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Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects.

Introduction: Vertigo, dizziness, and nausea encompass a spectrum of balance-related symptoms caused by a variety of etiologies. Balance is affected by many systems: Proprioceptive pathways and visual, cerebellar, vestibulocochlear, and vascular / vasovagal systems. Vertigo is a subtype of dizziness, in which a subject, as a result to a dysfunction of the vestibular system, improperly experiments the perception of motion. The most useful clinical subdivision is to categorize vertigo into true vertigo and pseudovertigo, whereas from a pathophysiological point of view, vertigo can be classified into central, peripheral, and psychogenic. It is not easy to identify the cause of vertigo since the patients often are not able to precisely describe their symptoms. An impressive list of drugs may cause vertigo or dizziness., Materials and Methods: The aim of the present study was to analyze the data extracted from the reporting cards of the ADRs (adverse drug reactions), received at our Pharmacovigilance Regional Center (Calabria, Italy) in 2012. In particular, the data concerning the occurrence of vertigo and dizziness, after taking certain classes of drugs, have been considered., Results: Our results show that, among the side-effects of different classes of drugs such as anti-convulsants, anti-hypertensives, antibiotics, anti-depressants, anti-psychotics, and anti-inflammatory, also vertigo or dizziness are included., Conclusions: Spontaneous reports of vertigo or dizziness, as side-effect of certain drugs, received at our Pharmacovigilance Center, represented the 5% of all reports in 2012. Considering the high incidence of such an ADR for several drugs' classes, it can be speculated that under-reporting also affect vertigo and dizziness. Despite the fact that these ADRs might not represent a direct threaten for life, indirectly they can cause secondary damage to patients such as falls, fractures etc. Balance should be accurately monitored during drug use and particularly in fragile patients.

β-Interferon therapy is known to be a potential trigger of suicidal behavior, but this effect has not been previously reported for other multiple sclerosis (MS) treatments, such as, natalizumab. Here we report the case history of a 32-year-old woman affected by relapsing-remitting MS, who attempted suicide during natalizumab treatment. This case suggests that a suicidal ideation might be a rare side effect of natalizumab. Nevertheless, this case represents the first evidence of the new adverse drug reaction related to natalizumab treatment. We should alert clinicians to be aware of the possibility of paradoxical activation of suicidality during its therapeutic use. The main purpose of the present article is to use this case to review the possible relationship between suicidal behavior and drugs.

Purpose: There is evidence that inflammatory mechanisms play a role in the pathogenesis of temporal lobe epilepsy (TLE). Coding variants in Toll-like receptor 4 (TLR4) gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether a functional polymorphism rs4986790 in the TLR4 gene is associated with susceptibility and clinical features of TLE., Methods: A total of 345 patients with TLE and 370 age-matched controls were genotyped using TaqMan Allelic Discrimination assays, on an Applied Biosystems PCR platform., Results: There was no significant difference in allele frequency or genotype of TLR4 between TLE patients and controls. Moreover, the clinical characteristics of these patients were unrelated to the presence of this polymorphism., Conclusion: Our data suggest that rs4986790 in the TLR4 gene is unlikely to influence significantly the risk of developing TLE or its severity., (Copyright © 2013. Published by Elsevier Ltd.)

