an Engel classification system47 to assess surgical outcome: class I, seizure free orfreeofdisablingseizures;classII,almostseizure-free;classIII,worthwhileimprovement;andclassIV,noworthwhileimprovement.Forpurposes of this review, Engel classes I and II were considered a good outcome and Engel classes III and IV a poor outcome.5 Selected studies reviewed used descriptive terminology (eg, excellent outcome). The results of all studies are summarized in Tables 1, 2, and 3.
Magnetic Resonance Imaging Seven studies7,13,27-31 indicated that patients with MRI-identified findings consistent with MTS (ie, hippocampal atrophy, mesial temporal signal intensity alteration, or both) concordant with the temporal lobe as the source of the seizures had a favorable operative outcome and were more likely to be rendered seizure free. However, one study32 showed a trend toward greater hippocampal atrophy being associated with worse surgical outcome. Surgery was less effective in patients with unremarkable MRI findings, but should be considered in (Reprinted) JAMA Neurology Published online February 29, 2016
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
Table 1. MRI Findings and Surgical Outcomes in Temporal Lobe Epilepsy No. of Patients
Source
Imaging Findings
Surgical Outcome
Radhakrishnan et al,7 1998
175
Unilateral MRI-identified hippocampal atrophy
MRI findings associated with a favorable outcome (P = .02)
Lin et al,32 2005
40
MRI volumetric studies for hippocampal atrophy
The “not seizure-free” group had smaller bilateral mean hippocampal volumes and greater ipsilateral atrophy
Roberti et al,29 2007
42
MRI-identified hippocampal abnormality
MRI abnormality predictive of excellent surgical outcome (P < .01)
Wieshmann et al,30 2008
76
MRI-identified hippocampal atrophy
MRI-identified hippocampal atrophy was predictive of favorable surgical outcome (P = .01)
Stefan et al,37 2009
64
MRI may not reflect severity of MTS or different subtypes
MTS type iB had best operative outcome
Bell et al,14 2009
40
All MRIs nonlesional; 11 patients had subtle MRI abnormalities: atrophy without signal change, amygdala enlargement, FLAIR-increased intensity without atrophy
24 Patients (60% of all) were rendered seizure free; patients with subtle medial temporal lobe MRI abnormalities had an improved operative outcome (P = .03)
Hajek et al,39 2009
35
Concordant MRI and MRS in 25 patients; nonlateralizing MRI and MRS in 6 patients; 4 patients with indeterminate MRI had unilateral MRS findings that correctly lateralized the temporal lobe
MRS may be useful to localize the temporal lobe of seizure origin in the presence of indeterminate or bilateral MRI abnormalities
Schijns et al,38 2011 116
MTS alone in 58 patients; MTS plus gray-white matter abnormalities in 58 patients
51 Patients (87.9%) in both groups had a favorable operative outcome; no difference between the 2 MRI groups
Vale et al,34 2012
86
All patients had nonlesional MRI studies
47 Patients (55%) had excellent operative outcomes (Engel class I)a
43
25
MRI-identified MTS in 6 patients, unremarkable in 5 patients, and findings other than MTS in 14 patients
No difference in operative outcome based on MRI findings
Lau et al,332014
241
MRI assessment of hippocampal pathology
Surgery is less effective in patients with unremarkable MRI vs those with MTS
Miserocchi et al,31 2013
68
MRI-identified focal lesion in 44 patients, dual pathology in 13 patients, MTS alone in 8 patients, and extratemporal lesion in 3 patients
Patients with temporal lobe focal lesion or MTS alone had a favorable operative outcome; extratemporal lesions had poorer outcome after temporal lobe surgery
Elsharkawy et al,28 2009
434
MRI suggestive of hippocampal atrophy was associated with better outcome (P = .02)
MRI showing hippocampal atrophy associated with better surgical outcome
Kasasbeh et al, 2012
these patients.14,33-36 Magnetic resonance imaging was limited in identifying and classifying the subtypes of MTS; however, pathologically severe MTS appeared to have the most favorable operative outcome.37In another investigation38 there was no statistically significant difference in surgical outcome between individuals with MTS and those with MTS plus gray-white matter abnormalities. Magnetic resonance spectroscopy was shown to be helpful when MRI-identified abnormalities were bilateral.39 Magnetic resonance imaging volume of resection did not have any statistically significant effect on surgical outcome.22
Positron Emission Tomography There are conflicting results regarding the prognostic importance of PET in patients with drug-resistant focal epilepsy undergoing an anterior temporal lobectomy. Abnormalities were noted on FDG-PET in patients with temporal lobe epilepsy and an MRI study with unremarkable findings. 15,40 A PET scan showing abnormalities in patients with none identified on MRI was a favorable prognostic indicator following an anterior temporal lobectomy.19,40 In 2 studies,40,41 individuals with an unremarkable MRI study but PET-identified focal hypometabolism had an E4
Abbreviations: FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MTS, mesial temporal sclerosis; MTS type iB, pathologically defined severe hippocampal sclerosis. a
The Engel classification system is presented in the Findings section.
operative outcome similar to that of individuals with MTS. However, other studies13,27,36,42 did not demonstrate that the results of PET scans correlated with the operative outcome. One study22 indicated that a larger area of focal hypometabolism corresponded to a better surgical outcome. The presence of focal extratemporal hypometabolism predicts a poorer outcome.23 One study35 found no significant difference in outcome in unilateral and bilateral PET findings or unremarkable PET.
Single-Photon Emission Computed Tomography None of the studies using SPECT13,27,36,42,44-46 that were analyzed indicated the prognostic importance of SPECT in patients with temporal lobe epilepsy undergoing surgical treatment. In addition, SPECT did not assist in the presurgical planning for patients with MTS and, overall, provided redundant information.45 In patients who had discordant MRI and EEG findings, SPECT studies were also not predictive of outcome.44 In patients with unremarkable MRI findings, the ictal EEG was a technique associated with better surgical outcome than was SPECT.42 One study46 looking at hippocampal segmentation on SPECT found this imaging modality to be a reliable indicator of ictal origin.
