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Temporal lobe epilepsy is one of the most common forms of epilepsy. Numerous contributing factors and compensatory mechanisms have been associated with temporal lobe epilepsy. One feature found in both humans and animal models is sprouting of hippocampal principal cell axons, which suggests that axonal sprouting may be a general phenomenon associated with temporal lobe epilepsy. This article highlights the evidence showing that hippocampal GABAergic interneurons also undergo axonal sprouting in temporal lobe epilepsy. The caveats and unanswered questions associated with the current data and the potential physiological consequences of reorganizations in GABAergic circuits are discussed.
Temporal lobe epilepsy is a partial epileptic disorder in which mesial structures are responsible for the principal ictal symptoms. Its characteristic feature is the recurrence of simple and complex partial seizures, associated with postictal confusion and amnesia of the event. The facilitating effect of NREM sleep on the propagation of the seizure, as well as the sleep abnormalities provoked by epilepsy were evident in our two patients. Yawning is a physiological reflex induced by arousal and drowsiness and may appear in different neurological conditions. Its relation with epilepsy of limbic origin has been rarely reported. We describe in a 95 year old male patient, the occurrence of yawning followed by complex partial seizure during a state of drowsiness. His EEG showed independent bilateral interictal foci of temporal sharp waves and after being medicated with carbamazepine 400 mg/day, the episode did not recur. Another patient, a 17 year old female, displayed complex partial seizures and secondarily generalized seizures with yawning during the posictal period, after naps. The EEG was normal and her polysomnography showed bilateral synchronous temporal spikes and slow waves with secondarily generalization during stage 2 of NREM sleep that produce paroxysmal microarousals and increased stages 1 and 2 of NREM sleep and REM sleep diminished. After being medicated with divalproex sodium 750 mg/day, she suffered no further seizures. Temporal lobe epilepsy, sleep-wake cycles and yawning seem not only to share the same anatomic structures but also the same neurochemical mechanisms. The fact that endogenous opiods are considered as part of a protective system that stop and prevent seizures may allow us to postulate that yawning would be the expression of the endogenous opiods induced mechanisms that stop and prevent the recurrence of the temporal lobe epilepsy. Another hypothesis may be that this is only a particular form of temporal lobe epilepsy.
Temporal lobe epilepsy, the most common type of epilepsy in adult humans, is characterized clinically by the progressive development of spontaneous recurrent seizures of temporal lobe origin and pathologically by hippocampal neuronal loss and mossy fiber sprouting. In this study, we sought to test the prominent hypothesis that neuronal loss and mossy fiber sprouting play a critical role in the genesis and progression of temporal lobe epilepsy. Rats receiving a single kainic acid injection experienced a single sustained episode of epileptic status with massive neuronal loss and mossy fiber sprouting, whereas rats receiving triple kainic acid injections experienced two priming episodes and one sustained episode of epileptic status with no detectable neuronal loss and mossy fiber sprouting. Early in the process of chronic seizure development, primed rats that failed to show detectable neuronal loss and mossy fiber sprouting exhibited a starting date and a frequency of spontaneous recurrent seizures similar to those of nonprimed rats that showed massive neuronal loss and mossy fiber sprouting. However, nonprimed rats displayed significantly prolonged episodes of spontaneous recurrent seizures over the whole process of chronic seizure development and more frequent severe seizures later in the process. Similar results were observed in both Fischer-344 and Wistar rats as well as in the rat pilocarpine preparation of temporal lobe epilepsy. These results fail to reveal a relation between neuronal loss-mossy fiber sprouting and the genesis of temporal lobe epilepsy but suggest that neuronal loss, mossy fiber sprouting, or both contribute to the intensification of chronic seizures.
Temporal lobe epilepsy is a common human disease that is difficult to treat. The pathogenesis of temporal lobe epilepsy, which holds many unresolved questions, and opportunities for creating more effective treatments and preventative strategies are reviewed herein. Laboratory animal models are essential to meet these challenges. How models are created, how they compare with each other and with the disease in human patients, and how they advance our understanding of temporal lobe epilepsy are described.
