Relationship between preoperative hypometabolism and surgical outcome in neocortical epilepsy surgery

Purpose: Fluorine‐18‐fluorodeoxyglucose–positron emission tomography (FDG‐PET) hypometabolism has been used to localize the epileptogenic zone. However, glucose hypometabolism remote to the ictal focus is common and its relationship to surgical outcome has not been considered in many studies. We investigated the relationship between surgical outcome and FDG‐PET hypometabolism topography in a large cohort of patients with neocortical epilepsy. Methods: We identified all patients (n = 68) who had interictal FDG‐PET between 1994 and 2004 and who underwent resective epilepsy surgery with follow up for more than 2 years. The volumes of significant FDG‐PET hypometabolism involving the resected epileptic focus and its surrounding regions (perifocal hypometabolism) and those distant to and not contiguous with the perifocal hypometabolism (remote hypometabolism) were determined statistically using Statistical Parametric Mapping (voxel threshold p = 0.01, extent threshold ≥250 voxels, uncorrected cluster‐level significance p < 0.05) and were compared with magnetic resonance imaging (MRI) and clinical and demographic variables using a multiple logistic regression model to identify independent predictors of seizure outcome. Key Findings: Remote hypometabolism was present in 39 patients. Seizure freedom was 49% (19 of 39 patients) in patients with glucose hypometabolism remote from the epileptogenic zone compared to 90% (26 of 29 patients) in patients without remote hypometabolism. In 43 patients with an MRI‐identified lesion, seizure freedom was 79% (34 of 43 patients). In patients with normal MRI, cortical dysplasia was the predominant pathologic substrate. Multiple logistic regression analysis identified a larger volume of significant remote hypometabolism (p < 0.005) and absence of a MRI‐localized lesion (p = 0.006) as independent predictors of continued seizures after surgery. Significance: In patients with widespread glucose hypometabolism that is statistically significant when compared to controls, epilepsy surgery may not result in complete seizure freedom despite complete removal of the MRI‐identified lesion. The volume of significant glucose hypometabolism remote to the ictal‐onset zone may be an independent predictor of the success of epilepsy surgery.     

Electroclinical correlates of flumazenil and fluorodeoxyglucose PET abnormalities in lesional epilepsy

OBJECTIVE: To analyze the clinical utility of [11C]flumazenil (FMZ) PET to detect perilesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to MRI, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) PET, and electrocorticographic (ECoG) findings as well as clinical characteristics of the epilepsy in epileptic patients with brain lesion. BACKGROUND: The success of resective surgery in patients with medically intractable epilepsy and brain lesion depends not only on removal of the lesion itself but also on the reliable presurgical delineation of the epileptic cortex that commonly extends beyond it. PET could provide a noninvasive identification of such epileptogenic areas. METHODS: Seventeen patients underwent high resolution MRI, FDG and FMZ PET, and presurgical EEG evaluation, including chronic intracranial ECoG monitoring or intraoperative ECoG. Regional cortical FDG/FMZ PET abnormalities were defined on partial volume-corrected PET images using an objective method based on a semiautomated definition of areas with abnormal asymmetry. Structural lesions were defined on coregistered MRI. The marked PET abnormalities visualized on three-dimensional cortical surface were compared with each other, to the extent of MRI-defined lesion, as well as to ECoG findings. RESULTS: The mean surface extent of FMZ PET abnormalities was significantly larger than the corresponding structural lesions, but it was significantly smaller than areas of glucose hypometabolism. The size of perilesional FDG PET abnormalities showed a correlation with the lifetime number of seizures (r = 0.93, p = 0.001). The extent of perilesional FMZ PET abnormalities was independent of the seizure number and showed an excellent correspondence with spiking cortex, the resection of which resulted in seizure-free outcome in all but one operated patient. Remote FMZ PET abnormalities (n = 6) were associated with early age at seizure onset (p = 0.048) and appeared in ipsilateral synaptically connected regions from the lesion area. CONCLUSIONS: Three-dimensional surface-rendered FMZ PET is able to delineate perilesional epileptic cortex, and it may be especially useful to localize such areas in patients with extensive perilesional glucose hypometabolism associated with a large number of seizures. Remote FMZ PET abnormalities in patients with early onset and long duration of epilepsy might represent secondary epileptogenesis, but this requires further study.     

Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy

OBJECTIVE: To compare abnormalities determined in 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET images with intracranial EEG data in patients with extratemporal lobe epilepsy. BACKGROUND: Although PET studies with FDG and FMZ are being used clinically to localize epileptogenic regions in patients with refractory epilepsy, the electrophysiologic significance of the identified PET abnormalities remains poorly understood. METHODS: We studied 10 patients, mostly children (4 boys, 6 girls, aged 2 to 19 years; mean age, 11 years), who underwent FDG and FMZ PET scans, intracranial EEG monitoring, and cortical resection for intractable epilepsy. EEG electrode positions relative to the brain surface were determined from MRI image volumes. Cortical areas of abnormal glucose metabolism or FMZ binding were determined objectively based on asymmetry measures derived from homotopic cortical areas at three asymmetry thresholds. PET data were then coregistered with the MRI and overlaid on the MRI surface. A receiver operating characteristics (ROC) analysis was performed to determine the specificity and sensitivity of PET-defined abnormalities against the gold standard of intracranial EEG data. RESULTS: FMZ PET detected at least part of the seizure onset zone in all subjects, whereas FDG PET failed to detect the seizure onset region in two of 10 patients. The area under the ROC curves was higher for FMZ than FDG PET for both seizure onset (p = 0.01) and frequent interictal spiking (p = 0.04). Both FMZ and FDG PET showed poor performance for detection of rapid seizure spread (area under the ROC curve not significantly different from 0.5). CONCLUSIONS: [11C]flumazenil (FMZ) PET is significantly more sensitive than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET for the detection of cortical regions of seizure onset and frequent spiking in patients with extratemporal lobe epilepsy, whereas both FDG and FMZ PET show low sensitivity in the detection of cortical areas of rapid seizure spread. The application of PET, in particular FMZ PET, in guiding subdural electrode placement in refractory extratemporal lobe epilepsy will enhance coverage of the epileptogenic zone.     

Spectroscopic evidence of hippocampal abnormalities in neocortical epilepsy

Lesional neocortical epilepsy (NE) can be associated with hippocampal sclerosis or hippocampal spectroscopic abnormalities without atrophy (dual pathology). In this study, magnetic resonance spectroscopic imaging (MRSI) was used to determine the frequency of hippocampal damage/dysfunction in NE with and without structural lesion. Sixteen patients with NE [seven temporal NE (NE-T), nine extratemporal (NE-ET)] and 16 controls were studied with a 2D MRSI sequence (Repetition time/echo time (TR/TE) = 1800/135 ms) covering both hippocampi. Seven NE patients had MR visible lesions (NE-Les), nine had normal MRI (NE-no). In each hippocampus, 12 voxels were uniformly selected. In controls, mean (+/- SD) NAA/(Cr + Cho) values for each voxel were calculated and voxels with NAA/(Cr + Cho) < or = (mean in controls--2SD in controls) were defined as 'pathological' in patients. Eight of 16 NE patients had at least two 'pathological' voxel (mean 2.5, range 2-5) in one hippocampus. Four were NE-Les and four NE-no. Three (43%) NE-T patients, had evidence for hippocampal damage/dysfunction and five (56%) had NE-ET. The ipsilateral hippocampus was affected in six of eight NE patients. Evidence for unilateral hippocampal damage/dysfunction was demonstrated in 50% of the NE patients. The type of NE, i.e. NE-Les or NE-no, NE-T or NE-ET, had no influence on the occurrence of hippocampal damage/dysfunction.     

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy

Objective

Epilepsy surgery fails to achieve seizure freedom in 30%–40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient-specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes.

Methods

Resting-state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band-power spatial maps were computed using source-localized recordings. Patient and region-specific band-power abnormalities were estimated as the maximum absolute z-score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom.

Results

Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC] = 0.80, p = .003; partial resection of epileptogenic zone: AUC = 0.68, p = .053; and insufficient cortical abnormality impact: AUC = 0.64, p = .096). Furthermore, 95% of those patients who were not seizure-free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure-free.

Significance

The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band-power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre-surgical evaluations.     

Localizing value of alpha-methyl-L-tryptophan PET in intractable epilepsy of neocortical origin.