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Table 2. MRI-PET or PET in Temporal Lobe Epilepsy: Surgical Outcome
Source
No. of Patients
Imaging Modality Studied
Imaging Findings
Surgical Outcomea Patients with mesial temporal lobe epilepsy were more likely to be SF
Boling et al,15 2008
27
MRI, FDG-PET More FDG-PET hypometabolism correlated with better outcome; MRI plus FDG-PET combined picked up all the SF patients
Tatum et al,42 2008
39
MRI, FDG-PET, SPECT
All MRI−; FDG-PET and SPECT scans were not predictive of a better surgical outcome
Uijl et al,27 2008
484
MRI, FDG-PET, SPECT
Abnormal MRI, ipsilateral MTS, and Engel class I outcome seemed to be correlated with abnormal MRI, FDG-PET abnormalities predicted ipsilateral MTS, and FGD-PET, but better outcomes individually none of these combined produced a model to predict outcome
Wong et al,23 2010
64
FDG-PET
All patients had MRI evidence of hippocampal sclerosis; 4 normal PET scans, 49 (77%) ipsilateral localized PET scans; 45 (70%) had extratemporal hypometabolism as well
Vinton et al,22 2007
26
MRI, FDG-PET MRI volume did not have any statistically significant difference in surgical outcome
The greater the resection of the FDG-PET hypometabolic area, the better the outcome from surgery
MRI, FDG-PET FDG-PET may be helpful in predicting a better outcome, comparable to the outcome of patients with MTS
No difference in outcomes from PET+/MRI− patients compared with MTS patients (21 [75%] had class I outcome)
MRI, FDG-PET FDG-PET correctly lateralized in concordance with EEG in 42 of 45 (95%) MRI+, 3 of 4 (75%) MRI equivocal, and 26 of 29 (90%) MRI−; 32 of 38 MRI− patients (84%) had lateralizing FDG-PET
No difference in outcomes from MRI− and equivocal patients; statistically significant difference in outcome of patients with unilateral FDG-PET (82 of 85 [96%] good) and nonunilateral FDG-PET (4 of 7 [57%] at last follow-up)
Yang et al,41 2014
115
Gok et al,19 2013
98
Jeong et al,13 2005
227
MRI, FDG-PET, SPECT
MRI pure ipsilateral HS: SF, 172 of 183 (93.5%); not SF, 33 of 43 (74.4%) (P = .02); PET and SPECT abnormalities were not statistically significant
The only predictor of better surgical outcome in MRI− patients was ictal EEG localization
A larger extent of extratemporal hypometabolism or remote hypometabolism predicted worse outcome
MRI showing unilateral HS was the only predictor of seizure freedom
Fong et al,35 2011
64
No significant difference in outcome MRI, FDG-PET All 64 patients had negative MRIs findings; 5 (7.8%) had normal PET in unilateral and bilateral PET findings or normal PET scans, 43 (67.2%) had unilateral PET abnormalities, and 14 (21.9%) had bilateral PET abnormalities
Smith et al,36 2011
21
MRI, FDG-PET, SPECT
LoPintoKhoury et al,40 2012
193
All patients were MRI−; 8 of 11 patients PET only were localizing; 0 of 2 SPECT/SISCOM were localizing
MRI, FDG-PET 46 Patients were PET+/MRI− and 147 had MTS on MRI
None of the imaging modalities helped predict surgical outcome
PET+/MRI− and MTS groups did not have significantly different outcomes from surgery
Abbreviations: EEG, electroencephalogram; FDG, fludeoxyglucose F 18; HS, hippocampal sclerosis; MRI, magnetic resonance imaging; MTS, mesial temporal sclerosis; PET, positron emission tomography; SF, seizure free; SISCOM, subtraction-ictal SPECT coregistered with MRI; SPECT, single-photon emission computed tomography; −, normal findings; +, abnormal findings. a
The Engel classification system is presented in the Findings section.
Table 3. MRI-SPECT or SPECT in Temporal Lobe Epilepsy: Surgical Outcome Source Castro et al,44 2008
No. of Patients 77
Velasco et al,45 2011
240
JafariKhouzani et al,46 2011
46
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Imaging Modality Studied
Imaging Findingsa
Surgical Outcome
MRI, SPECT
Divided into MRI-EEG concordant and discordant groups; ictal SPECT was performed in 48 of 77 patients (62.3%); 3 of 48 patients had discordant SPECT localization to the site of the MTS, but all 3 had good outcome
Discordant MRI and EEG findings may be due to false localization, and SPECT was not good at predicting outcome; MRI is superior
SPECT
Ictal SPECT scans were accurate in detecting the epileptogenic region, but this overlapped with MRI and EEG findings in 80% of the patients; accuracy was higher in those whose EEG was ipsilateral to the MRI findings of HS (85%)
SPECT did not offer localizing value over MRI and scalp EEG in presurgical evaluation of MTLE-HS; overall, SPECT provided redundant information
SPECT segmentation
Highest lateralization in the hippocampus (91%), then amygdala (87%), putamen (67%), and thalamus (61%)
Hippocampal segmentation on SPECT correlates well with ictal origin and is reliable
Abbreviations: EEG, electroencephalogram; HS, hippocampal sclerosis; MRI, magnetic resonance imaging; MTLE, mesial temporal lobe epilepsy; SPECT, single-photon emission computed tomography. a
A more complete breakdown of the data was not provided in some studies.
