Epileptogenic networks in nodular heterotopia: A stereoelectroencephalography study.

OBJECTIVE: Defining the roles of heterotopic and normotopic cortex in the epileptogenic networks in patients with nodular heterotopia is challenging. To elucidate this issue, we compared heterotopic and normotopic cortex using quantitative signal analysis on stereoelectroencephalography (SEEG) recordings. METHODS: Clinically relevant biomarkers of epileptogenicity during ictal (epileptogenicity index; EI) and interictal recordings (high-frequency oscillation and spike) were evaluated in 19 patients undergoing SEEG. These biomarkers were then compared between heterotopic cortex and neocortical regions. Seizures were classified as normotopic, heterotopic, or normoheterotopic according to respective values of quantitative analysis (EI ≥0.3). RESULTS: A total of 1,246 contacts were analyzed: 259 in heterotopic tissue (heterotopic cortex), 873 in neocortex in the same lobe of the lesion (local neocortex), and 114 in neocortex distant from the lesion (distant neocortex). No significant difference in EI values, high-frequency oscillations, and spike rate was found comparing local neocortex and heterotopic cortex at a patient level, but local neocortex appears more epileptogenic (p < 0.001) than heterotopic cortex analyzing EI values at a seizure level. According to EI values, seizures were mostly normotopic (48.5%) or normoheterotopic (45.5%); only 6% were purely heterotopic. A good long-term treatment response was obtained in only two patients after thermocoagulation and surgical disconnection. SIGNIFICANCE: This is the first quantitative SEEG study providing insight into the mechanisms generating seizures in nodular heterotopia. We demonstrate that both the heterotopic lesion and particularly the normotopic cortex are involved in the epileptogenic network. This could open new perspectives on multitarget treatments, other than resective surgery, aimed at modifying the epileptic network.

Positron emission tomography with α-[11C]methyl-L-tryptophan in tuberous sclerosis complex-related epilepsy.

OBJECTIVE: Tuberous sclerosis complex (TSC) is often associated with cerebral tubers and medically intractable epilepsy. We reevaluated whether increased uptake of α-[(11) C]methyl-l-tryptophan (AMT) in cerebral tubers is associated with tuber epileptogenicity. METHODS: We included 12 patients (six male, 4-53 years old) with TSC and refractory seizures who were evaluated for epilepsy surgery in our center, including video-electroencephalographic (EEG) monitoring, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI), and positron emission tomography (PET) with α-[(11) C]methyl-l-tryptophan (AMT-PET). Nine of these 12 patients also underwent intracerebral EEG recording. AMT uptake in each tuber was visually evaluated on PET coregistered with MRI. An AMT uptake index based on lesional/healthy cortex ratio was also calculated. Sensitivity and specificity values of AMT-PET in the detection of epileptogenic lesions were obtained, using the available electroclinical and neuroimaging evidence as the gold standard for epileptogenicity. RESULTS: A total of 126 tubers were identified. Two of 12 patients demonstrated a tuber with clearly increased AMT uptake, one of whom also showed a subtle increased AMT uptake in another contralateral tuber. Four other patients showed only subtle increased AMT uptake. The only two tubers with clearly increased AMT uptake proved to be epileptogenic based on intracerebral EEG data, whereas none of the tubers associated with subtle increased AMT uptake were involved at ictal onset. In a per-patient approach, this yielded a sensitivity of clearly increased AMT uptake in detecting tuber epileptogenicity of 17% (2/12 patients), whereas the per-lesion sensitivity and specificity were 12% (95% confidence interval [CI]: 3-34%) and 100% (95% CI: 97-100%), respectively. SIGNIFICANCE: AMT-PET is a specific neuroimaging technique in the identification of epileptogenic tubers in TSC. Despite its low sensitivity, the clinical usefulness of AMT-PET still deserves to be considered according to the challenging complexity of epilepsy surgery in tuberous sclerosis.

Electrical status epilepticus in sleep, a constitutive feature of Christianson syndrome?

Christianson syndrome (CS) is a X-linked neurodevelopmental disorder, including severe intellectual disability (ID), progressive microcephaly, ataxia, autistic behaviour (ASD), near absent speech, and epilepsy. Electrical status epilepticus in sleep (ESES) has been reported in two patients. We describe five male patients from three unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy-number variation involving SLC9A6. ESES was present in three out of the five patients in the critical age window between 4 and 8 years. All patients presented with severe intellectual disability, autistic features, and hyperactivity. Epilepsy onset occurred within the first two years of life. Seizures were of various types. In the two boys with a 20-years follow-up, epilepsy was drug-resistant during childhood, and became less active in early adolescence. Psychomotor regression was noted in two patients presenting with ESES. It was difficult to assess to what extent ESES could have contributed to the pathophysiological process, leading to regression of the already very limited communication skills. The two published case reports and our observation suggests that ESES could be a constitutive feature of Christianson syndrome, as it has already been shown for other Mendelian epileptic disorders, such as GRIN2A and CNKSR2-related developmental epileptic encephalopathies. Sleep EEG should be performed in patients with Christianson syndrome between 4 and 8 years of age. ESES occurring in the context of ID, ASD and severe speech delay, could be helpful to make a diagnosis of CS.

