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Keywords:

  • Epilepsy;
  • MRI ;
  • Presurgical evaluation;
  • MRI postprocessing;
  • MRI-negative epilepsy;
  • Voxel-based morphometry;
  • Orbitofrontal epilepsy;
  • Focal cortical dysplasia

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

Purpose

The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmed OF epilepsy and a negative magnetic resonance imaging (MRI) study. We aimed to examine the neuroimaging characteristics of MRI-negative OF epilepsy with the focus on a voxel-based morphometric MRI postprocessing technique.

Methods

We included six patients with OF epilepsy, who met the following criteria: surgical resection of the OF lobe with/without adjacent cortex, seizure-free for ≥12 months, invasive video–electroencephalography (EEG) monitoring showing ictal onset from the OF area, and preoperative MRI regarded as negative. Patients were investigated in terms of their image postprocessing and functional neuroimaging characteristics, electroclinical characteristics obtained from noninvasive and invasive evaluations, and surgical pathology. MRI postprocessing on T1-weighted high-resolution scans was implemented with a morphometric analysis program (MAP) in MATLAB.

Key Findings

Single MAP+ abnormalities were found in four patients; three were in the OF region and one in the ipsilateral mesial frontal area. These abnormalities were included in the resection. One patient had bilateral MAP+ abnormalities in the OF region, with the ipsilateral one completely removed. The MAP+ foci were concordant with invasive electrophysiologic data in the majority of MAP+ patients (four of five). The localization value of 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and ictal single-photon emission computed tomography (SPECT) is low in this cohort. Surgical pathology included focal cortical dysplasia, remote infarct, Rosenthal fiber formation and gliosis.

Significance

Our study highlights the importance of MRI postprocessing in the process of presurgical evaluation of patients with suspected orbitofrontal epilepsy and “normal” MRI. Using MAP, we were able to positively identify subtle focal abnormalities in the majority of the patients. MAP results need to be interpreted in the context of their electroclinical findings and can provide valuable targets in the process of planning invasive evaluation.

Among all cerebral regions, the orbitofrontal (OF) cortex is one of the least studied and understood region. It has vast bidirectional connectivity to a widely distributed network involving the frontal lobe, the temporal lobe, and the limbic system, making localization of ictal foci to this region particularly difficult (Cavada & Schultz, 2000; Alexopoulos & Tandon, 2008). Because of the hidden, deep location of the OF region in relation to the scalp electrode sampling, scalp electroencephalography (EEG) can be at times misleading with the lack of distinct ictal manifestations (Ebner, 2001; Pedley et al., 2003; Burgess et al., 2005).

High-resolution structural magnetic resonance imaging (MRI), when interpreted by experienced neuroradiologists, can be helpful to search for focal abnormalities in the OF region. When a patient presents with negative preoperative MRI, imaging with higher magnetic field or three-dimensional volume sequence, postprocessing analysis, as well as functional neuroimaging such as positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetoencephalography, may be important complements to the test battery of presurgical evaluation (Knowlton et al., 2008; Bien et al., 2009). In the literature, there are only rare cases documenting clear OF epilepsy with a negative preoperative MRI (Rugg-Gunn et al., 2002; Smith et al., 2004; Kriegel et al., 2012). Moreover, there was no study specifically reporting postprocessing neuroimaging characteristics of OF epilepsies in the setting of a normal preoperative MRI.

Recently, a voxel-based MRI postprocessing technique has been used to detect subtle cortical malformations missed with conventional MRI visual inspection (Huppertz et al., 2005, 2008; Wagner et al., 2011). This technique compares each individual patient with a normal control database, and yields three-dimensional (3D) feature maps of gray–white junction, cortical gyration, and cortical thickness. Abnormalities in these feature maps can indicate underlying focal cortical dysplasia (FCD; Krsek et al., 2008). The yield and specificity of the findings using this postprocessing technique in patients with OF epilepsy have not been reported previously.