Purpose: Cryptogenic focal epilepsy (CFE) is a heterogeneous clinical disorder including patients with severe refractory forms and patients with a fairly good prognosis. Predictors of prognosis in CFE are poorly understood. The aim of this retrospective study is to identify long-term (5-year) prognostic predictors in patients with newly diagnosed CFE., Methods: Subjects with cryptogenic focal epilepsy (CFE) seen from April 1987 to September 2011 in two twin Epilepsy Centres located in Reggio Calabria and Catanzaro, Calabria, Southern Italy, were screened. Patients were excluded if they had psychogenic seizures, major psychiatric disorders presence of brain lesions except for non-specific white matter T2-hyperintensities, short follow-up (less than five years) or for having received the diagnosis of CFE elsewhere. One hundred and eighty-six patients, firstly diagnosed in our Centres, constituted the study sample. Survival curves were generated according to the Kaplan-Meier method and compared with the log-rank test. The endpoint was the cumulative time-dependent chance of 5-year remission after treatment start. Independent predictors of remission were tested by multivariate analysis using Cox proportional hazards function models. The accuracy of the resulting model was tested with Receiver Operating Characteristics (ROC) curve analysis., Key Findings: The cumulative incidence of remission was 23%. At Kaplan-Meier analysis, the only factor predicting remission was family history of epilepsy or febrile seizures (FS; p=0.02). At Cox regression, family history and frontal lobe epilepsy showed to be independent predictors of outcome (p=0.02 and 0.03, respectively). The accuracy of these predictors was good (area under ROC curve 0.648, 95% CI 0.575-0.716). Interestingly, we also found a considerable (7 years) diagnostic delay that did not result in a worse prognosis., Significance: About one quarter of subjects with newly diagnosed CFE attains 5-year seizure remission during follow-up. Family history of epilepsy or FS and frontal localization are independent prognostic predictors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A recent study has implicated a tagging single nucleotide polymorphism (SNP) rs398702 located 3' of KCNMB4 (encoding calcium-activated potassium channel, subfamily M subunit beta 4) as a possible susceptibility allele for mesial temporal lobe epilepsy (mTLE). Such a finding warrants a further well-powered study in additional carefully phenotyped cohorts. Here we examined the role of the SNP (rs398702) in a cohort of 332 patients (182 women and 150 men; mean±SD age: 47.06±18.12) who had diagnoses of mTLE. None of the patients had a mass lesion, malformations of cortical development, or traumatic brain injury. Brain MRI study revealed hippocampal sclerosis (Hs) in 86/332 (26%) patients. Most patients (254/332, 76%) patients had drug-responsive mTLE. We also enrolled 335 healthy controls (164 women and 171 men; mean±SD age: 48.20±21.90), matched for age, sex and ethnicity. All patients and controls were Caucasian and were born in Italy. The genotype distribution of the SNP rs398702 in patients and controls was within Hardy-Weinberg equilibrium (p>0.05). There was no statistically significant difference in the genotype or allelic frequencies between patients and controls (p=0.878 and p=0.666 respectively). Moreover, such a variant did not influence the main clinical characteristics of mTLE, the presence of Hs or responsiveness to antiepileptic drugs. In conclusion, our data suggest that the rs398702 variant in the KCNMB4 gene is unlikely to influence significantly the risk of developing mTLE or its severity. They further highlight the importance of replication to confirm the validity of association study results., (Copyright © 2013. Published by Elsevier B.V.)

In patients with mesial temporal lobe epilepsy (MTLE), brain MRI often detects hippocampal sclerosis (HS). Almost half of patients with MTLE do not show any hippocampal damage on visual or volumetric assessment. Here, we wished to prospectively assess 65 patients with MTLE (41 women, mean age: 39±10years, range: 21-69; right (12/65 patients) (MRI-negative) nMTLE; right (14/65 patients) (MRI-positive with HS) pMTLE; left (24/65 patients) nMTLE; and left (15/65 patients) pMTLE) using shape analysis (SA). There were significant differences among pMTLE versus nMTLE for age at seizure onset (20.2±12.8 vs. 31.8±16.7years; p=.0029), duration of epilepsy (14.6±12.7 vs. 21.3±9.6years; p=.0227), risk of refractoriness (p=.0067), frequency of antecedent febrile convulsions (FCs) (p<.001), as well as a history of epilepsy or FCs (p=.0104). All the subjects underwent the same 3-Tesla MRI protocol. Shape analysis of hippocampal formation was conducted comparing each group versus 44 matched controls. In all four subgroups, SA detected a significant atrophy in the corresponding hippocampus that coincided with the epileptogenic area. The damage was significantly more severe in patients with pMTLE (F value: 5.00) than in subgroups with nMTLE (F value: 3.50) and mainly corresponded to the CA1 subregion and subiculum. In the patients with MTLE, SA detects hippocampal damage that lateralizes with the epileptogenic area. Such damage is most prominent in the CA1 subregion and subiculum that are crucial in the pathogenesis of MTLE., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.)

There is evidence that inflammatory mechanisms play a role in the pathogenesis of temporal lobe epilepsy (TLE). MicroRNAs (miRNAs), a class of small non-coding endogenous RNAs, which negatively regulate target gene expression, have shown different expression patterns in immune diseases. Recently, several miRNAs have been found to be differentially expressed in animal models of TLE. To understand the role of miRNAs in the molecular mechanisms of TLE, we sought to determine whether genetic variant rs2910164 in the pre-miR-146a gene could influence susceptibility to TLE in an Italian population sample. A cohort of 357 TLE patients and 543 healthy controls were genotyped for detection of this SNP using TaqMan Allelic Discrimination assays, on an Applied Biosystems PCR platform. Analysis of genotype or allelic frequencies between patients and controls showed no statistically significant differences (p=0.536 and p=0.361 respectively). Moreover, such variant did not influence the main clinical characteristics of TLE. In conclusion, our data suggest that the rs2910164 variant in the pre-miR-146a gene is unlikely to influence significantly the risk of developing TLE or its severity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Purpose: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct epileptic syndrome with a broad range of severity even amongst affected members of the same pedigree, and the level of pharmacoresistance may reach 30%, close to that seen in sporadic focal epilepsies., Methods: To investigate this issue of phenotypic heterogeneity, we prospectively carried out a high-resolution 3-T magnetic resonance imaging (MRI) study in an ADNFLE family containing 10 affected members including one pharmacoresistant patient and carrying the V287L mutation of the CHRN beta2 subunit (CHRNB2). MRI studies were evaluated in a manner blinded to the electro-clinical data., Results: The brain MRI showed normal results in all affected individuals except the 22-year-old right-handed woman (member III-7) who had refractory seizures and typical radiological signs of left hippocampal sclerosis. She also had a simple febrile seizure at the age of 10 months., Conclusion: The results of this study illustrate that hippocampal sclerosis has offered a fertile substrate for intractable ADNFLE to develop. The present findings also highlight the importance of acquired factors that are directly relevant to the epilepsy phenotype and its severity even in monogenic epilepsies., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

