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1.  Amygdala volumetry in "imaging-negative" temporal lobe epilepsy 
Objective: Although amygdala abnormalities are sometimes suspected in "imaging-negative" patients with video EEG confirmed unilateral focal epilepsy suggestive of temporal lobe epilepsy (TLE), amygdala asymmetry is difficult to assess visually. This study examined a group of "imaging-negative" TLE patients, estimating amygdala volumes, to determine whether cryptic amygdala lesions might be detected.
Methods: Review of video EEG monitoring data yielded 11 patients with EEG lateralised TLE and normal structural imaging. Amygdala volumes were estimated in this group, in 77 patients with pathologically verified hippocampal sclerosis (HS), and in 77 controls.
Results: Seven of 11 "imaging-negative" cases had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralisation. Although significant amygdala asymmetry occurred in 35 of 77 HS patients, it was never attributable to an abnormally large ipsilateral amygdala. Compared with patients with HS, patients with amygdala enlargement were less likely to have suffered secondarily generalised seizures (p<0.05), and had an older age of seizure onset (p<0.01).
Conclusion: Abnormal amygdala enlargement is reported in seven cases of "imaging-negative" TLE. Such abnormalities are not observed in patients with HS. It is postulated that amygdala enlargement may be attributable to a developmental abnormality or low grade tumour. It is suggested that amygdala volumetry is indicated in the investigation and diagnosis of "imaging-negative" TLE.
PMCID: PMC1738652  PMID: 12933928
2.  Microsurgical Anatomy of the Temporal Lobe and Its Implications on Temporal Lobe Epilepsy Surgery 
Objective. We review the neuroanatomical aspects of the temporal lobe related to the temporal lobe epilepsy. The neuronal, the ventricular, and the vascular structures are demonstrated. Methods. The previous articles published from the laboratory of the senior author are reviewed. Results. The temporal lobe has four surfaces. The medial surface has a complicated microanatomy showing close relation to the intraventricular structures, such as the amygdala or the hippocampus. There are many white matter bundles in the temporal lobe showing relation to the extra- and intraventricular structures. The surgical approaches commonly performed to treat temporal lobe epilepsy are discussed under the light of these data. Conclusion. A thorough knowledge of the microanatomy is necessary in cortical, subcortical, and intraventricular structures of the temporal lobe to achieve better results.
PMCID: PMC3420566  PMID: 22957242
3.  Perfusion patterns in postictal 99mTc-HMPAO SPECT after coregistration with MRI in patients with mesial temporal lobe epilepsy 
OBJECTIVES—To assess patterns of postictal cerebral blood flow in the mesial temporal lobe by coregistration of postictal 99mTc-HMPAO SPECT with MRI in patients with confirmed mesial temporal lobe epilepsy.
METHODS—Ten postictal and interictal 99mTc-HMPAO SPECT scans were coregistered with MRI in 10 patients with confirmed mesial temporal lobe epilepsy. Volumetric tracings of the hippocampus and amygdala from the MRI were superimposed on the postictal and interictal SPECT. Asymmetries in hippocampal and amygdala SPECT signal were then calculated using the equation:
 % Asymmetry =100 × (right − left) / (right + left)/2.
RESULTS—In the postictal studies, quantitative measurements of amygdala SPECT intensities were greatest on the side of seizure onset in all cases, with an average % asymmetry of 11.1, range 5.2-21.9.Hippocampal intensities were greatest on the side of seizure onset in six studies, with an average % asymmetry of 9.6, range 4.7-12.0.In four scans the hippocampal intensities were less on the side of seizure onset, with an average % asymmetry of 10.2, range 5.7-15.5.There was no localising quantitative pattern in interictal studies.
CONCLUSIONS—Postictal SPECT shows distinctive perfusion patterns when coregistered with MRI, which assist in lateralisation of temporal lobe seizures. Hyperperfusion in the region of the amygdala is more consistently lateralising than hyperperfusion in the region of the hippocampus in postictal studies.

