The use of neuroimaging to study behavior in patients with epilepsy

Structural and functional neuroimaging continues to play an increasing role in the presurgical evaluation of patients with epilepsy. In addition to its value in localizing the epileptogenic zone and eloquent cortex, neuroimaging is contributing to our understanding of mood comorbidity in epilepsy. Although the vast majority of research has focused on patients with temporal lobe epilepsy (TLE), neuroimaging studies of patients with extratemporal epilepsy and primary generalized epilepsy are increasing in number. In this review, structural and functional imaging modalities that have received considerable research attention in recent years are reviewed, and their strengths and limitations for understanding behavior in epilepsy are assessed. In addition, advances in multimodal imaging are discussed along with their potential application to the presurgical evaluation of patients with seizure disorders.     

Utility of the Boston naming test in predicting ultimate side of surgery in patients with medically intractable temporal lobe epilepsy

PURPOSE: Confrontation naming tasks have long been presumed to be sensitive to left temporal dysfunction and, consequently, are frequently used in the evaluation of surgical epilepsy patients. Despite wide and frequent use, few studies have examined the utility of confrontation naming tasks in individuals with temporal lobe epilepsy (TLE). METHODS: The current study examined the presurgical Boston Naming Test (BNT) performance of 217 right-handed adult patients with intractable TLE (left, 108; right, 109) to determine the utility of this measure in predicting ultimate side of surgery. RESULTS: The results support the clinical utility of the BNT in determining ultimate side of surgery and suggest that the BNT has incremental validity over and above presurgical delayed memory and intelligence scores. This relation was found to be moderated by Full Scale IQ (FSIQ), age at seizure onset, and duration of epilepsy. The use of a logistic regression equation to predict side of surgery revealed that prediction of left temporal surgery was best among patients with low BNT scores, high FSIQs, and late age at seizure onset. In contrast, right temporal surgery was best predicted among patients with high BNT scores, low FSIQs, and short duration of epilepsy. CONCLUSIONS: This study supports the clinical utility of the BNT in the preoperative evaluation of candidates for TLE surgery and highlights the importance of examining potential moderating variables when making predictions about side of surgery. This study further provides clinicians with a regression equation that can be used to predict side of surgery in patients with temporal lobe epilepsy.     

Recent developments in cognitive fMRI for temporal lobe epilepsy

Epilepsy is frequently accompanied by severe cognitive side effects. Temporal lobe epilepsy (TLE), and even successful surgical treatment, may affect cognitive function, in particular language as well as verbal and visual memory function. Epilepsy arising from the temporal lobe can be controlled surgically in up to 70% of patients. The goals of epilepsy surgery are to remove the brain areas generating the seizures without causing or aggravating neuropsychological deficits. This requires accurate localization of the brain areas generating the seizures (“epileptogenic zone”) and the areas responsible for motor and cognitive functions, such as language and memory (“essential brain regions”) during presurgical evaluation. In the past decades, functional magnetic resonance imaging (fMRI) has been increasingly used to noninvasively lateralize and localize not only primary motor and somatosensory areas, but also brain areas that are involved in everyday language and memory processes. The imaging modality also shows potential for predicting the effects of temporal lobe resection on language and memory function. Together with other MRI modalities, cognitive fMRI is a promising tool to improve surgical strategies tailored to individual patients with regard to functional outcome, by virtue of definition of epileptic cerebral areas that need to be resected and eloquent areas that need to be spared.

The aim of this review is to provide an overview of recent developments and practical recommendations for the clinical use of cognitive fMRI in TLE.

