Lacosamide monotherapy in clinical practice: A retrospective chart review.

OBJECTIVE: To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy for focal seizures. MATERIALS AND METHODS: Retrospective, non-interventional chart review of lacosamide monotherapy patients aged ≥16 years in Europe. Outcomes included retention rate at observational point (OP) 3 (12 ± 3 months), seizure freedom rates at OP2 (6 ± 3 months) and OP3 and adverse drug reactions (ADRs). RESULTS: A total of 439 patients were included (98 first-line and 341 conversion to monotherapy; 128 aged ≥65 years [25 first-line and 103 conversion to monotherapy]). First-line and conversion to monotherapy retention rates were 60.2% (59/98; 95% confidence interval [CI] 49.8%-70.0%) and 62.5% (213/341; 57.1%-67.6%), respectively. Kaplan-Meier estimates of 12-month retention rates were 81.2% and 91.4% for first-line and conversion to monotherapy, respectively. First-line and conversion to monotherapy retention rates in patients aged ≥65 years were 60.0% (38.7%-78.9%) and 68.9% (59.1%-77.7%), respectively. At OP2, 66.3% of first-line and 63.0% of conversion to monotherapy patients were seizure free. At OP3, 60.2% of first-line and 52.5% of conversion to monotherapy patients were seizure free. In the ≥65 years subgroup, seizure freedom rates at OP2 were 72.0% and 68.0% for first-line and converted to monotherapy, respectively, and at OP3, 68.0% and 56.3%, respectively. Overall, 52 of 439 (11.8%) patients reported ADRs (16.4% in ≥65 years subgroup), most commonly dizziness (5.0%), headache (2.1%) and somnolence (1.6%). CONCLUSIONS: Lacosamide was effective and well tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal seizures.

Novel mutation in STXBP1 gene in a patient with non-lesional Ohtahara syndrome. / Nueva mutación en el gen STXBP1 en un paciente con síndrome de Ohtahara no lesional.

INTRODUCTION: Ohtahara syndrome (OS, OMIM#308350, ORPHA1934) is an early-onset epileptic encephalopathy (EOEE) characterised by spasms, intractable seizures, suppression-burst pattern on the electroencephalogram, and severe psychomotor retardation. Mutations in STXBP1 -a gene that codes for syntaxin binding protein 1 and is involved in synaptic vesicle exocytosis- has been identified in most patients with OS. PATIENT AND RESULTS: We report the case of a 19-month-old child with OS who displays a previously unreported mutation in STXBP1 (c.1249+2T>C, G417AfsX7). This mutation is located in a donor splice site and eliminates exon 14, resulting in a truncated protein. CONCLUSION: This previously unreported STXBP1 mutation in a subject with Ohtahara syndrome and non-lesional magnetic resonance imaging (MRI) broadens the mutational spectrum associated with this devastating epileptic syndrome.

Socio-occupational and employment profile of patients with epilepsy.

OBJECTIVE: Epilepsy has a significant impact on quality of life. Many studies have observed higher unemployment rates among patients with epilepsy. However, unemployment rates vary according to the clinical conditions, country, and group studied. METHODS: Between October 2007 and February 2008, we performed a cross-sectional multicenter epidemiological study to evaluate the socio-occupational and employment profiles of 872 adult patients with epilepsy followed in outpatient epilepsy clinics in Spain. RESULTS: Fifty-eight percent of the patients were employed at the time of the survey, 10.9% of the patients were unemployed, and 12.5% were occupationally incapacitated. CONCLUSION: Patients with epilepsy had employment rates similar to those of the general population, and slightly higher levels of unemployment. The main factors associated with unemployment and incapacity were the presence of refractory epilepsy, the occurrence of a seizure in the last 12 months, level of education, and polytherapy.

Self-reported memory problems in everyday activities in patients with epilepsy treated with antiepileptic drugs.