PMCID: PMC2169655  PMID: 9285464
4.  Hemifacial motor and crying seizures of temporal lobe onset: case report and review of electro‐clinical localisation 
To report a case of temporal lobe epilepsy with clinical presentation of paroxysmal episodes of “tightness” over the right hemiface, and ictal crying, and review electroclinical localisation of this phenomenon.
Clinical semiology, neurophysiological localising tests, and epilepsy surgery outcome are reported in a subject presenting with paroxysmal right hemifacial movements and ictal crying. Pertinent past reports of somato‐motor signs and ictal crying in temporal lobe epilepsy are reviewed and the findings correlated with proposed human facial cortical representation.
Simple partial seizures caused by temporal lobe epilepsy presented with right sided tonic facial movements and ictal crying. Intracranial EEG monitoring documented a left medial temporal onset of seizures that remained asymptomatic until they propagated to the left cingulate region. Anterior temporal lobectomy with resection of the amygdala and anterior hippocampus resulted in cessation of seizures.
This is a rare example of epileptic seizures of medial temporal onset presenting with isolated somato‐motor manifestations and ictal crying. Anatomical‐electrical‐clinical correlations with cortical regions controlling facial movements were highly suggestive that this case represents secondary activation of “emotional” motor cortex M3 and M4 (rostral and caudal cingulate motor cortex), giving rise to focal hemifacial movements and ictal crying.
PMCID: PMC2117386  PMID: 16361607
temporal lobe epilepsy; crying; cingulate gyrus
5.  Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus 
Neuroscience  2011;178:208-217.
The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus.
Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala.
PMCID: PMC3048957  PMID: 21256929
human; pain; amygdala; hippocampus; causality; fear conditioning
6.  Non-Verbal Auditory Cognition in Patients with Temporal Epilepsy Before and After Anterior Temporal Lobectomy 
For patients with pharmaco-resistant temporal epilepsy, unilateral anterior temporal lobectomy (ATL) – i.e. the surgical resection of the hippocampus, the amygdala, the temporal pole and the most anterior part of the temporal gyri – is an efficient treatment. There is growing evidence that anterior regions of the temporal lobe are involved in the integration and short-term memorization of object-related sound properties. However, non-verbal auditory processing in patients with temporal lobe epilepsy (TLE) has raised little attention. To assess non-verbal auditory cognition in patients with temporal epilepsy both before and after unilateral ATL, we developed a set of non-verbal auditory tests, including environmental sounds. We could evaluate auditory semantic identification, acoustic and object-related short-term memory, and sound extraction from a sound mixture. The performances of 26 TLE patients before and/or after ATL were compared to those of 18 healthy subjects. Patients before and after ATL were found to present with similar deficits in pitch retention, and in identification and short-term memorisation of environmental sounds, whereas not being impaired in basic acoustic processing compared to healthy subjects. It is most likely that the deficits observed before and after ATL are related to epileptic neuropathological processes. Therefore, in patients with drug-resistant TLE, ATL seems to significantly improve seizure control without producing additional auditory deficits.
PMCID: PMC2791036  PMID: 20011222
epilepsy; audition; short-term memory; identification; environmental sounds; temporal lobe; resection
7.  Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats. 
Epilepsy & behavior : E&B  2006;9(4):557-563.
Temporal lobe epilepsy may be associated with emotional difficulties such as depression or anxiety. Since the amygdala is involved in both epilepsy and emotion, common neural mechanisms in this temporal lobe structure may underlie the emotional disturbances observed in people with epilepsy. The neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) is implicated in many psychopathologies, and 5-HT also modulates amygdala excitability. Therefore, the present study used the fear potentiated startle (FPS) paradigm to investigate the effect of neuronal excitability on fear behavior in rats treated with p-chlorophenylalanine (PCPA) to chronically inhibit 5-HT synthesis. PCPA treatment selectively enhanced FPS in individually-housed rats. The exaggerated FPS response was reduced to control level by the anticonvulsant phenytoin (10mg/kg) and phenytoin (30 mg/kg) further decreased FPS behavior. These data suggest that a sub-seizure state of neuronal excitability mediated by low 5-HT in brain fear circuits may be associated with pathological fear behavior.
