Vagal nerve stimulation cycles alter EEG connectivity in drug-resistant epileptic patients: A study with graph theory metrics.

OBJECTIVE: Vagal Nerve Stimulation (VNS) is an effective treatment for Drug-Resistant (DR) epilepsy. Albeit the corroborated effectiveness of VNS, little is known about how VNS works. We aim to leverage quantitative Electroencephalography (qEEG) to study how the brain responds to VNS cycles. METHODS: Eighteen subjects with DR epilepsy were enrolled in our study. 64-channel EEG was recorded during VNS stimulation. Periods of stimulation (VNS), preceding (preVNS) and following stimulation (postVNS) were identified via an electrode placed on the stimulator. We used qEEG analysis to assess changes in spectral and network activity that characterize these conditions. Graph theory metrics were used to calculate differences in network connectivity. RESULTS: No differences were found in spectral activity between preVNS, VNS, and postVNS. Graph theory showed consistent changes in network organization expressed by Small World Index (SWI), Betweenness Centrality (BtwC), and Global Efficiency (gE). These changes were most significant in the slow EEG bands. CONCLUSIONS: In DR epilepsy, VNS has a significant effect on brain network activity, as assessed by EEG connectivity, acting on widespread network distribution rather than band-power. SIGNIFICANCE: Our findings support the hypothesis that VNS acts on epilepsy by influencing diffuse network connectivity in the brain.

The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy.

BACKGROUND AND PURPOSE: The detection of antibodies binding neural antigens in patients with epilepsy has led to the definition of 'autoimmune epilepsy'. Patients with neural antibodies not responding to antiepileptic drugs (AEDs) may benefit from immunotherapy. Aim of this study was to evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to immunotherapy. METHODS: Eighty-one patients and 75 age- and sex-matched healthy subjects (HS) were enrolled in the study. Two groups of patients were included: 39 patients with epilepsy and other neurological symptoms and/or autoimmune diseases responsive to AEDs (group 1) and 42 patients with AED-resistant epilepsy (group 2). Patients' serum and cerebrospinal fluid were evaluated for the presence of autoantibodies directed to neural antigens by indirect immunofluorescence on frozen sections of mouse brain, cell-based assays and a radioimmunoassay. Patients with AED-resistant epilepsy and neural autoantibodies were treated with immunotherapy and the main outcome measure was the reduction in seizure frequency. RESULTS: Neural autoantibodies were detected in 22% of patients (18/81), mostly from the AED-resistant epilepsy group (P = 0.003), but not in HS. Indirect immunofluorescence on mouse brain revealed antibodies binding to unclassified antigens in 10 patients. Twelve patients received immunotherapy and nine (75%) achieved >50% reduction in seizure frequency. CONCLUSIONS: A significant proportion of patients with AED-resistant epilepsy harbor neural-specific autoantibodies. The detection of these antibodies, especially of those binding to synaptic antigens, may predict a favorable response to immunotherapy, thus overcoming AED resistance.

Hydroelastic behaviour of a structure exposed to an underwater explosion.

The hydroelastic interaction between an underwater explosion and an elastic plate is investigated num- erically through a domain-decomposition strategy. The three-dimensional features of the problem require a large computational effort, which is reduced through a weak coupling between a one-dimensional radial blast solver, which resolves the blast evolution far from the boundaries, and a three-dimensional compressible flow solver used where the interactions between the compression wave and the boundaries take place and the flow becomes three-dimensional. The three-dimensional flow solver at the boundaries is directly coupled with a modal structural solver that models the response of the solid boundaries like elastic plates. This enables one to simulate the fluid-structure interaction as a strong coupling, in order to capture hydroelastic effects. The method has been applied to the experimental case of Hung et al. (2005 Int. J. Impact Eng. 31, 151-168 (doi:10.1016/j.ijimpeng.2003.10.039)) with explosion and structure sufficiently far from other boundaries and successfully validated in terms of the evolution of the acceleration induced on the plate. It was also used to investigate the interaction of an underwater explosion with the bottom of a close-by ship modelled as an orthotropic plate. In the application, the acoustic phase of the fluid-structure interaction is examined, highlighting the need of the fluid-structure coupling to capture correctly the possible inception of cavitation.

Angioarchitectural features of brain arteriovenous malformations associated with seizures: a single center retrospective series.

