Simultaneous Surgical Approach with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients with Concurrent Peritoneal and Liver Metastases of Colon Cancer Origin.

Background: Simultaneous liver resection and peritoneal cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial today. The aim of the study was to analyze the postoperative outcomes and survival of patients with advanced metastatic colon cancer (peritoneal and/or liver metastases). Methods: Retrospective observational study from a prospective maintained data base. Patients who underwent a simultaneous peritoneal cytoreduction and liver resection plus HIPEC were studied. Postoperative outcomes and overall and disease free survival were analyzed. Univariate and multivariate analyses were performed. Results: From January 2010 to October 2022, 22 patients operated with peritoneal and liver metastasis (LR+) were compared with 87 patients operated with peritoneal metastasis alone (LR-). LR+ group presented higher serious morbidity (36.4 vs. 14.9%; p: 0.034). Postoperative mortality did not reach statistical difference. Median overall and disease free survival was similar. Peritoneal carcinomatosis index was the only predictive factor of survival. Conclusions: Simultaneous peritoneal and liver resection is associated with increased postoperative morbidity and hospital stay, but with similar postoperative mortality and OS and disease free survival. These results reflect the evolution of these patients, considered inoperable until recently, and justify the trend to incorporate this surgical strategy within a multimodal therapeutic plan in highly selected patients.

Reward-based decision-making in mesial temporal lobe epilepsy patients with unilateral hippocampal sclerosis pre- and post-surgery.

BACKGROUND: Correct functioning of the reward processing system is critical for optimizing decision-making as well as preventing the development of addictions and/or neuropsychiatric symptoms such as depression, apathy, and anhedonia. Consequently, patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis (mTLE-UHS) represent an excellent opportunity to study the brain networks involved in this system. OBJECTIVE: The aim of the current study was to evaluate decision-making and the electrophysiological correlates of feedback processing in a sample of mTLE-UHS patients, compared to healthy controls. In addition, we assessed the impact of mesial temporal lobe surgical resection on these processes, as well as general, neuropsychological functioning. METHOD: 17 mTLE-UHS patients and 17 matched healthy controls completed: [1] a computerized version of the Game of Dice Task, [2] a Standard Iowa Gambling Task, and [3] a modified ERP version of a probabilistic gambling task coupled with multichannel electroencephalography. Neuropsychological scores were also obtained both pre- and post-surgery. RESULTS: Behavioral analyses showed a pattern of increased risk for the mTLE-UHS group in decision-making under ambiguity compared to the control group. A decrease in the amplitude of the Feedback Related Negativity (FRN), a weaker effect of valence on delta power, and a general reduction of delta and theta power in the mTLE-UHS group, as compared to the control group, were also found. The beta-gamma activity associated with the delivery of positive reward was similar in both groups. Behavioral performance and electrophysiological measures did not worsen post-surgery. CONCLUSIONS: Patients with mTLE-UHS showed impairments in decision-making under ambiguity, particularly when they had to make decisions based on the outcomes of their choices, but not in decision-making under risk. No group differences were observed in decision-making when feedbacks were random. These results might be explained by the abnormal feedback processing seen in the EEG activity of patients with mTLE-UHS, and by concomitant impairments in working memory, and memory. These impairments may be linked to the disruption of mesial temporal lobe networks. Finally, feedback processing and decision-making under ambiguity were already affected in mTLE-UHS patients pre-surgery and did not show evidence of clear worsening post-surgery.

Verbal Learning and Longitudinal Hippocampal Network Connectivity in Temporal Lobe Epilepsy Surgery.