OBJECTIVE: The goal of this study was to assess everyday memory complaints in a large cohort of patients with epilepsy treated with antiepileptic drugs and to determine demographic, clinical, and emotional state factors associated with patients' self-perception of memory disturbances. METHODS: This cross-sectional epidemiological study was carried out in routine clinical practice using the Questionnaire of Memory Efficiency (QME) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Six hundred sixty-one patients were recruited. The time since epilepsy diagnosis was 17.3 years (SD=12.5); the number of seizures in the past year 13.8 (SD=4.8); the proportion of patients free of seizures in the last year 42.5%; the proportion of patients with partial seizures 73.2%; and the proportion of patients on monotherapy 56.3%. Total QME score was 110.0 (SD=18.6). Depression and anxiety scores and polytherapy explained 38.7% of the QME variance. CONCLUSIONS: Subjective memory functioning in this cohort of patients with epilepsy was relatively good. Complaints expressed by these patients are explained mainly by the presence of depressive and anxiety symptoms.

Strategies to detect adverse effects of antiepileptic drugs in clinical practice.

OBJECTIVE: The aim was to study the frequency and types of adverse effects (AEs) in patients treated with antiepileptic drugs (AEDs) according to the strategies used by the neurologist to detect them. METHOD: This cross-sectional epidemiological study was carried out in standard clinical practice. Two strategies were used to detect AEs: spontaneous reporting by the patient, and a checklist of possible treatment-related adverse reactions completed by the patient. RESULTS: A total of 579 patients were recruited for the study. Roughly a third (33.7%) reported AEs spontaneously, and 65.2% did so when administered the checklist. The main reason for changing medication was lack of efficacy, but significant side effects were also an important reason for modifying treatment in those patients who reported higher levels of discomfort. CONCLUSIONS: The use of an active approach is recommended for detection of AEs of AED treatment. AEs appear to have a key effect on the decision to change treatment.

[«Apuntes en Neurologia¼ (Notes in Neurology): a synthesis of the evidence on common paroxysmal neurological disorders and on neurodegenerative disorders]. / «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.

«Apuntes en Neurologia¼ is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases.

TITLE: «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.«Apuntes en Neurologia¼ es una iniciativa en la cual lideres de primera linea nacional e internacional, con amplio reconocimiento academico, se reunieron para sintetizar los aspectos clinicos mas destacables dentro de su area de interes y acercar las novedades en una lengua mas proxima. Entender los factores que afectan al inicio y progresion de cualquier enfermedad neurologica a traves de una revision es importante para el desarrollo de estrategias en pro de reducir la carga de estas enfermedades, y conocer los aspectos clinicos es esencial para poder resolver los problemas de la practica clinica diaria. Los datos aqui recogidos reflejan el peso de la evidencia y algunos de ellos anticipan un futuro prometedor en el tratamiento de estas enfermedades. Esta primera edicion se centra en trastornos neurologicos comunes paroxisticos como la migraña, la epilepsia y las alteraciones del sueño, y en trastornos neurodegenerativos como la enfermedad de Parkinson y el deterioro cognitivo. Se trata de patologias claramente diferentes, si bien algunas de ellas, como la migraña y la epilepsia, pueden compartir sintomatologia clinica. Los trastornos del sueño, por su parte, son manifestaciones importantes de enfermedades neurodegenerativas que, en ocasiones, son clinicamente evidentes mucho antes del inicio de otros sintomas neurologicos. Tras recordar la fisiopatologia y el diagnostico, la revision actual se centra en acercar los principales avances en cinco de las principales enfermedades neurologicas.

Phosphorylation of rat liver heterogeneous nuclear ribonucleoproteins A2 and C can be modulated by calmodulin.