BACKGROUND AND PURPOSE: Epileptic seizures account for 24-40% of all clinical onsets in patients with brain arteriovenous malformations (AVMs). METHODS: We retrospectively reviewed the angioarchitectural features of AVMs associated with seizures in 168 patients admitted to our Department from 1997 to 2012. Patients were dichotomized according to demographic characteristics, type of treatment, bleeding occurrence, and morphological and topographic features. Clinical status at admission and discharge was also recorded. The association of each one of these variables with seizures occurrence was statistically tested. Continuous variables and outcome were compared with Student's t-test, whereas categorical ones were compared using Fisher's exact test. The independent contribution of some seizures predictors was assessed with a logistic regression model. Associations were considered significant for P < 0.05. RESULTS: About 29% patients showed seizures and 47% bleeding. No significant difference in age and sex was observed between patients with and without seizures. AVMs > 4 cm (P = 0.001) and those fed by dilated arterial feeders (P = 0.02) were associated with increased risk of seizures. A higher risk of seizures occurrence was also observed in cortical AVMs compared with deeper ones (75.5% vs. 55.4%; P = 0.01), and in AVMs fed by middle and posterior cerebral arteries branches compared with the other vessels (81.6% vs. 45.3%; P < 0.001 and 48.9% vs. 23.5%; P = 0.002, respectively). No lobar predisposition was observed. A nidus > 4 cm also appeared as an independent risk factor of seizures occurrence (OR 2.82; 95% CI, 1.26-6.31; P = 0.009) at logistic regression analysis. CONCLUSIONS: AVM morphology, especially nidus dimension, appeared to more significantly influence seizures occurrence than their topography.

Functional connectivity MR imaging of the language network in patients with drug-resistant epilepsy.

BACKGROUND AND PURPOSE: Subtle linguistic dysfunction and reorganization of the language network were described in patients with epilepsy, suggesting the occurrence of plasticity changes. We used resting state FC-MRI to investigate the effects induced by chronic epilepsy on the connectivity of the language-related brain regions and correlated it with language performance. MATERIALS AND METHODS: FC-MRI was evaluated in 22 right-handed patients with drug-resistant epilepsy (11 with LE and 11 with RE) and in 12 healthy volunteers. Neuropsychological assessment of verbal IQ was performed. Patients and controls underwent BOLD fMRI with a verb-generation task, and language function was lateralized by an LI. Intrinsic activity fluctuations for FC analysis were extracted from data collected during the task. Six seeding cortical regions for speech in both hemispheres were selected to obtain a measure of the connectivity pattern among the language networks. RESULTS: Patients with LE presented atypical language lateralization and an overall reduced connectivity of the language network with respect to controls. In patients with both LE and RE, the mean FC was significantly reduced within the left (dominant) hemisphere and between the 2 hemispheres. In patients with LE, there was a positive correlation between verbal IQ scores and the left intrahemispheric FC. CONCLUSIONS: In patients with intractable epilepsy, FC-MRI revealed an overall reduction and reorganization of the connectivity pattern within the language network. FC was reduced in the left hemisphere regardless of the epileptogenic focus side and was positively correlated with linguistic performance only in patients with LE.

Provoked ictal SPECT in temporal and extratemporal drug-resistant epileptic patients: comparison of Statistical Parametric Mapping and qualitative analysis.

OBJECTIVE: To compare Statistical Parametric Mapping (SPM) with qualitative analysis of provoked ictal SPECT, in terms of both diagnostic yield and efficacy in identifying the epileptogenic zone of temporal and extratemporal epileptic patients. METHODS: We included in the study 27 drug-resistant epileptic patients submitted to provoked ictal SPECT and for whom both SPM and qualitative analysis were obtained. A comparison between visual SPECT analysis and SPM results was performed in terms of lateralization and localization of the ictal hyperperfusion areas. Then, hyperperfusion areas were compared to epileptogenic zones to assess whether they co-localized or not. RESULTS: In twenty patients, a co-localization was found between hyperperfusion areas detected by both qualitative and SPM analysis of provoked ictal SPECT and epileptogenic zones. A concordance between SPM and qualitative analysis in all but two patients was obtained. These findings were observed for both temporal and extratemporal epilepsies. CONCLUSIONS: The co-localization between provoked ictal SPECT hyperperfusion areas and epileptogenic zones found in most patients supports the usefulness of this technique in integrating data provided by neuroimaging and electroclinical correlations to correctly define epileptogenic zone. Moreover, this preliminary work suggests that SPM as entirely objective methodology is feasible and can be accurate also after provoked ictal SPECT.

New depth short-latency somatosensory evoked potential (SEP) component recorded in human SI area.