PMCID: PMC1764502  PMID: 17045847
Anticonvulsant; Amygdala; Hyperexcitability; Serotonin; Phenytoin; Fear-potentiated startle; Behavior; Rat
8.  Amygdala damage affects event-related potentials for fearful faces at specific time windows 
Human brain mapping  2010;31(7):1089-1105.
The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related-potentials (ERPs) to seen fearful face expressions, in pre-operative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, ~100-150msec, and for a later component at ~500-600msec. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions, nor a distinct emotional ERP effect at 150-250msec. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function.
PMCID: PMC3173845  PMID: 20017134
ERP; medial temporal lobe epilepsy; emotion; P1; late-P3; SPM5
9.  Amygdala Damage Affects Event-Related Potentials for Fearful Faces at Specific Time Windows 
Human Brain Mapping  2009;31(7):1089-1105.
The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related potentials (ERPs) to seen fearful face expressions, in preoperative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, ∼100–150 ms, and for a later component at ∼500–600 ms. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions nor a distinct emotional ERP effect at 150–250 ms. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc.
PMCID: PMC3173845  PMID: 20017134
ERP; medial temporal lobe epilepsy; emotion; P1; late-P3; SPM5
10.  Mesial Temporal Lobe Epilepsy: How do we improve surgical outcome? 
Annals of neurology  2010;68(4):424-434.
Surgery has become the standard of care for patients with intractable temporal lobe epilepsy with anterior temporal lobe resection the most common operation performed for adults with hippocampal sclerosis. This procedure leads to significant improvement in the lives of the overwhelming majority of patients. Despite improved techniques in neuroimaging that have facilitated the identification of potential surgical candidates, the short and long term success of epilepsy surgery has not changed substantially in recent decades. The basic surgical goal, removal of the amygdala, hippocampus, and parahippocampal gyrus, is based on the hypothesis that these structures represent a uniform and contiguous source of seizures in the mesial temporal lobe epilepsy syndrome. Recent observations from the histopathology of resected tissue, preoperative neuroimaging and the basic science laboratory suggest that the syndrome is not always a uniform entity. Despite clinical similarity, not all patients become seizure free. Improving surgical outcomes requires a re-examination of why patients fail surgery. This review will examine recent findings from the clinic and laboratory. Historically, we have considered MTLE a single disorder, but it may be time to view it as a group of closely related syndromes with variable type and extent of histopathology. That recognition may lead to identifying the appropriate subgroups that will require different diagnostic and surgical approaches to improve surgical outcomes.
PMCID: PMC2966035  PMID: 20976764
11.  Triple pathology in patients with temporal lobe epilepsy: A case report and review of the literature 
The coexistence of three intracranial lesions related to epileptic pathogenesis is known as ‘triple pathology’ and has rarely been reported. In this study we report a case of temporal lobe epilepsy (TLE) with the coexistence of hippocampal sclerosis (HS), focal cortical dysplasia (FCD) and ganglioglioma in the temporal lobe. A 29-year-old male who had experienced recurrent seizures for four years was admitted to hospital. Cerebral magnetic resonance imaging (MRI) was conducted and T2-weighted and fluid-attenuated inversion recovery sequence (FLAIR) images revealed a reduced hippocampal volume with an increased FLAIR signal on the right side and a slightly enlarged temporal horn, which are typical imaging findings for HS and FCD. The patient underwent resectioning of the right anterior temporal lobe, hippocampus and amygdala, in addition to the lesion located in the medial temporal lobe. Immunohistochemical analysis of the medial temporal lobe lesion confirmed a ganglioglioma (WHO grade I) in the medial temporal lobe. During the first eight months following surgery, the patient's seizures were controlled with zonisamide and phenytoin. Electroencephalogram (EEG) assessment post-surgery confirmed the absence of epileptic discharges. Based on a literature review and a detailed review of this case, we postulate two possible explanations for the pathogenesis of ‘triple pathology’: i) ‘triple pathology’ is a combination of pathological progression and occasionality; and ii) ‘triple pathology’ lesions have similar pathological origins.
