MicroRNAs miR-629-3p, miR-1202 and miR-1225-5p as potential diagnostic and surgery outcome biomarkers for mesial temporal lobe epilepsy with hippocampal sclerosis.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) is a symptomatic epilepsy syndrome clinically characterized by high prevalence, pharmacoresistance, good surgical prognosis and hippocampal sclerosis (HS); however, no singular criteria can be considered sufficient for the MTLE-HS diagnosis. MicroRNAs (miRNAs) are small non-coding molecules that act as important gene-expression regulators at post-transcriptional level. Evidences on the involvement of miRNAs in epilepsy pathogenesis as well as their potential to be employed as biomarkers claim for investigations on miRNAs' applicability as epilepsy diagnosis and prognosis biomarkers. Consequently, the present study aimed to evaluate the applicability of three specific miRNAs as biomarkers of diagnosis and surgical outcomes in adult patients with MTLE-HS. METHOD: Hippocampus, amygdala and blood samples from 20 patients with MTLE-HS were analyzed, 10 with favorable surgical prognosis (Engel I) and 10 with unfavorable surgical prognosis (Engel III-IV). For the control groups, hippocampus and amygdala from necropsy and blood samples from healthy individuals were adopted. The miRNAs expression analysis was performed using Real-Time Quantitative Polymerase Chain Reaction for miRNAs highlighted from microarray as being involved in GABAergic neurotransmission. RESULTS: The miRNAs miR-629-3p, miR-1202 and miR-1225-5p were found to be hyper-expressed in MTLE-HS patients' blood. CONCLUSIONS: Our data suggest the existence of three circulating miRNAs (miR-629-3p, miR-1202 and miR-1225-5p) that could possibly act as additional tools in the set of factors that contribute to MTLE-HS diagnose.

Extratemporal damage in temporal lobe epilepsy: magnetization transfer adds information to volumetric MR imaging.

BACKGROUND AND PURPOSE: MTS is characterized by gliosis and atrophy of the hippocampus and related limbic structures. However, the damage is not limited to those structures with atrophy and has been reported in extratemporal regions. Because volumetric studies are nonspecific, the pathophysiology of the brain damage remains to be solved. MTI is an MR imaging technique more sensitive to subtle neuropathologic changes than conventional MR imaging. Here we combined MTI with VBM analysis to evaluate extratemporal damage in patients with TLE. MATERIALS AND METHODS: We studied 23 healthy controls and 21 patients with TLE with mean ages, respectively, of 37.6 ± 10.9 and 38.6 ± 9.02 years. All subjects had a full clinical follow-up and MR imaging. We processed the images with VBM for volumetric analysis of WM and GM, as well as with voxel-based analysis of MTR for macromolecular integrity analysis. RESULTS: In addition to MTR decrease in the temporal lobes, we found a significant decrease in GM and WM volumes. In the WM, the MTR decrease was correlated to volume loss detected by VBM, indicating that brain atrophy may explain part of the MTR decrease. We also found areas in which the MTR decrease was not associated with volume loss, suggesting an additional pathophysiologic process other than neuronal loss and atrophy underlying the MTR changes. CONCLUSIONS: Our results support the hypothesis that there are widespread lesions in the brain, including the corpus callosum and the frontal lobe, affecting both GM and WM.

Improved outcomes in pediatric epilepsy surgery: the UCLA experience, 1986-2008.

OBJECTIVE: Epilepsy neurosurgery is a treatment option for children with refractory epilepsy. Our aim was to determine if outcomes improved over time. METHODS: Pediatric epilepsy surgery patients operated in the first 11 years (1986-1997; pre-1997) were compared with the second 11 years (1998-2008; post-1997) for differences in presurgical and postsurgical variables. RESULTS: Despite similarities in seizure frequency, age at seizure onset, and age at surgery, the post-1997 series had more lobar/focal and fewer multilobar resections, and more patients with tuberous sclerosis complex and fewer cases of nonspecific gliosis compared with the pre-1997 group. Fewer cases had intracranial EEG studies in the post-1997 (0.8%) compared with the pre-1997 group (9%). Compared with the pre-1997 group, the post-1997 series had more seizure-free patients at 0.5 (83%, +16%), 1 (81%, +18%), 2 (77%, +19%), and 5 (74%, +29%) years, and more seizure-free patients were on medications at 0.5 (97%, +6%), 1 (88%, +9%), and 2 (76%, +29%), but not 5 (64%, +8%) years after surgery. There were fewer complications and reoperations in the post-1997 series compared with the pre-1997 group. Logistic regression identified post-1997 series and less aggressive medication withdrawal as the main predictors of becoming seizure-free 2 years after surgery. CONCLUSIONS: Improved technology and surgical procedures along with changes in clinical practice were likely factors linked with enhanced and sustained seizure-free outcomes in the post-1997 series. These findings support the general concept that clearer identification of lesions and complete resection are linked with better outcomes in pediatric epilepsy surgery patients.

