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with an increased risk for developing epilepsy of unknown etiology. Additionally, loss of a child, a significant stressor, is associated with an increased risk for developing epilepsy in the parents. doi:10.1016/j.yebeh.2012.04.017 Effects of stress on the hippocampus in epilepsy and depression R. Sankar, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA The impact of stress on the brain involves many levels of brain function, incorporating the neocortex, the limbic system, the brain stem, and likely other structures such as the basal ganglia. While the commonly reported perception of stress by patients relates to external or environmental provocations, it is important to recognize that seizures themselves can constitute physiological stress and may impact on brain function. The relationship between stress as marked by the hypothalamo- pituitary-adrenal (HPA) axis and seizures has been studied for some time. Our laboratory has been studying the relationship between epilepsy and depression, and we have demonstrated behavioral markers of depression associated with kindling epileptogenesis as well as poststatus epilepticus epileptogenesis. In both models, we found altered serotonergic tone underlying this phenomenon. The alterations in presynaptic serotonergic (5HT-1A) function in the raphe nucleus in the brain stem and the postsynaptic changes in the Ammon's horn of the hippocampus were associated with enhanced circulating glucocorticoid and corticosterone in the animals that have been subjected to lithiumpilocarpine status epilepticus. Restoration of serotonergic function and behavior could be achieved by treatment with an antagonist of glucocorticoid receptor. We also found that seizure-induced cytokine release (inflammatory re- sponse) played a role in mediating the stress response, i.e., altered HPA function with exaggerated circulating corticosterone. The relationship between seizures and inflammation has been shown to be reciprocal. In our experiments, the serotonergic tone and the behavioral aspects of depression were not responsive to the selective serotonin uptake inhibitor (SSRI) fluoxetine. However, when fluoxetine treatment was combined with administration of the interleukin-1β (IL-1β) receptor antagonist anakinra, restoration of the serotonergic tone and reversal of the behavioral markers of depression were achieved. Resistance to SSRI in this model of epilepsy-driven depression may reflect enhanced IL-1β signaling, placing inflammation as an important link in connecting epilepsy, stress, and depression. doi:10.1016/j.yebeh.2012.04.018 Stress, depression and seizures C. Dubé, P. Maras, Y. Chen, T.Z. Baram, Anatomy & Neurobiology, Pediatrics, University of California-Irvine, Irvine, CA, USA The prevalence of depression in individuals with temporal lobe epilepsy (TLE) is much higher than that of other chronic disorders with apparent similar severity. The basis for this high prevalence of depression, as well as of cognitive defects including memory problems, is unclear. One obvious element is anatomical: The limbic structures, including the hippocampus, amygdala and related cortices, underlie memory and emotional functions; these are the brain regions impacted by the epileptic seizures. While this scenario infers that depression is a result of epilepsy, an alternative possibility is that both TLE and depression might arise independently from a common insult that affects the common anatomy of depression and TLE. Mechanistically, glutamate- mediated excitotoxicity, loss of neurons and appearance of abnormal networks have been proposed to account for TLE-related depression. In addition, a role for stress mediators in both the emotional and the cognitive correlates of epilepsy is emerging. Neurosteroids, glucocorti- coids and the excitatory stress hormone corticotropin releasing hormone are all strong candidates for mediating epilepsy-related depression and cognitive deficits. Neurosteroids enhance GABA-A receptors, with implication to cognition and depression. CRH is an excitant and, when released during severe stress such as during seizures, destroys dendritic spines and synapses, impacting memory in the hippocampus and emotional function in the amygdala. This presentation will discuss established and emerging information on stress-related mechanisms involved in epilepsy-related depressive and cognitive outcomes, with profound implication for prevention and therapy. Stress, depression, memory, epilepsy. doi:10.1016/j.yebeh.2012.04.019 Psychological and pharmacological treatments of stress in epilepsy M. Mula, Department of Clinical & Experimental Medicine, Amedeo Avogadro University, Division of Neurology, University Hospital Maggiore della Carità, Novara, Italy Treatments available for stress-related disorders span a variety of psychological and pharmacological domains. These interventions have been used both separately and in combination with one another, and both appear to be mainstays of treatment. Practical considera- tions or patient preferences may guide decisions. The selection of an initial treatment plan may depend largely on to whom a patient presents for treatment. A patient presenting to a nonphysician mental health provider is more likely to receive psychotherapy options, while presentation to a physician provider could offer either psychotherapy or pharmacologic therapy, or both. Subsequently, the selection of specific psychotherapies, or specific pharmacologic interventions, may depend to a large degree on the clinician's training. Specific psychological interventions that have been studied for the treatment of stress-related disorders include the following: cognitivebehavioral therapy such as cognitive restructuring, cognitive processing therapy, exposure-based therapies, and coping skills therapy (including stress inoculation therapy); psychodynamic therapy; eye movement desensitization and reprocessing (EMDR); interpersonal therapy; group therapy; hypnosis/hypnotherapy; eclectic psychotherapy; and brain- wave neurofeedback. These therapies are designed to minimize the intrusion, avoidance, and hyperarousal symptoms. Pharmacotherapies, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, mono- amine oxidase inhibitors, other second-generation antidepressants, atypical antipsychotics, anticonvulsants/mood stabilizers, adrenergic agents, benzodiazepines, and other treatments such as naltrexone, cycloserine, and inositol have also been used. doi:10.1016/j.yebeh.2012.04.020 Cognitive Effects of Aging in Epilepsy The aging brain and epilepsy: What do we know? G. Risse, P. Penovich, Minnesota Epilepsy Group, St. Paul, MN, USA, Department of Neurology, University of Minnesota, Minneapolis, MN, USA The last two decades have seen a dramatic increase in research dedicated to understanding age-related changes in the normal brain and to defining the relationship of these changes to the development Abstracts 307