Introduction: Learning new verbal information can be impaired in 20-40% of patients after mesial temporal lobe resection. In recent years, understanding epilepsy as a brain network disease, and investigating the relationship between large-scale resting networks and cognition has led to several advances. Aligned studies suggest that it is the integrity of the hippocampal connectivity with these large-scale networks what is relevant for cognition, with evidence showing a functional and structural heterogeneity along the long axis hippocampus bilaterally. Objective: Our aim is to examine whether pre-operative resting-state connectivity along the long hippocampal axis is associated with verbal learning decline after anterior temporal lobe resection. Methods: Thirty-one patients with epilepsy who underwent an anterior temporal lobe resection were pre-surgically scanned at 3-tesla, and pre/post-surgery evaluated for learning deficits using the Rey Auditory Verbal Learning Task (RAVLT). Eighteen controls matched by age, gender and handedness were also scanned and evaluated with the RAVLT. We studied the functional connectivity along the (anterior/posterior) long axis hippocampal subregions and resting-state functionally-defined brain networks involved in learning [executive (EXE), dorsal attention (DAN) and default-mode (DMN) networks]. Functional connectivity differences between the two groups of patients (learning intact or with learning decline) and controls were investigated with MANOVA and discriminant analysis. Results: There were significant differences in the pattern of hippocampal connectivity among the groups. Regarding the anterior connectivity hippocampal pattern, our data showed an increase of connectivity in the pathological side with the DAN (p = 0.011) and the EXE (p = 0.008) when comparing learning-decline vs. learning-intact patients. Moreover, the non-pathological side showed an increase in the anterior connectivity pattern with the DAN (p = 0.027) between learning-decline vs. learning-intact patients. In contrast, the posterior hippocampus showed a reduction of connectivity in the learning-decline patients with the DMN, both in the pathological (p = 0.004) and the non-pathological sides (p = 0.036). Finally, the discriminant analysis based on the pre-operative connectivity pattern significantly differentiated the learning-decline patients from the other groups (p = 0.019). Conclusion: Our findings reveal bilateral connectivity disruptions along the longitudinal axis of the hippocampi with resting-state networks, which could be key to identify those patients at risk of verbal learning decline after epilepsy surgery.

Mapping connectivity fingerprints for presurgical evaluation of temporal lobe epilepsy.

BACKGROUND: Surgery may render temporal lobe epilepsy (TLE) patients seizure-free. However, TLE is a heterogenous entity and surgical prognosis varies between patients. Network-based biomarkers have been shown to be altered in TLE patients and hold promise for classifying TLE subtypes and improving pre-surgical prognosis. The aim of the present study is to investigate a network-based biomarker, the weighted degree of connectivity (wDC), on an individual level, and its relation to TLE subtypes and surgical prognosis. METHODS: Thirty unilateral TLE patients undergoing the same surgical procedure (anterior temporal resection) and 18 healthy controls were included. All patients were followed-up in the same center for a mean time of 6.85 years and classified as seizure-free (SF) and non seizure-free (non-SF). Using pre-surgical resting state functional MRI, whole brain wDC values for patients and controls were calculated. Then, we divided both temporal lobes in three Regions-of-interest (ROIs) -mesial, pole and lateral- as these areas are known to behave differently in seizure onset and propagation, delimiting different TLE profiles. The wDC values for the defined ROIs of each individual patient were compared with the healthy group. RESULTS: After surgery, 14 TLE patients remained SF. As a group, patients had higher wDC than controls in both the temporal pole (p < 0.05) as well as in the mesial regions (p < 0.002) of the to-be-resected temporal lobe. When comparing between SF and non-SF patients, a step-wise binary logistic regression model including all the ROIs, showed that having an increased wDC of the temporal pole (p < 0.05) and the mesial area (p < 0.05) of the to-be-resected temporal lobe was associated with seizure freedom long-term after surgery. CONCLUSIONS: This study provides a network-based presurgical biomarker that could pave the way towards personalized prediction. In patients with TLE undergoing anterior temporal resections, having an increased wDC at rest could be a signature of the epileptogenic area, and could help identifying those patients who would benefit most from surgery.

Seizures and epilepsy of autoimmune origin: A long-term prospective study.