PMCID: PMC3797311  PMID: 24137291
epilepsy; triple pathology; hippocampal sclerosis; focal cortical dysplasia; ganglioglioma
12.  Temporal Lobe Epilepsy: Where Do the Seizures Really Begin? 
Epilepsy & behavior : E&B  2008;14(Suppl 1):32-37.
Defining precisely the site of seizure onset has important implication for our understanding of the pathophysiology of temporal lobe epilepsy as well as for the surgical treatment of the disorder. Removal of the limbic areas of the medial temporal lobe has led to a high rate of seizure control, but the relatively large number of patients for whom seizure control is incomplete as well as the low rate of surgical cure suggest that the focus extends beyond the usual limits of surgical resection. A reevaluation of the extent of the pathology as well as new data from animal models suggest that the seizure focus extends, at least in some cases, beyond the hippocampus and amygdala that are usually removed at the time of surgery. In this review we will examine current information about the pathology and physiology of the mesial temporal lobe epilepsy syndrome, with a special emphasis on the distribution of the changes and the patterns of seizure onset. We will then propose a hypothesis for the nature of the seizure focus in this disorder and discuss its clinical implications, with the ultimate goal of improving surgical outcomes and developing nonsurgical therapies that may improve seizure control.
PMCID: PMC2913468  PMID: 18848643
epilepsy; temporal lobe; limbic system; seizure focus
13.  Epilepsy (partial) 
Clinical Evidence  2011;2011:1214.
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy).
Key Points
During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission.
After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects, and their long-term benefit is unknown. Antiepileptic drug treatment after a single seizure does not reduce the risk of drug refractory epilepsy in the long term.
Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed partial epilepsy, but we found no RCTs comparing them with placebo, and a placebo-controlled trial would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs. Adding second-line drugs to usual treatment reduces seizure frequency in people with drug-resistant partial epilepsy, but it increases adverse effects such as dizziness and somnolence. We don't know if any one antiepileptic drug is more likely to reduce seizures compared with the others.
CAUTION: Vigabatrin, which may be used as second-line treatment, causes concentric visual-field abnormalities in about 40% of people, which are probably irreversible.
In people who have been seizure free for at least 2 years on treatment, almost 60% of those with partial or generalised epilepsy who withdraw from antiepileptic treatment will remain seizure free, compared with almost 80% of people who continue treatment.
Educational programmes may reduce seizure frequency and improve psychosocial functioning in people with partial or generalised epilepsy, but we don't know whether relaxation, yoga, biofeedback, CBT, relaxation plus behavioural modification, or family counselling are beneficial.
There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in people with drug-resistant temporal lobe epilepsy, but they can cause neurological adverse effects.
High-level vagus nerve stimulation may reduce seizure frequency in people with drug-resistant partial seizures, but it may cause hoarseness and dyspnoea, and long-term effects are unknown. We don't know whether different stimulation cycles are more effective at reducing seizure frequency or at increasing the proportion of responders.
We don't know whether lesionectomy improves seizure control in people with drug-resistant temporal lobe epilepsy.
PMCID: PMC3217777  PMID: 21549021
14.  Early Activation of Ventral Hippocampus and Subiculum during Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy 
The Journal of Neuroscience  2013;33(27):11100-11115.
Temporal lobe epilepsy is the most common form of epilepsy in adults. The pilocarpine-treated rat model is used frequently to investigate temporal lobe epilepsy. The validity of the pilocarpine model has been challenged based largely on concerns that seizures might initiate in different brain regions in rats than in patients. The present study used 32 recording electrodes per rat to evaluate spontaneous seizures in various brain regions including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. Compared with published results from patients, seizures in rats tended to be shorter, spread faster and more extensively, generate behavioral manifestations more quickly, and produce generalized convulsions more frequently. Similarities to patients included electrographic waveform patterns at seizure onset, variability in sites of earliest seizure activity within individuals, and variability in patterns of seizure spread. Like patients, the earliest seizure activity in rats was recorded most frequently within the hippocampal formation. The ventral hippocampus and ventral subiculum displayed the earliest seizure activity. Amygdala, olfactory cortex, and septum occasionally displayed early seizure latencies, but not above chance levels. Substantia nigra and dorsomedial thalamus demonstrated consistently late seizure onsets, suggesting their unlikely involvement in seizure initiation. The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine-treated rats that support the model's validity.
