Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms

Seizures in patients with Alzheimer's disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid β (Aβ) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neurobiological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying mechanisms may exist for at least some of the aspects of AD that are also found in TLE.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Could hippocampal neurogenesis be a future drug target for treating temporal lobe epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.     

Embryonic stem cell-derived neural precursor grafts for treatment of temporal lobe epilepsy

Complex partial seizures arising from mesial temporal lobe structures are a defining feature of mesial temporal lobe epilepsy (TLE). For many TLE patients, there is an initial traumatic head injury that is the precipitating cause of epilepsy. Severe TLE can be associated with neuropathological changes, including hippocampal sclerosis, neurodegeneration in the dentate gyrus, and extensive reorganization of hippocampal circuits. Learning disabilities and psychiatric conditions may also occur in patients with severe TLE for whom conventional anti-epileptic drugs are ineffective. Novel treatments are needed to limit or repair neuronal damage, particularly to hippocampus and related limbic regions in severe TLE and to suppress temporal lobe seizures. A promising therapeutic strategy may be to restore inhibition of dentate gyrus granule neurons by means of cell grafts of embryonic stem cell-derived GABAergic neuron precursors. “Proof-of-concept” studies show that human and mouse embryonic stem cell-derived neural precursors can survive, migrate, and integrate into the brains of rodents in different experimental models of TLE. In addition, studies have shown that hippocampal grafts of cell lines engineered to release GABA or other anticonvulsant molecules can suppress seizures. Furthermore, transplants of fetal GABAergic progenitors from the mouse or human brain have also been shown to suppress the development of seizures. Here, we review these relevant studies and highlight areas of future research directed toward producing embryonic stem cell-derived GABAergic interneurons for cell-based therapies for treating TLE.     

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.SIGNIFICANCE STATEMENT People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathologic bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE, and supports a long-standing hypothesis of episodic memory theories.     

Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical,pathological and neuroimaging evidence

Cognitive decline is increasingly described as a co‐morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)‐related TLE. Accelerated cognitive decline is described in groups of adult HS‐related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post‐temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post‐operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS‐related TLE and correlated to post‐operative cognitive decline in some patients. A traumatic head injury‐related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross‐sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine in vivo pathways and further explore cognitive decline in TLE.     

Spike–wave discharges in adult Sprague–Dawley rats and their implications for animal models of temporal lobe epilepsy

Spike–wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague–Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague–Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3 months of age, consistent with previous reports (Buzsáki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs.Spike–wave discharges were often accompanied by behaviors similar to stage 1–2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7–8 Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (> 250 Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague–Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1–2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE.     

Update on temporal lobe‐dependent information processing,in health and disease

The past decade has been characterized by a lot of remodeling in the field of learning and memory. Both of them, often associated with neuronal oscillations, an emergent property of brain networks, are governed by temporal lobe (TL) functional connectivity. An impairment of oscillatory mechanisms indeed often leads to TL‐dependent cognitive deficits. While the classical view assigned the TL a major role in spatial information processing, new theories rather confer to the TL a more general function in cognitive processes beyond space representation. The present review covers, both in humans and in animal models, (a) the updated role of the TL in cognitive processes, addressing current debates in the field and proposing a scenario on how TL structures cooperate in order to bind an integrated representation of afferent information, (b) the oscillatory mechanisms underlying these TL‐dependent cognitive functions (theta, gamma, sharp wave ripples) and (c) how TL‐dependent cognition is altered during temporal lobe epilepsy, proposing a scenario on how reorganized TL networks in TLE leads to rhythmopathies and cognitive deficits. Temporal lobe epilepsy (TLE) is a well‐studied neurological disease. Patients do not only suffer from epileptic seizures but also from cognitive and behavioral deficits between their seizures called comorbidities. TLE animal models are therefore used to understand how and when these comorbidities arise and what their underlying mechanisms are.     

Relevance of Seizure-Induced Neurogenesis in Animal Models of Epilepsy to the Etiology of Temporal Lobe Epilepsy

Summary:  Seizure induction in laboratory animals is followed by many changes in structure and function, and one of these is an increase in neurogenesis—the birth of new neurons. This phenomenon may be relevant to temporal lobe epilepsy (TLE), because one of the regions of the brain where seizure-induced neurogenesis is most robust is the dentate gyrus—an area of the brain that has been implicated in the pathophysiology of TLE. Although initial studies predicted that neurogenesis in the dentate gyrus would be important to normal functions, such as learning and memory, the new neurons that are born after seizures may not necessarily promote normal function. There appears to be a complex functional and structural relationship between the new dentate gyrus neurons and preexisting cells, both in the animal models of TLE and in tissue resected from patients with intractable TLE. These studies provide new insights into the mechanisms of TLE, and suggest novel strategies for intervention that could be used to prevent or treat TLE.     

