MRI-negative PET-positive temporal lobe epilepsy (TLE) and mesial TLE differ with quantitative MRI and PET: a case control study

Background: 'MRI negative PET positive temporal lobe epilepsy' represents a substantial minority of temporal lobe epilepsy (TLE). Clinicopathological and qualitative imaging differences from mesial temporal lobe epilepsy are reported. We aimed to compare TLE with hippocampal sclerosis (HS+ve) and non lesional TLE without HS (HS-ve) on MRI, with respect to quantitative FDG-PET and MRI measures.

Methods: 30 consecutive HS-ve patients with well-lateralised EEG were compared with 30 age- and sex-matched HS+ve patients with well-lateralised EEG. Cerebral, cortical lobar and hippocampal volumetric and co-registered FDG-PET metabolic analyses were performed.

Results: There was no difference in whole brain, cerebral or cerebral cortical volumes. Both groups showed marginally smaller cerebral volumes ipsilateral to epileptogenic side (HS-ve 0.99, p = 0.02, HS+ve 0.98, p < 0.001). In HS+ve, the ratio of epileptogenic cerebrum to whole brain volume was less (p = 0.02); the ratio of epileptogenic cerebral cortex to whole brain in the HS+ve group approached significance (p = 0.06). Relative volume deficits were seen in HS+ve in insular and temporal lobes. Both groups showed marked ipsilateral hypometabolism (p < 0.001), most marked in temporal cortex. Mean hypointensity was more marked in epileptogenic-to-contralateral hippocampus in HS+ve (ratio: 0.86 vs 0.95, p < 0.001). The mean FDG-PET ratio of ipsilateral to contralateral cerebral cortex however was low in both groups (ratio: HS-ve 0.97, p < 0.0001; HS+ve 0.98, p = 0.003), and more marked in HS-ve across all lobes except insula.

Conclusion: Overall, HS+ve patients showed more hippocampal, but also marginally more ipsilateral cerebral and cerebrocortical atrophy, greater ipsilateral hippocampal hypometabolism but similar ipsilateral cerebral cortical hypometabolism, confirming structural and functional differences between these groups.

Hippocampal deformation mapping in MRI-negative PET-positive temporal lobe epilepsy

Objectives: To compare hippocampal surface structure, using large deformation high dimensional mapping (HDM-LD), in subjects with temporal lobe epilepsy (TLE) with (HS+ve) and without (HS−ve) hippocampal sclerosis.

Methods: The study included 30 HS−ve subjects matched with 30 HS+ve subjects from the previously reported epilepsy patient cohort. To control for normal right–left asymmetries of hippocampal surface structure, subjects were regrouped based on laterality of onset of epileptic seizures and presence of HS. Gender ratio, age, duration of epilepsy and seizure frequency were calculated for each of the four groups. Final HDM-LD surface maps of the right and left TLE groups were compared to define differences in subregional hippocampal involvement within the groups.

Results: There were no significant differences in comparisons of the left TLE (left HS−ve compared with HS+ve) or right TLE (right HS−ve compared with HS+ve) groups with respect to age, duration of epilepsy or seizure severity scores. HDM-LD maps showed accentuated surface changes over the lateral hippocampal surface, in the region of the Sommer sector, in the hippocampi affected by HS. However, HS−ve hippocampi showed maximal surface changes in a different pattern, and did not involve the region of Sommer sector.

Conclusion: We conclude that differences in segmental volume loss between the HS−ve and HS+ve groups are suggestive that the underlying pathophysiology of hippocampal changes in the two groups is different, and not related to chronic seizure duration or severity.