OBJECTIVE: To follow prospectively a group of patients with seizures or epilepsy and suggestive clinical features of autoimmune aetiology and find out how many are finally diagnosed with acute symptomatic seizures (ASS) secondary to autoimmune encephalitis or autoimmune-related epilepsy, and how many develop epilepsy. METHODS: Consecutive patients meeting the inclusion criteria from 2010 to 2018 were identified. Patients were classified as confirmed, probable autoimmune, non-autoimmune, or unknown. RESULTS: One-hundred and nine patients were included, 64 (48.7 %) women, mean age 55.2 years (SD 17.9). ASS were reported by 61 patients (56 %), while 48 presented epilepsy (44 %). During follow-up 18 patients died (16.5 %). Final diagnosis was autoimmune-relatedepilepsy (confirmed + probable) in 22 cases and ASS secondary to autoimmune encephalitis (confirmed or probable) in 27, non-autoimmune aetiologies or other diagnosis in 49 (44 %), and unknown aetiology in 11 (10.2 %). Neuronal antibodies (ab) were found in 27 patients (24.7 %). T-lymphocyte infiltration in temporal lobes was observed in 2/8 patients (20 %). Neuronal ab were more frequent in the autoimmune groups: 17 patients (29.8 %) vs 1(2.3 %), p:0.001, and they suffered more autoimmune diseases: 37 (75.5 %) vs 12 (24.48 %), p:0.0001, and 34 (69 %) vs 22 (44.9 %) p:0.027, respectively. All patients with GAD ab 17/17 (100 %) evolved to chronic disease. Four patients (29 %) with ASS secondary to autoimmune encephalitis developed epilepsy. SIGNIFICANCE: ASS secondary to autoimmune encephalitis or autoimmune-related epilepsy will be diagnosed in nearly half of patients who have been suspected of it. The only diagnostic clue is neuronal ab. Patients who have suffered ASS secondary to autoimmune encephalitis may develop epilepsy over time.

Hippocampal microstructural architecture and surgical outcome: Hippocampal diffusivity could predict seizure relapse.

PURPOSE: Our aim was to study the microstructural architecture of the contralateral hippocampus to the affected side in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and its relation with surgical outcome. METHOD: We included 33 consecutive patients evaluated in our epilepsy surgery program during a five-year period. They underwent a presurgical MRI with volumetric T1 and diffusion weighted sequences. 22 patients with TLE-HS (13 women, 12 right TLE-HS) were finally selected. Median follow-up after surgery was 6.25 years (4.5-8.83 years). We segmented the hippocampal subfields of the contralateral hippocampus using FreeSurfer and calculated the fractional anisotropy (FA) and the mean diffusivity (MD) of each subfield. We also scanned 18 healthy age-matched controls. RESULTS: After surgery, 50 % of the patients (n = 11) remained seizure-free (SF) following surgery. Comparing non-SF to SF patients, the MD showed increased values of the CA1 (p = 0.035), the molecular layer (p = 0.010) and the dentate gyrus (p = 0.041) in the healthy hippocampus. Using a cut-off point for a survival analysis, we found that patients with lower values of MD of the molecular layer and the CA1 remained SF during long-term post-operative follow-up (p < 0.0001). CONCLUSIONS: The contralateral hippocampal internal microstructure may have be implicated in post-surgery seizure freedom in patients with TLE-HS.

Autobiographical memory in epileptic patients after temporal lobe resection or bitemporal hippocampal sclerosis.

The human hippocampus is believed to be a crucial node in the neural network supporting autobiographical memory retrieval. Structural mesial temporal damage associated with temporal lobe epilepsy (TLE) provides an opportunity to systematically investigate and better understand the local and distal functional consequences of mesial temporal damage in the engagement of the autobiographical memory network. We examined 19 TLE patients (49.21 ± 11.55 years; 12 females) with unilateral mesial TLE (MTLE; 12 with anterior temporal lobe resection: 6 right MTLE, 6 left MTLE) or bilateral mesial TLE (7 BMTLE) and 18 matched healthy subjects. We used functional MRI (fMRI) with an adapted autobiographical memory paradigm and a specific neuropsychological test (Autobiographical Memory Interview, AMI). While engaged in the fMRI autobiographical memory paradigm, all groups activated a large fronto-temporo-parietal network. However, while this network was left lateralized for healthy participants and right MTLE patients, left MTLE and patients with BMTLE also showed strong activation in right temporal and frontal regions. Moreover, BMTLE and left MTLE patients also showed significant mild deficits in episodic autobiographical memory performance measured with the AMI test. The right temporal and extra-temporal fMRI activation, along with the impairment in autobiographical memory retrieval found in left MTLE and BMTLE patients suggest that alternate brain areas-other than the hippocampus-may also support this process, possibly due to neuroplastic effects.

