Thalamic nuclei volumes and intrinsic thalamic network in patients with occipital lobe epilepsy.

INTRODUCTION: This study aimed to investigate the alterations in individual thalamic nuclei volumes in patients with occipital lobe epilepsy (OLE) compared with those of healthy controls, and to analyze the intrinsic thalamic network based on these volumes using graph theory. METHODS: Thirty adult patients with newly diagnosed OLE and 42 healthy controls were retrospectively enrolled (mean age, 33.8 ± 17.0 and 32.2 ± 6.6 years, respectively). The study participants underwent brain magnetic resonance imaging with three-dimensional T1-weighted imaging. The right and left total thalamic and individual thalamic nuclei volumes were obtained using the FreeSurfer program. Then, the intrinsic thalamic network was calculated based on the individual thalamic nuclei volumes and graph theory using a BRAPH program. RESULTS: There were no differences in the right and left whole-thalamic volumes between the two groups (0.445% vs. 0.469%, p = .142 and 0.481% vs. 0.490%, p = .575, respectively). However, significant differences were observed in the volumes of several thalamic nuclei between the two groups. The right medial geniculate and right suprageniculate nuclei volumes were increased (0.0077% vs. 0.0064%, p = .0003 and 0.0013% vs. 0.0010%, p = .0004, respectively), whereas the right and left parafascicular nuclei volumes were decreased in patients with OLE compared with those in healthy controls (0.0038% vs. 0.0048%, p < .0001 and 0.0037% vs. 0.0045%, p = .0001, respectively). There were no differences in the network measures regarding intrinsic thalamic network between the two groups. CONCLUSION: We successfully demonstrated the alterations in individual thalamic nuclei volumes, especially the increased medial geniculate and suprageniculate, and decreased parafascicular nuclei volumes in patients with OLE compared with those of healthy controls despite no changes in the whole-thalamic volumes. These findings suggest an important role of the thalamus in the epileptic network of OLE.

Hypothalamic hamartoma: Neuropathology and epileptogenesis.

Hypothalamic hamartomas (HHs) are congenital malformations of the ventral hypothalamus resulting in treatment-resistant epilepsy and are intrinsically epileptogenic for the gelastic seizures that are the hallmark symptom of this disorder. This paper reviews the neuropathologic features of HHs associated with epilepsy, with an emphasis on characterizing neuron phenotypes and an ultimate goal of understanding the cellular model of ictogenesis occurring locally within this tissue. We also present previously unpublished findings on Golgi staining of HH. The microarchitecture of HH is relatively simple, with nodular clusters of neurons that vary in size and abundance with poorly defined boundaries. Approximately 80-90% of HH neurons have an interneuron-like phenotype with small, round soma and short, unbranched processes that lack spines. These neurons express glutamic acid decarboxylase and likely utilize γ-aminobutyric acid (GABA) as their primary neurotransmitter. They have intrinsic membrane properties that lead to spontaneous pacemaker-like firing activity. The remaining HH neurons are large cells with pleomorphic, often pyramidal, soma and dendrites that are more likely to be branched and have spines. These neurons appear to be excitatory, projection-type neurons, and have the functionally immature behavior of depolarizing and firing in response to GABA ligands. We hypothesize that the irregular neuronal clusters are the functional unit for ictogenesis. Further research to define and characterize these local networks is required to fully understand the cellular mechanisms responsible for gelastic seizures.

Interictal activity is an important contributor to abnormal intrinsic network connectivity in paediatric focal epilepsy.

Patients with focal epilepsy have been shown to have reduced functional connectivity in intrinsic connectivity networks (ICNs), which has been related to neurocognitive development and outcome. However, the relationship between interictal epileptiform discharges (IEDs) and changes in ICNs remains unclear, with evidence both for and against their influence. EEG-fMRI data was obtained in 27 children with focal epilepsy (mixed localisation and aetiologies) and 17 controls. A natural stimulus task (cartoon blocks verses blocks where the subject was told "please wait") was used to enhance the connectivity within networks corresponding to ICNs while reducing potential confounds of vigilance and motion. Our primary hypothesis was that the functional connectivity within visual and attention networks would be reduced in patients with epilepsy. We further hypothesized that controlling for the effects of IEDs would increase the connectivity in the patient group. The key findings were: (1) Patients with mixed epileptic foci showed a common connectivity reduction in lateral visual and attentional networks compared with controls. (2) Having controlled for the effects of IEDs there were no connectivity differences between patients and controls. (3) A comparison within patients revealed reduced connectivity between the attentional network and basal ganglia associated with interictal epileptiform discharges. We also found that the task activations were reduced in epilepsy patients but that this was unrelated to IED occurrence. Unexpectedly, connectivity changes in ICNs were strongly associated with the transient effects of interictal epileptiform discharges. Interictal epileptiform discharges were shown to have a pervasive transient influence on the brain's functional organisation. Hum Brain Mapp 38:221-236, 2017. © 2016 Wiley Periodicals, Inc.