The aging brain and epilepsy: What do we know?

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Page 1: The aging brain and epilepsy: What do we know?

with an increased risk for developing epilepsy of unknown etiology.Additionally, loss of a child, a significant stressor, is associated with anincreased risk for developing epilepsy in the parents.

doi:10.1016/j.yebeh.2012.04.017

Effects of stress on the hippocampus in epilepsy and depression

R. Sankar, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

The impact of stress on the brain involves many levels of brainfunction, incorporating the neocortex, the limbic system, the brain stem,and likely other structures such as the basal ganglia.While the commonlyreported perception of stress by patients relates to external orenvironmental provocations, it is important to recognize that seizuresthemselves can constitute physiological stress and may impact on brainfunction. The relationshipbetweenstress asmarkedby thehypothalamo-pituitary-adrenal (HPA) axis and seizures hasbeen studied for some time.Our laboratory has been studying the relationship between epilepsy anddepression, andwehave demonstrated behavioralmarkers of depressionassociatedwith kindling epileptogenesis as well as poststatus epilepticusepileptogenesis. In both models, we found altered serotonergic toneunderlying this phenomenon. The alterations inpresynaptic serotonergic(5HT-1A) function in the raphe nucleus in the brain stem and thepostsynaptic changes in the Ammon's horn of the hippocampus wereassociated with enhanced circulating glucocorticoid and corticosteronein the animals that have been subjected to lithium–pilocarpine statusepilepticus. Restoration of serotonergic function and behavior could beachieved by treatment with an antagonist of glucocorticoid receptor. Wealso found that seizure-induced cytokine release (inflammatory re-sponse) played a role in mediating the stress response, i.e., altered HPAfunction with exaggerated circulating corticosterone. The relationshipbetween seizures and inflammation has been shown to be reciprocal. Inour experiments, the serotonergic tone and the behavioral aspects ofdepression were not responsive to the selective serotonin uptakeinhibitor (SSRI) fluoxetine. However, when fluoxetine treatment wascombined with administration of the interleukin-1β (IL-1β) receptorantagonist anakinra, restoration of the serotonergic tone and reversal ofthebehavioralmarkers of depressionwere achieved. Resistance to SSRI inthis model of epilepsy-driven depression may reflect enhanced IL-1βsignaling, placing inflammation as an important link in connectingepilepsy, stress, and depression.

doi:10.1016/j.yebeh.2012.04.018

Stress, depression and seizures

C. Dubé, P. Maras, Y. Chen, T.Z. Baram, Anatomy & Neurobiology,Pediatrics, University of California-Irvine, Irvine, CA, USA

The prevalence of depression in individuals with temporal lobeepilepsy (TLE) is much higher than that of other chronic disorders withapparent similar severity. Thebasis for this highprevalenceof depression,as well as of cognitive defects including memory problems, is unclear.One obvious element is anatomical: The limbic structures, including thehippocampus, amygdala and related cortices, underlie memory andemotional functions; these are the brain regions impacted by theepileptic seizures. While this scenario infers that depression is a resultof epilepsy, an alternative possibility is that both TLE and depressionmight arise independently from a common insult that affects thecommon anatomy of depression and TLE. Mechanistically, glutamate-mediated excitotoxicity, loss of neurons and appearance of abnormalnetworks have been proposed to account for TLE-related depression. In

addition, a role for stress mediators in both the emotional and thecognitive correlates of epilepsy is emerging. Neurosteroids, glucocorti-coids and the excitatory stress hormone corticotropin releasing hormoneare all strong candidates for mediating epilepsy-related depression andcognitive deficits. Neurosteroids enhance GABA-A receptors, withimplication to cognition and depression. CRH is an excitant and, whenreleased during severe stress such as during seizures, destroys dendriticspines and synapses, impacting memory in the hippocampus andemotional function in the amygdala. This presentation will discussestablished and emerging information on stress-related mechanismsinvolved in epilepsy-related depressive and cognitive outcomes, withprofound implication for prevention and therapy.