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
Discussion Few randomized studies have examined the prognostic importance of structural or functional neuroimaging studies in patients with drug-resistant focal epilepsy undergoing temporal lobe surgery. Previous investigations5-7,13,33 have confirmed the efficacy of anterior temporal lobectomy in individuals with medically refractory seizure disorders. Surgical treatment has compared favorably with antiepileptic drug therapy trials in these patients.6 The 27 studies included in the present review provide compelling evidence that the selected neuroimaging modalities commonly performed during the diagnostic evaluation of drugresistant epilepsy may be useful to localize the site of seizure onset, demonstrate the pathologic findings, and determine an operative strategy. However, MRI was the only neuroimaging technique shown to be of prognostic importance in individuals with drugresistant focal epilepsy undergoing an anterior temporal lobectomy. In particular, MRI-identified hippocampal formation atrophy, a surrogate for hippocampal neuronal loss and MTS, is the most important factor associated with a seizure-free outcome after epilepsy surgery.28 Patients with hippocampal formation atrophy are more likely to experience prolonged seizure remission following epilepsy surgery.28 An MRI with results considered to be normal was shown14 to correlate with a less favorable operative outcome. The present review was unable to confirm a prognostic importance of PET and SPECT in patients with no hippocampal atrophy. The inherent limitations of an evidence-based review need to be considered in interpreting the present findings regarding neuroimaging in temporal lobe epilepsy. The strict inclusion criteria necessary for a systematic review reduce the number of clinical studies available for analysis. The lack of appropriate studies, often with modest numbers of patients, may not always permit an appropriate conclusion regarding a specific neuroimaging modality. Use of the established criteria allowed only 3 studies that evaluated the prognostic importance of SPECT in individuals undergoing temporal lobe surgery to be included in the present review. The studies also may be difficult to compare because of differences in methodology and technique, as well as in experience at epilepsy centers. Selected imaging modalities (eg, SISCOM) are not available at all selected institutions.24,25 Inability to coregister PET and MRI may also reduce the diagnostic yield of PET imaging in temporal lobe epilepsy.21 Contemporary innovations in neuroimaging, such as statistical SPECT processing, were not evaluated in these evidencebased medicine trials.48
ARTICLE INFORMATION Accepted for Publication: December 18, 2015. Published Online: February 29, 2016. doi:10.1001/jamaneurol.2015.4996. Author Contributions: Drs Jones and Cascino had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Cascino. Acquisition, analysis, or interpretation of data: Both authors. Drafting of the manuscript: Both authors. Critical revision of the manuscript for important
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Decision making in the evaluation and surgical treatment of patients with drug-resistant focal epilepsy is never limited to one diagnostic study. Neuroimaging studies would be performed in the context of a comprehensive presurgical evaluation that includes a detailed seizure disorder history, outpatient routine EEG, long-term videoEEG recordings in an epilepsy monitoring unit, and neuropsychological studies. Magnetic resonance imaging has a pivotal role in demonstrating a structural alteration that may indicate the likely cause of the seizure disorder and suggest the region or zone of seizure onset. Specific MRI protocols should be used when performing these studies in patients with drug-resistant focal epilepsy who are being considered for epilepsy surgery.8,49,50 These high-resolution MRI head studies are more comprehensive than routine MRI of the head ordered for other indications (eg, headache). Advanced brain imaging may use volumetric analysis, double-inversion recovery sequences, and T2relaxometry for evaluation of patients with drug-resistant focal epilepsy.49-51 Studies using 7-T MRI may also increase the diagnostic yield of neuroimaging in individuals with MTS.52 Patients with an MRIidentified substrate-directed pathology (eg, MTS) require electrophysiologic studies because a structural abnormality may be remote from the epileptic brain tissue. Individuals with MRI-negative focal epilepsy should not receive a classification of “MRI-nonlesional” because these patients may be shown to have pathologically verified lesions, such as focal cortical dysplasia or other malformations of cortical development.20 The importance of a focal PET abnormality in individuals with an unremarkable MRI examination has been confirmed.40,41 Functional neuroimaging in patients with temporal lobe epilepsy is particularly important when the MRI study shows no abnormalities or is indeterminate.20
Conclusions Existing data confirm the pivotal role of the MRI study in evaluating individuals with drug-resistant focal epilepsy of temporal lobe origin for surgical treatment. There is a paucity of evidence-based medical studies in evaluating the usefulness of PET and SPECT in selecting patients for epilepsy surgery. The high diagnostic yield of PET has been confirmed in temporal lobe epilepsy; individuals with focal PET hypometabolism and an unremarkable MRI have an operative outcome similar to that of patients with MRI-identified MTS. Ultimately, the care of patients with drug-resistant focal epilepsy and management of their disease require a tailored, individualized neuroimaging workup to be performed in concert with the remainder of a comprehensive presurgical evaluation.
intellectual content: Cascino. Administrative, technical, or material support: Cascino. Study supervision: Cascino. Conflict of Interest Disclosures: None reported. REFERENCES
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25. O’Brien TJ, So EL, Mullan BP, et al. Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus. Neurology. 1998;50(2):445-454.
10. Cascino GD, Jack CR Jr, Parisi JE, et al. Magnetic resonance imaging–based volume studies in temporal lobe epilepsy: pathological correlations. Ann Neurol. 1991;30(1):31-36. 11. Kuzniecky RI, Bilir E, Gilliam F, et al. Multimodality MRI in mesial temporal sclerosis: relative sensitivity and specificity. Neurology. 1997; 49(3):774-778. 12. Janszky J, Janszky I, Schulz R, et al. Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome. Brain. 2005;128(pt 2):395-404. 13. Jeong SW, Lee SK, Hong KS, Kim KK, Chung CK, Kim H. Prognostic factors for the surgery for mesial temporal lobe epilepsy: longitudinal analysis. Epilepsia. 2005;46(8):1273-1279. 14. Bell ML, Rao S, So EL, et al. Epilepsy surgery outcomes in temporal lobe epilepsy with a normal MRI. Epilepsia. 2009;50(9):2053-2060. 15. Boling WW, Lancaster M, Kraszpulski M, Palade A, Marano G, Puce A. Fluorodeoxyglucose-positron emission tomographic imaging for the diagnosis of mesial temporal lobe epilepsy. Neurosurgery. 2008; 63(6):1130-1138.
26. Varghese GI, Purcaro MJ, Motelow JE, et al. Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures. Brain. 2009;132(pt 8):21022113. 27. Uijl SG, Leijten FS, Arends JB, Parra J, van Huffelen AC, Moons KG. Prognosis after temporal lobe epilepsy surgery: the value of combining predictors. Epilepsia. 2008;49(8):1317-1323. 28. Elsharkawy AE, Alabbasi AH, Pannek H, et al. Long-term outcome after temporal lobe epilepsy surgery in 434 consecutive adult patients. J Neurosurg. 2009;110(6):1135-1146. 29. Roberti F, Potolicchio SJ, Caputy AJ. Tailored anteromedial lobectomy in the treatment of refractory epilepsy of the temporal lobe: long term surgical outcome and predictive factors. Clin Neurol Neurosurg. 2007;109(2):158-165. 30. Wieshmann UC, Larkin D, Varma T, Eldridge P. Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy. Acta Neurol Scand. 2008;118(5):306-312.
16. Burneo JG, Poon R, Kellett S, Snead OC. The utility of positron emission tomography in epilepsy. Can J Neurol Sci. 2015;42(6):360-371.
31. Miserocchi A, Cascardo B, Piroddi C, et al. Surgery for temporal lobe epilepsy in children: relevance of presurgical evaluation and analysis of outcome. J Neurosurg Pediatr. 2013;11(3):256-267.
17. Theodore WH, Sato S, Kufta C, Balish MB, Bromfield EB, Leiderman DB. Temporal lobectomy for uncontrolled seizures: the role of positron emission tomography. Ann Neurol. 1992;32(6):789794.