A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging.

UNLABELLED: Neurotransmission imaging studies require normative data for the statistical assessment of neurophysiologic dysfunctions. 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) is a specific serotonin 5-HT1A antagonist PET tracer recently characterized, modeled, and used for clinical research to explore abnormalities in the serotoninergic system. Our study reports, to our knowledge, the first large normative imaging database of 18F-MPPF binding potential (BP) over aging, for both males and females. METHODS: Fifty-three healthy volunteers (27 females, 26 males; age, 20-70 y) were selected to undergo structural MRI and single-injection 18F-MPPF multiframe dynamic PET. 18F-MPPF BP values were computed using a nonlinear modeling method with tissue reference. The statistical assessment of the effect of age and sex was performed both at the anatomic structure level, using regions of interest drawn manually on individual MR images, and at the voxel level, using normalized BP parametric images in different statistical parametric mapping designs. RESULTS: A negative linear correlation between age and 18F-MPPF binding (3.6% decrease by decade) was found in females but not in males and involved most of the limbic and paralimbic regions; on the other hand, males in their 30s showed decreased binding in most cerebral regions. CONCLUSION: A comparison of males and females revealed higher BP values independent of age in females in the right hemisphere and a different evolution of BP over aging. These results confirm the necessity of a database for further statistical analysis in individuals or groups with pathology.

Automated detection of local normalization areas for ictal-interictal subtraction brain SPECT.

UNLABELLED: Whole-brain activity is often chosen to quantitatively normalize peri-ictal and interictal SPECT scans before their subtraction. This use is not justified, because significant and extended modification of the cerebral blood flow can occur during a seizure. We validated and compared 2 automatic methods able to determine the optimal reference region, using simulation and clinical data. METHODS: In the first method, the selected reference region is the intersection of peri-ictal-interictal areas with no significantly different z values. The other method relies on a 3-dimensional iterative voxel aggregation. The increase of the selected volume is stopped by using 2 different variance tests (Levene and SE). These algorithms were tested on 39 epileptic patients and were validated using 1 interictal and 10 peri-ictal scans simulated from the mean image of 22 healthy subjects. RESULTS: In the patient studies, the mean relative activity of the selected regions, compared with whole-brain activity (classic normalization), was 122.6%. Their average relative size (compared with the size of the whole brain) was 33.2% for the z map method, 22.8% for the SE test, and 11.8% for the Levene test. After application of our automatic processes, subtraction of the simulated images revealed a recovery of abnormal regions up to 45% larger than the region obtained with classic normalization. CONCLUSION: These results illustrate the role of normalization on the subtracted peri-ictal and interictal images. Our methods are automatic and objective and give good results on various simulated images. The z map construction is worth considering because it is simple, selects large parts of the brain, and requires little computation time.

Direct electrical stimulations of the temporal pole in human.

We report the results of 105 intracortical electrical stimulations of the temporo-polar cortex performed in 30 patients during stereo-electroencephalography (SEEG) investigation of drug-resistant temporal lobe epilepsy. Clinical responses were elicited in 50% of the patients during 26 of the 105 stimulations. Responses are coherent with data found in the literature with mostly psychic, viscero-sensitive, autonomic and viscero-motor phenomena being elicited. Nearly all responses were evoked by stimulation of the antero-medial part of the temporo-polar cortex whereas only once was a clinical response elicited during stimulation of the lateral part of the temporo-polar cortex. Induced auras were more frequently reported when there was an afterdischarge associated to the clinical response (60 and 75% of the stimulation followed by a localized or a diffusing after-discharge, respectively) then when there wasn't any after-discharge following stimulation. The clinical responses evoked during stimulation of the temporo-polar cortex only have a limited topographic specificity since they closely resemble symptoms elicited by stimulation of other limbic or paralimbic areas. Nonetheless these results do suggest that the antero-medial part of the temporo-polar cortex is included in the symptomatogenic zone in so-called "temporo-limbic" epilepsies.

Outcome and prognosis of status epilepticus in children.