In this study, we propose to examine the image postprocessing and functional neuroimaging (18F-fluorodeoxyglucose [FDG]-PET and ictal SPECT) characteristics of a strictly defined and highly selected, invasive EEG-confirmed group of patients with pharmacoresistant OF epilepsy with negative preoperative MRI. All patients were rendered seizure-free after resection of the OF region with/without adjacent cortex. In addition, we report the electroclinical features obtained from noninvasive and invasive studies and pathologic findings in these patients.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

Patients

This retrospective study was approved by the Cleveland Clinic institutional review board. From the consecutive surgical series of Cleveland Clinic Epilepsy Center between January 1999 and December 2011, patients with pharmacoresistant epilepsy were identified with the following criteria: (1) invasive video-EEG monitoring confirmed focal OF ictal onset during recorded habitual seizures; (2) surgical resection of the OF region with/without adjacent cortex rendered the patient seizure-free for >12 months (Engel class I outcome; Engel et al., 1993); (3) preoperative MRI was interpreted as normal; and (4) preoperative and postoperative MRI data were available. Clinical data were collated from medical charts, archived scalp and invasive video-EEG monitoring databases, and neuroimaging records.

Presurgical evaluations

All patients underwent one or more MRI 1.5 Tesla (1.5T) or 3 Tesla (3T) studies with a standard epilepsy protocol with Siemens scanners (Erlangen, Germany). Detailed imaging parameters can be found elsewhere (Wang et al., 2012). All patients underwent scalp video-EEG monitoring, PET, and subsequently intracranial electrode implantation. Ictal SPECT was performed whenever possible. Implantation and resection decisions were made at a multidisciplinary patient management conference (PMC) where all modalities were presented and consensus recommendations were made. MRI postprocessing was not available at the time of the evaluations and therefore was studied only retrospectively. Generally, patients who have no MRI lesion, present with poorly localized scalp EEG and hypermotor seizures, and those with seizures manifesting as temporal lobe seizures in the absence of temporal lobe pathology, are usually investigated with intracranial electrodes sampling from the OF region in our center.

PET scans were obtained after injection of 5–10 mCi 18F-FDG during the interictal state, with the patient resting in dimly lit room with eyes open. Scans were performed on Biograph PET CT (Siemens AG, Munich, Germany). Scans were coregistered to the volumetric MRI using vendor software. Visual analysis was performed first independent of other modalities, and then confirmed at PMC by a nuclear medicine physician. Presence and localization of relative focal hypometabolism were then reported.

SPECT images were acquired on a Siemens (Erlangen, Germany) Symbia dual-head camera (SPECT: 15 s per stop ×60 stops, 128 × 128 matrix, iterative reconstruction with attenuation correction; CT: 30 mAs, 5 mm slice). Interictal injection occurred after the patient was free of seizures for a minimum of 24 h. Ictal injection of radioisotope 99mTc-ECD (ethyl-cysteinate dimer; 1.6 ml) was administered by a specially trained nurse who remained at the bedside when the patient underwent scalp video-EEG monitoring. Within 2 h after injection, SPECT images were acquired. The interictal image was subtracted from the ictal image and analyzed following methodology of SISCOM (subtraction ictal SPECT coregistered to MRI; O'Brien et al., 1998).

MRI postprocessing

MRI postprocessing was performed using a morphometric analysis program (MAP) in Statistical Parametric Mapping (SPM;Wellcome Department of Cognitive Neurology, London, United Kingdom) within MATLAB 2007a (MathWorks, Natick, MA, U.S.A.) on preoperative T1-weighed Magnetization Prepared Rapid Acquisition with Gradient Echo (MPRAGE) images (Huppertz et al., 2005, 2008). Because the patients were selected from 1999 to 2011, three patients had 1.5T MRI (best available at that time) and three patients had 3T MRI. To ensure maximal sensitivity (Huppertz et al., 2010), we used different normal databases for 1.5T and 3T images. For 3T MRI, we used a database comprising 90 normal controls (41 female, 49 male, mean age 42.0 years, range 22–80 years), whose MRIs were acquired on the same 3T Siemens Trio scanner using the same MPRAGE sequence as the patients. For 1.5T MRI, we used an average database of 1.5T and 3T average normal database of 150 controls, 70 female, 80 male, mean age at MRI 30.9 years, range 15–77 years, with MRIs acquired on five different MRI scanners, which was kindly provided along with the MAP program (Huppertz et al., 2008). The output of MAP consists of three z-score feature maps in which brain structures deviating from the average normal brain have high z-scores, thus highlighting subtle abnormalities on the MRI. The junction file is sensitive to the blurring of the gray–white matter junction; the extension file is sensitive to abnormal gyration and extension of gray matter into white matter; the thickness file is sensitive to abnormal cortical thickness. More details can be found elsewhere (Huppertz et al., 2008). On a standard PC, each MAP processing took approximately 40 min.