32. Lin JJ, Salamon N, Dutton RA, et al. Three-dimensional preoperative maps of hippocampal atrophy predict surgical outcomes in temporal lobe epilepsy. Neurology. 2005;65(7): 1094-1097.
18. Theodore WH, Gaillard WD, De Carli C, Bhatia S, Hatta J. Hippocampal volume and glucose metabolism in temporal lobe epileptic foci. Epilepsia. 2001;42(1):130-132.
33. Lau T, Miller T, Klein T, Benbadis SR, Vale FL. Temporal lobe surgery in medically refractory epilepsy: a comparison between populations based on MRI findings. Seizure. 2014;23(1):20-24.
19. Gok B, Jallo G, Hayeri R, Wahl R, Aygun N. The evaluation of FDG-PET imaging for epileptogenic focus localization in patients with MRI positive and MRI negative temporal lobe epilepsy. Neuroradiology. 2013;55(5):541-550.
34. Vale FL, Effio E, Arredondo N, et al. Efficacy of temporal lobe surgery for epilepsy in patients with negative MRI for mesial temporal lobe sclerosis. J Clin Neurosci. 2012;19(1):101-106.
20. Kuba R, Tyrlíková I, Chrastina J, et al. “MRI-negative PET-positive” temporal lobe epilepsy: invasive EEG findings, histopathology, and postoperative outcomes. Epilepsy Behav. 2011;22 (3):537-541. 21. Salamon N, Kung J, Shaw SJ, et al. FDG-PET/MRI coregistration improves detection of cortical dysplasia in patients with epilepsy. Neurology. 2008;71(20):1594-1601.
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35. Fong JS, Jehi L, Najm I, Prayson RA, Busch R, Bingaman W. Seizure outcome and its predictors after temporal lobe epilepsy surgery in patients with normal MRI. Epilepsia. 2011;52(8):1393-1401. 36. Smith AP, Sani S, Kanner AM, et al. Medically intractable temporal lobe epilepsy in patients with normal MRI: surgical outcome in twenty-one consecutive patients. Seizure. 2011;20(6):475-479. 37. Stefan H, Hildebrandt M, Kerling F, et al. Clinical prediction of postoperative seizure control: structural, functional findings and disease histories. J Neurol Neurosurg Psychiatry. 2009;80(2):196-200.
38. Schijns OE, Bien CG, Majores M, et al. Presence of temporal gray-white matter abnormalities does not influence epilepsy surgery outcome in temporal lobe epilepsy with hippocampal sclerosis. Neurosurgery. 2011;68(1):98-106. 39. Hajek M, Krsek P, Dezortova M, et al. 1H MR spectroscopy in histopathological subgroups of mesial temporal lobe epilepsy. Eur Radiol. 2009;19 (2):400-408. 40. LoPinto-Khoury C, Sperling MR, Skidmore C, et al. Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy. Epilepsia. 2012;53(2):342-348. 41. 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. 42. Tatum WO IV, Benbadis SR, Hussain A, et al. Ictal EEG remains the prominent predictor of seizure-free outcome after temporal lobectomy in epileptic patients with normal brain MRI. Seizure. 2008;17(7):631-636. 43. Kasasbeh A, Hwang EC, Steger-May K, et al. Association of magnetic resonance imaging identification of mesial temporal sclerosis with pathological diagnosis and surgical outcomes in children following epilepsy surgery. J Neurosurg Pediatr. 2012;9(5):552-561. 44. Castro LH, Serpa MH, Valério RM, et al. Good surgical outcome in discordant ictal EEG-MRI unilateral mesial temporal sclerosis patients. Epilepsia. 2008;49(8):1324-1332. 45. 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(2):431-436. 46. Jafari-Khouzani K, Elisevich K, Karvelis KC, Soltanian-Zadeh H. Quantitative multi-compartmental SPECT image analysis for lateralization of temporal lobe epilepsy. Epilepsy Res. 2011;95(1-2):35-50. 47. Engel J, Cascino G, Ness P, Rasmussen T, Ojemann L. Outcome with respect to epileptic seizures. In: Engel J, ed. Surgical Treatment of the Epilepsies. New York, NY: Raven Press; 1993:609-621. 48. Sulc V, Stykel S, Hanson DP, et al. Statistical SPECT processing in MRI-negative epilepsy surgery. Neurology. 2014;82(11):932-939. 49. Bernasconi A, Bernasconi N, Caramanos Z, et al. T2 relaxometry can lateralize mesial temporal lobe epilepsy in patients with normal MRI. Neuroimage. 2000;12(6):739-746. 50. Bernasconi N, Bernasconi A, Caramanos Z, Antel SB, Andermann F, Arnold DL. Mesial temporal damage in temporal lobe epilepsy: a volumetric MRI study of the hippocampus, amygdala and parahippocampal region. Brain. 2003;126(pt 2): 462-469. 51. Zhang Q, Li Q, Zhang J, Zhang Y. Double inversion recovery magnetic resonance imaging (MRI) in the preoperative evaluation of hippocampal sclerosis: correlation with volumetric measurement and proton magnetic resonance spectroscopy (1H MRS). J Comput Assist Tomogr. 2011;35(3):406-410. 52. Henry TR, Chupin M, Lehéricy S, et al. Hippocampal sclerosis in temporal lobe epilepsy: findings at 7 T. Radiology. 2011;261(1):199-209.
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Review
Evidence on Use of Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy A Systematic Review Amy L. Jones, MD; Gregory D. Cascino, MD
IMPORTANCE Surgery is an effective treatment for drug-resistant focal epilepsy.
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Neuroimaging studies are considered essential in the diagnostic evaluation of individuals with medically refractory focal seizures being considered for surgical treatment. OBJECTIVES To review the evidence for the use of neuroimaging studies in the selection of patients with drug-resistant temporal lobe epilepsy for focal cortical resection and discuss the prognostic importance of selected techniques. EVIDENCE REVIEW Randomized clinical trials, meta-analyses, and clinical retrospective case studies (ⱖ20 patients with ⱖ1 year of follow-up) were identified using Medical Subject Headings and indexed text terms in EMBASE (1988-November 29, 2014); MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005-October 31, 2014). Twenty-seven articles describing 3163 patients were included. Neuroimaging techniques analyzed included magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Subpopulations and prognostic factors were identified. FINDINGS Of the 27 studies evaluated (3163 patients), 7 showed the outcome was more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis. Five additional studies indicated that the outcome was less favorable in patients with unremarkable MRI studies. There are conflicting findings regarding the prognostic importance of PET-identified focal hypometabolism; however, 2 investigations indicated that the presence of a PET imaging study demonstrating abnormalities in individuals with unremarkable MRI results showed an operative outcome similar to that in patients with mesial temporal sclerosis. The studies assessing SPECT use in temporal lobe epilepsy did not reveal a correlation with outcome. CONCLUSIONS AND RELEVANCE There is strong evidence that preoperative MRI-identified hippocampal atrophy consistent with mesial temporal sclerosis concordant with the seizure origin in the temporal lobe is a significant factor associated with a favorable outcome. PET studies may be valuable in individuals with unremarkable MRI findings. The current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery.
