Impact of methodologic choice for automatic detection of different aspects of brain atrophy by using temporal lobe epilepsy as a model.

BACKGROUND AND PURPOSE: VBM, DBM, and cortical thickness measurement techniques are commonly used automated methods to detect structural brain changes based on MR imaging. The goal of this study was to demonstrate the pathology detected by the 3 methods and to provide guidance as to which method to choose for specific research questions. This goal was accomplished by 1) identifying structural abnormalities associated with TLE with (TLE-mts) and without (TLE-no) hippocampal sclerosis, which are known to be associated with different types of brain atrophy, by using these 3 methods; and 2) determining the aspect of the disease pathology identified by each method. MATERIALS AND METHODS: T1-weighted MR images were acquired for 15 TLE-mts patients, 14 TLE-no patients, and 33 controls on a high-field 4T scanner. Optimized VBM was carried out by using SPM software, DBM was performed by using a fluid-flow registration algorithm, and cortical thickness was analyzed by using FS-CT. RESULTS: In TLE-mts, the most pronounced volume losses were identified in the ipsilateral hippocampus and mesial temporal region, bilateral thalamus, and cerebellum, by using SPM-VBM and DBM. In TLE-no, the most widespread changes were cortical and identified by using FS-CT, affecting the bilateral temporal lobes, insula, and frontal and occipital lobes. DBM revealed 2 clusters of reduced volume complementing FS-CT analysis. SPM-VBM did not show any significant volume losses in TLE-no. CONCLUSIONS: These results demonstrate that the 3 methods detect different aspects of brain atrophy and that the choice of the method should be guided by the suspected pathology of the disease.

Network-level analysis of cortical thickness of the epileptic brain.

Temporal lobe epilepsy (TLE) characterized by an epileptogenic focus in the medial temporal lobe is the most common form of focal epilepsy. However, the seizures are not confined to the temporal lobe but can spread to other, anatomically connected brain regions where they can cause similar structural abnormalities as observed in the focus. The aim of this study was to derive whole-brain networks from volumetric data and obtain network-centric measures, which can capture cortical thinning characteristic of TLE and can be used for classifying a given MRI into TLE or normal, and to obtain additional summary statistics that relate to the extent and spread of the disease. T1-weighted whole-brain images were acquired on a 4-T magnet in 13 patients with TLE with mesial temporal lobe sclerosis (TLE-MTS), 14 patients with TLE with normal MRI (TLE-no), and 30 controls. Mean cortical thickness and curvature measurements were obtained using the FreeSurfer software. These values were used to derive a graph, or network, for each subject. The nodes of the graph are brain regions, and edges represent disease progression paths. We show how to obtain summary statistics like mean, median, and variance defined for these networks and to perform exploratory analyses like correlation and classification. Our results indicate that the proposed network approach can improve accuracy of classifying subjects into two groups (control and TLE) from 78% for non-network classifiers to 93% using the proposed approach. We also obtain network "peakiness" values using statistical measures like entropy and complexity-this appears to be a good characterizer of the disease and may have utility in surgical planning.

Predictors of efficacy after stereotactic radiosurgery for medial temporal lobe epilepsy.

BACKGROUND: Stereotactic radiosurgery (RS) is a promising treatment for intractable medial temporal lobe epilepsy (MTLE). However, the basis of its efficacy is not well understood. METHODS: Thirty patients with MTLE were prospectively randomized to receive 20 or 24 Gy 50% isodose RS centered at the amygdala, 2 cm of the anterior hippocampus, and the parahippocampal gyrus. Posttreatment MRI was evaluated quantitatively for abnormal T2 hyperintensity and contrast enhancement, mass effect, and qualitatively for spectroscopic and diffusion changes. MRI findings were analyzed for potential association with radiation dose and seizure remission (Engel Ib or better outcome). RESULTS: Despite highly standardized dose targeting, RS produced variable MRI alterations. In patients with multiple serial imaging, the appearance of vasogenic edema occurred approximately 9-12 months after RS and correlated with onset of seizure remission. Diffusion and spectroscopy-detected alterations were consistent with a mechanism of temporal lobe radiation injury mediated by local vascular insult and neuronal loss. The degree of these early alterations at the peak of radiographic response was dose-dependent and predicted long-term seizure remission in the third year of follow-up. Radiographic changes were not associated with neurocognitive impairments. CONCLUSIONS: Temporal lobe stereotactic radiosurgery resulted in significant seizure reduction in a delayed fashion which appeared to be well-correlated with structural and biochemical alterations observed on neuroimaging. Early detected changes may offer prognostic information for guiding management.