Sequential 123-I-iododexetimide scans in temporal lobe epilepsy: comparison with neuroimaging scans (MR imaging and 18-F-FDG-PET imaging)

Purpose Muscarinic acetylcholine receptors (mAChRs) play an important role in the generation of seizures. Single-photon emission computed tomography (SPECT) with ¹²³I-iododexetimide (IDEX) depicts tracer uptake by mAChRs. Our aims were to: (a) determine the optimum time for interictal IDEX SPECT imaging; (b) determine the accuracy of IDEX scans in the localisation of seizure foci when compared with video EEG and MR imaging in patients with temporal lobe epilepsy (TLE); (c) characterise the distribution of IDEX binding in the temporal lobes and (d) compare IDEX SPECT and ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in identifying seizure foci.
Methods We performed sequential scans using IDEX SPECT imaging at 0, 3, 6 and 24 h in 12 consecutive patients with refractory TLE undergoing assessment for epilepsy surgery. Visual and region of interest analyses of the mesial, lateral and polar regions of the temporal lobes were used to compare IDEX SPECT, FDG PET and MR imaging in seizure onset localisation.
Results The 6-h IDEX scan (92%; κappa=0.83, p=0.003) was superior to the 0-h (36%; kappa=0.01, p>0.05), 3-h (55%;κappa=0.13, p>0.05) and 24-h IDEX scans in identifying the temporal lobe of seizure origin. The 6-h IDEX scan correctly predicted the temporal lobe of seizure origin in two patients who required intracranial EEG recordings to define the seizure onset. Reduced ligand binding was most marked at the temporal pole and mesial temporal structures. IDEX SPECT was superior to interictal FDG PET (75%; κappa=0.66, p=0.023) in seizure onset localisation. MR imaging was non-localising in two patients in whom it was normal and in another patient in whom there was bilateral symmetrical hippocampal atrophy.
Conclusion The 6-h IDEX SPECT scan is a viable alternative to FDG PET imaging in seizure onset localisation in TLE.

Depression in temporal lobe epilepsy surgery patients : an FDG-PET study

Summary: Purpose: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

Methods: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n = 9) versus those who did not (n = 14) and between those in whom postoperative depression developed (n = 13) versus those in whom it did not (n = 10). A significant region of hypometabolism was set at p < 0.001 for a cluster of ≥20 contiguous voxels.

Results: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t= 4.64; p < 0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t= 5.10; p < 0.001).

Conclusions: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.

Probabilistic ictal EEG sources and temporal lobe epilepsy surgical outcome

Objective - For patients with medication refractory medial temporal lobe epilepsy (MTLE), surgery offers the hope of a cure. However, up to 30% of patients with MTLE continue to experience disabling seizures after surgery. The reasons why some patients do not achieve seizure freedom are poorly understood. A promising theory suggests that epileptogenic networks are broadly distributed in surgically refractory MTLE, involving regions beyond the medial temporal lobe. In this retrospective study, we aimed to investigate the distribution of epileptogenic networks in MTLE using Bayesian distributed EEG source analysis from preoperative ictal onset recordings. This analysis has the advantage of generating maps of source probability, which can be subjected to voxel-based statistical analyses.Methods - We compared 10 patients who achieved post-surgical seizure freedom with 10 patients who continued experiencing seizures after surgery. Voxel-based Wilcoxon tests were employed with correction for multiple comparisons.Results - We observed that ictal EEG source intensities were significantly more likely to occur in lateral temporal and posterior medial temporal regions in patients with continued seizures post-surgery.Conclusions - Our findings support the theory of broader spatial distribution of epileptogenic networks at seizure onset in patients with surgically refractory MTLE.

Increased Metallothionein I/II Expression in Patients with Temporal Lobe Epilepsy

In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and patients with TLE associated with tumor or dysplasia (TLE-TD) were evaluated for expression of MT-I/II, for the vesicular zinc levels, and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis, microgliosis and reduced neuronal population. In TLE-TD, the same changes were observed, except that were mainly confined to fascia dentata. Increased vesicular zinc was observed only in the inner molecular layer of MTLE patients, when compared to control cases. Correlation and linear regression analyses indicated an association between increased MT-I/II and increased astrogliosis in TLE. MT-I/II levels did not correlate with any clinical variables, but MTLE patients with secondary generalized seizures (SGS) had less MT-I/II than MTLE patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from TLE patients and our data suggest that it is associated with astrogliosis and may be associated with different seizure spread patterns.