Author Affiliations: Division of Epilepsy, Department of Neurology, Mayo Clinic, Rochester, Minnesota. Corresponding Author: Gregory D. Cascino, MD, Division of Epilepsy, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). JAMA Neurol. doi:10.1001/jamaneurol.2015.4996 Published online February 29, 2016.
Section Editor: David E. Pleasure, MD.
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
E
pilepsy is one of the most common chronic neurologic disorders. An estimated 3 million individuals in the United States and 50 million people worldwide have epilepsy.1 The 2012 Institute of Medicine2 report indicated that 1 in 26 persons in the United States will develop a seizure disorder during their lifetime. Approximately one-third of individuals with epilepsy will have drugresistant seizures that are refractory to antiepileptic drug therapy.3 Pharmacoresistantepilepsymaybedefinedasfailureofadequatedrug trials of 2 tolerated, appropriately chosen, and correctly used antiepileptic drug regimens (monotherapy or combination therapy) to achieve seizure freedom.4 Individuals with disabling focal seizures may be considered candidates for an epilepsy surgical procedure to reduce seizure tendency and improve quality of life.5 The most effective operative management involves a focal cortical resection with excision of the epileptogenic cortex and the underlying pathologic findings.6 The most common operative procedure is an anterior temporal lobectomy that includes the lateral temporal neocortex and the amygdalohippocampal structures.5,7 There is level 1 evidence5,6 that surgical treatment is effective in the management of individuals with drug-resistant epilepsy of temporal lobe origin providing a grade A recommendation for epilepsy surgery. The evaluation of drug-resistant focal epilepsy is predicated on the localization of seizure onset and the identification of the pathologic findings underlying the epileptic brain tissue. Magnetic resonance imaging (MRI) has been shown8-10 to be the structural neuroimaging procedure of choice to identify the common pathologies associated with focal seizure disorders. The structural intracranial abnormalities commonly associated with chronic focal epilepsy include mesial temporal sclerosis (MTS), focal cortical dysplasia, ganglioglioma or dysembryoplastic neuroepithelial tumor, cavernous hemangioma, remote cerebral infarction, and posttraumatic encephalomalacia. With varying degrees of sensitivity and specificity, MRI has a high diagnostic yield for indicating the specific pathologic findings in these patients.9-11 The most common underlying pathology in individuals with temporal lobe epilepsy is MTS associated with medial temporal neuronal loss and gliosis (Figure 1).12 Patients with MTS often have medial temporal lobe epilepsy with
Key Points Question: What neuroimaging studies are of prognostic importance in patients with drug-resistant temporal lobe epilepsy undergoing surgical treatment? Findings: In this systematic review, the diagnostic yield of magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were evaluated in patients with drug-resistant focal seizures who had a surgically remediable epileptic syndrome. Hippocampal formation atrophy identified on MRI was a strong predictor of a seizure-free outcome; there were conflicting results regarding the importance of PET and SPECT. Meaning: Preoperative MRI-identified mesial temporal sclerosis concordant with the temporal lobe of seizure origin correlates with an excellent operative outcome in patients with temporal lobe epilepsy.
focal seizures arising from the amygdalohippocampal complex.13 The MRI findings in MTS include T1-weighted hippocampal atrophy and an increased T2-weighted and fluid-attenuated inversion recovery signal change.9-11 Studies11 on MRI volumetrics may reveal quantitative hippocampal volume loss. The diagnostic yield of MRI in patients with MTS is approximately 80% to 90%. Previous studies7 have indicated that identification of MTS in the excised hippocampus has correlated with an excellent operative outcome with nearly 90% of patients being rendered seizure free. Approximately 60% of individuals with unremarkable MRI findings who have temporal lobe epilepsy will be rendered seizure free after surgical treatment.14 The MRI changes of hippocampal atrophy and increased signal intensity have served as a surrogate for this focal pathology.8 Positron emission tomography (PET) is the most frequently performed functional neuroimaging technique in patients with drugresistant focal epilepsy being considered for surgical treatment.15-18 The role of PET, particularly using fludeoxyglucose F 18, is well established. In patients with temporal lobe epilepsy, the interictal
Figure 1. Coronal Magnetic Resonance Imaging in a Patient With Temporal Lobe Epilepsy A T1-weighted image
B
FLAIR sequence
A, T1-weighted volume image in the oblique-coronal plane (section thickness, 1.5 mm; the left temporal lobe is on the right side of the image). There is left hippocampal atrophy and volume loss (arrowhead) in this patient with pathologically verified mesial temporal sclerosis. B, Fluid-attenuated inversion recovery (FLAIR) sequence (section thickness, 1.5 mm; the left temporal lobe is on the right side of the image) in this patient reveals a prominent signal hyperintensity (arrowhead) in the left hippocampus. E2
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
PET study may reveal focal or regional hypometabolism in approximately 80% of patients (Figure 2).Of patients with medial temporal lobe epilepsy, 20% to 30% have no identifiable MRI abnormality.17,18 PET may correctly lateralize the seizure focus in 95% of patients with an abnormal MRI study and 84% of patients with an unremarkable MRI study.19 Individuals with focal PET hypometabolism and an unremarkable MRI study may have focal cortical dysplasia, gliosis, or no histopathologic alteration.20 Coregistration with MRI has become standard for PET studies in epilepsy. Simultaneous image acquisition using integrated PET/MRI scanners may facilitate comparison of structural and functional images.21 PET appears to have a higher diagnostic yield in patients with focal seizures of temporal lobe origin than for those with extratemporal seizures.15 The physiological basis for hypometabolism in the absence of MRI lesions is uncertain but may be related to a combination of factors including decreased synaptic activity or alterations in adjacent white matter tracts.15,19,22,23 Single-photon emission computed tomography (SPECT) may be used to identify focal or regional perfusion changes associated with focal seizures24-26 (eFigure in the Supplement). Seizure activity increases brain metabolism and cerebral blood flow in the epileptogenic zone during seizure initiation and propagation. Intravenous injection of a radiotracer makes it possible to measure local differences in cerebral blood flow. Subtraction-ictal SPECT coregistered with MRI (SISCOM) may increase the diagnostic yield of this neuroimaging study.25 These studies would be performed during long-term videoelectroencephalographic (EEG) monitoring while the patient is in an epilepsy monitoring unit. SISCOM may correctly indicate a localized focal hyperperfusion abnormality in 88% of patients with epilepsy. The rationale for the present evidence-based review is to analyze the prognostic importance of MRI, PET, and SPECT in patients with temporal lobe epilepsy undergoing surgical treatment for a drugresistant seizure disorder.