Usefulness of HMPAO-SPECT in the diagnosis of nonconvulsive status epilepticus.

BACKGROUND: The diagnosis of nonconvulsive status epilepticus (NCSE) can pose a challenge. Electroencephalogram (EEG) patterns can be difficult to interpret, and the absence of an EEG correlate does not rule out the diagnosis of NCSE. In this setting, neuroimaging tools to help in the diagnosis are crucial. Our aim was to evaluate the role of 99mTc-hexamethyl propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) and quantitative HMPAO-SPECT (QtSPECT) in patients with clinical suspicion of NCSE, and to evaluate their value in the final diagnosis of NCSE. METHODS: We recruited consecutive patients admitted in our center with suspicion of NCSE, and selected those who underwent an HMPAO-SPECT. All patients were admitted to the neurology ward and underwent an EEG. We divided the patients into those who were finally with diagnosed NCSE (NCSE-p) and those who were not (non-NCSE) according to the Salzburg Diagnostic EEG criteria. Sensitivity and specificity of the diagnostic tools were calculated. The SPECTs were acquired in a Skylight SPECT (Philips Healthcare, Amsterdam). The injections were done during the clinical episode suspected of being an NCSE. The HMPAO-SPECT was analyzed by two experts and was also quantified. All data were normalized to the SPM SPECT template. We used an external healthy normal database to obtain a Z-score map for each individual versus the normal database. The Z-score maximum (Zmax) was extracted from each region of the AAL atlas as was the percentage of voxels with a Z-score higher than 2.5 (N(%)). A logistic regression combining the Zmax, N(%), and the effect of patient age was fitted to predict the final NCSE diagnosis. A receiver operator characteristic (ROC) curve and the area under the curve (AUC) were obtained to evaluate the classification performance. RESULTS: We included 55 patients, 21 of them women (38.9%), with a median age of 62.1 years old (range 25-84). Thirty-six patients were with diagnosed NCSE (62.9%). Initial EEG had a sensitivity of 61.1% and a specificity of 89%. Most of the patients were critically ill with diagnostic difficulties, and it could be one of the main reasons to find low sensitivity of the Salzburg diagnostic EEG criteria. The Zmax and N(%) were significantly higher in NCSE-p than in non-NCSE (p = 0.005 and p < 0.001, respectively). The HMPAO-SPECT qualitative analysis had a sensitivity of 80.5% and specificity of 89.5% while QtSPECT had a sensitivity of 82% and specificity of 81%. CONCLUSION: Both 99mTc-HMPAO-SPECT and QtSPECT can be useful in the diagnosis of NCSE. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Use of intravenous brivaracetam in status epilepticus: A multicenter registry.

OBJECTIVE: The pharmacokinetics of brivaracetam (BRV), added to its effectiveness observed in animal models of status epilepticus (SE), makes this drug attractive for use in emergency situations. Our objective was to evaluate the use of intravenous BRV in a multicenter study. METHODS: A retrospective multicenter registry of SE cases treated with BRV was created. These patients were evaluated between January and December 2018 at seven hospitals in Spain. Demographic variables, SE characteristics, concomitant drugs, loading doses, and response to treatment were collected. RESULTS: Forty-three patients were registered. The mean age was 56 ± 23.1 years, 51.2% were male, 29 had previous epilepsy, 24 (55.8%) had prominent motor symptoms, and 19 had nonconvulsive symptoms. Regarding the etiology, 19 (44.2%) were considered acute symptomatic, 16 (17.2%) remote symptomatic, four (9.3%) progressive symptomatic, and four (9.3%) cryptogenic. Regarding concomitant antiepileptic drugs (AEDs), 17 had previously received levetiracetam (LEV). In 14 patients, BRV was used early (first or second AED). The median loading dose was 100 mg (range = 50-400), and the weight-adjusted dose was 1.8 mg/kg (range = 0.4-7.3). BRV was effective in 54% (n = 23), and a response was observed in <6 hours in 13 patients. We observed a tendency for it to be more effective when administered earlier (P = 0.09), but there were no differences regarding SE type and the concomitant use of LEV. In those with the fastest responses, we observed that both the total administered dose (300 mg vs 100 mg, P = 0.008) and the weight-adjusted dose (3.85 mg vs 1.43 mg, P = 0.006) were significantly higher. The receiver operating characteristic curve showed that the best cutoff point for a faster response was 1.82 mg/kg. SIGNIFICANCE: BRV is useful for the treatment of SE, even when patients are already being treated with LEV. The response rate seems higher when it is administered earlier and at higher doses (>1.82 mg/kg).