BACKGROUND: [(11)C] alpha-methyl-L-tryptophan (alpha-MTrp) has been developed as a tracer for the study of the synthesis of serotonin in the brain with PET. However, it has been shown that in pathologic conditions the tracer may reflect the activation of kynurenine metabolism. Increased levels of serotonin and quinolinic acid have been described in resected epileptogenic cortex, raising the possibility that alpha-MTrp can localize seizure foci in patients with intractable partial epilepsy. The authors assessed the uptake of alpha-MTrp in 18 patients (11 men, mean +/- SD age 27.1 +/- 10.1 years, range 13 to 54) with intractable partial epilepsy to correlate the PET findings with the epileptogenic area defined by electroclinical and neuroimaging data. METHOD: Seven patients with cortical dysplasia (CD) and 11 with partial epilepsy in which conventional MRI and fluorine-18-deoxyglucose ((18)FDG)-PET studies failed to detect any abnormality were studied. All underwent scalp EEG monitoring during the PET scan to exclude ictal events and estimate the interictal epileptic activity. RESULTS: In seven patients (39%; CD four and cryptogenic partial epilepsy three), PET showed focal increased uptake of alpha-MTrp corresponding to the epileptogenic area. alpha-MTrp uptake in the epileptic focus correlated with the frequency of interictal spikes (r = 0.7, p < 0.05). CONCLUSIONS: alpha-MTrp-PET may be of value in the localization of the epileptogenic area not only in patients with visible dysplastic lesions, but also in those with cryptogenic partial epilepsy.     

Surgical outcome and prognostic factors of cryptogenic neocortical epilepsy

Surgical treatment of cryptogenic neocortical epilepsy is challenging. The aim of this study was to evaluate surgical outcomes and to identify possible prognostic factors including the results of various diagnostic tools. Eighty-nine patients with neocortical epilepsy with normal magnetic resonance imaging (35 patients with frontal lobe epilepsy, 31 with neocortical temporal lobe epilepsy, 11 with occipital lobe epilepsy, 11 with parietal lobe epilepsy, and 1 with multifocal epilepsy) underwent invasive study and focal surgical resection. Patients were observed for at least 2 years after surgery. The localizing values of interictal electroencephalogram (EEG), ictal scalp EEG, interictal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and subtraction ictal single-photon emission computed tomography were evaluated. Seventy-one patients (80.0%) had a good surgical outcome (Engel class 1-3); 42 patients were seizure free. Diagnostic sensitivities of interictal EEG, ictal scalp EEG, FDG-PET, and subtraction ictal single-photon emission computed tomography were 37.1%, 70.8%, 44.3%, and 41.1%, respectively. Localization by FDG-PET and interictal EEG was correlated with a seizure-free outcome. The localizing value of FDG-PET was greatest in neocortical temporal lobe epilepsy. The focalization of ictal onset and also ictal onset frequency in invasive studies were not related to surgical outcome. Concordance with two or more presurgical evaluations was significantly related to a seizure-free outcome.     

Prognostic factors for surgery of neocortical temporal lobe epilepsy.

OBJECTIVES: In the current classification of epilepsies two forms of temporal lobe epilepsy (TLE) were included: mesial and lateral (neocortical) TLE. We aimed at identifying prognostic factors for the surgical outcome of lesional neocortical TLE. METHODS: We included consecutive patients who had undergone presurgical evaluation including ictal video-EEG and high-resolution MRI, who had TLE due to neocortical lateral epileptogenic lesions, who had a lesionectomy and who had >2-year follow-up. RESULTS: There were 29 patients who met the inclusion criteria. Twenty of them became postoperatively seizure-free. Patients' mean age was 34.8+/-9 years (range 18-52). The age at epilepsy onset was 20.1+/-8 years. We found that left-sided surgery (p=0.048) and focal cortical dysplasia (FCD) on MRI (p=0.005) were associated with non-seizure-free outcome, while lateralized/localized EEG seizure pattern (p=0.032), tumors on the MRI (p=0.013), and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom (p<0.001). Multivariate analysis indicated that the side of surgery was not an independent predictor. CONCLUSION: More than two-thirds of the patients with neocortical TLE became seizure-free postoperatively. Lateralized/localized EEG seizure pattern and tumors on the MRI were associated with postoperative seizure-freedom, while FCD were associated with a poor outcome. The 6-month postoperative outcome is a reliable predictor for the long-term outcome.     