Data Sources and Extraction We searched the EMBASE (1988-November 29, 2014), MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005 to October 31, 2014) databases using the Medical Subject Headings and the indexed text terms temporal lobe epilepsy, surgery, and neuroimaging to identify randomized clinical trials, meta-analyses, and clinical retrospective case studies (ⱖ20 patients with ⱖ1 year of follow-up). Excluding nonhuman studies and those published in languages other than English, 72 unique articles were identified. Inclusion criteria required that the studies included more than 20 patients with temporal lobe epilepsy who underwent epilepsy surgery and had a minimum postsurgical follow-up of 1 year, and that the investigations related the outcome of surgery to the neuroimaging modalities. Forty-five articles were excluded (13 studied extratemporal lobe epilepsy, 10 had short follow-up, full text could not be accessed in 5, 5 did not relate the outcome of surgery to imaging, 5 included an insufficient number of patients, 3 focused on an intra-arterial amobarbital sodium [Wada] test, 3 were systematic reviews, and 1 did not include surgery). Twenty-seven studies met the criteria and included 3163 patients. The quality of the studies was graded jamaneurology.com
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Figure 2. Coronal Positron Emission Tomography in a Patient With Temporal Lobe Epilepsy
Focal hypometabolism (arrowhead) involving the left temporal lobe is shown on the right side of the image.
using the Quality Assessment Tool for Quantitative Studies from the Effective Public Health Practice Project.
Findings Twenty-four studies7,13-15,19,22,23,27-43 included details on MRI imaging and its association with surgical outcome (18 retrospective, singlecenter studies; 4 prospective, single-center studies; and 2 retrospective, multicenter studies). Eleven studies (References 13, 15, 19, 22, 23, 27, 35, 36, 40-42) evaluated the prognostic importance of FDG-PET imaging (1 prospective, single-center study; 2 retrospective, multicenter studies; and 8 retrospective, single-center studies). Seven studies13,27,36,42,44-46 involved SPECT imaging and its association with surgical outcome (2 retrospective, multicenter studies; 4 retrospective, single-center studies, and 1 single-center, randomized controlled trial). Twelve (References 13, 15, 19, 22, 27, 35, 36, 39-42, 44) of the 27 studies presented the evaluation of 1 or more neuroimaging technique in patients with drug-resistant focal epilepsy undergoing an anterior temporal lobectomy. The studies predominantly used an Engel classification system47 to assess surgical outcome: class I, seizure free orfreeofdisablingseizures;classII,almostseizure-free;classIII,worthwhileimprovement;andclassIV,noworthwhileimprovement.Forpurposes of this review, Engel classes I and II were considered a good outcome and Engel classes III and IV a poor outcome.5 Selected studies reviewed used descriptive terminology (eg, excellent outcome). The results of all studies are summarized in Tables 1, 2, and 3.
Magnetic Resonance Imaging Seven studies7,13,27-31 indicated that patients with MRI-identified findings consistent with MTS (ie, hippocampal atrophy, mesial temporal signal intensity alteration, or both) concordant with the temporal lobe as the source of the seizures had a favorable operative outcome and were more likely to be rendered seizure free. However, one study32 showed a trend toward greater hippocampal atrophy being associated with worse surgical outcome. Surgery was less effective in patients with unremarkable MRI findings, but should be considered in (Reprinted) JAMA Neurology Published online February 29, 2016
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
Table 1. MRI Findings and Surgical Outcomes in Temporal Lobe Epilepsy No. of Patients
Source
Imaging Findings
Surgical Outcome
Radhakrishnan et al,7 1998
175
Unilateral MRI-identified hippocampal atrophy
MRI findings associated with a favorable outcome (P = .02)
Lin et al,32 2005
40
MRI volumetric studies for hippocampal atrophy
The “not seizure-free” group had smaller bilateral mean hippocampal volumes and greater ipsilateral atrophy
Roberti et al,29 2007
42
MRI-identified hippocampal abnormality
MRI abnormality predictive of excellent surgical outcome (P < .01)
Wieshmann et al,30 2008
76
MRI-identified hippocampal atrophy
MRI-identified hippocampal atrophy was predictive of favorable surgical outcome (P = .01)
Stefan et al,37 2009
64
MRI may not reflect severity of MTS or different subtypes
MTS type iB had best operative outcome
Bell et al,14 2009
40
All MRIs nonlesional; 11 patients had subtle MRI abnormalities: atrophy without signal change, amygdala enlargement, FLAIR-increased intensity without atrophy
24 Patients (60% of all) were rendered seizure free; patients with subtle medial temporal lobe MRI abnormalities had an improved operative outcome (P = .03)
Hajek et al,39 2009
35
Concordant MRI and MRS in 25 patients; nonlateralizing MRI and MRS in 6 patients; 4 patients with indeterminate MRI had unilateral MRS findings that correctly lateralized the temporal lobe
MRS may be useful to localize the temporal lobe of seizure origin in the presence of indeterminate or bilateral MRI abnormalities
Schijns et al,38 2011 116
MTS alone in 58 patients; MTS plus gray-white matter abnormalities in 58 patients
51 Patients (87.9%) in both groups had a favorable operative outcome; no difference between the 2 MRI groups
Vale et al,34 2012
86
All patients had nonlesional MRI studies
47 Patients (55%) had excellent operative outcomes (Engel class I)a
43
25
MRI-identified MTS in 6 patients, unremarkable in 5 patients, and findings other than MTS in 14 patients
No difference in operative outcome based on MRI findings
Lau et al,332014
241
MRI assessment of hippocampal pathology
Surgery is less effective in patients with unremarkable MRI vs those with MTS
Miserocchi et al,31 2013
68
MRI-identified focal lesion in 44 patients, dual pathology in 13 patients, MTS alone in 8 patients, and extratemporal lesion in 3 patients
Patients with temporal lobe focal lesion or MTS alone had a favorable operative outcome; extratemporal lesions had poorer outcome after temporal lobe surgery
Elsharkawy et al,28 2009
434
MRI suggestive of hippocampal atrophy was associated with better outcome (P = .02)
MRI showing hippocampal atrophy associated with better surgical outcome
Kasasbeh et al, 2012
these patients.14,33-36 Magnetic resonance imaging was limited in identifying and classifying the subtypes of MTS; however, pathologically severe MTS appeared to have the most favorable operative outcome.37In another investigation38 there was no statistically significant difference in surgical outcome between individuals with MTS and those with MTS plus gray-white matter abnormalities. Magnetic resonance spectroscopy was shown to be helpful when MRI-identified abnormalities were bilateral.39 Magnetic resonance imaging volume of resection did not have any statistically significant effect on surgical outcome.22
Positron Emission Tomography There are conflicting results regarding the prognostic importance of PET in patients with drug-resistant focal epilepsy undergoing an anterior temporal lobectomy. Abnormalities were noted on FDG-PET in patients with temporal lobe epilepsy and an MRI study with unremarkable findings. 15,40 A PET scan showing abnormalities in patients with none identified on MRI was a favorable prognostic indicator following an anterior temporal lobectomy.19,40 In 2 studies,40,41 individuals with an unremarkable MRI study but PET-identified focal hypometabolism had an E4
Abbreviations: FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MTS, mesial temporal sclerosis; MTS type iB, pathologically defined severe hippocampal sclerosis. a
The Engel classification system is presented in the Findings section.