MAP abnormalities were searched for in the entire brain. A blinded reviewer (ZIW) used the z-score of 4 to identify highlighted areas on the junction file. If an abnormality is detected on the junction file, the reviewer examined whether there was an accompanying z > 4 region on the extension file and the thickness file. Then with the guidance from these candidate areas of abnormality, a neuroradiologist (SEJ) conducted a focused re-review of the presurgical clinical MRI, with T1-weighted MPRAGE, T2-5 weighted fluid attenuated inversion recovery (FLAIR) and turbo spin echo (TSE) sequences, in order to confirm or dismiss each candidate MAP abnormality. Only the confirmed abnormalities were regarded as MAP+. This methodology is consistent with our previous report (Wang et al., 2012) and literature (Wagner et al., 2011). Images for this study were processed and reviewed as part of a large ongoing retrospective study, which examines the sensitivity and specificity of MAP to detect subtle abnormalities in a consecutive cohort of epilepsy patients with a negative MRI. Mixed with patient scans were control scans obtained from normal subjects. Neither the MAP reviewer nor the neuroradiologist was given prior information about the type of epilepsy, or whether it was a patient or control.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

Patient population

From January 1999 to December 2011, there were 1,841 resective surgeries of which 290 involved lobar or sublobar resections of the frontal lobe. A total of 28 patients underwent resections that involved the orbitofrontal region with or without additional sublobar areas. Among these 28 patients, only 9 had a clear MRI lesion within the orbitofrontal area. Six MRI-negative patients fulfilled the selection criteria (five right-handed patients, five females, mean age at surgery = 32.0 ± 16.1 years, age range: 8–51 years, mean epilepsy duration = 18.2 ± 12.7 years, epilepsy duration range: 6–40 years). Seizures were defined according to the semiologic seizure classification (Luders et al., 1998). Detailed clinical information is summarized in Table 1.

Table 1. Summary of data used during presurgical evaluation, including demographics data, semiology, seizure frequency, scalp-EEG evaluation, and subsequent ICEEG localization
Patient no.AgeSexHandED (y)Seizure semiology (Luders et al., 1998)Seizure frequencyInterictal scalp EEGIctal scalp EEG onsetInvasive procedure (n electrodes/n contacts)Invasive EEG onset
  1. F, female; M, male; L, left; R, right; ED, epilepsy duration; y, years; SEEG, stereotactic EEG; SDG, subdural grids; DE, depth electrodes; ICEEG, intracranial EEG.

  2. a

    Patient 1 had prior (13 years before) L anterior temporal lobectomy with seizures recurring shortly after.

P1a51FR14Nonspecific aura [RIGHTWARDS ARROW] Automotor seizure10/monthRegional L temporal (max T7)Regional L temporalSEEG (10/92)L orbitofrontal
P238FR24

Type 1: Nonspecific aura [RIGHTWARDS ARROW] Hypermotor seizure

Type 2: No aura [RIGHTWARDS ARROW] Hypermotor seizure

3–4/monthRegional L frontal (max SP1)NonlocalizableSDG (6/120)L orbitofrontal
P320FR18Abdominal aura [RIGHTWARDS ARROW] Hypermotor seizure10/month

Regional R temporal (max SP2, 70%)

Regional L temporal (max SP1, 30%)

Regional R temporal

SDG (7/174)

DE (3/24)