Thalamic abnormalities in children with continuous spike-wave during slow-wave sleep: An F-18-fluorodeoxyglucose positron emission tomography perspective.

OBJECTIVE: Thalamic injury has been implicated in the development of continuous spike-wave during slow-wave sleep (CSWS) in children with epilepsy. We studied thalamic abnormalities in children with CSWS using F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. METHODS: Twenty-three patients (12 male; mean age 9 years) with CSWS and normal thalami on brain magnetic resonance imaging (MRI) underwent FDG-PET. Thalamic glucose metabolism, represented by standardized uptake value normalized to whole brain (nSUV, RT for right thalamus and LT for left thalamus), and its asymmetry--absolute asymmetry index (AAI): ¦(RT-LT)¦*100/[(RT+LT)/2]--was calculated. These values were compared with those from 10 normal healthy controls (five female; mean age 11.1 years). RESULTS: Thalamic glucose metabolism was abnormal in 18 patients (78.3%). Thalamic nSUV was decreased (n = 6) or increased (n = 1) bilaterally in seven children without any asymmetry. Abnormal thalamic symmetry [AAI = 3.7-31.5% (0.8-3.3% in controls)] was seen in 11 children. Of these, six children had a unilateral thalamic metabolic abnormality (increased metabolism, n = 3 and decreased metabolism, n = 3), whereas 5 of 14 children had abnormal asymmetry index with bilaterally normal (n = 4) or increased (n = 1) thalamic metabolism. No clear association of thalamic metabolic abnormalities was seen with the stage of evolution of CSWS (prodromal, acute, or residual) or with the cortical FDG abnormalities. SIGNIFICANCE: Functional thalamic abnormalities, both unilateral and bilateral, are frequently seen in patients with CSWS. FDG-PET is a sensitive and quantifiable modality to detect these changes.

Cerebellar white matter changes in patients with newly diagnosed partial epilepsy of unknown etiology.

OBJECTIVE: We hypothesize that pre-existing susceptible structures in the brain may be associated with the development of newly diagnosed partial epilepsy of unknown etiology. METHODS: Twenty-two patients with newly diagnosed partial epilepsy of unknown etiology and 36 healthy controls were enrolled in this study. In addition, we included 24 patients with chronic partial epilepsy of unknown etiology as a disease control group. We analyzed whole-brain T1-weighted MRIs using FreeSurfer 5.1. The volumes of the hippocampus, amygdala, thalamus, caudate, putamen, pallidum, brainstem, cerebellar gray and white matter, as well as cerebral gray and white matter were compared between the groups. We also analyzed the changes in brain volumes associated with the chronicity of epilepsy in the patients with chronic epilepsy compared to newly diagnosed epilepsy. RESULTS: The volume of cerebellar white matter in patients with newly diagnosed epilepsy was significantly smaller than that which was observed in the healthy controls (p=0.0001). This finding was also observed in patients with chronic epilepsy (p<0.0001). Cerebral white matter volume was negatively correlated with the duration of epilepsy (r=-0.4, p=0.04). CONCLUSION: These findings support our hypothesis that cerebellar white matter changes may constitute a pre-existing susceptible structure in the brain that is associated with the development of partial epilepsy of unknown etiology. In addition, cerebral white matter was the structure that was the most vulnerable to the progression of epilepsy.

Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.

Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.

While animal models of epilepsy suggest that exogenous cannabinoids may have anticonvulsant properties, scant evidence exists for these compounds' efficacy in humans. Here, we report on two patients whose focal epilepsy was nearly controlled through regular outpatient marijuana use. Both stopped marijuana upon admission to our epilepsy monitoring unit (EMU) and developed a dramatic increase in seizure frequency documented by video-EEG telemetry. These seizures occurred in the absence of other provocative procedures, including changes to anticonvulsant medications. We review these cases and discuss mechanisms for the potentially anticonvulsant properties of cannabis, based on a review of the literature.

Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients.

Hypothalamic hamartomas present with isolated fits of ictal laughter (gelastic epilepsy) or a combination of gelastic and other types of seizures. Many of these patients also suffer from cognitive decline, neuropsychiatric comorbidities and precocious puberty. Although there is a large body of anecdotal evidence about hypothalamic hamartomas and gelastic seizures, many questions still remain to be answered. For instance, which specific hypothalamic regions are most affected by the location of hamartomas causing laughing versus other types of seizures? Does the neuroanatomical localization of the lesions differ in cases with only gelastic seizures or a combination of gelastic and other types of seizures? Does the location of the lesions correlate with the presence of precocious puberty, and does the type of lesion influence the severity or the type of seizures? In a retrospective review of clinical and structural neuroimaging data from 100 cases of gelastic epilepsy and hypothalamic hamartoma, we aimed to address these questions by analysing the clinical presentation and the neuroanatomical features of the hypothalamic lesions in these patients. Our findings suggest that in all 100 cases, lesions were centred at the level of the mammillary bodies in the posterior hypothalamus. Compared with the patients with pure gelastic seizures (n = 32), those with gelastic and other types of seizures (n = 68) had significantly longer duration of epilepsy (P < 0.001), whereas age of seizure onset, the volume of lesions and the proximity to the mammillary bodies were not different between the two groups. In contrast, patients with cognitive or developmental impairment and those with precocious puberty had significantly larger lesions involving the anterior and posterior hypothalamus.

Surgical outcome of gelastic epilepsy of frontal lobe origin: a case report.

Gelastic seizure is an uncommon type of seizure which is characterized by recurrent bouts of unprovoked and stereotyped laughter. It is commonly observed in patients with hypothalamic hamartoma, while its association with other cerebral lesions is rare. The patient was a 15-year-old right-handed male. His chief complaints were recurrent onsets of laughter and unconsciousness for 10 years. On average, he had several to dozens of onsets per day and had failed most antiepileptic medications before admission. Presurgical evaluation included MRI, video-EEG, MEG and subdural electrode EEG. The results of MEG and subdural electrode EEG suggested that the epileptogenic focus was located on the lateral surface of the right frontal lobe, chiefly on the anterior part of the inferior frontal gyrus. The focus was removed under intraoperative ECoG monitoring which was consistent with the results of MEG and subdural electrode EEG. Histopathology revealed focal cortical dysplasia with balloon cells (type II). The patient kept seizure-free during the short-term follow up of 3 months. In the past literature, the medial frontal and basal temporal lobes, besides the hypothalamus, were thought to play major roles in the case of gelastic seizure. Our results suggest that the lateral surface of the frontal lobe might also be one part of the epileptogenic network in gelastic seizures. Removal of the epileptogenic focus under thorough pre-surgical evaluation might result in good seizure control in patients with gelastic seizures.

Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: Correlation with other seizure and epilepsy models.

Chronic electrical stimulation via corneal electrodes can rapidly yield large numbers of kindled mice with a seizure phenotype reflective of secondarily generalized partial seizures. The corneal kindled mouse model has been found to be a highly sensitive and efficient screening model for antiepileptic drug (AED) discovery. The present study further evaluates the utility of the corneal kindled mouse model as a tool for rapid screening of investigational AEDs. Results obtained with nine AEDs (valproic acid, lamotrigine, phenytoin, carbamazepine, levetiracetam, vigabatrin, topiramate, tiagabine, and ezogabine) with varying mechanisms of action and clinical spectrums, as well as six investigational compounds were evaluated in the corneal kindled mouse. ED(50) values are compared to those obtained in the hippocampal kindled rat, the mouse maximal electroshock (MES) model, the 6Hz partial psychomotor seizure model, and the subcutaneous pentylenetetrazol (scPTZ) test. The results obtained in the corneal kindled mouse demonstrate a positive correlation with those attained employing established preclinical models: MES (r² = 0.9511), scPTZ (r² = 0.9697), 6Hz (r² = 0.9519), and hippocampal kindling (r² = 0.9037). The demonstrated predictive ability of the corneal kindled mouse model supports its use in the early evaluation of investigational AEDs.

Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures.