The ultimate goal of treating status epilepticus is to provide the best opportunity for a good outcome. This review discusses the current literature on the outcome after status epilepticus in children, including the risk of recurrence, morbidity, and mortality. The outcome seems most dependent on etiology, with age and duration of status epilepticus also contributing. Convulsive status epilepticus has considerably more supporting literature, whereas the data on nonconvulsive status epilepticus are hindered by the lack of a standard definition and presumed under recognition. Future studies will need to address some of these methodological issues to provide the best information when discussing outcome with the family members of children with status epilepticus.

Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation.

We studied painful and non-painful somaesthetic sensations elicited by direct electrical stimulations of the insular cortex performed in 43 patients with drug refractory temporal lobe epilepsy, using stereotactically implanted depth electrodes. Painful sensations were evoked in the upper posterior part of the insular cortex in 14 patients, mostly in the right hemisphere. Non-painful sensations were elicited in the posterior part of the insular cortex in 16 patients, in both hemispheres. Thus, painful and non-painful somaesthetic representations in the human insula overlap. Both types of responses showed a trend toward a somatotopic organization. These results agree with previous anatomical and unit recording studies in monkeys indicating a participation of the posterior part of the insular cortex in processing both noxious and innocuous somaesthetic stimuli. In humans, both a posterior and an anterior pain-related cortical area have been described within the insular cortex using functional imaging. Our results help to define the respective functional roles of these two insular areas. Finally, lateralization in the right hemisphere of sites where painful sensations were evoked is coherent with the hypothesis of a preponderant role of this hemisphere in species survival.

5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study.

The aim of our study was to assess abnormalities in 5-hydroxytryptamine-1A (5-HT1A) receptor density in patients suffering from refractory temporal lobe epilepsy (TLE). Experimental data in animals show that 5-HT1A receptors are predominantly located in limbic areas, and that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In TLE patients, we quantified 5-HT1A receptor density in epileptogenic and non-epileptogenic areas, as defined by intracranial recordings with stereo-electroencephalography (SEEG). Nine TLE patients and 53 control subjects were studied by PET using a 5-HT1A receptor antagonist ([18F]MPPF). Anatomical regions of interest (ROIs) were drawn on patient and control MRIs co-registered with PET. PET data were quantified using a simplified model to assess binding potential (BP) values in each ROI, with cerebellum as reference. For each patient, a normalized percentage BP change was calculated as the relative variation of BP in each ROI compared with the corresponding ROI in control subjects. In patients, ROIs explored by SEEG were categorized according to their degree of epileptic activity (ictal onset, ictal spreading, interictal spikes, no epileptic activity) and according to their lesional aspect and volume (lesional with volume loss, lesional without volume loss, non-lesional). Compared with control values, the binding to 5-HT1A receptors in TLE patients was decreased in the epileptogenic temporal lobe. BP decrease was significantly greater in: (i) regions involved in the seizure onset than regions where only interictal paroxysms or no epileptic activity was recorded; and (ii) regions where the discharge propagated than regions where only interictal paroxysms or no epileptic activity was recorded. BP decrease was shown to be significantly influenced by the existence of a lesion on MRI. However, in the group of ROIs with normal quantitative and qualitative MRI aspect, BP decrease remained strongly correlated to the degree of epileptic activity. This study shows that in vivo availability of 5-HT1A receptors is decreased in epileptic patients compared with normal subjects. This decrease is highly correlated to the degree of epileptogenicity of cortical areas explored by intracerebral recordings, and does not reflect only pathological changes or neuronal loss in the epileptic focus.

Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG.

Experimental data in animals show that 5-HT(1A) receptors are predominantly located in limbic areas and suggest that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In this PET study, we used an antagonist of the 5-HT(1A) receptor, [(18)F]MPPF, to assess the extent of 5-HT(1A) receptor binding changes in a group of seven temporal lobe epilepsy (TLE) patients with hippocampal ictal onset demonstrated by intracerebral EEG recording. On the basis of MRI-measured hippocampal volumes (HV), patients were classified into "normal HV" or "hippocampal atrophy" (HA). Voxel-based analyses (SPM99) were performed to objectively assess the differences in [(18)F]MPPF binding potential (BP) between patients (taken as a group or as individuals) and a database of 48 controls subjects. In the full group of patients, a significant decreased BP was detected ipsilateral to the epileptogenic zone in the hippocampus, temporal pole, insula, and temporal neocortex. This result was confirmed in the subgroup of patients with HA. In patients with normal HV, the BP decrease was restricted to the temporal pole. TLE patients also demonstrated an increased BP in various regions contralateral to the epileptogenic zone. These data suggest that in TLE patients with hippocampal seizure onset, the decrease in 5-HT(1A) receptor binding partly reflects hippocampal neuronal loss, but is also observed in various regions involved in temporo-limbic epileptogenic networks that appeared normal on MRI. Further studies are warranted to evaluate the clinical usefulness of [(18)F]MPPF-PET as compared to other established PET tracers in drug resistant TLE.