Temporal lobe epilepsy is diagnosed by clinical symptoms and signs and by localization of an epileptogenic focus. A brain SPECT study of two patients with temporal lobe epilepsy, using 99mTc-HMPAO, was used to demonstrate a perfusion abnormality in the temporal lobe, while brain CT and MRI were non-contributory. The electroencephalogram, though abnormal, did not localize the diseased area. The potential role of the SPECT study in diagnosis and localization of temporal lobe epilepsy is discussed.
Temporal lobe epilepsy is not a single clinicopathologic entity but a group of syndromes requiring different surgical solutions. Anatomic resections planned for the treatment of these syndromes are aimed at pathologic substrates minimizing ablation of normal tissue. Most of these procedures involve mesial and lateral temporal resections. The syndrome of mesial temporal sclerosis should be treated with resection aimed at hippocampus and the PHG, including entorhinal cortex, and at part of the amygdala. Improvement in diagnostic methods and refinement of anatomic surgical procedures that maximize resection of hippocampus resulted in excellent outcome in the treatment of patients with this syndrome. Mass lesions in patients with intractable seizures should be resected with some surrounding margins, but additional clinical studies will be required to determine the role of anatomic resections, including hippocampectomy, in the treatment of these patients. Extrahippocampal temporal lobe epilepsy is the most difficult to evaluate and treat. Tailored individualized resections based on acute or chronic EEG recordings may be required until and if discrete anatomically based syndromes can be identified in this patient population.
Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy. The mechanisms of epileptogenesis and seizure semiology of the mesial and neocortical temporal lobe epilepsy are discussed. The evaluation and selection of patients for TLE surgery requires team work: the different clinical aspects of neuropsychological evaluation, magnetic resonance and functional imaging (positron emission tomography, single photon emission computed tomography and magnetoenephalography) are reviewed. In our programme of epilepsy surgery at Kuopio University Hospital, Finland, we have performed 230 temporal resections from 1988 until 2002. Preoperative diagnostic EEG-videotelemetry often required intracranial monitoring and it has proved to be safe and efficient. The indications and technique for tailored temporal lobe resection with amygdalohippocampectomy used in our institution, as well as the complications, are described. Our analysis of outcome after temporal lobe surgery included 140 consecutive adult patients between 1988 and 1999; one year after the operation in unilateral TLE the Engel I-II outcome was observed in 68% of the patients. Outcome of surgery improved significantly after introduction of the standardised MR imaging protocol from 1993; 74% of patients with unilateral TLE achieved Engel I-II outcome.
Temporal lobe epilepsy remains one of the most widespread seizure disorders in man, the etiology of which is controversial. Using new rat models of temporal lobe epilepsy that are either prone or resistant to develop complex partial seizures, we provide evidence that this seizure susceptibility may arise from arrested development of the GABAA receptor system. In seizure-prone (Fast kindling) and seizure-resistant (Slow kindling) rat models, both the mRNA and protein levels of the major alpha subunit expressed in adult brain (alpha1), as well as those highly expressed during development (alpha2, alpha3, and alpha5), were differentially expressed in both models compared with normal controls. We found that alpha1 subunit mRNA expression in the Fast kindling strain was approximately half the abundance of control rats, whereas in the Slow kindling strain, it was approximately 70% greater than that of controls. However, Fast rats overexpressed the alpha2, alpha3, and alpha5 ("embryonic") subunits, having a density 50-70% greater than controls depending on brain area, whereas the converse was true of Slow rats. Using subunit-specific antibodies to alpha1 and alpha5 subunits, quantitative immunoblots and immunocytochemistry revealed a concordance with the mRNA levels. alpha1 protein expression was approximately 50% less than controls in the Fast strain, whereas it was 200% greater in the Slow strain. In contrast, alpha5 subunit protein expression was greater in the Fast strain than either the control or Slow strain. These data suggest that a major predispositional factor in the development of temporal lobe epilepsy could be a failure to complete the normal switch from the GABAA receptor alpha subunits highly expressed during development (alpha2, alpha3, and alpha5) to those highly expressed in adulthood (alpha1).