PMCID: PMC3718374  PMID: 23825415
15.  Seizure-Induced Neuronal Injury: Vulnerability to Febrile Seizures in an Immature Rat Model 
The Journal of Neuroscience  1998;18(11):4285-4294.
Febrile seizures are the most common seizure type in young children. Whether they induce death of hippocampal and amygdala neurons and consequent limbic (temporal lobe) epilepsy has remained controversial, with conflicting data from prospective and retrospective studies. Using an appropriate-age rat model of febrile seizures, we investigated the acute and chronic effects of hyperthermic seizures on neuronal integrity and survival in the hippocampus and amygdala via molecular and neuroanatomical methods. Hyperthermic seizures–but not hyperthermia alone–resulted in numerous argyrophilic neurons in discrete regions of the limbic system; within 24 hr of seizures, a significant proportion of neurons in the central nucleus of the amygdala and in the hippocampal CA3 and CA1 pyramidal cell layer were affected. These physicochemical alterations of hippocampal and amygdala neurons persisted for at least 2 weeks but were not accompanied by significant DNA fragmentation, as determined by in situ end labeling. By 4 weeks after the seizures, no significant neuronal dropout in these regions was evident. In conclusion, in the immature rat model, hyperthermic seizures lead to profound, yet primarily transient alterations in neuronal structure.
PMCID: PMC3387924  PMID: 9592105
seizures; animal model; febrile seizures; epilepsy; neuronal death; excitotoxicity; apoptosis; in situ end labeling
16.  Voxel based morphometry of grey matter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration 
Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure.
Methods: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as confounding covariates in analyses.
Results: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epileptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epileptogenic zone compared with patients without such a history. Left amygdala volume was also reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral thalamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy.
Conclusions: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the presumed epileptogenic zone and may result from recurrent seizures.
PMCID: PMC1757338  PMID: 12438464
17.  Age-accelerated Psychomotor Slowing in Temporal Lobe Epilepsy 
Epilepsy research  2012;103(2-3):231-236.
Cognitive and psychomotor slowing is a complication of epilepsy and is less often a focus of investigation relative to other cognitive domains (e.g., memory). A diversity of tasks has been used to examine psychomotor slowing in epilepsy, but it remains unknown whether the degree of epilepsy-related slowing is fixed or is exacerbated with increasing task demand. Also unknown is to what degree age related slowing is accelerated in epilepsy. Participants with temporal lobe epilepsy (n = 50) were compared to healthy controls (n = 69) across three tasks of psychomotor speed with varied complexity. Performance was examined as a function of group (epilepsy, controls), task complexity (simple, intermediate, complex), and chronological age. The results showed that speed of performance declined across the epilepsy and control participants as a function of task complexity. Epilepsy participants were significantly slower than controls across the three tasks, and there was a significant three way interaction (group by task complexity by age). These results demonstrate that psychomotor slowing is related to task complexity in both epilepsy and healthy control participants, always greater in epilepsy participants, and there is a significant age acceleration of psychomotor slowing in the epilepsy group that is magnified by complex tasks.
PMCID: PMC3563928  PMID: 22989854
Temporal lobe epilepsy; psychomotor slowing; cognition; aging; progression
18.  Early Life Stress as an Influence on Limbic Epilepsy: An Hypothesis Whose Time has Come? 
The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative – or complementary – perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research.
PMCID: PMC2762371  PMID: 19838325
temporal lobe epilepsy; early life stress; depression; hippocampus; hypothalamic–pituitary–adrenal axis
19.  Major depression in temporal lobe epilepsy with hippocampal sclerosis: clinical and imaging correlates 
Refractory temporal lobe epilepsy (TLE) is often associated with hippocampal sclerosis (HS). Patients with major depression (MD) may also show structural abnormalities in the limbic system. Co‐occurrence of TLE with HS and MD is not uncommon. We have investigated the clinical and morphological characteristics of TLE patients in relation to MD.