R orbitofrontal
P445MR40Abdominal aura [RIGHTWARDS ARROW] Axial tonic seizure [RIGHTWARDS ARROW] Hypermotor seizure20/monthRegional L temporal (max SP1 = T7)Regional L frontocentralSEEG (14/126)L orbitofrontal
P58FR6No aura [RIGHTWARDS ARROW] Hypermotor seizure150/dayRegional R frontal (max Fp2 = F4 = F8)Regional R frontalSDG (7/210)R orbitofrontal
P630FL7Abdominal and gustatory aura [RIGHTWARDS ARROW] Hypermotor seizure12/monthRegional R frontotemporal (max T8/FT10/F10 = T10/FT8/SP2)Regional R frontotemporalSEEG (12/112)R orbitofrontal

Scalp EEG and invasive EEG findings

On scalp EEG, interictal epileptiform discharges were recorded in all six patients (ipsilateral temporal = 2, ipsilateral frontal = 2, ipsilateral frontotemporal = 1, bilateral temporal = 1). In the majority of the patients, ictal onset of scalp EEG was mapped to the ipsilateral frontal and/or temporal region (temporal = 2, frontal = 1, frontocentral = 1, frontotemporal = 1). Ictal onset in one patient was nonlocalizable.

Three patients had subdural grid implantation with depth electrodes, and three patients underwent stereotactic EEG depth electrodes (SEEG) implantations. In all patients, invasive video-EEG confirmed ipsilateral OF focal ictal onset during their habitual seizures (see Table 1, Figs. 1-3).

image

Figure 1. Four OF epilepsy patients with positive MAP findings shown on gray-white junction file. In this and Figure 2, first column: presurgical T1-weighted image; second column: coregistered MAP junction file; third column: postsurgical MRI indicating resection of the OF region. The red crosses show the location of the subtle abnormalities. The rest of the column(s) contain illustrations of neuroimaging/intracranial EEG (ICEEG) findings when applicable (nonlocalizable or discordant findings were not shown but reported in Tables 1 and 2). Red electrode contacts indicate ictal onset during invasive monitoring.

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image

Figure 2. An OF epilepsy patient who had three abnormalities indicated by MAP junction file; each abnormality is shown on a separate row. Surgical resection occurred only in the right OF region, concordant with PET and ictal onset on intracranial EEG.

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image

Figure 3. An OF epilepsy patient with negative MAP findings. The left column shows the postsurgical MRI, the middle column is an illustration of SPECT localization, and the right column indicates intracranial EEG ictal onset zone from the OF region.

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MAP findings

MAP+ abnormalities were found in five of six patients. In P1, P2, and P3, MAP gray–white junction file pinpointed a subtle abnormality in the OF area, concordant with ictal invasive findings. In P4, MAP+ abnormality was in the mesial frontal area, separated from the OF region. Resection included the MAP+ abnormality in all four patients. Given that all patients were seizure-free, these lesions were considered true positives. P5 was unique: she is the only patient with bilateral OF MAP+ changes. A contralateral epileptogenic focus was not suspected by the electroclinical and other noninvasive data. The patient underwent exploration with subdural electrodes targeting the right hemisphere and remains seizure-free following resection restricted to the right OF region. P2, P3, and P4 were found to have abnormalities on the MAP extension file in the same or adjacent region as the junction file, among which only P2 and 3 had accompanying abnormalities in the MAP thickness file. Details of neuroimaging, surgical, and pathology data can be found in Table 2, and the MAP+ abnormalities are shown in Figs. 1 and 2, side-by-side with coregistered T1-weighted images. Figure 3 shows neuroimaging and SEEG data for the MAP-negative patient, who did not have any abnormalities identified in OF or other cortical areas.

Table 2. Summary of neuroimaging data (including MRI postprocessing, FDG-PET and ictal SPECT), area of surgical resection and surgical pathology
Patient no.MAPFDG-PET (S/L/M)Ictal SPECT (injection time) (S/L/M)SurgeryPathology
  1. L, left; R, right; S, sublobar; L, lobar; M, multilobar; FCD, focal cortical dysplasia; HS, hippocampal sclerosis.