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

OBJECTIVE: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). METHODS: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. RESULTS: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. SIGNIFICANCE: In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.

Hippocampus and Insula Are Targets in Epileptic Patients With Glutamic Acid Decarboxylase Antibodies.

Background: Antibodies to glutamic acid decarboxylase (GAD ab) have been found in patients with limbic encephalitis (LE) and chronic pharmacoresistant focal epilepsy (FE). The objectives of the study were to: (1) analyze the clinical and neuroimaging course of patients with FE+GAD ab, (2) compare these characteristics with a control group, and (3) describe the most affected cerebral areas with structural and functional imaging. Methods: Patients with FE + high titers of GAD ab and a follow-up of at least 5 years were selected. Titers of serum GAD ab exceeding 2,000 UI/ml were considered high. Evolutive clinical and radiological characteristics were studied in comparison to two different control groups: patients with bilateral or with unilateral mesial temporal sclerosis (BMTS or UMTS) of a non-autoimmune origin. Results: A group of 13 patients and 17 controls were included (8 BMTS, 9 UMTS). The most frequent focal aware seizures (FAS) reported by patients were psychic (5/13: 33%). Somatosensorial, motor, and visual FAS (4/13:32%) (p: 0.045), musicogenic reflex seizures (MRS), and a previous history of cardiac syncope were reported only patients (2/13:16% each) (p: NS). Comparing EEG characteristics between patients and controls, a more widespread distribution of interictal epileptiform discharges (IED) was observed in FE+ GAD ab patients than in controls (p:0.01). Rhythmic delta activity was observed in all controls in anterior temporal lobes while in patients this was less frequent (p: 0.001). No IED, even in 24 h cVEEG, was seen in 6 patients (46%).First MRI was normal in 4/5 (75%) patients. During the follow-up mesial temporal lobe (MTsL) sclerosis was observed in 5/8 (62%) of patients. All patients had abnormal FDG-PET study. MTL hypometabolism was observed in 10/11 (91%) patients, being bilateral in 7/11 (63%). In controls, this was observed in 16/17 (94%), and it was bilateral in 8/17 (47%) (p: NS). Insular hypometabolism was observed in 5/11 (45%) patients (P:0.002). Conclusions: Clinical, EEG, and FDG-PET findings in FE+GAD ab suggest a widespread disease not restricted to the temporal lobe. Progressive MTL sclerosis may be observed during follow-up. In comparison to what is found in patients with non-autoimmune MTL epilepsy, insular hypometabolism is observed only in patients with GAD ab, so it may be an important diagnostic clue.

Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses.

Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen-presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T cells under different TCR-ligation conditions leads to surface downregulation of CD6 expression. This phenomenon was (i) concomitant to increased levels of soluble CD6 (sCD6) in culture supernatants, (ii) partially reverted by protease inhibitors, (iii) not associated to CD6 mRNA down-regulation, and (iv) reversible by stimulus removal. CD6 down-modulation inversely correlated with the upregulation of CD25 in both FoxP3- (Tact) and FoxP3+ (Treg) T-cell subsets. Furthermore, ex vivo analysis of peripheral CD4+ and CD8+ T cells with activated (CD25+) or effector memory (effector memory T cell, CD45RA-CCR7-) phenotype present lower CD6 levels than their naïve or central memory (central memory T cell, CD45RA-CCR7+) counterparts. CD6lo/- T cells resulting from in vitro T-cell activation show higher apoptosis and lower proliferation levels than CD6hi T cells, supporting the relevance of CD6 in the induction of proper T-cell proliferative responses and resistance to apoptosis. Accordingly, CD6 transfectants also showed higher viability when exposed to TCR-independent apoptosis-inducing conditions in comparison with untransfected cells. Taken together, these results provide insight into the origin of sCD6 and the previously reported circulating CD6-negative T-cell subset in humans, as well as into the functional consequences of CD6 down-modulation on ongoing T-cell responses, which includes sensitization to apoptotic events and attenuation of T-cell proliferative responses.