The decay of memory between delayed and long-term recall in patients with temporal lobe epilepsy

OBJECTIVES: Impairment of long-term recall may worsen everyday functioning of patients with epilepsy even if the standard short-term or delayed recall tests do not show significant abnormalities. We evaluated prospectively the decay of memory between delayed and long-term recall in patients with temporal lobe epilepsy (TLE) and controls with the aim of identifying the determinants of long-term memory impairment. METHODS: Seventy patients with TLE and 59 controls underwent neuropsychological assessment of verbal and nonverbal memory, attention, and executive functions at visit 1. Long-term verbal and nonverbal memory was tested with the same word list, verbal logical story, and Rey-Osterrieth complex figure test 4 weeks later at visit 2. The decay in memory was estimated as information recalled at visit 2 as a percentage of the delayed recall at visit 1. RESULTS: Frequent seizures (> or = 4 per month) during the study period were related to poor long-term recall, even for those patients who did relatively well on delayed recall tests. On all long-term memory tests, patients with complex partial and/or secondary generalized seizures did significantly worse than patients with simple partial seizures. The presence of interictal generalized or focal temporal epileptiform activity was associated with more accelerated forgetting of the word list and complex figure. Multiple regression analysis confirmed that number of complex partial seizures, age of patient, and abnormal interictal EEG are significant predictors of accelerated forgetting. CONCLUSIONS: Uncontrolled seizures, especially with ictal impairment of consciousness, can be a significant factor in the accelerated decay of memory, although subclinical interictal epileptiform EEG activity may also be relevant.     

Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP

Recently, hippocampal neuropeptide Y (NPY) gene therapy has been shown to effectively suppress both acute and chronic seizures in animal model of epilepsy, thus representing a promising novel antiepileptic treatment strategy, particularly for patients with intractable mesial temporal lobe epilepsy (TLE). However, our previous studies show that recombinant adeno-associated viral (rAAV)-NPY treatment in naive rats attenuates long-term potentiation (LTP) and transiently impairs hippocampal learning process, indicating that negative effect on memory function could be a potential side effect of NPY gene therapy.Here we report how rAAV vector-mediated overexpression of NPY in the hippocampus affects rapid kindling, and subsequently explore how synaptic plasticity and transmission is affected by kindling and NPY overexpression by field recordings in CA1 stratum radiatum of brain slices. In animals injected with rAAV-NPY, we show that rapid kindling-induced hippocampal seizures in vivo are effectively suppressed as compared to rAAV-empty injected (control) rats. Six to nine weeks later, basal synaptic transmission and short-term synaptic plasticity are unchanged after rapid kindling, while LTP is significantly attenuated in vitro. Importantly, transgene NPY overexpression has no effect on short-term synaptic plasticity, and does not further compromise LTP in kindled animals. These data suggest that epileptic seizure-induced impairment of memory function in the hippocampus may not be further affected by rAAV-NPY treatment, and may be considered less critical for clinical application in epilepsy patients already experiencing memory disturbances.     

Risk factors for spatial memory impairment in patients with temporal lobe epilepsy

At present, the risk factors for world-centered (allocentric) navigation impairment in patients with temporal lobe epilepsy (TLE) are not known. There is some evidence on the importance of the right hippocampus but other clinical features have not been investigated yet. In this study, we used an experimental human equivalent to the Morris water maze to examine spatial navigation performance in patients with drug-refractory unilateral TLE. We included 47 left-hemisphere speech dominant patients (25 right sided; 22 left sided). The aim of our study was to identify clinical and demographic characteristics of TLE patients who performed poorly in allocentric spatial memory tests.Our results demonstrate that poor spatial navigation is significantly associated with younger age at epilepsy onset, longer disease duration, and lower intelligence level. Allocentric navigation in TLE patients was impaired irrespective of epilepsy lateralization. Good and poor navigators did not differ in their age, gender, or preoperative/postoperative status.This study provides evidence on risk factors that increase the likelihood of allocentric navigation impairment in TLE patients. The results indicate that not only temporal lobe dysfunction itself but also low general cognitive abilities may contribute to the navigation impairment.     