  2. a

    Patient 1 had prior (13 years before) L anterior temporal lobectomy with seizures recurring shortly after.

P1aL orbitofrontalR anterior mesial temporal (S)NAL orbitofrontal resectionFCD IA
P2L orbitofrontalNormalR parietoccipital (27 s) (M)L orbitofrontal resection extending to L frontal poleNonspecific gliosis
P3R orbitofrontal

R temporal pole

R mesial frontal (M)

R middle to anterior temporal (10 s) (L)R orbitofrontal resection extending to R frontal poleNonspecific gliosis
P4L mesial frontalBilateral frontoparietal (M)L mesial frontal (11 s) (S)L orbitofrontal resection extending to L frontal poleRemote infarct with gliosis and Rosenthal fiber formation
P5R orbitofrontal L orbitofrontalL superior parietal, bilateral temporal and occipital, R orbitofrontal (M)NAR orbitofrontal resectionFCD IIA
P6NegativeBilateral mild hypometabolism in anterior and mesial temporal, minimally worse on the R (M)R anterior mesial temporal and orbitofrontal (9 s) (M)R orbitofrontal resection plus temporal lobe and mesial structuresFCD IA (both orbitofrontal and temporal specimens) No HS

Functional neuroimaging findings

FDG-PET and ictal SPECT findings are summarized in Table 2 and illustrated in Figs. 1-3, when concordant with the OF region. Interictal FDG-PET falsely localized to ipsilateral mesial temporal region in one patient and was nonlocalizing in the remaining patients (normal FDG-PET = 1; multilobar glucose hypometabolism = 4). Upon retrospective analysis, the MAP+ focus was concordant with hypometabolism on PET in P3; in P5, one of the MAP+ foci was concordant with PET, was subsequently resected, and rendered the patient seizure-free.

Ictal SPECT was successfully obtained in four of the six patients (ictal injection time: 9–27 s). In P6, SISCOM analysis showed ictal hyperperfusion in ipsilateral OF and mesial temporal region. Hyperperfusion areas in the other patients included the ipsilateral frontal lobe, contralateral parietooccipital cortex, and ipsilateral temporal lobe, suggesting rapid propagation of seizures from the OF region. MAP+ focus was concordant with ictal SPECT hyperperfusion in only one patient (P4).

Surgery and pathology

Left-sided surgical resection was performed in three patients. Temporal structures were removed along with the OF region in P6. Anterior temporal resection of P1 was performed 13 years earlier without seizure improvement. Postsurgical MRI is shown in Figs. 1-3 for each patient. Surgical pathology revealed focal cortical dysplasia (FCD) in three patients, including FCD type IIA (n = 1) and type IA (n = 2; Palmini et al., 2004). In P4, pathology in tissue resected near the MAP+ focus was consistent with remote infarct with gliosis and Rosenthal fiber formation; in the OF region, nonspecific gliosis was found. Surgical pathology of P2 and P3 showed nonspecific gliosis (Table 2).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

We present here the largest series to date of MRI-negative orbitofrontal epilepsy. Our cohort of OF epilepsy was confirmed by invasive EEG recordings and postoperative seizure freedom. Our data show that voxel-based morphometric MRI postprocessing can identify subtle abnormalities in the majority of patients we studied. Our results suggest that a MAP+ abnormality may guide a more focused invasive EEG strategy and a subsequent tailored surgical resection.

Despite the significant improvements in MRI technology, a significant number of patients with frontal lobe (and in particular orbitofrontal) epilepsy continue to have “normal” MRI studies upon visual analysis (Lorenzo et al., 1995; Noe et al., 2013; See et al., 2013). The difficulty in identifying lesions within the OF region in particular may be due to the following possibilities: (1) the sulcation pattern in the OF region is highly variable and densely packed; (2) some MRI sequences (in particular, T2-weighted sequences) have higher susceptibility artifacts/geometric distortion due to the proximity of the OF region to the air-filled sinuses; therefore, they are not providing adequate anatomic information at times (Kringelbach & Rolls, 2004). For these reasons, subtle lesions in the OF region may not be obvious upon conventional MRI visual inspection. When noninvasive evaluation data (e.g., scalp EEG) do not point to a specific area of interest, MRI readers lack a testable anatomic hypothesis, and subsequently the study may be read as negative. Under these circumstances, a whole-brain MRI postprocessing technique that directs the reader's attention to suspicious abnormalities may prove to be helpful.