Stress, depression, memory, epilepsy.

doi:10.1016/j.yebeh.2012.04.019

Psychological and pharmacological treatments of stressin epilepsy

M. Mula, Department of Clinical & Experimental Medicine, AmedeoAvogadro University, Division of Neurology, University Hospital Maggioredella Carità, Novara, Italy

Treatments available for stress-related disorders span a variety ofpsychological and pharmacological domains. These interventionshave been used both separately and in combination with one another,and both appear to be mainstays of treatment. Practical considera-tions or patient preferences may guide decisions. The selection of aninitial treatment plan may depend largely on to whom a patientpresents for treatment. A patient presenting to a nonphysician mentalhealth provider is more likely to receive psychotherapy options, whilepresentation to a physician provider could offer either psychotherapyor pharmacologic therapy, or both. Subsequently, the selection ofspecific psychotherapies, or specific pharmacologic interventions,may depend to a large degree on the clinician's training.

Specific psychological interventions that have been studied for thetreatment of stress-related disorders include the following: cognitive–behavioral therapy such as cognitive restructuring, cognitive processingtherapy, exposure-based therapies, and coping skills therapy (includingstress inoculation therapy); psychodynamic therapy; eye movementdesensitization and reprocessing (EMDR); interpersonal therapy; grouptherapy; hypnosis/hypnotherapy; eclectic psychotherapy; and brain-wave neurofeedback. These therapies are designed to minimize theintrusion, avoidance, and hyperarousal symptoms. Pharmacotherapies,including selective serotonin reuptake inhibitors (SSRIs), serotonin andnorepinephrine reuptake inhibitors, tricyclic antidepressants, mono-amine oxidase inhibitors, other second-generation antidepressants,atypical antipsychotics, anticonvulsants/mood stabilizers, adrenergicagents, benzodiazepines, and other treatments such as naltrexone,cycloserine, and inositol have also been used.

doi:10.1016/j.yebeh.2012.04.020

Cognitive Effects of Aging in Epilepsy

The aging brain and epilepsy: What do we know?

G. Risse, P. Penovich, Minnesota Epilepsy Group, St. Paul, MN, USA,Department of Neurology, University of Minnesota, Minneapolis, MN, USA

The last two decades have seen a dramatic increase in researchdedicated to understanding age-related changes in the normal brainand to defining the relationship of these changes to the development

Abstracts 307

Page 2: The aging brain and epilepsy: What do we know?

of neuropathologic disease processes such as dementia, which arecommon in the later decades. Significant decreases in volume of bothgray and white matter associated with increased ventricular sizebeginning around the sixth decade have been well documented inMRI studies. Many of these studies have reported greater involve-ment of the frontal and parietal regions compared to the temporaland occipital lobes, particularly in healthy older individuals. Hemi-spheric asymmetry in brain volume (typically RNL) that becomes lesspronounced with age, and may differ between the sexes (MNF) hasalso been reported. Decreased cognitive efficiency considered normalfor age often accompanies these structural changes and has beenwidely described in functional neuroimaging studies of brainactivation during cognitive tasks, particularly memory processing.Areas of activation may decrease or change in older subjects,sometimes in the absence of a decline in performance, and this hasled to speculation that these changes may represent recruitment ofalternative brain regions, possibly in compensation for age-relateddecreases in processing efficiency. There is also evidence that some ofthis cognitive decline can be arrested or reversed by hormonetherapy in both men and women.

Changes in cognitive functioning over the lifespan of people withintractable epilepsy are poorly understood and remain controversial.This introductory presentationwill briefly review the latest research onneuroanatomic and cognitive changes in the brain during normal aging,and consider how these changes may be affected by temporal lobeepilepsy. The questions of whether the timetable for normal aging isaltered by chronic seizures, the possible interaction between post-surgical cognitive impairment and age-related decline, and the long-itudinal impact of AEDs in the later decades of life will be explored.

doi:10.1016/j.yebeh.2012.04.021

Is the risk of postsurgery memory decline after temporal lobesurgery age dependent?