Relative frequency, clinical, neuroimaging, and postsurgical features of pediatric temporal lobe epilepsy

We describe the relative frequency, clinical features, neuroimaging and pathological results, and outcome after pharmacological or surgical intervention for a series of pediatric patients with temporal lobe epilepsy (TLE) from an epilepsy center in Brazil. The medical records of children younger than 12 years with features strongly suggestive of TLE were reviewed from January 1999 to June 1999. Selected children were evaluated regarding clinical, EEG, and magnetic resonance imaging (MRI) investigation and divided into three groups according to MRI: group 1 (G1, N = 9), patients with hippocampal atrophy; group 2 (G2, N = 10), patients with normal MRI, and group 3 (G3, N = 12), patients with other specific temporal lesions. A review of 1732 records of children with epilepsy revealed 31 cases with TLE (relative frequency of 1.79 percent). However, when the investigation was narrowed to cases with intractable seizures that needed video-EEG monitoring (N = 68) or epilepsy surgery (N = 32), the relative frequency of TLE increased to 19.11 (13/68) and 31.25 percent (10/32), respectively. At the beginning of the study, 25 of 31 patients had a high seizure frequency (80.6 percent), which declined to 11 of 31 (35.5 percent) at the conclusion of the study, as a consequence of pharmacological and/or surgical therapy. This improvement in seizure control was significant in G1 (P < 0.05) and G3 (P < 0.01) mainly due to good postsurgical outcome, and was not significant in G2 (P > 0.1, McNemar's test). These results indicate that the relative frequency of TLE in children was low, but increased considerably among cases with pharmacoresistant seizures. Patients with specific lesions were likely to undergo surgery, with good postoperative outcomes.

Relative frequency, clinical, neuroimaging, and postsurgical features of pediatric temporal lobe epilepsy.

We describe the relative frequency, clinical features, neuroimaging and pathological results, and outcome after pharmacological or surgical intervention for a series of pediatric patients with temporal lobe epilepsy (TLE) from an epilepsy center in Brazil. The medical records of children younger than 12 years with features strongly suggestive of TLE were reviewed from January 1999 to June 1999. Selected children were evaluated regarding clinical, EEG, and magnetic resonance imaging (MRI) investigation and divided into three groups according to MRI: group 1 (G1, N = 9), patients with hippocampal atrophy; group 2 (G2, N = 10), patients with normal MRI, and group 3 (G3, N = 12), patients with other specific temporal lesions. A review of 1732 records of children with epilepsy revealed 31 cases with TLE (relative frequency of 1.79%). However, when the investigation was narrowed to cases with intractable seizures that needed video-EEG monitoring (N = 68) or epilepsy surgery (N = 32), the relative frequency of TLE increased to 19.11 (13/68) and 31.25% (10/32), respectively. At the beginning of the study, 25 of 31 patients had a high seizure frequency (80.6%), which declined to 11 of 31 (35.5%) at the conclusion of the study, as a consequence of pharmacological and/or surgical therapy. This improvement in seizure control was significant in G1 (P < 0.05) and G3 (P < 0.01) mainly due to good postsurgical outcome, and was not significant in G2 (P > 0.1, McNemar's test). These results indicate that the relative frequency of TLE in children was low, but increased considerably among cases with pharmacoresistant seizures. Patients with specific lesions were likely to undergo surgery, with good postoperative outcomes.

[Evaluation of the drug interaction between carbamazepine and lamotrigine in the treatment of refractory epilepsy patients]. / Evaluación de la interacción medicamentosa de la carbamacepina y la lamotrigina en el tratamiento de los pacientes epilépticos refractarios.

INTRODUCTION: Carbamazepine (CBZ) is a pharmacological agent used to control epileptic syndromes. In refractory epilepsy patients, however, a second anticonvulsive drug such as lamotrigine (LTG) is often added. This association can reduce the frequency of the epileptic seizures and favour control over them. AIMS: This study was conducted to evaluate the plasma concentration of CBZ throughout a period of mono and polytherapy. Furthermore, tests were also carried out to determine whether any alterations were caused in the haematological parameters or in plasma concentrations by adding LTG to the therapy with CBZ. PATIENTS AND METHODS: This study involved a sample of refractory epilepsy patients who were following monotherapy with CBZ and who had a wholly unsatisfactory control over their bouts of seizures. LTG was thus added to these patients' treatment in an attempt to improve their control over the seizures. RESULTS AND CONCLUSIONS: On ending the study, we found that LTG did not interfere with the plasma concentrations of CBZ or give rise to any kind of alteration in the haematological parameters of any of the patients. Nevertheless, one patient did break out in a rash, which shows that therapeutic monitoring may be a key tool, especially when the treatment that is prescribed includes two drugs with a narrow therapeutic range.