Widespread neocortical abnormalities in temporal lobe epilepsy with and without mesial sclerosis.

PURPOSE: Extrafocal structural abnormalities have been consistently described in temporal lobe epilepsy (TLE) with mesial temporal lobe sclerosis (TLE-MTS). In TLE without MTS (TLE-no) extrafocal abnormalities are more subtle and often require region of interest analyses for their detection. Cortical thickness measurements might be better suited to detect such subtle abnormalities than conventional whole brain volumetric techniques which are often negative in TLE-no. The aim of this study was to seek and characterize patterns of cortical thinning in TLE-MTS and TLE-no. METHODS: T1 weighted whole brain images were acquired on a 4 T magnet in 66 subjects (35 controls, 15 TLE-MTS, 16 TLE-no). Cortical thickness measurements were obtained using the FreeSurfer software routine. Group comparisons and correlation analyses were done using the statistical routine of FreeSurfer (FDR, p=0.05). RESULTS: TLE-MTS and TLE-no showed both widespread temporal and extratemporal cortical thinning. In TLE-MTS, the inferior medial and posterior temporal regions were most prominently affected while lateral temporal and opercular regions were more affected in TLE-no. The correlation analysis showed a significant correlation between the ipsilateral hippocampal volume and regions of thinning in TLE-MTS and between inferior temporal cortical thickness and thinning in extratemporal cortical regions in TLE-no. CONCLUSION: The pattern of thinning in TLE-no was different from the pattern in TLE-MTS. This finding suggests that different epileptogenic networks could be involved in TLE-MTS and TLE and further supports the hypothesis that TLE-MTS and TLE-no might represent two distinct TLE syndromes.

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.

Limitations of Wada memory asymmetry as a predictor of outcomes after temporal lobectomy.

BACKGROUND: The intracarotid amobarbital (Wada) test can be used to evaluate hemispheric memory capacity before anterior temporal lobectomy (ATL). Most patients demonstrate better memory with injection ipsilateral to planned resection (expected asymmetry [EA]), but a substantial minority show better memory with contralateral injection (unexpected asymmetry [UA]). Both degree and direction of Wada memory asymmetry (WMA) have been associated with worse surgical outcome in small series. Reports also suggest that UA is associated with greater decline in verbal memory after left ATL (L-ATL). METHODS: The relationship between WMA and surgical outcome (at 3 months, 1 year, and last follow-up) was examined in a large group of ATL patients (108 L, 119 R) with both EA and UA. Also, memory in a subgroup (96 L, 108 R) was examined, comparing subscores of the Rey Auditory Verbal Learning Test obtained preoperatively, at 3 months, and at 1 year. RESULTS: Thirty-six percent of L-ATL and 8% of R-ATL patients had UA. UA was associated with worse surgical outcome at 1 year for R-ATL patients but was not associated with worse outcome for L-ATL patients. There was no correlation between WMA and persistent postoperative verbal memory change for patients with L- or R-ATL. CONCLUSIONS: Unexpected asymmetry is uncommon in patients with right anterior temporal lobectomy (R-ATL) and may be a risk marker of poor surgical outcome. This relationship may be obscured by language confounds in patients with L-ATL. The results suggest that Wada asymmetry (using mixed stimuli) does not predict postoperative verbal memory; it is unclear whether this finding is generalizable to centers using only nonverbal stimuli.

Metabolic characteristics of cortical malformations causing epilepsy.

PURPOSE: Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM. METHODS: Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone. RESULTS: 30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr. CONCLUSION: In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.

Potentially misleading extratemporal lobe lesions in patients with temporal lobe epilepsy.

From a series of 217 consecutive temporal resections for intractable epilepsy between 1993 and 2000, we identified all patients with large non-neoplastic extratemporal lesions. Only patients with known postsurgical outcomes with follow up for more than two years were included. Fifteen patients were identified. All patients had a history of medically refractory epilepsy with clinical and ictal evidence of mesial temporal seizure onset. Eleven patients had extratemporal lesions ipsilateral to the seizure focus, whereas four patients had the lesions contralateral to the seizure focus. Nine of the 15 patients had evidence of hippocampal atrophy on magnetic resonance imaging (MRI). Following temporal resection, nine of these patients (60%) became seizure free (Engel class 1A), two patients were free of disabling seizures only (Engel class 1B), and two patients had a few early seizures but then became seizure free for at least two years (Engel class 1C). Two patients had significant improvement (Engel class 2). Thus, the finding of large extratemporal lesions on MRI was potentially misleading. When clinical semiology and ictal EEG recordings provide evidence of temporal onset seizures, anterior temporal resection should be considered in patients with extratemporal lesions.