34 TLE patients with HS were assessed at a Comprehensive Epilepsy Programme. All relevant clinical data were obtained, including the history of antecedent events to epilepsy. MD was diagnosed based on detailed psychiatric investigation. MRI was used to measure the volume and tissue signal (T2 relaxometry) of the hippocampus and amygdala. The imaging data were expressed as a percentage of the values obtained in a series of 55 controls.
A history of MD was present in 15 (44%) of 34 patients. Patients with MD had a longer duration of their epilepsy (p<0.05) and a lower frequency of antecedent events (13% with MD, 58% without MD, p<0.05). Both groups had a similar degree of ipsilateral HS (small hippocampal volume, increased hippocampal T2 relaxation time) and demonstrated bilateral amygdaloid atrophy. However, the contralateral amygdala showed lower signal in the presence of MD (97 (9) ms; no MD 103 (8) ms; ANCOVA, p = 0.02).
The integrity of the amygdala may influence mood disturbances in TLE patients with HS, as depression was associated with a relative preservation of the contralateral amygdala. In contrast, hippocampal abnormalities were not related to the presence of depression.
PMCID: PMC2117607  PMID: 17259350
20.  Increased seizure severity and seizure-related death in mice lacking HCN1 channels 
Epilepsia  2010;51(8):1624-1627.
Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy and generalized epilepsy animal models, as well as patients with epilepsy. However, the role and importance of HCN1 downregulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure induction method used. Thus, downregulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor to seizure behavior.
PMCID: PMC2952649  PMID: 20384728
intrinsic excitability; Ih conductance; HCN channels; limbic seizures; kindling; pilocarpine
21.  Ganaxolone Suppression of Behavioral and Electrographic Seizures in the Mouse Amygdala Kindling Model 
Epilepsy research  2010;89(2-3):254-260.
Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABAA receptors, may represent a new treatment approach for epilepsy. Here we demonstrate that pretreatment with ganaxolone (1.25–20 mg/kg, s.c.) causes a dose-dependent suppression of behavioral and electrographic seizures in fully amygdala kindled female mice, with nearly complete seizure protection at the highest dose tested. The ED50 for suppression of behavioral seizures was 6.6 mg/kg. The seizure suppression produced by ganaxolone was comparable to that of clonazepam (ED50, 0.1 mg/kg, s.c.). To the extent that amygdala kindling represents a model of mesial temporal lobe epilepsy, this study supports the utility of ganaxolone in the treatment of patients with temporal lobe seizures.
PMCID: PMC2854307  PMID: 20172694
ganaxolone; neurosteroid; clonazepam; GABAA receptor; amygdala kindling; epilepsy; seizure; female mice
22.  Characteristics and treatment of temporal lobe epilepsy with a history of complicated febrile convulsion 
This study aimed to examine the close correlation between complicated febrile convulsions (CFC) and medial temporal lobe epilepsy and to delineate characteristics of temporal lobe epilepsy with CFC. Patients with temporal lobe epilepsy were divided into those with a prior episode of CFC (n=52), those with febrile convulsions other than CFC, and those witout either (n=345). Clinical constellations, neuroimaging, drug resistance, and effects of temporal lobectomy of the three groups were compared. A close association between CFC and temporal lobe epilepsy was confirmed. The salient features of temporal lobe epilepsy with CFC were early age at onset of habitual seizures (about 10 years), the predominance of autonomic auras, and a high incidence of MRI evidence of unilateral medial temporal sclerosis. Patients with temporal lobe epilepsy with prior CFC had an excellent outcome after surgery, by contrast with an unfavourable response to drug therapy. The surgical results were discouraging in patients with temporal lobe epilepsy without history of any febrile convulsions and without solid brain tumours. These results indicate surgical intervention as the choice of therapy in a substantial number of patients with temporal lobe epilepsy with a history of CFC.

PMCID: PMC2169958  PMID: 9489540
23.  Role of the Left Amygdala and Right Orbital Frontal Cortex in Emotional Interference Resolution Facilitation in Working Memory 
Neuropsychologia  2011;49(12):3201-3212.
