Reversible dementia and insomnia in ABGA related encephalitis.

BACKGROUND: ABGAs are historically associated with Encephalitis Lethargica (EL). Typically ABGAs are also found in children resulting in a variety of neuropsychiatric and extrapyramidal disorders, rare cases are reported in adults with atypical movement disorders. No description of basal ganglia reversible lesions related to ABGAs are reported and these antibodies are not included in the list of autoimmune encephalitis. METHODS AND RESULTS: A 55 years old female presented sub-acute onset of an anxious-depressive disorder and obsessive-compulsive behavior associated with intractable insomnia affecting sleep onset and sleep maintenance. Brain-MRI showed diffuse hyperintensities on FLAIR sequences in the basal ganglia. A therapy with IV-immunoglobulin was started and the clinical condition improved dramatically and insomnia and psychiatric symptoms resolved completely. CONCLUSION: Our case highlights the importance of making a fast diagnosis. When caught early ABGAs-related encephalitis is susceptible of a good outcome and response to treatment. Reversible insomnia and dementia in our case expand ABGA clinical presentation in adults and favors the hypothesis of an immune pathogenesis for Encephalitis Lethargica, especially in the hyperkinetic form as previously suggested, as in our case.

Footloose (footloose), footloose.

A 78-year-old woman without past relevant medical history presented to the emergency department for acute transient dysarthria. NIHSS was 0/42. Neurological examination revealed chorea-like movements over the left limbs, especially the foot. No other neurological signs were present. CT perfusion showed right cortical hypoperfusion due to right M2 occlusion, basal-ganglia perfusion was normal. Brain MRI revealed a small focus of restricted diffusion in the right insula, sparing basal ganglia. Based on the neuroimaging features and clinical correlation, despite the NIHSS score, we decided to treat the patient with alteplase, after iv-thrombolysis hyperkinetic movements ceased completely. Brain-MRI performed 72 h after symptom onset confirmed a confined insular ischemic lesion without the involvement of deep gray matter structures. Hyperkinetic movement disorders, such as hemichorea hemiballismus, are rare presentations of stroke, basal ganglia are mainly involved even if the insular cortex has been described too. Clinical decision on whether to treat ischemic stroke does not include movement disorders. Our case underscores NIHSS limitations in clinical practice.

Role of Pharmacogenomics in Antiepileptic Drug Therapy: Current Status and Future Perspectives.

BACKGROUND: Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine. OBJECTIVE: In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future. METHODS: We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs. RESULTS: Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity. CONCLUSION: To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis.

Validation Study of Italian Version of Inventory for Déjà Vu Experiences Assessment (I-IDEA): A Screening Tool to Detect Déjà Vu Phenomenon in Italian Healthy Individuals.

The Inventory Déjà Vu Experiences Assessment (IDEA) is the only screening instrument proposed to evaluate the Déjà vu (DV) experience. Here, we intended to validate the Italian version of IDEA (I-IDEA) and at the same time to investigate the incidence and subjective qualities of the DV phenomenon in healthy Italian adult individuals on basis of an Italian multicentre observational study. In this study, we report normative data on the I-IDEA, collected on a sample of 542 Italian healthy subjects aging between 18-70 years (average age: 40) with a formal educational from 1-19 years. From September 2013 to March 2016, we recruited 542 healthy volunteers from 10 outpatient neurological clinics in Italy. All participants (i.e., family members of neurological patients enrolled, medical students, physicians) had no neurological or psychiatric illness and gave their informed consent to participate in the study. All subjects enrolled self-administered the questionnaire and they were able to complete I-IDEA test without any support. In total, 396 (73%) of the 542 healthy controls experienced the DV phenomenon. The frequency of DV was inversely related to age as well as to derealisation, jamais vu, precognitive dreams, depersonalization, paranormal activity, remembering dreams, travel frequency, and daydreams (all p < 0.012). The Italian version of IDEA maintains good properties, thus confirming that this instrument is reliable for detecting and characterising the DV phenomenon.

Advanced morphological neuroimaging study in lateral temporal lobe epilepsy: A multicentric study.

