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Focal Epilepsy Including Temporal Lobe Epilepsy [keywords]
- A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy. [Journal Article]
- Epilepsia 2013 May.:75-9.
Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross-sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug-naive patients with either first seizure or new-onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.
- Amygdalar neuromelanosis intractable epilepsy without leptomeningeal involvement. [JOURNAL ARTICLE]
- J Neurosurg Pediatr 2013 May 3.
Neurocutaneous melanosis (NCM) is a rare, congenital neuroectodermal dysplasia generally resulting in early death from neurological decline due to leptomeningeal involvement. Nonmeningeal CNS epileptogenic lesions presenting in later childhood in the absence of leptomeningeal disease are rare. This report summarizes a rare presentation and curative epilepsy surgery. The authors discuss the case of a 14-year-old girl with NCM who originally presented with intractable partial-onset seizures. The MRI, PET, and SPECT studies subsequently revealed a focal epileptogenic source in the right temporal lobe. Results of video-electroencephalography monitoring concurred with the imaging findings, and a right temporal lobectomy was performed including the medial structures. Following surgery, histopathological features of the lesion included multiple scattered mononuclear cells with brown pigmentation in the amygdala specimen. The patient remains seizure free 2 years postresection, and no longer needs medication for seizure management. This patient presented with an atypical CNS manifestation of NCM that is curable by epilepsy surgery. Her intractable epilepsy developed secondary to amygdalar neuromelanosis, which had no associated leptomeningeal melanosis, an uncommon occurrence. As evidenced by the lack of seizure activity following resection, the patient's quality of life greatly improved after neurological surgery.
- Cognitive disorders in pediatric epilepsy. [Journal Article]
- Handb Clin Neurol 2013.:691-5.
Childhood epilepsy may cause cognitive disorders and the intellectual quotient is indeed not normally distributed in epileptic children, a fair proportion of whom show an IQ in the deficient range. Some epileptic syndromes happen during vulnerability periods of brain maturation and interfere with the development of specific cognitive functions. This is the case for the Landau-Kleffner syndrome, which generally appears during speech development and affects language. Similarly, West syndrome - or infantile spasms - is an epileptogenic encephalopathy appearing during the first years of life and induces a major delay in social and oculo-motor development. Specific impairments can also be identified in partial childhood epilepsies in relation with seizure focus localization. For instance, left temporal and frontal epilepsies are frequently associated with verbal impairments. Moreover, episodic memory disorders have been described in children suffering from temporal lobe epilepsy whereas executive deficits (planning, self-control, problem solving) have been reported in frontal lobe epilepsy. In most cases, including its mildest forms, childhood epilepsy induces attention deficits, which may affect academic achievement. These observations militate in favor of individual neuropsychological assessments as well as early interventions in order to provide the child with an optimal individualized treatment program.
- Quantification of opioid receptor availability following spontaneous epileptic seizures: Correction of [(11)C]diprenorphine PET data for the partial-volume effect. [JOURNAL ARTICLE]
- Neuroimage 2013 Apr 15.
Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist [(11)C]diprenorphine (DPN) did not detect any changes in mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE. Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures (Hammers et al., 2007a). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); (Shidahara et al., 2012)). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; (Heckemann et al., 2010)). [(11)C]diprenorphine volume-of-distribution (VT) was quantified in six regions of interest. Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in [(11)C]DPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in [(11)C]DPN VT. This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures.
- Surgical pathology of epilepsy-associated non-neoplastic cerebral lesions: A brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia. [JOURNAL ARTICLE]
- Neuropathology 2013 Mar 27.