To analyse short and long-latency (SEPs) recorded by chronically stereotactically electrodes implanted in SI area of two epileptic patients. Two drug-resistant epileptic patients (2 females, 38 and 15 years, respectively) suffering from left temporal and right frontal epilepsy respectively, were investigated by an electrode-chronically implanted in SI area. Short and long latency somatosensory evoked potentials were recorded by depth electrodes 10 days after implantation. This is the first study to describe a depth N36 response by an intracerebral recording electrode in the SI area, probably generated by a radially oriented generator, located in area 1. Furthermore, we confirmed a role of SI in the genesis of N60 component. Finally, our present data suggest that the SI area is still active at 120 ms after the stimulus, since in one patient (no. 2) we identified a N120 potential, reaching its maximal amplitude at the same depth as the N20 response.

Short and middle-latency Median Nerve (MN) SEPs recorded by depth electrodes in human pre-SMA and SMA-proper.

OBJECTIVE: To analyse waveforms, latencies and amplitudes of Median Nerve (MN) SEPs recorded by stereotactically electrodes implanted in the SMA of 14 epileptic patients (9 in pre-SMA,3 in SMA-proper, 2 in both) in order to evaluate which short and middle-latency SEPs are generated in this area and which could be the physiological relevance of these responses. METHODS: Short and middle-latency MN SEPs were recorded by chronically implanted electrodes in the fronto-temporal cortex and in particular in the mesial frontal region of 14 drug-resistant epileptic patients. MN stimulations of 100 micros were delivered by skin electrodes at the wrist; stimulus intensity was adjusted slightly above the motor threshold. RESULTS: The main result of this study is that middle-latency SEPs were originated in pre-SMA but not in SMA-proper as demonstrated by both referential and bipolar recordings. In particular off-line computed bipolar traces between neighbouring contacts implanted in the pre-SMA and in the frontal external regions showed a phase reversal at the deepest contacts located in pre-SMA. Conversely, bipolar recordings between neighbouring contacts implanted in the SMA-proper and in the frontal external regions showed inversion recovery at more superficial contacts, implanted in area 6. Finally, we confirmed that no short-latency MN SEP (and in particular the N30) is originated in the whole SMA. CONCLUSIONS: Among premotor areas, somatosensory inputs seem to reach pre-SMA and area 6 but not SMA-proper. SIGNIFICANCE: This study assessed that no scalp SEP in the first 100 ms after MN stimulus could be generated in SMA-proper.

Unusual ipsilateral hyperkinetic automatisms in SMA seizures.

PURPOSE: To describe repetitive movements of the right arm possibly originating from the ipsilateral SMA area in two drug-resistant epileptic patients. METHODS: Two epileptic patients (one female, one male, 35 and 36 years old, respectively) were submitted to pre-surgical evaluation including history, neurological examination, long-term video-EEG monitoring, interictal and ictal SPET, MRI and fMRI, neuropsychological assessment. Invasive recordings (stereoelectroencephalography) were also performed. RESULTS: In both patients ictal semiology was characterized by very stereotyped repetitive right arm movements, i.e. tapping towards the thorax (movement rate of 6-7 Hz and 3-4 Hz for the two subjects, respectively). Seizures in the first patient, whose epilepsy was cryptogenetic, originated from the right pre-SMA area, which was surgically removed. She is seizure free 2 years after the operation. In the second patient, in whom a right pre-frontal post-abscess porencephaly was disclosed, the epileptogenic zone included the lesion and surrounding areas, while the SMA area was involved less consistently. CONCLUSIONS: Even if, according to literature, SMA epilepsy is predominantly characterized by postural manifestations, ipsilateral repetitive movements could be a relevant sign in this kind of epilepsy, as showed in our first patient. The presence of similar semiology in the second patient, might suggest that the symptomatogenic zone involved SMA area.

Retrospective analysis of variables favouring good surgical outcome in posterior epilepsies.

AIM: to determine variables favouring good surgical outcome in posterior epilepsies. METHODS: Fourteen patients submitted to epilepsy surgery were included in the study. The epileptogenic zone was located in temporo-parieto-occipital areas as assessed by both invasive and non-invasive pre-surgical evaluation. Several variables (age at first seizure; age at surgery; disease duration; type, frequency and clinical semiology of seizures; presence of lesion; scalp ictal and interictal EEG; localization and extension of epileptogenic zone; completeness of surgical resection) were compared (Fisher's exact test) with freedom from seizures to determine whether surgical outcome (Engel's classification) could be related to any of them. RESULTS: Seven patients were seizure free (Ia) and very satisfying results were obtained for 3 patients (2 Ib, 1 Ic). New post-surgical visual deficits occurred only in 3 patients. Surgical outcome was related significantly to two variables: scalp ictal EEG (focal versus non-focal; p: 0.014) and completeness of surgical resection of epileptogenic zone (p: 0.0023). A significant trend towards a better outcome for focal interictal intracranial activity versus a non-focal one (p: 0.07) was found. CONCLUSIONS: The correlation between completeness of epileptogenic zone resection and surgical outcome suggests that a presurgical protocol, allowing a precise definition of the area of resection, could help in obtaining more satisfying results in posterior epilepsies.