Unraveling the Role of the Hippocampus in Reversal Learning.

Research in reversal learning has mainly focused on the functional role of dopamine and striatal structures in driving behavior on the basis of classic reinforcement learning mechanisms. However, recent evidence indicates that, beyond classic reinforcement learning adaptations, individuals may also learn the inherent task structure and anticipate the occurrence of reversals. A candidate structure to support such task representation is the hippocampus, which might create a flexible representation of the environment that can be adaptively applied to goal-directed behavior. To investigate the functional role of the hippocampus in the implementation of anticipatory strategies in reversal learning, we first studied, in 20 healthy individuals (11 women), whether the gray matter anatomy and volume of the hippocampus were related to anticipatory strategies in a reversal learning task. Second, we tested 20 refractory temporal lobe epileptic patients (11 women) with unilateral hippocampal sclerosis, who served as a hippocampal lesion model. Our results indicate that healthy participants were able to learn the task structure and use it to guide their behavior and optimize their performance. Participants' ability to adopt anticipatory strategies correlated with the gray matter volume of the hippocampus. In contrast, hippocampal patients were unable to grasp the higher-order structure of the task with the same success than controls. Present results indicate that the hippocampus is necessary to respond in an appropriately flexible manner to high-order environments, and disruptions in this structure can render behavior habitual and inflexible.SIGNIFICANCE STATEMENT Understanding the neural substrates involved in reversal learning has provoked a great deal of interest in the last years. Studies with nonhuman primates have shown that, through repetition, individuals are able to anticipate the occurrence of reversals and, thus, adjust their behavior accordingly. The present investigation is devoted to know the role of the hippocampus in such strategies. Importantly, our findings evidence that the hippocampus is necessary to anticipate the occurrence of reversals, and disruptions in this structure can render behavior habitual and inflexible.

Auditory Target and Novelty Processing in Patients with Unilateral Hippocampal Sclerosis: A Current-Source Density Study.

The capacity to respond to novel events is crucial for adapting to the constantly changing environment. Here, we recorded 29-channel Event Related Brain Potentials (ERPs) during an active auditory novelty oddball paradigm and used for the first time Current Source Density-transformed Event Related Brain Potentials and associated time-frequency spectra to study target and novelty processing in a group of epileptic patients with unilateral damage of the hippocampus (N = 18) and in healthy matched control participants (N = 18). Importantly, we used Voxel-Based Morphometry to ensure that our group of patients had a focal unilateral damage restricted to the hippocampus and especially its medial part. We found a clear deficit for target processing at the behavioral level. In addition, compared to controls, our group of patients presented (i) a reduction of theta event-related synchronization (ERS) for targets and (ii) a reduction and delayed P3a source accompanied by reduced theta and low-beta ERS and alpha event-related synchronization (ERD) for novel stimuli. These results suggest that the integrity of the hippocampus might be crucial for the functioning of the complex cortico-subcortical network involved in the detection of novel and target stimuli.

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test.

BACKGROUND: Rodent approach-avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach-avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. METHODS: In a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. RESULTS: Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. CONCLUSIONS: Our results establish the translational validity of human approach-avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior.

Could Adult European Pharmacoresistant Epilepsy Patients Be Treated With Higher Doses of Zonisamide?

OBJECTIVE: To examine the clinical effect (efficacy and tolerability) of high doses of zonisamide (ZNS) (>500 mg/d) in adult patients with pharmacoresistant epilepsy. METHODS: Between 2006 and 2013, all epileptic outpatients treated with high doses of ZNS were selected. Safety and efficacy were assessed based on patient and caregiver reports. Serum levels of ZNS and other concomitant antiepileptic drugs were evaluated if available. RESULTS: Nine patients (5 female): 8 focal/1 generalized pharmacoresistant epilepsy. Mean age: 34 years. Most frequent seizure type: complex partial seizures; other seizure types: generalized tonic-clonic, tonic, myoclonia. Zonisamide in polytherapy in all (100%), administered in tritherapy in 3 (33%) of 9 patients; mean dose: 633 (600-700) mg/d; efficacy (>50% seizure reduction) was observed in 5 (55%) of 9 patients. Five of 9 patients are still taking high doses of ZNS (more than 1 year). Adverse events were observed in 3 (37%) of 8 patients. Good tolerance to high doses of other antiepileptic drugs had been observed in 6 (66%) of 9 patients. Plasma levels of ZNS were only available in 2 patients; both were in the therapeutic range (34.95, 30.91) (10-40 mg/L). CONCLUSIONS: High doses of ZNS are effective and safe in pharmacoresistant epileptic patients. Therapeutic drug monitoring of ZNS may be considered at therapeutic failure.