Hypothalamic hamartomas (HHs) are congenital, benign masses in the hypothalamus and tuber cinereum that may cause central precocious puberty and gelastic seizures. Nodules of small neurons are thought to be a universal feature of the microarchitecture of HH lesions associated with epilepsy. Here we describe the case of a 5-year-old boy with gelastic seizures who underwent resection of a HH that contained nodules of glial cells, but only few, randomly distributed neurons. HHs that contain few or no neurons have only been reported thus far in cases associated with precocious puberty. This case demonstrates that few solitary neurons in HHs can drive the development of gelastic seizures, and nodules of small neurons may not be a universal feature of HHs associated with epilepsy. This finding is clinically important since hypothalamic hamartomas with rare neurons can easily be misdiagnosed as pilocytic astrocytomas or subependymomas if their presence is overlooked. A neuronal stain is helpful in making the correct diagnosis in these cases.

Mirthful gelastic seizures with ictal involvement of temporobasal regions.

Ictal laughter is the cardinal clinical sign of gelastic seizures in hypothalamic hamartomas and may also occur in extrahypothalamic epilepsies. Laughing consists of an affective and a motor component. It has been suggested that the affective component may result from an involvement of temporobasal structures, whereas the motor part is related to an involvement of the mesial frontal cortex. So far, evidence is based on a limited number of cases with spontaneously recorded seizures or in whom electrical stimulation of invasive intracranial EEG recordings has been performed. We report a patient who suffered from epigastric psychic auras, complex partial seizures with a gelastic component and secondarily generalized seizures. To evaluate a possible epileptogenic role of the hippocampus and dysplastic region in the right mid-temporal gyrus, intracranial monitoring with subdural electrodes over the temporobasal and temporolateral regions, as well as a deep brain electrode in the hippocampus, were performed. During the intial part of the seizure, consisting of an intense retrosternal ascending feeling with sexual connotation, rhythmic spikes in temporolateral contacts were detected. Concomitant with the development of smiling and laughter, a rhythmic activity over the temporobasal regions evolved. The patient became seizure-free following right temporal lobe resection. This case supports the assumption that ictal involvement of temporobasal structures is crucial for gelastic seizure components in patients with temporal lobe epilepsy. Progression to temporobasal regions was associated with the feeling of happiness whereas motor components of laughter occurred later. These findings are in accordance with the interpretation of surface recordings by Dericioglu and co-workers in a similar previous case. [Published with video sequences].

Visual activation and audiovisual interactions in the auditory cortex during speech perception: intracranial recordings in humans.

Hemodynamic studies have shown that the auditory cortex can be activated by visual lip movements and is a site of interactions between auditory and visual speech processing. However, they provide no information about the chronology and mechanisms of these cross-modal processes. We recorded intracranial event-related potentials to auditory, visual, and bimodal speech syllables from depth electrodes implanted in the temporal lobe of 10 epileptic patients (altogether 932 contacts). We found that lip movements activate secondary auditory areas, very shortly (approximately equal to 10 ms) after the activation of the visual motion area MT/V5. After this putatively feedforward visual activation of the auditory cortex, audiovisual interactions took place in the secondary auditory cortex, from 30 ms after sound onset and before any activity in the polymodal areas. Audiovisual interactions in the auditory cortex, as estimated in a linear model, consisted both of a total suppression of the visual response to lipreading and a decrease of the auditory responses to the speech sound in the bimodal condition compared with unimodal conditions. These findings demonstrate that audiovisual speech integration does not respect the classical hierarchy from sensory-specific to associative cortical areas, but rather engages multiple cross-modal mechanisms at the first stages of nonprimary auditory cortex activation.

Influence of subtraction ictal SPECT on surgical management in focal epilepsy of indeterminate localization: a prospective study.

The impact of functional imaging tests on the decision-making and planning process for epilepsy surgery has never been prospectively assessed. We prospectively evaluated 50 consecutively eligible patients whose noninvasive evaluations showed nonlocalized findings and determined how their SISCOM (subtraction ictal SPECT [single photon emission computed tomography] co-registered to MRI [magnetic resonance imaging]) data altered consensus decisions for epilepsy surgery. At an epilepsy surgery conference where each patient was discussed, consensus decisions were documented after a standardized presentation of data from the noninvasive evaluation (SISCOM findings initially were excluded). Consensus decisions were again documented after presentation of SISCOM data. Consensus decisions changed for 10 of 32 patients (31%) with localizing SISCOM results, whereas the decision changed in only 1 of 18 patients (6%) with nonlocalizing SISCOM results (P<.05). Changes in consensus decisions were as follows: (1) intracranial electrode implantation (IEI) was obviated and resective surgery was recommended (n=2); (2) resective surgery or further evaluation for patients initially not considered surgical candidates (n=2); (3) IEI in patients for whom it was not recommended initially (n=3); (4) increased IEI coverage (n=3); and (5) antiepileptic drug trial or vagal nerve stimulation was recommended instead of IEI (n=1). For some patients whose noninvasive evaluations did not clearly localize a surgical focus, SISCOM data can have a major impact on decisions to recommend resective epilepsy surgery or IEI.