Calcified cysticercotic lesions and intractable epilepsy: a cross sectional study of 512 patients.

BACKGROUND: Neurocysticercosis is a major cause of epilepsy in developing countries and is endemic in Brazil. To test the hypothesis that the aetiological profile of patients with intractable epilepsy in Brazil includes neurocysticercosis, we conducted a cross sectional study investigating the aetiology of intractable epilepsy. METHODS: A total of 512 patients evaluated at the outpatient clinic for intractable epilepsy at the Ribeirão Preto School of Medicine were included in the survey. Medical intractability was determined on the basis of seizure incidence and severity, and response to appropriate epilepsy management. Neuroimaging included brain CT with non-contrasted and contrasted phases and high resolution MRI. Patients were divided into neurocysticercosis and non-neurocysticercosis groups according to previous diagnostic criteria. RESULTS: The most common epileptogenic lesions were mesial temporal sclerosis (MTS; 56.0%), malformations of cortical development (12.1%), and brain tumours (9.9%). Neuroimaging was normal in 8.7% of patients. Calcifications were found in 27% of patients and were significantly more common in patients with MTS than in those without MTS (p<0.001). Isolated neurocysticercosis was found in only eight patients (1.56%). CONCLUSIONS: These data suggest that neurocysticercosis is an uncommon cause of intractable epilepsy, even in an endemic region such as Brazil, and that it may only represent a coexistent pathology. However, an analysis of our findings reveals that neurocysticercosis was more common in patients with MTS. This finding could suggest either that there is a cause-effect relationship between MTS and neurocysticercosis, or that MTS and neurocysticercosis co-vary with a missing variable, such as socio-economic status.

Neuroethology application for the study of human temporal lobe epilepsy: from basic to applied sciences.

The aim of this investigation was to apply neuroethology to the study of human temporal lobe epilepsy (TLE). For this purpose, 42 seizures in 7 patients recorded during video/EEG monitoring (1997-1998) were analyzed by means of a behavioral glossary containing all behaviors. Video recordings were reobserved, and all patients' behaviors were annotated second-by-second. Data were analyzed using Ethomatic software and displayed as flowcharts including frequency, mean duration, and sequential statistic interaction of behavioral items (chi2 > or = 10.827, P<0.001). Flowcharts of (1) a group of seizures from a single patient, (2) the sum of four seizures per patient of two patients with right and five patients with left TLE, and (3) the comparison of left versus right TLE are shown. Well-established data in the literature were confirmed, such as aura (especially epigastric), contralateral lateralization value of dystonia and version, consciousness and language alterations in ictal and postictal periods, mostly with respect to dominant hemisphere involvement, among others. Less well established data such as awakening seizures in TLE patients, lateralization value of facial wiping (ipsilateral to the focus), statistically significant associations between behavioral pairs (dyads), and new behavioral sequences in TLE were also observed. We suggest that neuroethology also has great potential in the study of human epilepsy semiology. This work had an important role in method standardization for human epilepsy, setting the basis for the development of future clinical studies including correlation with other diagnostic methods (EEG, magnetic resonance, and SPECT). The next step will be the comparative study of seizures of patients with left and right TLE, with a greater number of patients, and the development of a digital video library.

Suppression of obsessive-compulsive symptoms after epilepsy surgery.

We report two male patients with medically intractable epilepsy and obsessive-compulsive disorder (OCD) symptoms. Both patients experienced remission of obsessive-compulsive symptoms after surgical treatment of epilepsy. Although the surgeries targeted different brain regions, the two patients had in common unilateral anterior cingulate cortex ablation. On the basis of these observations, we discuss the pathophysiology of OCD symptoms, emphasizing the role of corticosubcortical pathways in their genesis. Our data suggest that surgeries that affect neural loops associated with obsessive-compulsive symptoms can lead to an improvement of OCD; however, the structures responsible for this effect cannot be conclusively determined.

Cortical malformations are associated with a rare polymorphism of cellular prion protein.

Studies in animals lacking the cellular prion protein (PrP(c)) gene (Prnp) showed higher neuronal excitability in vitro and increased sensitivity to seizures in vivo. The authors previously reported a rare polymorphism at codon 171 (Asn-->Ser) of human Prnp to be associated with mesial temporal lobe epilepsy related to hippocampal sclerosis. They demonstrated that the same variant allele is also associated with symptomatic epilepsies related to different forms of malformations of cortical development.

Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant.