operative outcome similar to that of individuals with MTS. However, other studies13,27,36,42 did not demonstrate that the results of PET scans correlated with the operative outcome. One study22 indicated that a larger area of focal hypometabolism corresponded to a better surgical outcome. The presence of focal extratemporal hypometabolism predicts a poorer outcome.23 One study35 found no significant difference in outcome in unilateral and bilateral PET findings or unremarkable PET.
Single-Photon Emission Computed Tomography None of the studies using SPECT13,27,36,42,44-46 that were analyzed indicated the prognostic importance of SPECT in patients with temporal lobe epilepsy undergoing surgical treatment. In addition, SPECT did not assist in the presurgical planning for patients with MTS and, overall, provided redundant information.45 In patients who had discordant MRI and EEG findings, SPECT studies were also not predictive of outcome.44 In patients with unremarkable MRI findings, the ictal EEG was a technique associated with better surgical outcome than was SPECT.42 One study46 looking at hippocampal segmentation on SPECT found this imaging modality to be a reliable indicator of ictal origin.
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Table 2. MRI-PET or PET in Temporal Lobe Epilepsy: Surgical Outcome
Source
No. of Patients
Imaging Modality Studied
Imaging Findings
Surgical Outcomea Patients with mesial temporal lobe epilepsy were more likely to be SF
Boling et al,15 2008
27
MRI, FDG-PET More FDG-PET hypometabolism correlated with better outcome; MRI plus FDG-PET combined picked up all the SF patients
Tatum et al,42 2008
39
MRI, FDG-PET, SPECT
All MRI−; FDG-PET and SPECT scans were not predictive of a better surgical outcome
Uijl et al,27 2008
484
MRI, FDG-PET, SPECT
Abnormal MRI, ipsilateral MTS, and Engel class I outcome seemed to be correlated with abnormal MRI, FDG-PET abnormalities predicted ipsilateral MTS, and FGD-PET, but better outcomes individually none of these combined produced a model to predict outcome
Wong et al,23 2010
64
FDG-PET
All patients had MRI evidence of hippocampal sclerosis; 4 normal PET scans, 49 (77%) ipsilateral localized PET scans; 45 (70%) had extratemporal hypometabolism as well
Vinton et al,22 2007
26
MRI, FDG-PET MRI volume did not have any statistically significant difference in surgical outcome
The greater the resection of the FDG-PET hypometabolic area, the better the outcome from surgery
MRI, FDG-PET FDG-PET may be helpful in predicting a better outcome, comparable to the outcome of patients with MTS
No difference in outcomes from PET+/MRI− patients compared with MTS patients (21 [75%] had class I outcome)
MRI, FDG-PET FDG-PET correctly lateralized in concordance with EEG in 42 of 45 (95%) MRI+, 3 of 4 (75%) MRI equivocal, and 26 of 29 (90%) MRI−; 32 of 38 MRI− patients (84%) had lateralizing FDG-PET
No difference in outcomes from MRI− and equivocal patients; statistically significant difference in outcome of patients with unilateral FDG-PET (82 of 85 [96%] good) and nonunilateral FDG-PET (4 of 7 [57%] at last follow-up)
Yang et al,41 2014
115
Gok et al,19 2013
98
Jeong et al,13 2005
227
MRI, FDG-PET, SPECT
MRI pure ipsilateral HS: SF, 172 of 183 (93.5%); not SF, 33 of 43 (74.4%) (P = .02); PET and SPECT abnormalities were not statistically significant
The only predictor of better surgical outcome in MRI− patients was ictal EEG localization
A larger extent of extratemporal hypometabolism or remote hypometabolism predicted worse outcome
MRI showing unilateral HS was the only predictor of seizure freedom
Fong et al,35 2011
64
No significant difference in outcome MRI, FDG-PET All 64 patients had negative MRIs findings; 5 (7.8%) had normal PET in unilateral and bilateral PET findings or normal PET scans, 43 (67.2%) had unilateral PET abnormalities, and 14 (21.9%) had bilateral PET abnormalities
Smith et al,36 2011
21
MRI, FDG-PET, SPECT
LoPintoKhoury et al,40 2012
193
All patients were MRI−; 8 of 11 patients PET only were localizing; 0 of 2 SPECT/SISCOM were localizing
MRI, FDG-PET 46 Patients were PET+/MRI− and 147 had MTS on MRI
None of the imaging modalities helped predict surgical outcome
PET+/MRI− and MTS groups did not have significantly different outcomes from surgery
Abbreviations: EEG, electroencephalogram; FDG, fludeoxyglucose F 18; HS, hippocampal sclerosis; MRI, magnetic resonance imaging; MTS, mesial temporal sclerosis; PET, positron emission tomography; SF, seizure free; SISCOM, subtraction-ictal SPECT coregistered with MRI; SPECT, single-photon emission computed tomography; −, normal findings; +, abnormal findings. a
The Engel classification system is presented in the Findings section.