Preference-based quality-of-life measures for neocortical epilepsy surgery

Critical to decision analysis studies are measures of outcome utilities. In epilepsy surgery the benefit versus risk ratio is of particular interest in neocortical resections. Using the standard gamble, we measured preferences of 30 epilepsy patients for 10 outcome states specific to neocortical epilepsy surgery. Although considered preliminary, the findings suggest that the value of being seizure-free may be greater than that of continued disabling seizures, even if some deficits typical of "eloquent" cortex injury are incurred with surgery. Seizure freedom achieved with polytherapy medical management may be less desirable than that achieved with surgery and monotherapy.     

Pre-surgical evaluation and surgical outcome of 41 patients with non-lesional neocortical epilepsy.

Pre-surgical evaluation and the surgical treatment of non-lesional neocortical epilepsy is one of the most challenging areas in epilepsy surgery. The aim of this study was to evaluate the surgical outcome and the diagnostic role of ictal scalp electroencephalography (EEG), interictal (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET), and ictal technetium-99m hexamethylpropyleneamine oxime single photon emission tomography ( (99m)Tc-HMPAO SPECT). In 41 non-lesional neocortical epilepsy patients (16 frontal lobe epilepsy, 11 neocortical temporal lobe epilepsy, seven occipital lobe epilepsy, four parietal lobe epilepsy, and three with multifocal onset) who underwent surgical treatment between December 1994 and July 1998, we evaluated the surgical outcome with a follow-up of at least 1 year. The localizing and lateralizing values of ictal scalp EEG, interictal FDG-PET, and ictal SPECT were evaluated in those patients with good surgical outcome. Ictal scalp EEG had the highest diagnostic sensitivity in the localization of epileptogenic foci (69.7% vs. 42.9% for FDG-PET and 33.3% for ictal SPECT; P= 0.027). However, no significant difference was found in the lateralization of the epileptogenic hemisphere among the three modalities (78.8% for ictal scalp EEG, 57.2% for FDG-PET, and 55.5% for ictal SPECT; P= 0.102). During a mean follow-up of 2.77 +/- 1.12 years, 33 (80.5%) showed good surgical outcome (seizure free or seizure reduction >90%), including 16 (39.0%) seizure free patients. Ictal scalp EEG was the most useful diagnostic tool in the localization of epileptogenic foci. Interictal FDG-PET and ictal SPECT were found to be useful as complementary and, sometimes, independent modalities. Many patients with non-lesional neocortical epilepsy would benefit from surgical treatment.     

Clinical outcome of epilepsy surgery

PURPOSE OF REVIEW: The outcome from current surgical methods of treating drug-resistant epilepsy will be considered, looking at changes in classical resective surgery and new methodology being introduced in the functional treatment of these patients. RECENT FINDINGS: There is now class I evidence that temporal lobe surgery is effective. Sophisticated and appropriate magnetic resonance imaging sequences, together with an assessment of the electroclinical syndrome, allow patients to be assessed for resective surgery. The concept of 'surgically remediable syndromes' determines the type of procedure that is effective for particular patients. Technical advances such as neuronavigation techniques and intra-operative magnetic resonance imaging have improved the effectiveness of these procedures. Other techniques of disconnection, such as multiple subpial transection, and stimulation both indirectly using the vagus nerve and directly using various intracranial targets, are currently effective and have potential for future development. SUMMARY: This review will demonstrate that current surgical techniques are safe and effective in relieving drug-resistant epilepsy.     