Temporal lobectomy for epilepsy: recovery of the contralateral hippocampus measured by (1)H MRS.

(1)H MRS imaging was obtained from 10 patients with mesial temporal lobe epilepsy before and after surgery. After surgery, metabolic recovery in the contralateral hippocampus was detected. Preoperatively, reduced N-acetylaspartate (p < 0.04) increased after surgery nonsignificantly to equal control values. Cholines increased after surgery (p < 0.02) and creatine-phosphocreatine showed a trend to higher values. The results suggest that the contralateral hippocampus is affected by repeated seizure activity in the ipsilateral hippocampus, rather than presence of bilateral mesial temporal sclerosis.

1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy.

1H MRS imaging (MRSI) was performed on 15 patients with MRI-negative temporal lobe epilepsy (TLE) who underwent seizure surgery. The non-seizure-free patients (NSF) ipsilateral hippocampal N-acetylaspartate (NAA)/(Cr+Cho) z scores were lower than the contralateral scores (p = 0.04), and the NSF ipsilateral z scores were lower than the seizure-free patients' (SF) ipsilateral z scores (p = 0.0049). Similarly, NSF contralateral scores were lower than contralateral SF (p = 0.02). These findings suggest NAA predicts the surgical outcome in patients with TLE without evidence of mesial temporal sclerosis on MRI.

In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy.

BACKGROUND: The appearance of decreased 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) uptake in the mesial temporal region in temporal lobe epilepsy may simply reflect loss of gray matter due to hippocampal atrophy. Increased partial volume effects due to atrophic hippocampi may further increase appearance of hypometabolism. METHODS: The authors used a combination of MRI-PET coregistration, with MRI-based gray matter segmentation, and partial volume correction to improve the examination of hippocampal specific glucose uptake in FDG PET. The goal was to determine 1) if relative mesial temporal hypometabolism is an artifact of gray matter (hippocampal) atrophy, 2) whether hippocampal metabolism correlates with atrophy evaluated on MRI, and 3) if MRI-based partial volume correction influences measurement of hippocampal metabolic-volume relationships, including epilepsy lateralization. RESULTS: Findings showed that ipsilateral hippocampi of mesial temporal lobe epilepsy (MTLE) are relatively hypometabolic per unit of gray matter volume, and that hippocampal metabolism directly correlates with hippocampal volume. Specifically, partial volume corrected hippocampal metabolism correlated strongly (r = 0.613, p < 0.001) with hippocampal volume. Without partial volume correction, a weaker, but still significant, correlation was present (r = 0.482, p < 0.001). Degree of asymmetry was consistently greater and provided higher sensitivity of lateralization with partial volume vs non-partial volume corrected metabolic measurements. CONCLUSIONS: Although, decreased metabolism may occur in the absence of neuronal cell loss, hippocampal atrophy and presumed degree of neuronal cell loss appears to be a primary factor involved in the cause of decreased metabolism in epileptogenic hippocampi. Partial volume correction is recommended for optimal interpretation of hippocampal structure and function relationships.

Vagus nerve stimulation for the treatment of bilateral independent temporal lobe epilepsy.

PURPOSE: We studied the effect of vagus nerve stimulation (VNS) on seizure reduction in patients with intractable epilepsy with bilateral independent temporal lobe foci. METHODS: Ten patients who met the criterion of the presence of two distinctive clinical and ictal EEG seizure patterns were identified and followed up for 1 year. RESULTS: Six patients had >50% reduction in their seizure frequency that persisted up to > or =1 year of follow-up, whereas four patients reported small or no reduction in their partial seizures. CONCLUSIONS: VNS is often effective and well tolerated in this select group of intractable epilepsy patients.

False lateralization by subdural electrodes in two patients with temporal lobe epilepsy.

The authors present two patients with medically refractory partial seizures who had invasive recordings with stereotactic depth EEG (SEEG) and subdural electrodes (SDE) as part of their presurgical workup. SDE recordings were falsely lateralizing in both of these patients with pathologically proven mesial temporal sclerosis. In temporal lobe epilepsy, SEEG electrodes should be considered when presurgical studies are discordant.

Temporal lobe epilepsy: qualitative reading of 1H MR spectroscopic images for presurgical evaluation.