     

Temporal lobe epilepsy with bilateral seizure origin studied by [18F]FDG-positron emission tomography

Nine patients who underwent presurgical evaluation because of medically refractory temporal lobe epilepsy (TLE) showed either unilateral, although alternating in side, or bilateral simultaneous seizure onsets in both temporal lobes (TL). EEG recordings with semi-invasive foramen ovale electrodes revealed in seven patients a predominance of seizure onset in one TL of between 50% and 88%. In two patients the majority of seizures originated simultaneously in both TL. In four patients a unilateral selective amygdalohippocampectomy resulted in a good to excellent seizure outcome without noteworthy memory deficits and confirmed the preoperative lateralization of the primary epileptogenic focus by interictal ¹⁸F-fluorodeoxyglucose positron emission tomography (PET). Five patients were rejected from surgery due to strong bilaterality of their epilepsy and/or divergent presurgical findings. PET contributed to the decision of whether surgery should be performed: all patients who underwent surgery had a unilateral TL hypometabolism which was concordant with the findings of other tests. Patients in whom surgery was denied had either bilateral temporal hypometabolism or the PET findings were discordant with other results obtained during the presurgical evaluation.     

Lateralization of temporal lobe epilepsy using resting functional magnetic resonance imaging connectivity of hippocampal networks

Purpose: Early surgical intervention can be advantageous in the treatment of refractory temporal lobe epilepsy (TLE). The success of TLE surgery relies on accurate lateralization of the seizure onset. The purpose of this study was to determine whether resting functional MRI (fMRI) connectivity mapping of the hippocampus has the potential to complement conventional presurgical evaluations in distinguishing left from right TLE. In addition, we sought to determine whether this same network might separate patients with favorable from unfavorable postoperative outcomes. Methods: Resting fMRI acquisitions were performed on 21 patients with TLE and 15 healthy controls. The patients included seven patients with left TLE and seven patients with right TLE with seizure-free postoperative outcome, and five patients with left TLE and two patients with right TLE with recurring seizures after surgery. Functional connectivity maps to each hippocampus were determined for each subject and were compared between the controls and the seizure-free patients with left TLE and with right TLE. The one network identified was then quantified in the patients with TLE and recurring seizures. Key Findings: The resting functional connectivity between the right hippocampus and the ventral lateral nucleus of the right thalamus was the most statistically significant network to distinguish between seizure-free patients with left TLE and with right TLE with high sensitivity and specificity. This connectivity was also significantly greater in the seizure-free patients with left TLE than the healthy controls. Finally, six of the seven patients in whom seizures recurred after surgery had connectivity values in this network unlike those who were seizure-free. Significance: This study identified a region in the ventral lateral nucleus of the right thalamus whose connectivity to the hippocampi separates left from right TLE subjects. This suggests that the quantification of resting-state functional magnetic resonance imaging (MRI) connectivity across this network may be a potential indicator of lateralization of TLE that may be added to other presurgical MRI assessments. Further validation in a larger, independent cohort is required.     

Memory outcome 2 years after anterior temporal lobectomy in patients with drug-resistant epilepsy

PURPOSE: Memory decline is often observed after anterior temporal lobectomy (ATL), particularly in patients with dominant hemisphere resections. However, the follow-up length has been 1 year or less in most studies. Our aims were to examine postoperative memory changes over a longer period and to identify baseline demographic and clinical predictors of memory outcome. METHODS: We administered material-specific memory tests at baseline, and 1 and 2 years after surgery to 82 consecutive right-handed patients (52% males) who underwent ATL for drug-resistant temporal lobe epilepsy (TLE) (35 left, 47 right) after a non-invasive presurgical protocol. Repeated measures multivariate analysis of variance (RM-MANOVA) was used to examine the relationship between changes in memory tests scores over time and side of TLE and pathology. Also, standardized residual change scores were calculated for each memory test and entered in multiple linear regression models aimed at identifying baseline predictors of better memory outcome. RESULTS: RM-MANOVA revealed a significant change in memory test scores over time, with an interaction between time and side of surgery, as 2 years after surgery patients with RTLE were improved while patients with LTLE were not worse as compared with baseline. Pathology was not associated with changes in memory scores. In multiple regression analysis, significant associations were found between right TLE and greater improvement in verbal memory, younger age and greater improvement in visuospatial memory, and male gender and greater improvement in both verbal and visuospatial memory. CONCLUSIONS: Our results suggest that the long-term memory outcome of TLE patients undergoing ATL without invasive presurgical assessment may be good in most cases not only for right-sided but also for left-sided resections.     