Verbal semantic memory in temporal lobe epilepsy

OBJECTIVES: Temporal lobe epilepsy (TLE) may determine memory difficulties not explained by episodic memory impairment. The present study was aimed to verify the presence of specific semantic memory dysfunctions in TLE and to explore their relations to epilepsy variables. SUBJECTS AND METHODS: Forty-seven patients with lateralized temporal (n = 26) or extra-temporal lobe epilepsy (n = 21) and 23 healthy subjects were compared. Picture Naming and Pointing to a Picture were used to explore expressive and receptive vocabulary and the Semantic Questionnaire evaluated semantic judgment of verbally presented items. The Selective Reminding Procedure for word list learning and Story Recall were used to assess episodic memory. Spontaneous speech and the Token Test controlled for language disturbances, and Raven's Coloured Progressive Matrices were used to evaluate abstract reasoning ability. RESULTS: Multivariate analysis of variance of test scores showed significant impairment of semantic memory in patients with left TLE compared to healthy controls, whereas episodic memory was impaired in left temporal and extra-temporal epilepsy (as measured by word learning) and all epilepsy groups (as measured by Story Recall). In the TLE groups, naming abilities were more compromised than single-word comprehension and semantic judgment - which were not significantly affected. No deficits in language abilities or in abstract reasoning were found in any patient group. Factor analysis of memory tests scores in the patients produced two factors, one semantic and the other episodic. Regression analysis revealed that the semantic factor was related to abstract reasoning, left hemisphere lateralization of seizures, and age of seizure onset; while the episodic factor was related to age. CONCLUSIONS: Left TLE may determine significant verbal semantic memory compromise, maybe due to impaired access to the semantic-lexical storage. In non-aphasic epilepsy patients, comparison of performance on semantic and episodic memory tests may be useful for assessing the nature of memory failures, and may complement clinical and neurophysiological means for defining the epileptic center.     

Seizures in Alzheimer Disease: Clinical and Epidemiological Data

Alzheimer disease (AD) and epilepsy are disorders commonly seen in the elderly. Many studies have shown that patients with AD are at increased risk for developing seizures and epilepsy. Whereas, patients with specific types of epilepsy, such as temporal lobe epilepsy (TLE), experience some degree of cognitive dysfunction, questions have been raised as to whether these disorders share some underlying pathophysiologic mechanisms or whether one is an epiphenomenon of the other. In this report, we review some of the available clinical and epidemiologic literature on various aspects of the topic of seizures in AD, including seizure rates and types, risk factors for seizures, electroencephalographic findings, treatment options, limitations, and methodological issues. Overall, multiple aspects of the literature on seizures and epilepsy in AD, including diagnosis, risk factors, the role of EEG in diagnosis, and the response to treatment are not clear and suffer from many methodological limitations and gaps.Epilepsy and AD are common neurologic disorders for which increasing age is a common and well-established risk factor (1, 2). The potential relation between these two disorders has been supported by experimental and clinical data. From a clinical aspect, patients with AD have an increased risk of developing seizures and epilepsy; thus AD may be an important cause of epilepsy in the elderly. AD and other neurode-generative conditions represent the presumed etiology for 10% of new onset epilepsy in patients older than 65 (3).The diagnosis of seizures in patients with AD is not always easy because the manifestation of partial seizures might be hard to recognize and distinguish from other behaviors common in these patients. This may lead to underestimation of the real frequency of seizures in AD. At the same time, the possibility that “funny” or “unusual” behaviors of demented patients are considered seizures, particularly by nonepileptologists, may lead to overestimation of seizure rates.We briefly review and comment on studies reporting on the risk of seizures in AD, the possible factors modifying this risk, the role of EEG in the diagnosis of epilepsy and its limitations, the efficacy of antiepileptic drugs and the relationship between seizures and interictal epileptiform activity and AD course.     

Is physical activity beneficial for recovery in temporal lobe epilepsy? Evidences from animal studies

Exposure to different physical and cognitive stimulus have been shown to induce extensive neuronal plasticity in both undamaged and injured central nervous system, such as enhanced neurogenesis in the dentate gyrus of the hippocampus, up-regulation of neurotrophic factors and improved learning and memory. Neuronal plasticity also is found during certain neurodegenerative conditions, including the temporal lobe epilepsy (TLE). TLE is the most common form of partial epilepsy, characterized by atrophy of mesial temporal structures, mossy fiber sprouting, spontaneous recurrent seizures and cognitive deficits. In view of the fact that physical activity has been found to be beneficial for treating animal models of Parkinson's, Alzheimer's and Huntington's diseases, there is considerable interest in determining the efficacy of this strategy for preventing or treating chronic TLE. This review discusses the positive effects of program of physical exercise in experimental models of epilepsy. Thus, considerations of the potential application of physical exercise strategy for preventing or treating TLE are highlighted.     

Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy

Temporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF), in which memories are retained normally over short delays but are then lost at an accelerated rate over days or weeks. The causes of ALF, and whether it represents a consolidation deficit distinct from the one associated with forgetting over short delays, remain unclear. In addition, methodological issues have made results of some previous studies difficult to interpret. This study used improved methodology to investigate the role of seizure activity in ALF. Forgetting was assessed in participants with TLE (who have involvement of temporal lobe structures) and idiopathic generalised epilepsy (IGE; in which seizures occur in the absence of identified structural pathology in the temporal lobes). Learning of novel stimuli was matched between patients with TLE, patients with IGE and healthy controls matched for age and IQ. Results indicated that the TLE group showed accelerated forgetting between 30-min and three-weeks, but not between 40-s and 30-min. In contrast, rates of forgetting did not differ between patients with IGE and controls. We conclude that (1) ALF can be demonstrated in TLE in the absence of methodological confounds; (2) ALF is unlikely to be related to the experience of epilepsy that does not involve the temporal lobes; (3) neither seizures during the three-week delay nor polytherapy was associated with ALF.     

Accelerated cognitive decline in a rodent model for temporal lobe epilepsy

ObjectiveCognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy.MethodsNeurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance.ResultsRats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits.SignificanceThe effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy.     

Drug-resistant temporal lobe epilepsy is associated with postural control abnormalities

Epilepsy is responsible for falls that are not systematically associated with seizures and that therefore suggest postural impairment. There are very few studies of postural control in patients with epilepsy and none of them focus on temporal lobe epilepsy (TLE), although part of the vestibular cortex is located in the temporal cortex. The aim of this study was to evaluate the characteristics of postural control in a homogeneous population of patients with complex partial TLE. Twenty-six patients with epilepsy and 26 age-matched healthy controls underwent a sensory organization test combining six conditions, with and without sensory conflicting situations. Patients with epilepsy displayed poorer postural control, especially in situations where vestibular information is necessary to control balance. In addition to potential antiepileptic drug side effects, vestibular dysfunction could be related to the temporal pathology. Our study allows for a better understanding of the mechanism underlying falls in this population of patients.     

The neurobiology of cognitive disorders in temporal lobe epilepsy

Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy. This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of how our understanding of these disorders has been improved by studying the outcomes of anterior temporal lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy, present a challenge to neurologists.     

Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy

Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.     

Day/night patterns of focal seizures

PURPOSE: In many patients with epilepsy seizures occur with a day/night pattern. Our aims were to compare day/night patterns in seizure frequency among patients with different epileptogenic regions. METHODS: We analyzed video-EEG recordings in 15 patients with temporal lobe (TLE) and 11 with extratemporal lobe epilepsy (XTLE). Each seizure was classified according to subject group (TLE vs XTLE), sleep/wake state, and time of day of seizure occurrence (grouped into 6 x 4-hour "bins"). RESULTS: Of 90 seizures, 41 occurred in TLE and 49 in XTLE patients. There were day/night patterns of seizure occurrence in each group, with differences in the patterns between groups. In TLE, 50% of seizures occurred between the hours of 15:00 and 19:00 (17% would be expected by chance in each 4-hour "bin": F=3.59, P<0.006). In XTLE, there was a peak between 19:00 and 23:00 (47%: F=4.72, P<0.0018). The effect of time on seizures was least pronounced in the XTLE patients who had more than one epileptogenic region. The proportion of seizures occurring from sleep was significantly less in TLE (19%) than in XTLE patients (41%) [P<0.04, Fisher's exact test]. CONCLUSIONS: There are clear day/night patterns of seizure occurrence in epilepsy, with differences in the patterns between TLE and XTLE. There is an additional interaction with sleep/wake state, with relatively few seizures occurring from sleep in TLE compared with XTLE. Thus, it appears that both sleep/wake state and day/night or circadian rhythms may affect seizure proclivity, with different effects depending on the location of the epileptogenic region.