Left thalamomegaly in a patient with partial epilepsy.

Temporal lobe epilepsy (TLE) is associated with modification in thalamic structure and function. In particular, thalamic atrophy and hypometabolism can occur, affecting ipsilateral, contralateral thalami or both. We describe a 28-year-old epileptic woman, who presented peculiar neuroimaging findings, with enlargement of the thalamus contralateral to the epileptic focus. The patient was born from dystocic delivery, she presented partial motor seizures in the left side of the body, followed by generalisation, and the EEG showed a right temporal epileptic focus. Serial CT and MRI scan, performed along 11 years, showed a non-evolutive left thalamomegaly. 18-FDG PET showed reduced metabolic activity in the upper right temporal gyrus and in the ipsilateral thalamus. Thalamic asymmetry in our patient could be an occasional finding.

Extraction and localization of mesoscopic motor control signals for human ECoG neuroprosthetics.

Electrocorticogram (ECoG) recordings for neuroprosthetics provide a mesoscopic level of abstraction of brain function between microwire single neuron recordings and the electroencephalogram (EEG). Single-trial ECoG neural interfaces require appropriate feature extraction and signal processing methods to identify and model in real-time signatures of motor events in spontaneous brain activity. Here, we develop the clinical experimental paradigm and analysis tools to record broadband (1Hz to 6kHz) ECoG from patients participating in a reaching and pointing task. Motivated by the significant role of amplitude modulated rate coding in extracellular spike based brain-machine interfaces (BMIs), we develop methods to quantify spatio-temporal intermittent increased ECoG voltages to determine if they provide viable control inputs for ECoG neural interfaces. This study seeks to explore preprocessing modalities that emphasize amplitude modulation across frequencies and channels in the ECoG above the level of noisy background fluctuations in order to derive the commands for complex, continuous control tasks. Preliminary experiments show that it is possible to derive online predictive models and spatially localize the generation of commands in the cortex for motor tasks using amplitude modulated ECoG.

Status gelasticus associated with levetiracetam as add-on treatment.

We report the case of a five-year-old girl, presenting with difficult-to-treat, symptomatic focal epilepsy, who developed status gelasticus following the introduction of levetiracetam as add-on treatment to oxcarbazepine and diazepam. Gelastic seizures were documented by video-EEG and were responsive to i.v. administration of diazepam. A possible causative role of levetiracetam is suggested. Specific susceptibility to some AEDs is also discussed, as this patient, at the age of four years, had presented an episode of non-convulsive status epilepticus, following introduction of tiagabine, in association with vigabatrin and nitrazepam.[Published with video sequences].

Cortical and thalamic fMRI responses in partial epilepsy with focal and bilateral synchronous spikes.

OBJECTIVE: To determine the blood oxygen level-dependent (BOLD) responses to epileptic discharges in the thalamus and cerebral cortex in patients with partial epilepsy. METHODS: Among 64 tested patients, 40 had EEG spikes during scanning and were divided in two groups: unilateral or bilateral independent spikes (29 patients) and bilaterally synchronous spikes (11 patients). Each spike topography was analyzed separately, yielding 40 studies in the first group and 17 in the second. RESULTS: Forty-five percent of focal spike studies showed significant BOLD responses. Cortical activation (positive BOLD) represented the dominant response and had a better correlation with spike location than cortical deactivation (negative BOLD). In the second group, all patients had significant BOLD responses; they were more widespread compared to the first group, and deactivated areas were as important as activated regions. A thalamic response was seen in 12.5% of studies in the first group and 55% in the second. CONCLUSIONS: The thalamus is involved in partial epilepsy during interictal discharges. This involvement and also cortical deactivation are more commonly seen with bilateral spikes than focal discharges. SIGNIFICANCE: These findings show evidence for a role for the thalamus and a more important role for inhibition in secondary bilateral synchrony.