Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures

Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazoleinduced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100 mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (�10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic–clonic seizures. These results extend the anticonvulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.

Temporal lobe epilepsy and social behavior: An animal model

Social behavior depends on the integrity of social brain circuitry. The temporal lobe is an important part of the social brain, and manifests morphological and functional alterations in autism spectrum disorders (ASD). Rats with temporal lobe epilepsy (TLE), induced with pilocarpine, were subjected to a social discrimination test that has been used to investigate potential animal models of ASD, and the results were compared with those for the control group. Rats with TLE exhibited fewer social behaviors than controls. No differences were observed in nonsocial behavior between groups. The results suggest an important role for the temporal lobe in regulating social behaviors. This animal model might be used to explore some questions about ASD pathophysiology. (c) 2008 Elsevier Inc. All rights reserved.

Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy

Reactive oxygen species (ROS) appear to be involved in several neurodegenerative disorders. We tested the hypothesis that oxidative stress could have a role in the hippocampal neurodegeneration observed in temporal lobe epilepsy induced by pilocarpine. We first determined the spatio-temporal pattern of ROS generation, by means of detection with dihydroethidium oxidation, in the CA1 and CA3 areas and the dentate gyrus of the dorsal hippocampus during status epilepticus induced by pilocarpine. Fluoro-Jade B assays were also performed to detect degenerating neurons. ROS generation was increased in CA1, CA3 and the dentate gyrus after pilocarpine-induced seizures, which was accompanied by marked cell death. Treatment of rats with a NADPH oxidase inhibitor (apocynin) for 7 days prior to induction of status epilepticus was effective in decreasing both ROS production (by an average of 20%) and neurodegeneration (by an average of 61%). These results suggest an involvement of ROS generated by NADPH oxidase in neuronal death in the pilocarpine model of epilepsy. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

The sleep-wake cycle in adult rats following pilocarpine-induced temporal lobe epilepsy

The relationship between sleep and epilepsy is both complex and clinically significant. Temporal lobe epilepsy (TLE) influences sleep architecture, while sleep plays an important role in facilitating and/or inhibiting possible epileptic seizures. The pilocarpine experimental model reproduces several features of human temporal lobe epilepsy and is one of the most widely used models in basic research. The aim of the present study was to characterize, behaviorally and electrophysiologically, the phases of sleep-wake cycles (SWC) in male rats with pilocarpine-induced epilepsy. Epileptic rats presented spikes in all phases of the SWC as well as atypical cortical synchronization during attentive wakefulness and paradoxical sleep. The architecture of the sleep-wake phases was altered in epileptic rats, as was the integrity of the SWC. Because our findings reproduce many relevant features observed in patients with epilepsy, this model is suitable to study sleep dysfunction in epilepsy. (C) 2009 Elsevier Inc. All rights reserved.

Alteration of purinergic P2X(4) and P2X(7) receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine

Although ATP and P2X receptor activity have been lately associated with epilepsy, little is known regarding their exact roles in epileptogenesis. Temporal-lobe epilepsy (TLE) in rat was induced by pilocarpine in order to study changes of hippocampal P2X(2), P2X(4) and P2X(7) receptor expression during acute, latent or chronic phases of epilepsy. During acute and chronic phases increased P2X(7) receptor expression was principally observed in glial cells and glutamatergic nerve terminals, suggesting participation of this receptor in the activation of inflammatory and excitotoxic processes during epileptogenesis. No significant alterations of hippocampal P2X(2) and P2X(4) receptor expression was noted during the acute or latent phase when compared to the control group, indicating that these receptors are not directly involved with the initiation of epilepsy. However, the reduction of hippocampal P2X(4) receptor immunostaining in the chronic phase could reflect neuronal toss or decreased GABAergic signaling. (C) 2008 Elsevier B.V. All rights reserved.

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.

Supracerebellar transtentorial approach-resection of the tentorium instead of an opening-to provide broad exposure of the mediobasal temporal lobe: anatomical aspects and surgical applications Clinical article

Object. The aim of this study was to describe the surgical anatomy of the mediobasal aspect of the temporal lobe and the supracerebellar transtentorial (SCTT) approach performed not with an opening, but with the resection of the tentorium, as an alternative route for the neurosurgical management of vascular and tumoral lesions arising from this region. Methods. Cadaveric specimens were used to illustrate the surgical anatomy of the mediobasal region of the temporal lobe. Demographic aspects, characteristics of lesions, clinical presentation, surgical results, follow-up findings, and outcomes were retrospectively reviewed for patients referred to receive the SCTT approach with tentorial resection. Results. Ten patients (83%) were female and 2 (17%) were male. Their ages ranged from 6 to 59 years (mean 34.5 +/- 15.8 years). All lesions (3 posterior cerebral artery aneurysms, 3 arteriovenous malformations, 3 cavernous malformations, and 3 tumors) were completely excluded or resected. After a mean follow-up period of 143 months (range 10-240 months), the mean postoperative Glasgow Outcome Scale score was 4.9. Conclusions. Knowledge of the surgical anatomy provides improvement for microsurgical approaches. The evolution from a small opening to a resection of the tentorium absolutely changed the exposure of the mediobasal aspect of the temporal lobe. The SCTT approach with tentorial resection is an excellent alternative route to the posterior part of mediobasal aspect of the temporal lobe, and it was enough to achieve the best neurosurgical management of tumoral and vascular lesions located in this area. (http://thejns.org/doi/abs/10.3171/2011.12.JNS111256)

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.