Focal cortical dysplasia, a common substrate in patients with refractory epilepsies, is frequently associated with blurring in gray–white junction (Krsek et al., 2008). Therefore, it is not surprising to find abnormalities on MAP junction file to be associated with FCD histopathology in two patients (P1 and P5). Of interest, histopathology findings also showed two MAP+ patients had nonspecific gliosis, and the MAP-negative patient had FCD in the resected specimen. One explanation could be the limited sampling issue of the pathologic tissue undergoing examination, under which circumstances single/isolated/small lesions could be missed. Another possible explanation is the hypothesis that MAP, as a postprocessing technique of structural MRI, is not sensitive strictly to FCD per se, but to any pathologic substrate (or combinations of them) causing T1 signal alteration leading to a blurred gray–white junction. This hypothesis is also consistent with the non-FCD pathology finding in P4. Consistent with our study, a 2004 study also reported one patient with “nonlesional” OF epilepsy whose surgical pathology showed only gliosis; the patient remained seizure-free at 5-year follow-up (Smith et al., 2004). A 2002 case study presented another patient without abnormality on conventional MRI but with increased diffusivity in the OF region. The patient underwent inferior frontal lobe resection and remained Engel class IIa. Pathology also showed gliosis but not dysplasia (Rugg-Gunn et al., 2002).

Although most identified MAP+ abnormalities were correlated with in situ epileptogenicity, our data show that the presence of MAP+ abnormalities does not always correlate directly with active epileptogenicity. These abnormalities were not resected and no information regarding the histologic characteristics can be obtained. As observed in P5, the resection of the structurally abnormal and EEG-proven epileptic abnormality leads to long-lasting seizure control (>5 years). The finding of structural abnormalities in areas outside the presumed epileptic focus is consistent with the literature (Colliot et al., 2006; Salmenpera et al., 2007; Fauser et al., 2009; Yasuda et al., 2010). These postprocessing imaging changes could be due to potentially epileptic/proepileptic abnormalities that were not epileptic at the time of invasive recordings, and may be the underlying cause of late seizure recurrence following epilepsy surgery (Najm et al., 2013). Another explanation of the presence of “nonepileptic” focal abnormalities on MAP is the possibility of false-positive changes. Previously published automated voxel-based morphometry studies had reported false-positive findings in the control group, particularly when the sensitivity of the patient group was maximized (Focke et al., 2008). The significance of MAP+ regions should therefore be interpreted in the context of all other clinical test results.

Interictal and ictal scalp EEG rarely provide localizing information in OF epilepsy due to the large distance between the epileptogenic zone and the electrodes (Alexopoulos & Tandon, 2008); however, they can still have lateralizing value, as suggested by our data. Similar to several previous studies, we found interictal and ictal EEG often falsely localized to the ipsilateral temporal region, although it is interesting to note that bifrontal discharges and onset were not seen in our group (Ludwig et al., 1975; Chang et al., 1991; Jobst & Williamson, 2005). False localization to the temporal region occurs probably due to the close bidirectional connections between the temporal and OF region, as demonstrated by a classic study in 1958 using strychnine neuronography, in which the authors found that spikes generated in the OF region can quickly propagate to the ipsilateral temporal cortex and vice versa (Kendrick & Gibbs, 1958).

Intracranial EEG remains the corner stone of orbitofrontal epilepsy evaluation. It is especially illustrative once a reasonable implantation hypothesis has been made based on the noninvasive evaluation. Intracranial EEG studies in all our patients sufficiently covered the OF region and exclusively pointed ictal onset to the OF region in all patients. The basal frontal region is usually sampled by a four-by-four subdural electrode array (shown in Fig. 1, P2, P3 and Fig. 2, P5), whereas stereotactic EEG can be especially useful to explore the generators located in the mesial and lateral aspects of the OF region (Fig. 1, P1, P4, and Fig. 3, P6; Munari & Bancaud, 1992). Due to the widespread connection from the OF area, coverage of the anterior and mesial temporal regions, insula, operculum, and cingulate gyrus is recommended to improve the investigators' ability to differentiate seizure onset and propagation (Alexopoulos & Tandon, 2008).

