Cortical dysplastic lesions (CDyLs) are often associated with severe partial epilepsies. We describe the electrographic counterpart of this high degree of epileptogenicity, manifested by continuous or frequent rhythmic epileptogenic discharges recorded directly from CDyLs during intraoperative electrocorticography (ECoG). These ictal or continuous epileptogenic discharges (I/CEDs) assumed one of the following three patterns: (1) repetitive electrographic seizures, (2) repetitive bursting discharges, or (3) continuous or quasicontinuous rhythmic spiking. One or more of these patterns were present in 23 of 34 patients (67%) with intractable partial epilepsy associated with CDyLs, and in only 1 of 40 patients (2.5%) with intractable partial epilepsy associated with other types of structural lesions. I/CEDs were usually spatially restricted, thus contrasting with the more widespread interictal ECoG epileptic activity, and tended to colocalize with the magnetic resonance imaging-defined lesion. Completeness of excision of cortical tissue displaying I/CEDs correlated positively with surgical outcome in patients with medically intractable seizures; i.e., three-fourths of the patients in whom it was entirely excised had favorable surgical outcome; in contrast, uniformly poor outcome was observed in those patients in whom areas containing I/CEDs remained in situ. We conclude that CDyLs are highly and intrinsically epileptogenic, and that intraoperative ECoG identification of this intrinsically epileptogenic dysplastic cortical tissue is crucial to decide the extent of excision for best seizure control.

The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.

Experiential phenomena occurring in spontaneous seizures or evoked by brain stimulation were reported by 18 of 29 patients with medically intractable temporal lobe epilepsy who were investigated with chronic, stereotaxically implanted intracerebral electrodes. The phenomena mainly consisted of perceptual (visual or auditory) hallucinations or illusions, memory flashbacks, illusions of familiarity, forced thinking, or emotions. Experiential phenomena did not occur unless a seizure discharge or electrical stimulation involved limbic structures. For such phenomena to occur, seizure discharge or electrical stimulation did not have to implicate temporal neocortex. This was true even for perceptual experiential phenomena. Many experiential responses elicited by electrical stimulation, particularly when applied to the amygdala, were not associated with electrical afterdischarge. Limbic activation by seizure discharge or electrical stimulation may add an affective dimension to perceptual and mnemonic data processed by the temporal neocortex, which may be required for endowing them with experiential immediacy.

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer's disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.

Despite neuropathological and electrophysiological evidence for the involvement of parahippocampal structures in temporal lobe epilepsy (TLE), little attention has been paid to morphometric measurements of these structures in patients with TLE. Using high resolution MRI, we previously showed that the volume of the entorhinal cortex was decreased in patients with TLE. The purpose of this study was: (i) to determine whether changes in the volume of the perirhinal cortex and posterior parahippocampal cortex were detectable by MRI; and (ii) to study the distribution and degree of atrophy in mesial temporal structures including the hippocampal head, body and tail, amygdala, entorhinal cortex, perirhinal cortex and posterior parahippocampal cortex. MRI volumetric analysis was performed using a T(1)-weighted three-dimensional gradient echo sequence in 20 healthy subjects and 25 TLE patients with intractable TLE. In patients with either left or right TLE, the hippocampal head, body and tail and the entorhinal and perirhinal cortices ipsilateral to the seizure focus were significantly smaller than in normal controls. The mean volume of the posterior parahippocampal cortex was not different from that of normal controls. Within the hippocampus, the hippocampal head was more atrophic than the hippocampal body and hippocampal tail. Within the parahippocampal region, the entorhinal cortex was more severely affected than the perirhinal cortex. Our MRI results confirm pathological findings of damage in the mesial temporal lobe, involving not only the hippocampus and the amygdala, but also the entorhinal and perirhinal cortices. The pattern of atrophy may be explained by cell loss secondary to a disruption of entorhinal-hippocampal connections as a result of privileged electrical dialogue between these two structures.

The objectives of this study were to evaluate the haemodynamic response of the cerebral cortex and thalamus during generalized spike and wave or polyspike and wave (GSW) bursts in patients with idiopathic generalized epilepsy (IGE). The haemodynamic response is measured by fMRI [blood oxygenation level-dependent (BOLD) effect]. We used combined EEG-functional MRI, a method that allows the unambiguous measurement of the BOLD effect during bursts, compared with measurements during the inter-burst interval. Fifteen patients with IGE had GSW bursts during scanning and technically acceptable studies. fMRI cortical changes as a result of GSW activity were present in 14 patients (93%). Changes in the form of activation (increased BOLD) or deactivation (decreased BOLD) occurred symmetrically in the cortex of both hemispheres, involved anterior as much as posterior head regions, but were variable across patients. Bilateral thalamic changes were also found in 12 patients (80%). Activation predominated over deactivation in the thalamus, whereas the opposite was seen in the cerebral cortex. These results bring a new light to the pathophysiolocal mechanisms generating GSW. The spatial distribution of BOLD responses to GSW was unexpected: it involved as many posterior as anterior head regions, contrary to the usual fronto-central predominance seen in EEG. The presence of a thalamic BOLD response in most patients provided, for the first time in a group of human patients, confirmation of the evidence of thalamic involvement seen in animal models. The possible mechanisms underlying these phenomena are discussed.

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.

Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.