Lateral temporal lobe epilepsy (lTLE) is a rare condition characterized by auditory auras or receptive aphasia, negative MRI, and relatively benign evolution. With the low number of cases in the world, our objective was to analyze a cohort of sporadic cases with lTLE (slTLE), in order to investigate possible cerebral morphological alterations. Forty patients with lTLE (34.93±12.08years of age) and 38 healthy controls (CTRL, 34.55±9.08years of age) were enrolled from four tertiary Italian epilepsy centers, which provided brain MRI T1-weighted images following a standard protocol for patients with epilepsy. We performed group comparison by following different approaches: voxel-based morphometry (VBM, SPM8), cortical thickness (CT), and local gyrification index (lGI) (FreeSurfer 5.3). At a more conservative threshold (p<0.05, FWE correction), no significant differences between groups survived, neither in VBM nor CT/lGI. Multicenter studies have more power than smaller studies in conducting sophisticated evaluations of rare diseases, and further investigations are required to develop a full picture of this rare phenotype.

Adverse Drug Reactions Related to Drug Administration in Hospitalized Patients.

INTRODUCTION: Drug treatment may be related to the development of adverse drug reactions (ADRs). AIM: In this paper, we evaluated the ADRs in patients admitted to Catanzaro Hospital. METHODS: After we obtained the approval by local Ethical Committee, we performed a retrospective study on clinical records from March 01, 2013 to April 30, 2015. The association between drug and ADR or between drug and drug-drug-interactions (DDIs) was evaluated using the Naranjo's probability scale and Drug Interaction Probability Scale (DIPS), respectively. RESULTS: During the study period, we analyzed 2870 clinical records containing a total of 11,138 prescriptions, and we documented the development of 770 ADRs. The time of hospitalization was significantly higher (P<0.05) in women with ADRs (12.6 ± 1.2 days) with respect to men (11.8± 0.83 days). Using the Naranjo score, we documented a probable association in 78% of these reactions, while DIPS revealed that about 22% of ADRs were related to DDIs. Patients with ADRs received 3052 prescriptions on 11,138 (27.4%) having a mean of 6.1±0.29 drugs that was significantly higher (P<0.01) with respect to patients not experiencing ADRs (mean of 3.4±0.13 drugs). About 19% of ADRs were not diagnosed and were treated as new diseases. CONCLUSION: Our results indicate that drug administration induces the development of ADRs also during the hospitalization, particularly in elderly women. Moreover, we also documented that ADRs in some patients are under-diagnosed, therefore, it is important to motivate healthcare to report the ADRs in order to optimize the patients' safety.

Adverse drug reactions reporting in Calabria (Southern Italy) in the four-year period 2011-2014: impact of a regional pharmacovigilance project in light of the new European Legislation.

BACKGROUND: The number of suspected adverse drug reactions (ADRs) yearly submitted to the Italian Network of Pharmacovigilance (RNF) has progressively increased after the new European Pharmacovigilance legislation (July 2012). These results have mostly reflected the agreements between Italian Medicines Agency (AIFA) and Italian Regions, enabling the implementation of active pharmacovigilance projects. A project was funded by the AIFA in Calabria region (Southern Italy) in 2010 to increase ADRs reporting and promote a safer medicines' use. Based on this background, we investigated the trend of ADRs in Calabria in 2011-2014, trying to analyze the possible entailments of the new law. METHODS: Quantitative and descriptive analysis of ADRs submitted by Calabrian healthcare professionals and patients to the RNF database between 2011 and 2014. RESULTS: A sharp rise in regional reporting rate was observed over study period. Calabrian Pharmacovigilance system completely fulfilled the World Health Organization gold standard for ADR reporting rate, both in 2013 and 2014. However, heterogeneity was observed regarding reporting health facilities, healthcare professionals and patients among the study years. CONCLUSIONS: These findings reflect the success of the project performed in Calabria. However, this initiative should go on in the next future to obtain better and more homogeneous reporting behavior.

Deep Learning Representation from Electroencephalography of Early-Stage Creutzfeldt-Jakob Disease and Features for Differentiation from Rapidly Progressive Dementia.

A novel technique of quantitative EEG for differentiating patients with early-stage Creutzfeldt-Jakob disease (CJD) from other forms of rapidly progressive dementia (RPD) is proposed. The discrimination is based on the extraction of suitable features from the time-frequency representation of the EEG signals through continuous wavelet transform (CWT). An average measure of complexity of the EEG signal obtained by permutation entropy (PE) is also included. The dimensionality of the feature space is reduced through a multilayer processing system based on the recently emerged deep learning (DL) concept. The DL processor includes a stacked auto-encoder, trained by unsupervised learning techniques, and a classifier whose parameters are determined in a supervised way by associating the known category labels to the reduced vector of high-level features generated by the previous processing blocks. The supervised learning step is carried out by using either support vector machines (SVM) or multilayer neural networks (MLP-NN). A subset of EEG from patients suffering from Alzheimer's Disease (AD) and healthy controls (HC) is considered for differentiating CJD patients. When fine-tuning the parameters of the global processing system by a supervised learning procedure, the proposed system is able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from RPD. Similar results are obtained for CJD versus AD and CJD versus HC.