Prognostic factors in neocortical epilepsy surgery: multivariate analysis

PURPOSE: Defining prognostic factors for neocortical epilepsy surgery is important for the identification of ideal candidates and for predicting the prognosis of individual patients. We use multivariate analysis to identify favorable prognostic factors for neocortical epilepsy surgery. METHODS: One hundred ninety-three neocortical epilepsy patients, including 91 without focal lesions on MRI, were included. Sixty-one had frontal lobe epilepsy (FLE), 80 had neocortical temporal lobe epilepsy (nTLE), 21 had parietal lobe epilepsy (PLE), and 22 had occipital lobe epilepsy (OLE). The primary outcome variable was patient status >or=2 years after surgery (i.e., seizure free or not). Clinical characteristics and the recent presurgical diagnostic modalities were considered as probable prognostic factors. Univariate and standard multiple logistic regression analyses were used to identify favorable prognostic factors. RESULTS: The seizure-free rate was 57.5%. By univariate analysis, a focal lesion on MRI, localized ictal onset on surface EEG, epilepsies other than FLE, localized hypometabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET), and pathologies other than cortical dysplasia were significantly associated with a seizure-free outcome (p<0.05). Multivariate analysis revealed that a focal lesion on MRI (p=0.003), correct localization by FDG-PET (p=0.007), and localized ictal onset on EEG (p=0.01) were independent predictors of a good outcome. CONCLUSIONS: The presence of a focal lesion on MRI, correct localized hypometabolism on FDG-PET, or localized ictal rhythms on EEG were identified as predictors of a seizure-free outcome. Our results suggest that these findings allow the selection of better candidates for neocortical epilepsy surgery.     

Extent of neocortical resection and surgical outcome of epilepsy: Intracranial EEG analysis

Purpose: Intracranial electroencephalography (EEG) monitoring is an important process in the presurgical evaluation for epilepsy surgery. The objective of this study was to identify the ideal resection margin in neocortical epilepsy guided by subdural electrodes. For this purpose, we investigated the relationship between the extent of resection guided by subdural electrodes and the outcome of epilepsy surgery. Methods: Intracranial EEG studies were analyzed in 177 consecutive patients who had undergone resective epilepsy surgery. We reviewed various intracranial EEG findings and resection extent. We analyzed the relationships between the surgical outcomes and intracranial EEG factors: the frequency, morphology, and distribution of ictal‐onset discharges, the propagation speed, and the time lag between clinical and intracranial ictal onset. We also investigated whether the extent of resection, including the area showing ictal rhythm and various interictal abnormalities—such as frequent interictal spikes, pathologic delta waves, and paroxysmal fast activity—influenced the surgical outcome. Results: Seventy‐five patients (42%) were seizure free. A seizure‐free outcome was significantly associated with a resection that included the area showing ictal spreading rhythm during the first 3 s or included all the electrodes showing pathologic delta waves or frequent interictal spikes. However, subgroup analysis revealed that the extent of resection did not affect the surgical outcome in lateral temporal lobe epilepsy. Conclusions: The extent of resection is closely associated with surgical outcome, especially in extratemporal lobe epilepsy. Resection that includes the area with total pathologic delta waves and frequent interictal spikes predicts a good surgical outcome.     

Socioeconomic status influences time to surgery and surgical outcome in pediatric epilepsy surgery

The aims of this study were to evaluate the influence of socioeconomic status (SES) on time-to-surgery (TTS) and surgical outcome in children with treatment-resistant epilepsy in a universal health care system. The cohort consisted of children who had undergone resective epilepsy surgery between 2001 and 2013 in Canada. The patients' postal codes were linked to Statistics Canada National Household Survey data to obtain dissemination area income, which was used to infer SES. Time-to-surgery was defined as the interval from date of epilepsy onset to date of surgery. Seizure outcome was classified using ILAE classification. The associations between SES and TTS, as well as SES and surgical outcome, were assessed. Two hundred eighty-four children who had epilepsy surgery were included. Patients in the lowest income quintile had a significantly higher TTS relative to the highest income quintile (β = 0.121, p = 0.044). There were no significant associations between income quintiles and seizure-free surgical outcome (odds ratio (OR) = 0.746–1.494, all p > 0.05). However, patients in the lowest income quintile had a significantly lower odds of an improvement in seizure frequency relative to the highest income quintile (OR = 0.262, p = 0.046). The TTS was not uniform across SES in spite of the existence of a universal health care system. This finding highlights the need to address social and economic barriers for epilepsy surgery to improve access to this potentially curative treatment. Those with lower SES had lower likelihood of improvement in seizure control following epilepsy surgery and may require additional support including social and financial support to mitigate the discrepancies in seizure control following surgery between SES levels.