Differential aberrant sprouting in temporal lobe epilepsy with psychiatric co-morbidities

Psychiatric co-morbidities in epilepsy are common in patients with temporal lobe epilepsy (TLE). Pathological alterations in TLE are well characterised; however, neuropathologic data are relatively scale regarding the association between psychiatric diseases and epilepsy. Our objective was to evaluate the clinical data of 46 adult TLE patients with and without psychiatric co-morbidities and to correlate the data with hippocampal neuronal density and mossy fiber sprouting. Accordingly, patients were grouped as follows: TLE patients without history of psychiatric disorder (TLE, n = 16), TLE patients with interictal psychosis (TLE + P, n = 14), and TLE patients with major depression (TLE + D, n = 16). Hippocampi from autopsies served as non-epileptic controls (n = 10). TLE + P exhibited significantly diminished mossy fiber sprouting and decreased neuronal density in the entorhinal cortex when compared with TLE. TLE + P showed significantly poorer results in verbal memory tasks. TLE + D exhibited significantly increased mossy fiber sprouting length when compared with TLE and TLE + P. Further, a higher proportion of TLE + D and TLE + P presented secondarily generalised seizures than did TLE. Our results indicate that TLE patients with psychiatric disorders have distinct features when compared with TLE patients without psychiatric co-morbidities and that these changes may be involved in either the manifestation or the maintenance of psychiatric co-morbidities in epilepsy. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Psychiatric comorbidities in temporal lobe epilepsy: Possible relationships between psychotic disorders and involvement of limbic circuits

Objective: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. Methods: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. Conclusions: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

Amygdala gene expression of NMDA and GABAA receptors in patients with mesial temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and affects 40% of the patients. Seizures arising from the mesial temporal lobe structures (i.e., amygdala and hippocampus) are common, whereas neocortical seizures are rare. In recent years, many studies aimed to identify the pattern of gene expression of neurotransmitters involved in molecular mechanisms of epilepsy. We used real-time PCR to quantify the expression of GABAA (subunits a1, beta 1, beta 2) and NMDA (subunits NR1, NR2A, and NR2B) receptor genes in amygdalae of 27 patients with TLE and 14 amygdalae from autopsy controls. The NR1 subunit was increased in patients with epilepsy when compared with controls. No differences were found in expression of NMDA subunits NR2A and NR2B or in a1, beta 1, and beta 2 subunits of GABAA receptors. Our results suggest that the NR1 subunit of NMDA receptors is involved in the amygdala hyperexcitability in some of the patients with TLE. (C) 2010 Wiley Periodicals, Inc., Inc.

Pathophysiology of mood disorders in temporal lobe epilepsy

Objective: There is accumulating evidence that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological, neurochemical and electrophysiological aspects might contribute to the development of psychiatric symptoms in TLE and the putative neurobiological mechanisms that cause mood disorders in this patient subgroup. Methods: In this review, clinical, experimental and neuropathological findings, as well as neurochemical features of the limbic system were examined together to enhance our understanding of the association between TLE and psychiatric comorbidities. Finally, the value of animal models in epilepsy and mood disorders was discussed. Conclusions: TLE and psychiatric symptoms coexist more frequently than chance would predict. Alterations and neurotransmission disturbance among critical anatomical networks, and impaired or aberrant plastic changes might predispose patients with TLE to mood disorders. Clinical and experimental studies of the effects of seizures on behavior and electrophysiological patterns may offer a model of how limbic seizures increase the vulnerability of TLE patients to precipitants of psychiatric symptoms.

Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction

An association between memory and executive dysfunction (ED) has been demonstrated in patients with mixed neurological disorders. We aimed to investigate the impact of ED in memory tasks of children with temporal lobe epilepsy (TLE). We evaluated 36 children with TLE and 28 controls with tests for memory, learning, attention, mental flexibility, and mental tracking. Data analysis was composed of comparison between patients and controls in memory and executive function; correlation between memory and executive function tests; and comparison between patients with mild and severe ED in memory tests. Children with TLE had worse performance in focused attention, immediate and delayed recall, phonological memory, mental tracking, planning, and abstraction. Planning, abstraction, and mental tracking were correlated with visual and verbal memory. Children with severe ED had worse performance in verbal and visual memory and learning tests. This study showed that ED was related to memory performance in children with TLE. (C) 2012 Elsevier Inc. All rights reserved.