Among epilepsy-associated non-neoplastic lesions, mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) and malformation of cortical development (MCD), including focal cortical dysplasia (FCD), are the two most frequent causes of drug-resistant focal epilepsies, constituting about 50% of all surgical pathology of epilepsy. Several distinct histological patterns have been historically recognized in both HS and FCD, and several studies have tried to perform clinicopathological correlations. However, results have been controversial, particularly in terms of post-surgical seizure outcome. Recently, the International League Against Epilepsy constituted a Task Forces of Neuropathology and FCD within the Commission on Diagnostic Methods, to establish an international consensus of histological classification of HS and FCD, respectively, based on agreement with the recognition of the importance of defining a histopathological classification system that reliably has some clinicopathological correlation. Such consensus classifications are likely to facilitate future clinicopathological studies. Meanwhile, we reviewed the neuropathology of 41 surgical cases of mTLE, and confirmed three type/patterns of HS along with no HS, based on the qualitative evaluation of the distribution and severity of neuronal loss and gliosis within hippocampal formation, that is, HS type 1 (61%) equivalent to "classical" Ammon's horn sclerosis, HS type 2 (2%) representing CA1 sclerosis, HS type 3 (17%) equivalent to end folium sclerosis, and no HS (19%). Furthermore, we performed a neuropathological comparative study on mTLE-HS and dementia-associated HS (d-HS) in the elderly, and confirmed that neuropathological features differ between mTLE-HS and d-HS in the distribution of hippocampal neuronal loss and gliosis, morphology of reactive astrocytes and their protein expression, and presence of concomitant neurodegenerative changes, particularly Alzheimer type and TDP-43 pathologies. These differences may account, at least in part, for the difference in pathogenesis and epileptogenicity of HS in mTLE and senile dementia. However, the etiology and pathogenesis of most epileptogenic lesions are yet to be elucidated.
- Cortico-cortical evoked potentials and stimulation-elicited gamma activity preferentially propagate from lower- to higher-order visual areas. [JOURNAL ARTICLE]
- Clin Neurophysiol 2013 Mar 19.
OBJECTIVE:The lower-order visual cortex in the medial-occipital region is suggested to send feed-forward signals to the higher-order visual cortex including ventral-occipital-temporal and dorsal-occipital regions. We determined how stimulation-elicited cortical-signals propagate between lower- and higher-order visual cortices, and whether the magnitudes of stimulation-elicited cortical-signals recorded in the higher-order visual cortex differed from those recorded in the lower-order one.
METHODS:We studied 10 patients with focal epilepsy who underwent extraoperative electrocorticography recording. Trains of 1-Hz stimuli with an intensity of 3mA were delivered to an electrode pair within the medial-occipital region; then, cortico-cortical evoked-potential (CCEP) and stimulation-elicited gamma-activity at 80-150Hz were measured in the ventral-occipital-temporal and dorsal-occipital regions. Likewise, CCEP and stimulation-elicited gamma-activity, driven by stimuli within the higher-order visual cortex, were measured in the lower-order visual cortex.
RESULTS:CCEPs generated, via feed-forward propagations, in the higher-order visual cortex were significantly larger than those generated, via feed-back propagations, in the lower-order visual cortex. Stimulation of the lower-order visual cortex elicited augmentation of gamma-activity in the higher-order visual cortex after the preceding CCEP subsided.
CONCLUSION:The propagation manners of stimulation-elicited cortical-signals differ between feed-forward and feed-back directions in the human occipital lobe.
SIGNIFICANCE:: Such difference may need to be taken into consideration for future clinical application of CCEPs and stimulation-elicited gamma-augmentation in presurgical evaluation for epilepsy surgery.
- Subventricular zone-derived neural stem cell grafts protect against hippocampal degeneration and restore cognitive function in the mouse following intrahippocampal kainic acid administration. [Journal Article, Research Support, Non-U.S. Gov't]
- Stem Cells Transl Med 2013 Mar; 2(3):185-98.
Temporal lobe epilepsy (TLE) is a major neurological disease, often associated with cognitive decline. Since approximately 30% of patients are resistant to antiepileptic drugs, TLE is being considered as a possible clinical target for alternative stem cell-based therapies. Given that insulin-like growth factor I (IGF-I) is neuroprotective following a number of experimental insults to the nervous system, we investigated the therapeutic potential of neural stem/precursor cells (NSCs) transduced, or not, with a lentiviral vector for overexpression of IGF-I after transplantation in a mouse model of kainic acid (KA)-induced hippocampal degeneration, which represents an animal model of TLE. Exposure of mice to the Morris water maze task revealed that unilateral intrahippocampal NSC transplantation significantly prevented the KA-induced cognitive decline. Moreover, NSC grafting protected against neurodegeneration at the cellular level, reduced astrogliosis, and maintained endogenous granule cell proliferation at normal levels. In some cases, as in the reduction of hippocampal cell loss and the reversal of the characteristic KA-induced granule cell dispersal, the beneficial effects of transplanted NSCs were manifested earlier and were more pronounced when these were transduced to express IGF-I. However, differences became less pronounced by 2 months postgrafting, since similar amounts of IGF-I were detected in the hippocampi of both groups of mice that received cell transplants. Grafted NSCs survived, migrated, and differentiated into neurons-including glutamatergic cells-and not glia, in the host hippocampus. Our results demonstrate that transplantation of IGF-I producing NSCs is neuroprotective and restores cognitive function following KA-induced hippocampal degeneration.