Table 3. MRI-SPECT or SPECT in Temporal Lobe Epilepsy: Surgical Outcome Source Castro et al,44 2008
No. of Patients 77
Velasco et al,45 2011
240
JafariKhouzani et al,46 2011
46
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Imaging Modality Studied
Imaging Findingsa
Surgical Outcome
MRI, SPECT
Divided into MRI-EEG concordant and discordant groups; ictal SPECT was performed in 48 of 77 patients (62.3%); 3 of 48 patients had discordant SPECT localization to the site of the MTS, but all 3 had good outcome
Discordant MRI and EEG findings may be due to false localization, and SPECT was not good at predicting outcome; MRI is superior
SPECT
Ictal SPECT scans were accurate in detecting the epileptogenic region, but this overlapped with MRI and EEG findings in 80% of the patients; accuracy was higher in those whose EEG was ipsilateral to the MRI findings of HS (85%)
SPECT did not offer localizing value over MRI and scalp EEG in presurgical evaluation of MTLE-HS; overall, SPECT provided redundant information
SPECT segmentation
Highest lateralization in the hippocampus (91%), then amygdala (87%), putamen (67%), and thalamus (61%)
Hippocampal segmentation on SPECT correlates well with ictal origin and is reliable
Abbreviations: EEG, electroencephalogram; HS, hippocampal sclerosis; MRI, magnetic resonance imaging; MTLE, mesial temporal lobe epilepsy; SPECT, single-photon emission computed tomography. a
A more complete breakdown of the data was not provided in some studies.
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Clinical Review & Education Review
Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
Discussion Few randomized studies have examined the prognostic importance of structural or functional neuroimaging studies in patients with drug-resistant focal epilepsy undergoing temporal lobe surgery. Previous investigations5-7,13,33 have confirmed the efficacy of anterior temporal lobectomy in individuals with medically refractory seizure disorders. Surgical treatment has compared favorably with antiepileptic drug therapy trials in these patients.6 The 27 studies included in the present review provide compelling evidence that the selected neuroimaging modalities commonly performed during the diagnostic evaluation of drugresistant epilepsy may be useful to localize the site of seizure onset, demonstrate the pathologic findings, and determine an operative strategy. However, MRI was the only neuroimaging technique shown to be of prognostic importance in individuals with drugresistant focal epilepsy undergoing an anterior temporal lobectomy. In particular, MRI-identified hippocampal formation atrophy, a surrogate for hippocampal neuronal loss and MTS, is the most important factor associated with a seizure-free outcome after epilepsy surgery.28 Patients with hippocampal formation atrophy are more likely to experience prolonged seizure remission following epilepsy surgery.28 An MRI with results considered to be normal was shown14 to correlate with a less favorable operative outcome. The present review was unable to confirm a prognostic importance of PET and SPECT in patients with no hippocampal atrophy. The inherent limitations of an evidence-based review need to be considered in interpreting the present findings regarding neuroimaging in temporal lobe epilepsy. The strict inclusion criteria necessary for a systematic review reduce the number of clinical studies available for analysis. The lack of appropriate studies, often with modest numbers of patients, may not always permit an appropriate conclusion regarding a specific neuroimaging modality. Use of the established criteria allowed only 3 studies that evaluated the prognostic importance of SPECT in individuals undergoing temporal lobe surgery to be included in the present review. The studies also may be difficult to compare because of differences in methodology and technique, as well as in experience at epilepsy centers. Selected imaging modalities (eg, SISCOM) are not available at all selected institutions.24,25 Inability to coregister PET and MRI may also reduce the diagnostic yield of PET imaging in temporal lobe epilepsy.21 Contemporary innovations in neuroimaging, such as statistical SPECT processing, were not evaluated in these evidencebased medicine trials.48
ARTICLE INFORMATION Accepted for Publication: December 18, 2015. Published Online: February 29, 2016. doi:10.1001/jamaneurol.2015.4996. Author Contributions: Drs Jones and Cascino had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Cascino. Acquisition, analysis, or interpretation of data: Both authors. Drafting of the manuscript: Both authors. Critical revision of the manuscript for important
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Decision making in the evaluation and surgical treatment of patients with drug-resistant focal epilepsy is never limited to one diagnostic study. Neuroimaging studies would be performed in the context of a comprehensive presurgical evaluation that includes a detailed seizure disorder history, outpatient routine EEG, long-term videoEEG recordings in an epilepsy monitoring unit, and neuropsychological studies. Magnetic resonance imaging has a pivotal role in demonstrating a structural alteration that may indicate the likely cause of the seizure disorder and suggest the region or zone of seizure onset. Specific MRI protocols should be used when performing these studies in patients with drug-resistant focal epilepsy who are being considered for epilepsy surgery.8,49,50 These high-resolution MRI head studies are more comprehensive than routine MRI of the head ordered for other indications (eg, headache). Advanced brain imaging may use volumetric analysis, double-inversion recovery sequences, and T2relaxometry for evaluation of patients with drug-resistant focal epilepsy.49-51 Studies using 7-T MRI may also increase the diagnostic yield of neuroimaging in individuals with MTS.52 Patients with an MRIidentified substrate-directed pathology (eg, MTS) require electrophysiologic studies because a structural abnormality may be remote from the epileptic brain tissue. Individuals with MRI-negative focal epilepsy should not receive a classification of “MRI-nonlesional” because these patients may be shown to have pathologically verified lesions, such as focal cortical dysplasia or other malformations of cortical development.20 The importance of a focal PET abnormality in individuals with an unremarkable MRI examination has been confirmed.40,41 Functional neuroimaging in patients with temporal lobe epilepsy is particularly important when the MRI study shows no abnormalities or is indeterminate.20
Conclusions Existing data confirm the pivotal role of the MRI study in evaluating individuals with drug-resistant focal epilepsy of temporal lobe origin for surgical treatment. There is a paucity of evidence-based medical studies in evaluating the usefulness of PET and SPECT in selecting patients for epilepsy surgery. The high diagnostic yield of PET has been confirmed in temporal lobe epilepsy; individuals with focal PET hypometabolism and an unremarkable MRI have an operative outcome similar to that of patients with MRI-identified MTS. Ultimately, the care of patients with drug-resistant focal epilepsy and management of their disease require a tailored, individualized neuroimaging workup to be performed in concert with the remainder of a comprehensive presurgical evaluation.
intellectual content: Cascino. Administrative, technical, or material support: Cascino. Study supervision: Cascino. Conflict of Interest Disclosures: None reported. REFERENCES
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Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy
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