Temporal lobe epilepsy in adults is a relatively homogenous syndrome with hippocampal sclerosis being its most common pathologic substrate. In the pediatric age group, low-grade neoplasms and cortical dysplasia are much more common than hippocampal sclerosis. Pediatric temporal lobe epilepsy has distinct semiologic, electrophysiologic and imaging characteristics as compared with its adult counterpart. The various treatment options for pediatric temporal lobe epilepsy include antiepileptic drugs, resective surgery, vagal nerve stimulation and the ketogenic diet. In spite of the multiple antiepileptic drugs currently available, 5-10% of all newly diagnosed cases will remain intractable to medical therapy and should be referred for presurgical evaluation. Resective surgery offers the best chance of seizure freedom in carefully selected patients. Future areas of research include new drug development, better imaging and localization techniques, and brain stimulation.
Temporal lobe epilepsy is associated with a characteristic pattern of synaptic reorganization in the hippocampal formation, consisting of neuronal loss and aberrant growth of mossy fiber collaterals into the dentate gyrus inner molecular layer. We have used the rat pilocarpine model of temporal lobe epilepsy to study the functional consequences of mossy fiber sprouting on excitatory activity and kappa-opioid receptor-mediated inhibition. Using the whole cell voltage-clamp technique, we found that abnormal excitatory activity was evident in granule cells of the dentate gyrus from pilocarpine-treated rats. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) was increased greatly in cells from tissue in which significant mossy fiber sprouting had developed. In the presence of bicuculline, giant spontaneous EPSCs, with large amplitudes and long durations, were seen only in association with mossy fiber sprouting. Giant EPSCs also could be evoked by low-intensity stimulation of the perforant path. Mossy fibers release not only excitatory amino acids, but also opioid peptides. kappa-Opioid receptor-mediated inhibition in normal Sprague-Dawley rats was seen only in hippocampal sections from the ventral pole. In pilocarpine-treated rats, however, kappa receptor-mediated effects were seen in both ventral and more dorsal sections. Thus in this model of temporal lobe epilepsy, several types of abnormal excitatory activity were observed, thereby supporting the idea that mossy fiber sprouting leads to recurrent excitatory connections. At the same time, inhibition of excitatory activity by kappa-opioid receptors was increased, perhaps representing an endogenous anticonvulsant mechanism.
Temporal lobe epilepsy is the most common type of epilepsy in adults, and its underlying mechanisms are unclear. To investigate how the medial entorhinal cortex might contribute to temporal lobe epilepsy, we evaluated the histology and electrophysiology of slices from rats 3-7 d after an epileptogenic injury (pilocarpine-induced status epilepticus). Nissl staining, NeuN immunocytochemistry, and in situ hybridization for GAD65 mRNA were used to verify the preferential loss of glutamatergic neurons and the relative sparing of GABAergic interneurons in layer III. From slices adjacent to those that were used for anatomy, we obtained whole-cell patch recordings from layer II medial entorhinal cortical neurons. Recordings under current-clamp conditions revealed similar intrinsic electrophysiological properties (resting membrane potential, input resistance, single spike, and repetitive firing properties) to those of controls. Spontaneous IPSCs were less frequent (68% of controls), smaller in amplitude (57%), and transferred less charge (51%) than in controls. However, the frequency, amplitude, and rise time of miniature IPSCs were normal. These findings suggest that after epileptogenic injuries the layer II entorhinal cortical neurons receive less GABA(A) receptor-mediated synaptic input because presynaptic inhibitory interneurons become less active. To investigate the possible consequences of reduced spontaneous inhibitory input to layer II neurons, we recorded field potentials in the dentate gyrus, their major synaptic target. At 5 d after pilocarpine-induced status epilepticus the spontaneous field potentials recorded in vivo were over three times more frequent than in controls. These findings suggest that an epileptogenic injury reduces inhibition of layer II neurons and results in excessive synaptic input to the dentate gyrus.