- Changes in singing performance and fMRI activation following right temporal lobe surgery. [JOURNAL ARTICLE]
- Cortex 2013 Jan 18.
INTRODUCTION:This study arose in the context of having to estimate risk to the musical abilities of a trained singer (patient A.M.) recommended for right anterior temporal lobectomy (RATL) to ameliorate medically intractable seizures. To date there has been no systematic investigation of reorganisation of musical functions in the presence of epileptogenic lesions, although it is well established that RATL can impair pitch processing in nonmusicians.
METHODS:Using fMRI, we compared the network activated by covert singing with lyrics in A.M. before and after surgery, while taking language activation and singing expertise into consideration. Before surgery, A.M. showed lower pitch accuracy of singing relative to individuals of similar experience (experts), thus we compared her to 12 healthy controls matched for singing pitch accuracy.
RESULTS:We found atypical organisation of A.M.'s singing network before surgery in the presence of a malformation of cortical development, including partial activation of the singing network of pitch-matched controls, and diffuse activation along the midline spreading laterally into association cortex, typical of generalised cortical hyperexcitability in intractable epilepsy. After tailored RATL, A.M. showed striking behavioural and neuroimaging changes, including significant improvement in pitch accuracy of singing relative to controls (p = .026) and the subjective experience of being a more technically proficient singer. This was accompanied by a significant reduction in cortical activation (p < .05, corrected), with a more focal, expert-like pattern of singing activation emerging, including decreased involvement of frontal language regions. These changes were largely specific to singing, with A.M. showing language activation and performance similar to controls.
CONCLUSIONS:This case provides evidence for selective disruption of the singing network that reorganised after successful resection of an epileptogenic lesion and likely occurred through decoupling of the singing and language networks.
- Word-finding difficulties confound performance on verbal cognitive measures in adults with intractable left temporal lobe epilepsy. [Journal Article]
- Epilepsia 2013 Mar; 54(3):e37-40.
This study sought to determine if word-finding difficulties (WFDs), which are common in adults with dominant temporal lobe epilepsy (TLE), are related to performance on verbal cognitive measures, including memory. One hundred six individuals with left TLE and pathologically confirmed mesial temporal sclerosis completed comprehensive preoperative neuropsychological evaluations. Patients were divided into two groups based on the degree of benefit received from phonemic cueing on a confrontation naming task. Cognitive performance was then compared between patients with greater and fewer WFDs. Patients with greater WFDs demonstrated poorer performance on many verbal cognitive measures compared to those with fewer WFDs. In contrast, there were no significant differences between groups on any of the nonverbal cognitive measures. Chi-square analyses indicated that below average verbal memory performance occurred at a significantly higher rate for patients with greater WFDs (42-46%) as compared to patients with fewer WFDs (18-24%). Results showed that WFDs confound performance on verbal cognitive measures in adult patients with left TLE, particularly on measures with high demands for lexical retrieval. This suggests that when patients have word-retrieval difficulties, measures of verbal memory and verbal intelligence may be underestimated and potentially lead to misinterpretation of test performance and misinformation regarding risk of declines after surgical resection.
- Molecular pathways controlling inhibitory receptor expression. [Journal Article, Research Support, N.I.H., Extramural, Review]
- Epilepsia 2012 Dec.:71-8.
Epilepsy is a disease of complex etiology, and multiple molecular mechanisms contribute to its development. Temporal lobe epilepsy (TLE) may result from an initial precipitating event such as hypoxia, head injury, or prolonged seizure (i.e., status epilepticus [SE]), that is followed by a latent period of months to years before spontaneous seizures occur. γ-Aminobutyric acid (GABA)(A) receptor (GABA(A) R) subunit changes occur during this latent period and may persist following the onset of spontaneous seizures. Research into the molecular mechanisms regulating these changes and potential targets for intervention to reverse GABA(A) R subunit alterations have uncovered seizure-induced pathways that contribute to epileptogenesis. Several growth or transcription factors are known to be activated by SE, including (but not limited to): brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), inducible cAMP early repressor (ICER), and early growth response factors (Egrs). Results of multiple studies suggest that these factors transcriptionally regulate GABA(A) R subunit gene expression in a way that is pertinent to the development of epilepsy. This article focuses on these signaling elements and describes their possible roles in gene regulatory pathways that may be critical in the development of chronic epilepsy.