PURPOSE: To study the feasibility and clinical potential of visual inspection of hydrogen 1 magnetic resonance (MR) spectroscopic metabolite images for the lateralization of unilateral nonlesional temporal lobe epilepsy (TLE). MATERIALS AND METHODS: MR imaging and 1H MR spectroscopic imaging were performed of the temporal lobes in 50 patients with TLE and 23 age-matched healthy volunteers. N-acetylaspartate (NAA) and creatine plus choline metabolite images were read by two neuroradiologists who determined lateralization according to the side of lower NAA signal intensity. Quantitative estimates of NAA were calculated by using an automated fitting program. RESULTS: Agreement in lateralization between readers was significant with a kappa score of 0.53 for all patients with TLE and 0.63 for patients displaying mild or marked NAA asymmetry. Among the 50 patients with TLE, lateralization was determined correctly by reader 1 in 38 (76%) patients and by reader 2 in 31 (62%) patients. If limited to patients with mild or marked NAA asymmetry, correct lateralization improved to 30 (77%) of 39 and 16 (80%) of 20 patients, respectively. Combined qualitative reading and quantitative spectral fitting enabled lateralization in 34 (85%) of 40 patients with TLE for reader 1 and 30 (77%) of 39 for reader 2, including nine of 14 patients with TLE with negative MR images. CONCLUSION: Reading of metabolite images is a feasible and fast means for noninvasive evaluation of patients with TLE who are candidates for surgery and enables lateralization in some patients with negative MR images.

Hippocampal structures: anteroposterior N-acetylaspartate differences in patients with epilepsy and control subjects as shown with proton MR spectroscopic imaging.

PURPOSE: To determine the distribution of proton metabolites along the long axis of the hippocampus. MATERIALS AND METHODS: Proton magnetic resonance (MR) spectroscopic imaging measurements were performed in the hippocampi of 14 control subjects and nine patients with unilateral mesial temporal lobe epilepsy. RESULTS: Control subjects showed significantly lower ratios of N-acetylaspartate (NAA) to choline-containing compounds (Ch) and creatine plus phosphocreatine (CR) (NAA/[Cr + Ch]) in the anterior as compared with the posterior part of the hippocampus. Furthermore, a similar anteroposterior (AP) difference in NAA/(Cr + Ch) values was found in both ipsilateral and contralateral hippocampi of patients. In the patients compared with the control subjects, ipsilateral NAA/(Cr + Ch) levels were reduced in every part of hippocampal tissue with an average reduction of 17%, and contralateral NAA/(Cr + Ch) was reduced by about 10%. In the patients compared with the control subjects, the proportional reduction in ipsilateral NAA/(Cr + Ch) was greatest in voxels from anterior hippocampal regions. CONCLUSION: AP differences could be a result of fewer neurons in the anterior compared with the posterior hippocampus or of the increasing thickness of the hippocampus from posterior to anterior, which leads to different contributions from adjacent tissue. Measurements of T2 showed that T2 differences are probably not responsible for these changes.

Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures.

OBJECTIVE: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS: Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Semiology of temporal lobe seizures: value in lateralizing the seizure focus.

PURPOSE: To determine the lateralizing value of the clinical manifestations of seizures in patients with temporal lobe epilepsy (TLE), we made a retrospective videotape analysis of complex partial seizures (CPS) in 55 patients who underwent temporal lobectomy and were seizure-free postoperatively for >2 years. METHODS: Blinded to clinical details, we reviewed videotapes from video-EEG telemetry monitoring with attention paid to seizure semiology. RESULTS: Useful lateralizing features included unilateral clonic activity (with the seizure focus contralateral in all patients), unilateral dystonic or tonic posturing (with the seizure focus contralateral in 90 and 86%, respectively), unilateral automatisms (with the seizure focus ipsilateral in 80%), and ictal speech preservation (with the seizure focus contralateral to the language-dominant hemisphere in 80%). Versive head rotation occurring < or = 10 s before seizures secondarily generalized consistently predicted a contralateral focus. Seizure manifestations less predictive but suggestive of lateralization included ictal speech arrest and postictal speech status, with predictive values of 67%. Seizure manifestations not providing reliable lateralizing information included eye deviation, type of aura, and versive head movements occurring at times other than immediately before seizures secondarily generalized. CONCLUSIONS: In TLE, several clinical seizure manifestations are useful in lateralizing the seizure focus, although some provide no reliable information. Therefore, ictal semiology can assist in the evaluation of patients for seizure surgery, providing additional information in the lateralization of TLE.