I. Tyrlikova, I. Rektor, Z. Hummelova, R. Kubikova, S. Telecka, Departmentof Neurology, Masaryk University, St Anne's University Hospital, Brno,Czech Republic

Objective. Memory decline after resective temporal lobe epilepsysurgery is a consistent finding in many studies.Methods. Two groups of patients who underwent temporal lobeepilepsy surgery were compared: a group up to 30 (31) and a groupover 45 years of age (18). The memory (Wechsler test) was evaluatedrepeatedly: before the surgery, a year after and three to five yearsafter the surgery. With regard to improvement/worsening ofmemory, we split the sample into unchanged and worsened patients.The groups were compared according to etiology of epilepsy, durationof the disease, MRI finding, type of surgery, surgery in dominanthemisphere, Engel's outcome and Wada test result.Results. We found memory worsening in 29% of patients in the groupunder 30, compared to 52% of patients in the group over 45. Thesepercentages did not differ with regard to whether the surgery was doneon the languagedominancehemisphereornot. In theMTSetiologygroup,worsening was found in 16.7% of younger and in 46.7% of older patients.

We foundconsiderably lessmemoryworsening in theyounger group(14%) of patients who underwent the selective amygdalohippocam-pectomy. Also among patients with 1a outcome of Engel's classificationhave older group got worse more. The figure of deteriorated patientsincreased from 36% to 75% during five years after surgery in the oldergroup while the figure remained below 38% in the younger one.Conclusions. Our results prove the expectation that the post-surgicalmemory of surgically treated patients aged over 45 decreases.However, the worsening is rather moderate; it is more apparent

with MTS etiology. The declination evince rather five and more yearsafter surgery.

doi:10.1016/j.yebeh.2012.04.022

Neurodevelopmental impact of chronic temporal lobe epilepsy inthe maturing versus aging brain

C. Helmstaedter, University Clinic of Epileptology, Bonn, Germany

There is an ongoing discussion in epileptology regarding thequestion as to whether and under which conditions chronic epilepsymay cause mental decline. While cross sectional studies favor theidea that cognitive impairments develop along the course of thedisease and that cognition becomes increasingly worse with ongoingepilepsy, there is now increasing evidence that impairments existfrom the beginning of epilepsy if not before and that active epilepsyin particular appears to interfere with brain maturation. A negativeeffect of the active epilepsy on cognition, however, should not beneglected. Seizure control, even when achieved late, may partlyreverse the impairments seen in chronic epilepsy. Apart fromindividual conditions where epilepsy is the expression of aprogressive disease, cerebral pathology, seizure-/treatment-relatedimpairments, and processes of the aging brain appear the major riskfactors for accelerated mental decline in chronic epilepsy. Overall, thepresented data strongly emphasize to differentiate seizures from theetiologies of epilepsy, to appreciate the cognitive impairments inepilepsy within a neurodevelopmental neuropsychological frame-work, and to change the focus from chronic to the beginning epilepsy.

doi:10.1016/j.yebeh.2012.04.023

Effects of long-term epilepsy and of temporal lobe resection oncognitive aging

M. Jones-Gotman, S.J. Banks, Dept. of Neurology & Neurosurgery, McGillUniversity, Montreal, Canada

Objective. Healthy adults experience cognitive decline as they age.People with focal temporal lobe epilepsy (TLE) demonstrate specificmemory deficits related to their epilepsy, and those who undergosurgical treatment show further impairment. We investigatedwhether the effect of aging on memory is greater in TLE patientsthan in healthy individuals and ask how resective surgery for TLEimpacts cognition as the patient ages.Methods. Cognitive tests were administered to operated or unoperatedpatients with unilateral TLE, age 55 or older and whose epilepsy wasdiagnosed at least 20 years earlier, and to 20 healthy control subjects(HC) who matched to the patients with respect to age and years ofeducation. Tests focusedonmemory, but sampled allmajordomains.Wealso highlight an 82-year-old woman (MP) with left TLE who wasoperated by Wilder Penfield and tested first by Brenda Milner.Results. Results from 45 subjects (9 left operated, 10 right operated, 6left unoperated, 20 HC) show the following: compared to HC, left-operated patients have significantly worse verbal memory and moreword-finding difficulties; right-operated patients differ from HC onfour measures (not verbal memory); left TLE operated patientsshowed further verbal memory decline from 1 year post-operation,whereas the right TLE operated group's results were more variable;unoperated patients with left TLE performed worse than HC onseveral verbal measures including memory. MP has fared well in the56 years since surgery, living on her own and working as an artist, but

Abstracts308