Absence of gender effect on amygdala volume in temporal lobe epilepsy

Sexual dimorphism has already been described in temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS). This study evaluated the effect of gender on amygdala volume in patients with TLE-MTS. One hundred twenty-four patients with refractory unilateral or bilateral TLE-MTS who were being considered for epilepsy surgery underwent a comprehensive presurgical evaluation and MRI. Amygdalas of 67 women (27 with right; 32 with left, and 8 with bilateral TLE) and 57 men (22 with right, 30 with left, and 5 with bilateral TLE) were manually segmented. Significant ipsilateral amygdala volume reduction was observed for patients with right and left TLE. No gender effect on amygdala volume was observed. Contralateral amygdalar asymmetry was observed for patients with right and left TLE. Although no gender effect was observed on amygdala volume, ipsilateral amygdala volume reductions in patients with TLE might be related to differential rates of cerebral maturation between hemispheres.     

Funktionelle Magnetresonanztomographie von Ged?chtnisfunktionen

Chronic epilepsy is frequently accompanied by cognitive deficits. Temporal lobe epilepsy (TLE) as well as resection surgery on the temporal lobe may affect cognitive function, in particular verbal and visual memory but also working memory. Epilepsy arising from the brain??s temporal lobe can be controlled surgically in up to 70% of patients. The goals of epilepsy surgery are to remove the brain areas generating the seizures without causing or aggravating memory dysfunction. This requires accurate localization of areas responsible for memory function (eloquent cortex). Functional magnetic resonance imaging (fMRI) is increasingly being used to lateralize and localize brain areas involved in memory processes and shows promise for predicting the effects of temporal lobe resection on memory function, especially when combined with other structural as well as functional imaging methods.     

The relevance of somatosensory auras in refractory temporal lobe epilepsies

The purpose of this study is to look at the prevalence, characteristics, and prognostic value of somatosensory auras (SSAs) in patients who have undergone temporal lobe epilepsy (TLE) surgery to treat drug‐resistant focal epilepsy. We retrospectively reviewed all patients with drug‐resistant epilepsy who underwent TLE surgery at Cleveland Clinic between 2005 and 2010 (n = 333) to study the prevalence, characteristics, and prognostic implications of SSA in the context of TLE surgery. Analyses were performed using two seizure outcome definitions: complete seizure freedom and Engel classification. Of the 333 patients, 26 (7.8%) had SSA. Almost half (12 patients) had unilateral sensory symptoms, whereas the rest had bilateral symptoms. Tingling and numbness were the most frequently reported sensations. Compared to their non‐SSA counterparts, patients with SSA had the same clinical and imaging characteristics, but had a higher rate of breakthrough seizures (p = 0.03), although most (54%) were still able to achieve Engel class of I (p = 0.02). Based on our results we would encourage detailed presurgical testing, which may include an invasive evaluation to analyze the extent of the epileptogenic zone in patients with SSA and suspected TLE.     

Depression and anxiety before and after temporal lobe epilepsy surgery.

PURPOSE: To examine the course of depression and anxiety in patients with temporal lobe epilepsy (TLE) treated with epilepsy surgery (and anticonvulsant drugs) or medical means alone. METHODS: Of 94 TLE patients evaluated for epilepsy surgery, 76 underwent a resective procedure, 18 continued on medical treatment alone. Depression (Beck Depression Inventory (BDI)) and anxiety scores (Self-Rating Anxiety Scale (SRAS)) were examined during presurgical evaluation (T1) and after a mean of 16 months (T2), or 12 months after surgery. Depression and anxiety scores were related to type of intervention, underlying epileptogenic lesion, change of seizure control and anticonvulsant therapy. RESULTS: At T1, depression and anxiety scores were higher in patients with TLE than scores in published normal populations. At T2, depression but not anxiety scores were significantly lower than at T1. Change of depression scores interacted with improvements of seizure control. CONCLUSIONS: Evidence of depression and anxiety is commonly found in patients with TLE. Depression improves not because of epilepsy surgery per se, but because of improved seizure control. This is more commonly achieved by surgery than medical treatment. The results are consistent with the hypothesis that depression in TLE is caused by pathological epileptic activity rather than a fixed structural defect.     