Refractory status epilepticus due to SMART syndrome.

INTRODUCTION: Stroke-like migraine attacks after radiation therapy (SMART) is a late-onset complication of brain irradiation of unknown physiopathology. Our aim was to present three patients with SMART syndrome who had clinical and neuroimage studies suggestive of status epilepticus. PATIENTS: Patient 1. A 69-year-old woman, who was treated with radiation therapy 14 years before her first admission to the Neurology Department, presented with several episodes of headache, speech disturbances, and weakness of left limbs with altered awareness. Patient 2. A 49-year-old man, who was treated with whole brain radiation 20 years before the onset of symptoms, developed some episodes consisting of headache and numbness of the right side of face and right arm; the latest episodes were accompanied by visual disturbances followed by generalized tonic-clonic seizures. Patient 3. A 40-year-old man, who received cranial irradiation 20 years before, suffered three episodes of behavioral disturbance, aphasia, headache, and visual aura followed by left homonymous hemianopia. RESULTS: All three patients suffered seizures mostly with visual aura. Electroencephalography showed interictal epileptiform discharges or focal slowing. Brain magnetic resonance image (MRI), positron emission tomography (PET), or ictal-single-photon emission computed tomography (SPECT) showed focal cortical hyperperfusion. Focal diffusion restriction and focal gadolinium-enhancement were observed on MRI. All patients were treated with antiepileptic drugs, being effective in one of them. One patient needed anesthesic coma, and the other patient responded to therapy with corticosteroids. CONCLUSIONS: Taking into account clinical evolution and ictal neuroimaging studies, status epilepticus could explain the origin of these episodes in SMART syndrome. Although most patients have reversible symptoms, in some cases, aggressive treatment to avoid sequelae is needed. This article is part of a Special Issue entitled "Status Epilepticus".

Interhemispheric microstructural connectivity in bitemporal lobe epilepsy with hippocampal sclerosis.

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. The most frequent pathologic finding in this condition is hippocampal sclerosis (HS). In addition, in a small proportion (14-23%) of refractory TLE patients, the presence of HS is bilateral. TLE involves grey matter (GM) and white matter (WM) abnormalities in a wide cortico-subcortical network. However, the impact of neuronal loss on specific WM fiber pathways and associated functional systems as well as seizure propagation pathways remains unclear. There is still much controversy regarding the role of the commissures (corpus callosum, hippocampal commissure and anterior commissure) in interhemispheric seizure propagation. This study aimed to investigate the integrity of WM interhemispheric connectivity in a singular sample of patients with TLE and bilateral HS using structural magnetic resonance imaging (MRI). We performed multimodal structural MRI [high resolution T1-weighted and diffusion tensor imaging (DTI)] analyses of seven patients with medically refractory TLE with bilateral HS, fourteen unilateral left TLE patients and fifteen matched healthy individuals. Whole-brain voxel-wise analysis techniques were used. These patients evidenced WM derangement [reduced fractional anisotropy (FA), increased mean diffusivity (MD) or reduced WM volume] in temporal and extratemporal tracks, but also in commissural pathways, compared to the unilateral left TLE patients and the control group. Presence of reduced FA or increased MD in the fornix, cingulum and uncinate fasciculus in addition to reduced WM volume in the fornix was also encountered. Neuropsychological assessment was performed without significant correlations with structural data. The current results support the idea that commissural pathways play a contributory role in interhemispheric TLE seizure propagation in bilateral HS and offer new perspectives about the long-term effects on interhemispheric connectivity associated with seizure propagation patterns in TLE patients.