Effects of vagus nerve stimulation on cortical excitability in epileptic patients.

Vagus nerve stimulation (VNS) is used as adjunctive treatment for medically refractory epilepsy, but little is known about its mechanisms of action. The effects of VNS on the excitatory and inhibitory circuits of the motor cortex were evaluated in five patients with epilepsy using single- and paired-pulse transcranial magnetic stimulation (TMS). Patients were examined with the stimulator on and off. VNS determined a selective and pronounced increase in the inhibition produced by paired-pulse TMS with no effects on the excitability by single-pulse TMS.

Parietal generators of low- and high-frequency MN (median nerve) SEPs: data from intracortical human recordings.

OBJECTIVE: To identify low and high-frequency median nerve (MN) somatosensory evoked potential (SEP) generators by means of chronically implanted electrodes in the parietal lobe (SI and neighbouring areas) of two epileptic patients. METHODS: Wide-pass short-latency and long-latency SEPs to electrical MN stimulation were recorded in two epileptic patients by stereotactically chronically implanted electrodes in the parietal lobe (SI and neighbouring areas). To study high-frequency responses (HFOs) an off-line digital filtering of depth short-latency SEPs was performed (500-800 Hz, 24 dB roll-off). Spectral analysis was performed by fast Fourier transform. RESULTS: In both patients we recorded a N20/P30 potential followed by a biphasic N50/P70 response. A little negative response in the 100 ms latency range was the last detectable wide-pass SEP in both patients. Two HFOs components (called iP1 and iP2) were detected by mere visual analysis and spectral analysis, and were supposed to be originated within the parietal cortex. CONCLUSIONS: This was the very first study that recorded wide bandpass and high frequency SEPs by electrodes, exploring both the lateral and the mesial part of the parietal lobe and particularly that of the post-central gyrus.

The human supplementary motor area-proper does not receive direct somatosensory inputs from the periphery: data from stereotactic depth somatosensory evoked potential recordings.

Somatosensory evoked potentials to median nerve (MN) stimulation were recorded by stereotactically implanted electrodes in the frontal lobe of two epileptic patients in order to evaluate whether short-latency cortical responses could be generated in the supplementary motor area (SMA)-proper. In both patients two potentials, called P20 and N30 responses, showed a decreasing amplitude from the most superficial to the deepest contacts and were recorded in the white as well in the grey matter of the frontal lobe. Furthermore, no phase reversal of both P20 and N30 potentials was identifiable along electrode trajectories. Our results suggest that short-latency somatosensory evoked responses recorded in the SMA-proper contralateral to MN stimulation are volume conducted from remote cortical generators.

Factors of surgical outcome in tumoural epilepsy.

OBJECTIVES: The purposes of the study were the assessment of the role of surgery in the suppression of epilepsy due to low-grade primitive cerebral tumours and the search for factors relevant to the surgical outcome. PATIENTS AND METHODS: Forty-eight patients with epilepsy due to low-grade supratentorial cerebral tumours were considered. They presented drug-resistant daily to monthly seizures since for least one year (mean 7 yrs). Twenty-four patients underwent a combined tumour and epileptogenic zone resection ("epilepsy surgery") and 24 tumour resection alone ("lesionectomy"). The surgical outcome was evaluated two years after surgery. Several variables related to the characteristics of the epilepsy, the tumour and surgery, were considered for a possible association with the outcome. Statistical analyses were performed. RESULTS: Seizure freedom, including aura, was obtained in 35 patients (72.9%). Mild permanent complications occurred in 6 cases. Seizure suppression was significantly associated with complete tumour resection (post-surgical CT or MRI) and relatively low presurgical seizure frequency; it was also related, though not significantly, to small tumour size and histological grade I. The surgical outcome was only slightly better following "epilepsy surgery" than "lesionectomy". However: i) the extent of tumour resection was not relevant regarding the "epilepsy surgery" outcome, while significantly influencing the outcome after "lesionectomy"; ii) the presurgical frequency of seizures and, to a less extent, the tumour size, had a higher influence on the outcome after "lesionectomy". CONCLUSION: Long-lasting and drug-resistant epilepsy due to cerebral tumours can be suppressed surgically in the majority of cases. The extent of tumour resection and the frequency of the seizures are the most relevant prognostic factors. Both "epilepsy surgery" and "lesionectomy" can provide good results. However, the two approaches should not be regarded as interchangeable: a choice of the approach based on the characteristics of seizures and of the tumour appears relevant to improve the surgical prognosis.

