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Objective: Corpus callosum (CC) abnormalities are frequently reported in patients with refractory mesial temporal lobe epilepsy (rMTLE). However, whether CC structural alterations are related to the epileptic syndrome itself or to refractoriness is still unknown. Thus, we aimed to compare patterns of CC change in patients with rMTLE and benign MTLE (bMTLE), the latter of which represents a useful resource to better disentangle factors that contribute to refractoriness., Methods: The study group included 79 patients with bMTLE (mean age 43.2 ± 14. 8 years), 61 with rMTLE (mean age 45.2 ± 12.4 years) and 134 healthy volunteers. Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed to measure thickness, mean diffusivity (MD), and fractional anisotropy (FA) over 50 regions of interest along the cross-sectional CC profile. Statistical analysis comprised analysis of variance (ANOVA) followed by post hoc Tukey's Honest Significant Difference test., Results: We found that all imaging metrics of the CC splenium were altered in rMTLE patients compared to bMTLE and controls. We also found significantly reduced thickness and FA of the anterior CC in rMTLE compared to controls and that FA was reduced only in rMTLE compared to bMTLE. Patients with bMTLE did not differ from controls. Differences between disease subgroups were found in the midbody composed of sensorimotor fibers., Significance: We found altered multimodal imaging metrics of the CC in rMTLE but not in bMTLE. These findings were independent of the radiologic presence of hippocampal sclerosis, suggesting that differences in the distribution of such alterations might be related to refractoriness., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objective: Temporal and extratemporal white matter abnormalities have been identified frequently in patients with refractory mesial temporal lobe epilepsy (rMTLE). However, the identification of potential water diffusion abnormalities in patients with drug-responsive, benign MTLE (bMTLE) is still missing. The aim of this study was to identify markers of refractoriness in MTLE., Methods: The study group included 48 patients with bMTLE (mean age 42.8 + 13.5 years), 38 with rMTLE (mean age 41.7 + 14.1 years) and 54 healthy volunteers. Diffusion tensor imaging (DTI) was performed to measure mean diffusivity (MD) and fractional anisotropy (FA) in a regions-of-interest analysis comprising hippocampi and temporal lobe gray and white matter regions. The presence of hippocampal sclerosis (Hs) was assessed using automated magnetic resonance imaging (MRI) evaluation. For statistics we used chi-square test; two-tailed, two-sample t-test; and stratified linear regression., Results: The significant demographic differences between the two patient groups were sex (p = 0.003), duration of epilepsy (p = 0.003) and complex febrile convulsions (p = 0.0001). In rMTLE, temporal white matter MD was higher and FA lower, as compared to bMTLE. The analysis of diagnostic accuracy (area under the receiver operator characteristic [ROC] curve [AUC]) showed that FA had an AUC for discriminating patients affected from those unaffected by refractory MTLE of 74.0% (p < 0.001), a value that was higher than that of temporal MD (64.0%), hippocampus volume (65.0%), and Hs (66.0%)., Significance: We performed DTI measurements in MTLE and found a significant reduction of FA along the white matter of the temporal lobes in rMTLE, suggesting it as a valuable measure of refractoriness in MTLE., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Genetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty-seven unrelated patients (35 women; mean age ± standard deviation [SD], 24.1 ± 7.7; mean age ± SD at onset, 15.3 ± 2.4) with JME were enrolled. Twenty-three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease-causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Purpose: To report the identification of the T1174S SCN1A (NaV 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism., Methods: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA-201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K)., Key Findings: The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I(NaP)), consistent with gain of function. The I(NaP) increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions., Significance: Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype-phenotype relationship of SCN1A mutations., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Heterozygous mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6-44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD--mental retardation, episodic ataxia, and absences--who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Psychogenic nonepileptic seizures (PNES) are among the most common clinical manifestations of conversion disorder and consist of paroxysmal behavior that resembles epileptic seizures. Preliminary data from functional neuroimaging studies gave plausible evidence that limbic circuits and sensorimotor cortex might be engaged in conversion disorder. Nonetheless, no