The Natural History of Epilepsy in 163 Untreated Patients: Looking for "Oligoepilepsy".

The clinical evolution of untreated epilepsy has been rarely studied in developed countries, and the existence of a distinct syndrome characterized by rarely repeated seizures (oligoepilepsy) is debated. The aim of this study is to assess the natural history of 163 untreated patients with epilepsy in order to evaluate whether oligoepilepsy retains specific features. We retrospectively evaluated 7344 patients with ≥2 unprovoked seizures. INCLUSION CRITERIA: sufficient anamnestic/EEG data, disease duration ≥10 years, follow-up ≥3 years. EXCLUSION CRITERIA: psychogenic seizures, natural history of disease <5 years. The 163 included subjects were divided into 2 groups according to seizure frequency: oligoepilepsy (≤1/year; 47 subjects) and controls (>1/year; 116 subjects). We also evaluated seizure frequency during the natural history. There were no differences between groups regarding duration of natural history, family history of epilepsy/febrile seizures, interictal EEG. Subjects with oligoepilepsy differed from controls in terms of sex (females 38% vs. 58%, p = 0.03) and drug resistance (6% vs 28%; p = 0.003). Juvenile myoclonic epilepsy was more frequent in controls (9.5% vs 0%, p = 0.04). Patients with oligoepilepsy, differently from controls, had stable seizure frequency. Oligoepilepsy represents a favourable evolution of different epileptic syndromes and keeps a stable seizure frequency over time.

Pharmacological modulation in mesial temporal lobe epilepsy: Current status and future perspectives.

Mesial temporal lobe epilepsy (MTLE) is frequently associated with hippocampal sclerosis (Hs), possibly caused by a primary brain injury that occurs a long time before the appearance of neurological symptoms. MTLE-Hs is, however, a heterogeneous condition that evolves with time, involving both environmental and genetic components. Recent experimental studies emphasize that drugs or drug combinations that target modulation and circuitry reorganization of the epileptogenic networks favorably modify the complex molecular and cellular alterations underlying MTLE. In particular, the link between neuroinflammation, GABAAR and epilepsy has been extensively studied mainly because of the relevant therapeutic implications that the pharmacological modulation of these phenomena would have in the clinical practice. In this review, we briefly summarize the studies that could pave the road to develop new disease-modifying therapeutic strategies for pharmacoresistant MTLE patients. Both clinical observations in human MTLE and experimental findings will be discussed, highlighting the potential modulatory crosstalk between the deregulation of the inhibitory (GABAergic) transmission and the sustained activation of the innate immune response.

Long-term outcome of mild mesial temporal lobe epilepsy: A prospective longitudinal cohort study.

OBJECTIVE: To identify clinical and imaging features at presentation that might predict long-term outcome in patients with mild mesial temporal lobe epilepsy (mMTLE), which is defined by at least 24 seizure-free months with or without antiepileptic medication. METHODS: In the setting of a prospective, population-based, longitudinal cohort study, we followed up 101 patients, all with mMTLE at enrolment. By protocol, patients underwent clinical evaluation every 3-12 months. Independent t test, Mann-Whitney test, or χ(2) test was used for comparing 2 groups. The incidence rate of refractory MTLE (rMTLE) was expressed as number of cases every 100 person-years. RESULTS: After a mean follow-up of 12.2 ± 3.7 years, 16 patients dropped out and 85/101 (mean age 46.5 ± 13.3 years) were available for the present analysis. Of these, 64/85 (75%) patients remained seizure-free and 21/85 (25%) became refractory (rMTLE), the latter corresponding to 2.0 cases per 100 persons per year. Patients with rMTLE showed a longer duration of epilepsy (p < 0.001), earlier age at epilepsy onset (p = 0.006), more frequent febrile convulsions (p = 0.02), and hippocampal sclerosis (HS) at MRI (p = 0.004) as compared to those with mMTLE. CONCLUSIONS: mMTLE is a syndrome representing the mildest form of the wide spectrum of MTLE. Earlier age at onset, history of febrile convulsions, longer duration of epilepsy, and the presence of HS on MRI predict a worse outcome.

An SNP site in pri-miR-124, a brain expressed miRNA gene, no contribution to mesial temporal lobe epilepsy in an Italian sample.

Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy and is usually associated with hippocampal sclerosis (Hs). The pathogenesis of MTLE involves many biological pathways, some of which seem to be regulated by microRNAs (miRNAs). Increasing evidence shows that single nucleotide polymorphisms (SNPs) or mutations in miRNAs sequence may affect the processing and function of miRNAs and participate in the occurrence of diseases. In this study, the effect of the SNP of one neuronal miRNA, miR-124, on susceptibility to MTLE was investigated using a case control study. To understand the role, a common C/G polymorphism designated rs531564 in the molecular mechanisms of MTLE, we sought to determine whether this genetic variant could influence susceptibility to disease in a cohort of 307 MTLE patients and 306 healthy controls, using TaqMan allelic discrimination assay, on an Applied Biosystems PCR platform. No statistically significant differences were found in the allele or genotype distributions of the miR-124 rs531564 polymorphism among MTLE patients and MTLE-free control subjects (p > 0.05). Our results demonstrate that this SNP has no major role in genetic susceptibility to MTLE, at least in the population studied here.

Lacosamide in patients with temporal lobe epilepsy: An observational multicentric open-label study.

PURPOSE: The aim of this study was to evaluate the efficacy and tolerability of lacosamide (LCM) both as add-on therapy and monotherapy in patients with temporal lobe epilepsy (TLE) based on an observational, prospective, multicenter study. METHODS: We enrolled 100 patients (mean age: 43.4±12.53years, 57 females) with nonlesional TLE and TLE with hippocampal sclerosis (HS) that did not respond to the first drug and who were referred to epilepsy centers of the University of Catanzaro, University of Palermo, IRCSS Neuromed of Pozzilli, and Otto-von-Guericke University of Magdeburg. In this open-label, multicenter trial, patients were initiated on oral LCM as add-on therapy to first AED monotherapy or as a later add-on to two concomitant AEDs. Seizure frequency changes and adverse events were recorded for at least six months after LCM was added. RESULTS: Fourteen patients dropped out because of positive MRI findings other than HS. Patients received LCM at 200-400mg/day. Fifty-eight out of these 86 patients with seizures that were previously drug-resistant had reduced seizure frequency after introduction of LCM. Forty-five out of 86 patients were classified as responders (12 were seizure-free, 33 achieved a reduction >50%). Interestingly, five patients out of 86 achieved seizure freedom for at least one year and progressively switched to monotherapy with LCM, and all five remained seizure-free at follow-up (6-48months). CONCLUSIONS: Our results may suggest that LCM at doses of 200 to 400mg/day reduces seizure frequency in adults with TLE regardless of the presence of HS, and that it may be considered as a first add-on treatment for patients with pharmacoresistant TLE.

Integrity of the corpus callosum in patients with benign temporal lobe epilepsy.

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.

Profile of brivaracetam and its potential in the treatment of epilepsy.

Brivaracetam (BRV) (UCB 34714) is currently under review by the US Food and Drug Administration and European Medicines Agency for approval as an add-on treatment for adult patients with partial seizures. Similar to levetiracetam (LEV), BRV acts as a high-affinity ligand of the synaptic vesicle protein 2A, however, it has been shown to be 10- to 30-fold more potent than LEV. Moreover, BRV does not share the LEV inhibitory activity on the high voltage Ca(2+) channels and AMPA receptors, and it has been reported to act as a partial antagonist on neuronal voltage-gated sodium channels. The pharmacokinetic profile of BRV is favorable and linear, and it undergoes an extensive metabolism into inactive compounds, mainly through the hydrolysis of its acetamide group. Furthermore, it does not significantly interact with other antiepileptic drugs and more than 95% is excreted through the urine, with an unchanged fraction of 8%-11%. BRV has a half-life of approximately 8-9 hours and it is usually given twice daily. To date, a wide range of experimental studies have reported the effectiveness of BRV with regards to partial and generalized seizures. In humans, six randomized, placebo-controlled trials and two meta-analyses highlighted the efficacy, or good tolerability, of BRV as an add-on treatment for patients with uncontrolled partial seizures. A wide dose range of BRV has been evaluated in those trials (5-200 mg), but the most suitable for clinical use appears to be 50-100 mg/day. The most common adverse reactions to BRV are mild to moderate, transient, often improve during the course of the treatment, and mainly consist of central nervous system symptoms, such as fatigue, dizziness, and somnolence. The aim of this paper is to critically review the literature data regarding experimental animal models and clinical trials on BRV, and to define its potential usefulness for the clinicians who manage patients with epilepsy.