Callosotomy for drug resistant generalized seizures.

We report our series of drug resistant epileptic patients submitted to callosotomy. The 25 patients were affected by severe epilepsy with invalidating generalized seizures with fall, lacking of indication for ablative surgery. Nineteen patients, with at least 1 year of follow-up, were considered for this study. The surgical outcome was classified as: class A), seizure disappearance; class B) 80%, class C) 80-50%, class D) less than 50% seizure reduction; E) increase of seizure frequency. The follow-up analysis shows that the better results are obtained with the generalized seizures, in particular the GTA. Our surgical results are discussed considering the data of the literature: about the functional anatomy of the Corpus Callosum, the experimental studies and the clinical series published on callosotomized epileptic patients.

Callosotomy for severe epilepsies with generalized seizures: outcome and prognostic factors.

The purpose of the present study was to verify the effect of callosotomy on generalized seizures, to check the effect on other seizure types and to search for possible prognostic factors. Twenty patients with a minimum follow-up of one year (mean 3.5 years) were available for our analysis. In six of them the callosotomy was performed in two stages (total: 26 surgical procedures). Age ranged from 14 to 40 years (mean 23 years). Different aetiologies were known in 15 patients. Duration of epilepsy ranged from 6 to 23 years (mean 15 years). The frequency of seizures ranged between 19 and 750 per month. The most significant effect of surgery was the complete suppression of the generalized seizures associated with falling in 9/19 and their reduction of more than 80% in 7/19 patients (total "good results": 16/19). The generalized tonic-clonic seizures were less affected. The surgical effect on the partial seizures was very variable, the partial simple seizures being the most affected. A positive statistical association with the outcome of the generalized seizures with fall was found for a presurgical seizure frequency below 90 per month, a prevalent bilateral EEG epileptic activity and, to a less extent, the absence of cerebral structural lesions. The role of age, aetiology, duration of the disease, single or more seizure types, mental impairment and extent of callosotomy remains uncertain. Disconnection syndrome does not appear if the splenium is spared. The present findings confirm that the main indication for callosotomy is the occurrence of generalized seizures with fall. Surgery can be initially limited to the anterior 2/3 of the corpus callosum; further posterior section of the corpus, excluding the splenium, should be regarded as a second step, when necessary.

Resection surgery for partial epilepsy. Relation of surgical outcome with some aspects of the epileptogenic process and surgical approach.

In spite of the progressive improvement of the results of resective surgery for epilepsy, the number of not significantly benefited patients remains high. An attempt was made to find out a relation between outcome and some aspects of the pathophysiological organization of the epileptogenic process and of the surgical procedure. Chi-square and logistic regression statistic analyses were utilized. The study was retrospectively performed on 138 surgically treated patients having a minimum follow-up of three years. Three classes of surgical outcome were considered: completely seizure free (including aura; 86 cases, 62.3%), significant seizure reduction (31 cases, 22.5%), and no significant improvement (21 cases, 15.2%). What follows was brought into evidence by the study. 1) On the diagnostic side, the spatial arrangement (focal, unilateral, multifocal) of both the interictal and the ictal epileptic electrocerebral activities are significantly associated with the surgical outcome. Their relative impact on outcome is related to the presence of a structural lesion: when a lesion is documented, the interictal activity has the higher value: vice versa, when no lesion is apparent, the role of the ictal activity is prevalent. However, the presence, as well as the nature of the lesion, per se, are not significantly associated with outcome. 2) On the surgical side, the extent of resection of both the structural lesion and of the epileptogenic zone are highly associated with the surgical result; the extent of lesion resection prevails on that of the epileptogenic zone. The type of surgical approach (hemispherectomy: 17 cases; temporal lobectomy: 67 cases; extratemporal resection: 54 cases) has no significant relation to the outcome. The value and the limits of the results obtained are discussed.

Callosotomy for generalized seizures associated with hypothalamic hamartoma.

A case is reported of intractable epilepsy associated with a hypothalamic hamartoma in an 18 year old man. The patient underwent a two-third anterior callsotomy and, subsequently, removal of the hamartoma. Callosotomy did not affect the generalized seizure pattern. The authors believe this to be the first documented case of hypothalamic hamartoma in which callosotomy for seizure control was attempted. The poor response to callosotomy suggests the extracallosal diffusion of the generalized seizures from hypothalamic hamartomas.