advanced magnetic resonance imaging (MRI) studies have focused on patients with PNES., Methods: We enrolled 20 consecutive patients in whom the diagnosis of PNES was based on ictal video-electroencephalography (EEG) of the habitual episodes and 40 healthy subjects matched for age and sex All patients underwent a formal neuropsychological investigation and a neuropsychiatric assessment. All of the patients also underwent two distinct morphologic whole-brain MR measurements, voxel-based morphometry (VBM), and cortical thickness analysis, in a multimethod approach., Key Findings: None of the patients had serious medical or neurologic illness, substance abuse, or psychotic disorder, or were taking antipsychotic drugs. VBM and cortical thickness analyses in the patients with PNES revealed abnormal cortical atrophy of the motor and premotor regions in the right hemisphere and the cerebellum bilaterally. We also observed a significant association between increasing depression scores and atrophy involving the premotor regions., Significance: The results of this study illustrate that motor and premotor regions in the right hemisphere and the cerebellum bilaterally play an important role in the pathogenesis of PNES and that these structures are correlated with depressive symptoms. Our findings suggest a multistep model in the pathogenesis of PNES, in which the phenomenology is driven by psychological factors interacting with specific biologic abnormalities., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: In refractory mesial temporal lobe epilepsy (MTLE) extrahippocampal and neocortical abnormalities have been described in patients with or without mesial temporal sclerosis (MTS). Recently we observed gray matter reductions in regions outside the hippocampus in benign MTLE with or without MTS. Cortical thickness has been proposed as a viable methodologic alternative for assessment of neuropathologic changes in extratemporal regions. Herein, we aimed to use this technique to describe cortical abnormalities in patients with benign TLE., Methods: Whole-brain cortical thickness analysis (FreeSurfer) was performed in 32 unrelated patients with benign TLE [16 patients with signs of MTS on magnetic resonance imaging (MRI), pMTLE; 16 without, nMTLE] and 44 healthy controls., Key Findings: In the pMTLE group, the most significant thinning was found in the sensorimotor cortex bilaterally but was more extensive in the left hemisphere (false discovery rate, p < 0.05). Other areas were localized in the occipital cortex, left supramarginal gyrus, left superior parietal gyrus, left paracentral sulcus, left inferior/middle/superior frontal gyrus, left inferior frontal sulcus, right cingulate cortex, right superior frontal gyrus, right inferior parietal gyrus, right fusiform gyrus, and cuneus/precuneus. In the nMTLE, a similar neurodegenerative pattern was detected, although not surviving correction for multiple comparisons. Direct comparison between pMTLE and nMTLE did not reveal significant changes., Significance: Patients with either benign pMTLE or nMTLE showed comparable cortical thinning, mainly confined to the sensorimotor cortex. This finding that is not appreciated on routine MRI supports the hypothesis that similar to refractory MTLE, even in benign MTLE, pathology in neocortical regions maybe implicated in the pathophysiology of this syndrome., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: In refractory temporal lobe epilepsy (rTLE), gray matter (GM) abnormalities are not confined to the hippocampus but also are found in extrahippocampal structures. Very recently we observed in mild TLE (mTLE) with or without mesiotemporal sclerosis (MTS), GM reductions in regions outside the presumed epileptogenic focus. To date, there are no studies that directly investigate whether whole-brain GM volume differs between rTLE and mTLE. Herein, we used optimized voxel-based morphometry (VBM) to identify GM abnormalities beyond the hippocampus in both rTLE and mTLE with evidence of MTS., Methods: Brain magnetic resonance imaging (MRI) and optimized VBM were performed in 19 unrelated patients with mTLE, 19 patients with rTLE, and 37 healthy controls. MRI diagnosis of MTS was based on the atrophy of the hippocampal formation and/or mesiotemporal hyperintensity on fluid-attenuated inversion recovery (FLAIR) or T(2) images, or both., Results: No patients (rTLE and mTLE) had generalized tonic-clonic or complex partial seizures for at least 3 weeks before scanning. Both mTLE and rTLE patients showed GM volume reduction of the bilateral thalamus, left hippocampus, and sensorimotor cortex compared with controls. No significant GM difference was found between rTLE and mTLE groups., Discussion: In both rTLE and mTLE, VBM shows GM reductions not confined to the hippocampus involving mainly the thalamus bilaterally. This finding together with the lack of significant GM differences between the two TLE groups supports the hypothesis that mTLE and rTLE might lie along a biologic continuum, suggesting a pathophysiologic role of the thalamus in partial epilepsy.