Although FDG-PET has some diagnostic value in nonlesional frontal lobe epilepsies as a whole (Lee et al., 2005; Salamon et al., 2008), there is no previous literature specifically studying its effectiveness in OF epilepsies. In all patients included in this study, PET was negative, multilobar, or falsely localizing to the temporal lobe. Only on retrospective review can one find concordance between hypometabolism on PET and the MAP+ foci/intracranial EEG onset. Several reasons could contribute to the relative low yield of PET to OF epilepsies, including complicated gyration pattern in the OF region, which may lead to partial volume effect smearing the image resolution, and the fact that PET was visually inspected after coregistration with the MRI, without further quantitative analysis. Alternatively, perhaps epileptic activities originating from the OF region just spreads more quickly. As illustrated in previous studies, fast propagation of epileptic activities can be associated with widespread hypometabolism, or hypometabolism remote to the ictal-onset zone (Wong et al., 2010, 2012).

No previous studies specifically examined the effectiveness of SPECT SISCOM in localizing seizures from the OF region. In our cohort, SPECT was recorded in four of the six patients, but none localized exclusively to the OF region despite early injection. The hyperperfusion always existed in multiple adjacent areas. The low efficacy of SPECT in this cohort can be explained by rapid propagation of seizures to regions closely connected with OF area (Noachtar et al., 1998).

The gold standard for accurate localization of the epileptogenic zone is invasive EEG recording over the seizure-onset zone, with postresective seizure freedom (Engel et al., 1981; Rosenow & Luders, 2001; Kellinghaus & Luders, 2004). Patients with OF epilepsy carrying the strongest proof should not only have ictal onset exclusively from the OF region, but should also be rendered seizure-free after exclusive resection of the OF cortex. However in practice, the OF cortex is rarely the only area of resection. Overall, multiple concordant modalities generally lead to a more confined resection. It is our hope that this study, with the addition of MRI postprocessing findings, could shed light on future refinement of surgical strategies of orbitofrontal epilepsies.

Another potential benefit of our study is the contribution of MRI postprocessing in the identification of a possibly epileptogenic lesion in an area of the brain that is rarely suspected as an anatomic location of frontal lobe epilepsy and frequently mislocalized to other neighboring regions. This hypothesis can be tested through MAP analyses of patients who failed previous frontal or temporal lobe resections, and verification of seizure-free status with subsequent resection of MAP+ areas (e.g., P1).

In summary, our study highlights the importance of MRI postprocessing as a promising tool to complement conventional visual inspection of the MRI in terms of identifying potentially epileptogenic but subtle cortical abnormalities. This tool, when used in conjunction with other noninvasive modalities, has the potential to assist the planning of invasive electrode implantation and surgical resection in patients with MRI-negative pharmacoresistant orbitofrontal lobe epilepsy.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

The authors acknowledge Professor Hans-Jürgen Huppertz for his gracious support to our research. The authors also acknowledge the reviewers for their constructive critiques to improve this manuscript. This research was supported by the Cleveland Clinic Epilepsy Center Fund, the Epilepsy Foundation Post-doctoral Fellowship Grant, and NIH Grant R01-NS074980.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

Andreas V. Alexopoulos serves on the editorial board of Epileptic Disorders, and has received research support from UCB, Pfizer Inc, and from the American Epilepsy Society. Imad M. Najm is on the speakers' bureau of UCB Inc, and receives research funding from the US Department of Defense. Stephen E. Jones and Jorge A. Gonzalez-Martinez have received research support from Citizens United for Research in Epilepsy (CURE). Shuang Wang has received research support from the Chinese National Natural Science Foundation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biographies
  10. Supporting Information
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