Temporal lobe epilepsy is the most common type of epilepsy in adults, and its pathophysiology remains unclear. Layer II stellate cells of the entorhinal cortex, which are hyperexcitable in animal models of temporal lobe epilepsy, provide the predominant synaptic input to the hippocampal dentate gyrus. Previous studies have ascribed the hyperexcitability of layer II stellate cells to GABAergic interneurons becoming "dormant" after disconnection from their excitatory synaptic inputs, which has been reported to occur during preferential loss of layer III pyramidal cells. We used whole-cell recording from slices of entorhinal cortex in pilocarpine-treated epileptic rats to test the dormant interneuron hypothesis. Hyperexcitability appeared as multiple action potentials and prolonged depolarizations evoked in layer II stellate cells of epileptic rats but not controls. However, blockade of glutamatergic synaptic transmission caused similar percentage reductions in the frequency of spontaneous IPSCs in layer II stellate cells of control and epileptic rats, suggesting similar levels of excitatory synaptic input to GABAergic interneurons. Direct recordings and biocytin labeling revealed two major types of interneurons in layer III whose excitatory synaptic drive in epileptic animals was undiminished. Interneurons in layer III did not appear to be dormant; therefore, we tested whether loss of GABAergic synapses might underlie hyperexcitability of layer II stellate cells. Stereological evidence of fewer GABAergic interneurons, fewer gephyrin-immunoreactive punctae, and reduced frequency of spontaneous IPSCs and miniature IPSCs (recorded in tetrodotoxin) confirmed that layer II stellate cell hyperexcitability is attributable, at least in part, to reduced inhibitory synaptic input.
Temporal lobe epilepsy is the most common type of epilepsy in adults. It frequently develops in previously normal nervous tissue, secondary to trauma, tumour or stroke. The disease has a tendency to progress toward generalization and neurologic deficits. The pathogenesis of temporal lobe epilepsy is still unclear. In this article, a hypothesis is proposed suggesting that a cascade of biological events may underlie its development and progression. These include increased excitatory amino acid release, NMDA receptor activation, influx of calcium into neurones, activation of calcium-dependent enzymes (including phospholipase A2), immediate early gene expression, and synthesis of new proteins. Positive and negative feedback loops as well as other events, taking place in parallel, are also hypothesized. The clinical and pharmacological ramifications of this working hypothesis are discussed.
Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS), mesial TLE (MTLE), is the commonest medically refractory adult epilepsy syndrome. Corpora amylacea (CoA) have been shown to be a marker of MTS. We compared 9 patients with MTS who had dense deposition of CoA in their hippocampi with 25 patients with MTS who did not have CoA. The patients with CoA were significantly older and they showed a trend towards having a significantly longer duration of epilepsy. The postoperative seizure outcome at 2 years was not different in the 2 groups. Our results could indicate the progressive nature of the pathology of MTS, probably indicating excitotoxic damage due to recurrent seizures, but they need to be verified by clinicopathological correlation among a larger number of patients with MTLE.
Temporal lobe gliosis and neuronal loss are pathological hallmarks of complex partial seizures. However, the specificity of glial cell changes is not clear. To assess this we studied surgically resected temporal lobes containing either medial temporal sclerosis (MTS) or temporal lobe epilepsy with tumour (TLET) and compared them with idiopathic epilepsy cases and normal controls. We quantitatively assessed glial cell density and mean nuclear volume in the white matter of various temporal gyri and the deep white matter. There was an increase in mean glial cell nuclear volume in MTS and TLET cases in the white matter of superior temporal gyrus, parahippocampal gyrus and deep white matter but not in the white matter of the middle temporal gyrus. In contrast, the densities of glial cells immunopositive for glial fibrillary acidic protein in the MTS and TLET groups were reduced in all white matter regions when compared with the controls. These changes may indicate that glial cells in the white matter have an active role to play in epilepsy pathogenesis.
Temporal lobe epilepsy produces distinct, interictal cognitive and behavioral changes. A constellation of ideative-emotive traits may be aligned with left and right epileptogenic involvement of mesolimbic structures.
Temporal lobe epilepsy is the most prevalent seizure disorder in adults. Compromised inhibitory neurotransmitter function in the hippocampus contributes to the hyperexcitability generating this condition, but the underlying molecular mechanisms are unknown. Combining patch-clamp recording and single-cell mRNA amplification (aRNA) techniques in single dentate granule cells, we demonstrate that expression of GABA(A) receptor subunit mRNAs is substantially altered in neurons from epileptic rats. These changes in gene expression precede epilepsy onset by weeks and correlate with profound alterations in receptor function, indicating that aberrant GABA(A) receptor expression and function has an essential role in the process of epileptogenesis.