Presurgical assessment of memory-related brain structures: the Wada test and functional neuroimaging.

Medial temporal lobe structures are known to play a major role in memory processing. Recent work has revealed that extratemporal structures (e.g. the frontal lobe and thalamus) may also be important in memory function. In candidates for epilepsy surgery, particularly in those with temporal lobe seizures, presurgical evaluation of memory function is essential, since seizures may originate in the neural substrate that is critical for memory. In this article, we review the tools used for presurgical evaluation and their contribution to the understanding of memory function, focusing on the Wada test, [18F]fluorodeoxy-glucose positron emission tomography ([18F]FDG-PET) and functional magnetic resonance imaging (fMRI). We also explore perspectives on future studies that may elucidate the role of the temporal and extratemporal structures in memory function and the mechanisms of cerebral plasticity.     

Concept of epilepsy surgery and presurgical evaluation

Epilepsy surgery is a well‐accepted treatment for drug‐resistant epilepsy. The success of the epilepsy surgery depends upon an appropriate presurgical evaluation process which should ensure the selection of suitable patients who are likely to become seizure‐free following surgery without any unacceptable deficit. The two basic goals of the presurgical evaluation are the accurate localization and delineation of the extent of the epileptogenic zone, and its complete and safe resection. The process of the presurgical evaluation requires a multimodality approach wherein each modality provides unique and complimentary information which is combined with the information provided by other modalities to generate a hypothesis with regard to the likely epileptogenic zone. The basic modalities for the presurgical evaluation are clinical history, long‐term video‐EEG recording, high‐resolution MRI, and neuropsychological evaluation. The additional modalities include functional imaging studies, electrical and magnetic source imaging, functional MRI, and intracranial monitoring. Each modality has its own limitations and the information provided by none of them is absolute. Hence, a concordance among the different modalities is the key to surgical success. The presurgical evaluation is a step‐wise process starting form the most basic and most reliable tests and progressing to more complex and invasive modalities. The number of tests required varies according to the complexity involved and may include very basic minimum investigations in a given case, to the use of all the available investigations in more complex cases. The proper selection of various investigations and their accurate interpretation at each stage is required to ensure a successful outcome. In this article, we intend to review some of these basic concepts of presurgical evaluation and epilepsy surgery, and try to provide a frame work of the presurgical evaluation process.     

Functional and structural changes in the memory network associated with left temporal lobe epilepsy

Understanding functional plasticity in memory networks associated with temporal lobe epilepsy (TLE) is central to predicting memory decline following surgery. However, the extent of functional reorganization within memory networks remains unclear. In this preliminary study, we used novel analysis methods assessing network‐level changes across the brain during memory task performance in patients with TLE to test the hypothesis that hippocampal functions may not readily shift between hemispheres, but instead may show altered intra‐hemispheric organization with unilateral damage. In addition, we wished to relate functional differences to structural changes along specific fibre pathways associated with memory function. Nine pre‐operative patients with intractable left TLE and 10 healthy controls underwent functional MRI during complex scene encoding. Diffusion tensor imaging was additionally performed in the same patients. In our study, we found no evidence of inter‐hemispheric shifts in memory‐related activity in TLE using standard general linear model analysis. However, tensor independent component analysis revealed significant reductions in functional connectivity between bilateral MTL, occipital and left orbitofrontal regions among others in left TLE. This altered orbitofrontal activity was directly related to measures of fornix tract coherence in patients (P < 0.05). Our results suggest that specific fibre pathways, potentially affected by MTL neurodegeneration, may play a central role in functional plasticity in TLE and highlight the importance of network‐based analysis approaches. Relative to standard model‐based methods, novel objective functional connectivity analyses may offer improved sensitivity to subtle changes in the distribution of memory functions relevant for surgical planning in TLE. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Quantitative and qualitative MRI changes in temporal lobe epilepsy. A comparison with normal parameters of nuclear magnetic resonance tomography]