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.)

The 1354C>T polymorphism of the 5-hydroxytryptamine receptor 2A gene (5-HTR2A) was implicated in human memory performance. We investigated the relationship between this polymorphism and cognitive function in patients with temporal lobe epilepsy (TLE). We also evaluated if this polymorphism could influence the phenotype. There were 138 patients with TLE: 25% (34/138) of them found to be cognitively impaired, while the remaining 104 of 138 (75%) were found to be cognitively preserved after a comprehensive neuropsychological evaluation. dHPLC followed by DNA sequencing was used to detect the genetic variation. The distribution of 1354C>T did not differ between these two TLE groups, both in the comparison of genotype distribution (P= 0.177) and allele frequencies (P = 0.065). Nonetheless, patients with the T allele had a significantly earlier age at onset of the disease (P= 0.006). This effect was even stronger in patients with impaired memory (P= 0.00015). A second independent sample of 86 individuals with TLE satisfactorily confirmed the relationship between T allele and age at epilepsy onset. The results of this study have demonstrated that the T variant of 5-HTR2A may influence an earlier age of onset of TLE, especially in those with impaired memory. Nonetheless, this polymorphism has no major impact on memory functions in such TLE patients., (© 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.)

Purpose: To evaluate the efficacy and tolerability of topiramate (TPM) as monotherapy for patients with temporal lobe epileptic seizures based on an observational study., Methods: We evaluated 41 patients (20 female, mean age 54+18 years) with temporal lobe epilepsy (TLE) referred to the Epilepsy Unit, University of Catanzaro, Italy. Patients received TPM as monotherapy directly or after having taken other antiepileptic drugs. Seizure frequency changes and adverse events were recorded. Follow-up was conducted for a period of at least two years after treatment., Results: Patients received TPM, 50-600 mg/day, de novo (n=29) or initially as add-on therapy before the switch (n=12). In total, 28 of 41 patients achieved seizure freedom, whereas 10 showed a ≥ 50% reduction of seizure frequency. Two patients did not respond well and one patient discontinued TPM due to adverse effects., Conclusions: Our results confirm that TPM as either monotherapy or add-on therapy at doses of 50-600 mg/day effectively reduces seizure frequency in TLE. TPM is particular effective and very well tolerated in patients with mild TLE.

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: To study prognosis and prognostic predictors of sporadic non-lesional temporal lobe epilepsy (TLE)., Method: 474 patients with TLE were consecutively seen from April 1987 to April 2004. 190 had a sporadic non-lesional TLE and a follow-up longer than 2 years. 284 patients were excluded because of family history for TLE, incomplete history, poor compliance with treatment, psychogenic seizures, no brain MRI study, presence of intracranial lesions except for scattered T2 hyperintense spots on hemispheric white matter or mesial temporal sclerosis (MTS). The following prognostic predictors were considered: age at onset of epilepsy, gender, family history of non-TLE or febrile seizures, perinatal factors, history of febrile seizures, ictal phenomena, MTS and interictal EEG. The end point was time to 24 month seizure freedom after treatment onset. The χ(2) test, Student's t test, Kaplan-Meier survival curves with log rank test (univariate analysis) and Cox proportional hazards regression models (multivariate analysis) were used to assess seizure prognosis and prognostic predictors., Results: At univariate analysis, patients achieving 24 month seizure freedom had a significantly older age at onset of epilepsy (33.5 ± 19.9 vs 17.2 ± 14.4 years), and lower occurrence of febrile seizures (11.0% vs 24.4%) and MTS (19.0% vs 35.6%). The chance of remission was directly correlated to age at onset of seizures and inversely correlated to a history of febrile seizures and to the presence of MTS. At multivariate analysis, age at onset of epilepsy was the only significant prognostic predictor., Conclusion: Older age at onset predicts better prognosis in sporadic non-lesional TLE.

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.