BACKGROUND: Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is the most common surgically remediable epileptic syndrome. Ablation of the cellular prion protein (PrP(c)) gene (PRNP) enhances neuronal excitability of the hippocampus in vitro and sensitivity to seizure in vivo, indicating that PrP(c) might be related to epilepsy. OBJECTIVE: To evaluate the genetic contribution of PRNP to MTLE-HS. METHODS: The PRNP coding sequence of DNA from peripheral blood cells of 100 consecutive patients with surgically treated MTLE-HS was compared to that from a group of healthy controls adjusted for sex, age, and ethnicity (n = 180). The presence of PRNP variant alleles was correlated with clinical and presurgical parameters as well as surgical outcome. RESULTS: A variant allele at position 171 (Asn-->Ser), absent in controls, was found in heterozygosis (Asn171Ser) in 23% of patients (p < 0.0001). The PRNP genotypes were not correlated with any clinical or presurgical data investigated. However, patients carrying the Asn171Ser variant had a five times higher chance of continuing to have seizures after temporal lobectomy (95% CI 1.65 to 17.33, p = 0.005) than those carrying the normal allele. At 18 months after surgery, 91.8% of patients with the normal allele at codon 171 were seizure free, in comparison to 68.2% of those carrying Asn171Ser (p = 0.005). CONCLUSIONS: The PRNP variant allele Asn171Ser is highly prevalent in patients with medically untreatable MTLE-HS and influences their surgical outcome. The results suggest that the PRNP variant allele at codon 171 (Asn171Ser) is associated with epileptogenesis in MTLE-HS.

Accuracy of ictal SPECT in mesial temporal lobe epilepsy with bilateral interictal spikes.

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the rate of correct seizure lateralization of ictal semiology and ictal EEG is better for patients with unilateral interictal spikes (UIS) than for patients with bilateral interictal spikes (BIS), possibly due to rapid seizure propagation patterns associated with bilateral epileptogenesis. In this study, the authors investigated if ictal SPECT is a reliable diagnostic test for both UIS and BIS patients. METHODS: Video-EEG recording was used as the gold standard to examine the accuracy of ictal SPECT and its relationship with interictal and ictal EEG. Ninety-three consecutive patients with MTLE associated with hippocampal sclerosis were included in the analysis. Ictal SPECT was considered accurate if two blinded observers independently lateralized the scan correctly. RESULTS: Ictal SPECT correctly lateralized 75 (80.6%) of 93 scans. The rate of correct seizure lateralization was 87.6% for the UIS group and only 55.0% for the BIS group (p = 0.0027). In the EEG epochs, 66.7% of BIS patients vs 43.4% of UIS patients had nonlateralized ictal EEG (p < 0.001). CONCLUSION: The authors conclude that the accuracy of ictal SPECT is worse for MTLE patients with BIS than for those with UIS. The role of ictal SPECT in presurgical evaluation of patients with BIS must be reviewed.

Typical and atypical perfusion patterns in periictal SPECT of patients with unilateral temporal lobe epilepsy.

PURPOSE: To characterize perfusion patterns of periictal single-photon emission tomography (SPECT) in patients with unilateral temporal lobe epilepsy (TLE) and to determine their relationship to the epileptogenic zone (EZ). METHODS: We studied periictal SPECT scans of 53 patients after anterior mesial temporal lobectomy who had good seizure outcome after surgery. Ictal SPECT scans were performed during video-EEG monitoring. Typical SPECT patterns consisted of ipsilateral ictal hyperperfusion or ipsilateral postictal hypoperfusion. Atypical ictal patterns included normal scans, bilateral temporal hyperperfusion, or contralateral patterns. These perfusion patterns were retrospectively analyzed searching for concordance rate with the EZ. RESULTS: We obtained 51 ictal and two early postictal scans. In the typical group, 40 (75.4%) patients had ipsilateral ictal temporal lobe hyperperfusion, and one (1.9%) patient had ipsilateral postictal temporal lobe hypoperfusion. Twelve (22.7%) patients exhibited atypical perfusion patterns: seven (13.2%) patients had bitemporal ictal hyperperfusion (four cases showed asymmetric temporal lobe changes), four (7.6%) patients had contralateral hyperperfusion, and one (1.9%) patient had a normal SPECT scan. All four patients with bitemporal asymmetric hyperperfusions showed greater perfusion lateralized to the side of the EZ. Three of the four patients who had contralateral hyperperfusion also had a complex postictal-like pattern in the ipsilateral temporal lobe consisting of anteromesial hyperperfusion with adjacent lateral hypoperfusion. CONCLUSIONS: This study analyzed typical and atypical perfusion patterns in unilateral TLE, and suggested that not only typical, but also some atypical perfusion patterns may contribute to the lateralization of EZ.