Magnetic resonance imaging (MRI) often reveals no pathology in patients with temporal lobe epilepsy (TLE) who are candidates for surgery, even though post-surgery histology reveals atrophy or sclerosis. To differentiate these pathologies in MRI, we performed a standardized acquisition and a quantitative analysis of MRI data (qMRI). The standard values of 43 healthy subjects (both sex, left and right handed) were compared with those of 10 patients with TLE and unilateral EEG focus. A reduced estimated total brain extension, a significant atrophy of both temporal lobes with accentuation on the focus side and a significant hippocampal atrophy on focus-side were seen even in patients with no visually detectable pathology. The analysis of the signal intensities did not give additional information. Thus, qMRI is a helpful additional tool in the course of presurgical evaluation for focus lateralization.     

Postsurgical outcome of children and adolescents with medically refractory frontal lobe epilepsies

OBJECTS: In the adult population surgical treatment is generally less favorable for refractory frontal lobe epilepsy (FLE) than for temporal lobe epilepsy (TLE). Predictive factors and outcome of FLE surgery had not previously been described for the pediatric and adolescent population. Therefore, 32 children and adolescents who underwent FLE surgery were analyzed in this study. METHODS: Medical records were reviewed for demographic data, presurgical evaluation procedures, surgical procedures, pathological findings and follow-up. RESULTS: Mean age at operation was 10.8 years, with seizure onset at 4.6 years. Excellent outcomes were observed in 21 of the 32 patients following evaluation a mean of 34.5 months after surgery. Nineteen of 22 patients became seizure free after tailored resections, versus 2 out of 10 after lobectomy. Transient neurological and surgical complications occurred in 4 patients. Focal neoplastic lesions detectable by MRI were associated with a favorable outcome. CONCLUSIONS: As seen in adult FLE series, the detection of a resectable ictal neoplastic lesion on preoperative MRI is associated with an excellent outcome comparable to that of TLE surgery.     

The cognitive consequence of resecting nonlesional tissues in epilepsy surgery--results from MRI- and histopathology-negative patients with temporal lobe epilepsy

Purpose: Because more selective and individual versus extended standard surgery in the treatment of epilepsy appears to result in similar seizure outcomes, the issue of sparing nonlesional and hypothetically still‐functioning tissues has become a central topic in epilepsy surgery. Within this framework we hypothesized that surgery in magnetic resonance imaging (MRI)‐ and histopathologically negative patients with temporal lobe epilepsy (TLE) may serve as a proof of principle about the negative cognitive consequences of resecting nonlesional tissue. Methods: Verbal and figural memory outcomes after temporal lobe surgery in 15 MRI‐ and histopathologically negative patients (MRH−) were compared to those obtained in 15 MRI‐ and histopathologically positive patients (MRH+). In the MRH− group, 53% were male, 66% were resected on the left side, 13% underwent selective amygdalohippocampectomy, and 20% became seizure‐free. MRH+ patients were selected from >1,000 TLE patients, and provided matched pairs in regard to chronological age, sex, IQ, attention performance, onset of epilepsy, side and type of surgery, age at surgery, and seizure outcome. Individual and combined standardized scores for verbal/figural memory were evaluated. Key findings: Preoperatively, memory was significantly better and less frequently impaired in MRH− as opposed to MRH+ patients. Postoperatively, memory losses in MRH− were more severe as opposed to MRH+ patients who did not change, on average. Losses in individual test parameters were seen in between 27% and 80% in MRH− patients as compared to between 13% and 47% in MRH+ patients. After surgery, outcomes for both groups were at comparably poor performance levels. Significance: Preoperative group differences in memory and the finding that, after surgery, both groups had comparably poor performance levels indicate a major relevance of morphologic structural lesions for memory impairment in TLE. The findings in particular confirm the negative impact of the resection of nonlesional functional tissue for cognitive surgical outcome. Absence of MRI lesion and unimpaired memory appear as significant risk factors for postoperative memory loss in temporal lobe surgery.     

Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: A series of 100 patients

Surgery is a safe and effective treatment for drug-resistant temporal lobe epilepsy (TLE). However, bilateral electroencephalographic (EEG) abnormalities are frequently present, making presurgical lateralization difficult. New magnetic resonance (MR) techniques can help; proton magnetic resonance spectroscopic imaging (MRSI) can detect and quantify focal neuronal damage or dysfunction based on reduced signals from the neuronal marker N-acetylaspartate, and magnetic resonance imaging (MRI)-based measurements of amygdala-hippocampal volumes (MRIVol) can improve the detection of atrophy of these structures. We performed proton MRSI and MRIVol in 100 consecutive patients with medically intractable TLE to determine how well these techniques agreed with the lateralization by extensive EEG investigation. We found that the EEG, MRSI, and MRIVol findings were highly concordant. The MRSI was abnormal in 99 of 100 patients (bilateral in 54%). The MRIVol was abnormal in 86 of 98 patients (bilateral in 28%). We obtained lateralization in 83% of patients using MRIVol alone, in 86% using MRSI alone, and in 90% by combining MRSI and MRIVol (vs 93% lateralization by EEG). MRSI was abnormal in 12 patients with normal MRIVol. The combination of proton MRSI and MRIVol can lateralize TLE accurately and noninvasively in the great majority of patients. By reducing reliance on EEG, these imaging techniques could reduce prolonged presurgical evaluation and make seizure surgery available to more patients.     

Lateralizing seizure focus in presurgical patients with temporal lobe epilepsy: Utility of the Ruff–Light Trail Learning Test

From a neuropsychological perspective, left or right temporal lobe abnormalities underlying seizures in patients with temporal lobe epilepsy (TLE) are thought to contribute to selective deficits in verbal or nonverbal memory abilities, respectively. The Ruff–Light Trail Learning Test (RULIT) is specifically designed to detect right hemisphere dysfunction. The purpose of our study was to examine the utility of the RULIT in distinguishing between patients with right (n = 20) and patients with left (n = 32) TLE in presurgical evaluations. We identified a significant between-group difference in RULIT scores, but not in the expected direction; that is, patients with right TLE had significantly better scores than patients with left TLE. These findings indicate that the RULIT may not be an appropriate test for presurgical epilepsy evaluations. Findings are discussed within the context of results from other lateralizing neuropsychological tests.     

Dipole density of low-frequency and spike magnetic activity: a reliable procedure in presurgical evaluation of temporal lobe epilepsy.

Conventional visual analysis and dipole density analysis of magnetoencephalographic data for both spike and low-frequency magnetic activity were compared for presurgical evaluation in temporal lobe epilepsy (TLE) in a sample of 26 drug-resistant operated TLE patients. A series of logistic regression analyses were performed. Dipole density sensitivity was superior to visual localization analysis. Three separated logistic models were calculated for interictal spikes, low-frequency magnetic activity, and the combination of both measures. A combined interictal spike/low-frequency magnetic activity model predicted correctly the operated temporal lobe in all patients. Clear-cut criteria for the probability model are proposed that are valid for 92.3% of cases in the sample. The quantitative approach proposed by this study is an evidence-based model for presurgical evaluation of temporal lobe epilepsy, which improves previous magnetoencephalographic investigations and establishes working clinical criteria for patient evaluation in TLE.