Previous research has shown that emotional information aids conflict resolution in working memory (Levens and Phelps, 2008). Using a Recency-probes working memory (WM) paradigm, Levens and Phelps found that positive and negative emotional stimuli reduced the amount of interference created when information that was once relevant conflicted with currently relevant information, suggesting that emotional information facilitates interference resolution in WM. To determine what regions of the prefrontal cortex (PFC) and temporal lobes are critical to the influence of emotional stimuli on interference resolution, we conducted a Recency-probes emotion paradigm with right and left unilateral frontal and temporal lobe lesion patients. The frontal lobe lesion patient group comprised individuals with unilateral ventral and dorsal PFC lesions. The temporal lobe lesion patient group comprised individuals with lesions of the amygdala and surrounding structures. Results indicate that when the left amygdala is damaged, emotional facilitation of interference resolution is absent (equal emotional and neutral interference levels), when the right orbital frontal cortex (OFC) is damaged, in contrast, emotional interference resolution is impaired (emotional interference levels are higher than neutral levels are). Based on these unique patterns we propose specific contributions for these regions in the emotional facilitation of interference resolution in WM.
PMCID: PMC3192243  PMID: 21835189
interference resolution; emotion; working memory; orbital frontal cortex; amygdala; prefrontal cortex
24.  Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A 
Kasperavičiūtė, Dalia | Catarino, Claudia B. | Matarin, Mar | Leu, Costin | Novy, Jan | Tostevin, Anna | Leal, Bárbara | Hessel, Ellen V. S. | Hallmann, Kerstin | Hildebrand, Michael S. | Dahl, Hans-Henrik M. | Ryten, Mina | Trabzuni, Daniah | Ramasamy, Adaikalavan | Alhusaini, Saud | Doherty, Colin P. | Dorn, Thomas | Hansen, Jörg | Krämer, Günter | Steinhoff, Bernhard J. | Zumsteg, Dominik | Duncan, Susan | Kälviäinen, Reetta K. | Eriksson, Kai J. | Kantanen, Anne-Mari | Pandolfo, Massimo | Gruber-Sedlmayr, Ursula | Schlachter, Kurt | Reinthaler, Eva M. | Stogmann, Elisabeth | Zimprich, Fritz | Théâtre, Emilie | Smith, Colin | O’Brien, Terence J. | Meng Tan, K. | Petrovski, Slave | Robbiano, Angela | Paravidino, Roberta | Zara, Federico | Striano, Pasquale | Sperling, Michael R. | Buono, Russell J. | Hakonarson, Hakon | Chaves, João | Costa, Paulo P. | Silva, Berta M. | da Silva, António M. | de Graan, Pierre N. E. | Koeleman, Bobby P. C. | Becker, Albert | Schoch, Susanne | von Lehe, Marec | Reif, Philipp S. | Rosenow, Felix | Becker, Felicitas | Weber, Yvonne | Lerche, Holger | Rössler, Karl | Buchfelder, Michael | Hamer, Hajo M. | Kobow, Katja | Coras, Roland | Blumcke, Ingmar | Scheffer, Ingrid E. | Berkovic, Samuel F. | Weale, Michael E. | Delanty, Norman | Depondt, Chantal | Cavalleri, Gianpiero L. | Kunz, Wolfram S. | Sisodiya, Sanjay M.
Brain  2013;136(10):3140-3150.
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
PMCID: PMC3784283  PMID: 24014518
mesial temporal lobe epilepsy; mesial temporal sclerosis; SCN1A; association; complex genetics
25.  Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy 
Objective: The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE).
Methods: We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p<0.05.
Results: Patients with right and left MTLE showed a reduction in volume of the entorhinal (p<0.001) and perirhinal (p<0.01) cortices ipsilateral to the HA, compared with normal controls. Patients with right MTLE exhibited a significant asymmetry of all studied structures; the right hemisphere structures had smaller volume than their left side counterparts. We did not observe linear correlations between the volumes of different structures of the medial temporal lobe in patients with MTLE.
Conclusion: Patients with refractory MTLE have damage in the temporal lobe that extends beyond the hippocampus, and affects the regions with close anatomical and functional connections to the hippocampus.
PMCID: PMC1757422  PMID: 14638879

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