It was previously reported that the phosphorylation of three proteins of 36, 40 to 42, and 50 kDa by casein kinase 2 is inhibited by calmodulin in nuclear extracts from rat liver cells (R. Bosser, R. Aligué, D. Guerini, N. Agell, E. Carafoli, and O. Bachs, J. Biol. Chem. 268:15477-15483, 1993). By immunoblotting, peptide mapping, and endogenous phosphorylation experiments, the 36- and 40- to 42-kDa proteins have been identified as the A2 and C proteins, respectively, of the heterogeneous nuclear ribonucleoprotein particles. To better understand the mechanism by which calmodulin inhibits the phosphorylation of these proteins, they were purified by using single-stranded DNA chromatography, and the effect of calmodulin on their phosphorylation by casein kinase 2 was analyzed. Results revealed that whereas calmodulin inhibited the phosphorylation of purified A2 and C proteins in a Ca(2+)-dependent manner, it did not affect the casein kinase 2 phosphorylation of a different protein substrate, i.e., beta-casein. These results indicate that the effect of calmodulin was not on casein kinase 2 activity but on specific protein substrates. The finding that the A2 and C proteins can bind to a calmodulin-Sepharose column in a Ca(2+)-dependent manner suggests that this association could prevent the phosphorylation of the proteins by casein kinase 2. Immunoelectron microscopy studies have revealed that such interactions could also occur in vivo, since calmodulin and A2 and C proteins colocalize on the ribonucleoprotein particles in rat liver cell nuclei.

Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.

BACKGROUND: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterised by seizures and conglomerates of neural cells around the lateral ventricles of the brain, caused by FLNA mutations. FLNA encodes filamin A, an actin binding protein involved in cytoskeletal organisation. The amino-terminal actin binding domain (ABD) of filamins contains two tandem calponin homology domains, CHD1 and CHD2. OBJECTIVE: To report clinical and genetic analyses in a Spanish family affected by a connective tissue disorder suggestive of EDS type III and PNH. METHODS: A clinical and molecular study was undertaken in the three affected women. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies, and skin biopsies were done. Genetic analysis of the FLNA gene was undertaken by direct sequencing and restriction fragment length polymorphism analysis. RESULTS: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383C-->T) segregating with the combination of both syndromes. This mutation results in a substitution of an alanine residue (A128V) in CHD1. CONCLUSIONS: The findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype. This association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA.

EFSA scientific risk assessment on animal health and welfare aspects of avian influenza (EFSA-Q-2004-075).

Outbreaks of highly pathogenic avian influenza (HPAI) (2000-2003) resulted in 50 million EU birds culled or dead. The circulation of H5N1 in Asia could represent the origin of a human pandemic. Questions have been raised to combat the ongoing AI crisis. HPAI H5N1 has spilled over to resident and migratory wild bird populations which could represent a means of the virus reaching the EU, but lack of data make any forecast imprudent. Poultry holdings located close to migratory bird breeding and resting sites are considered at greater risk of exposure and methods to prevent exposure should be implemented. Legal safeguards for importation of poultry commodities currently only apply to HPAI and rely on detection of clinical signs that may not be observable during incubation period. Illegal imports represent an additional risk. Insufficient data on the effectiveness of commodity processing are available and few indications can be deducted. Biosecurity is the primary tool to prevent AI introduction and secondary spread. Massive spread was observed in densely populated poultry areas resulting in vaccination programs. Vaccination should be used to support eradication together with enhanced biosecurity and restriction measures, which shall also be implemented in case of prophylactic vaccination. Animal welfare aspects of AI include use of appropriate culling methods, correct vaccine application, and availability of trained staff. EFSA has recently set up a new scientific work group to further assess the risk of HPAI introduction and spread posed in particular by wild, migratory birds, as well as further follow-up of recent AI developments.

Efficacy and safety of eslicarbazepine-acetate in elderly patients with focal epilepsy: Case series.

PURPOSE: Eslicarbazepine-acetate (ESL) is a third generation antiepileptic drug licensed as adjunctive therapy in adults with focal seizures. Efficacy and safety of ESL have been established in real-life setting. However, data about outcomes in elderly patients are scarce. Primary endpoint was to evaluate outcomes of ESL in elderly patients. METHOD: This was a retrospective survey that included patients >65years with focal seizures who started ESL between January 2010 and July 2012 at 12 Spanish Hospitals. ESL was prescribed individually according to real-life practice. Efficacy and safety were evaluated over 1year. These patients were included within the bigger study ESLIBASE. RESULTS: We included 29 patients, most of them males (18). Mean age was 71.2 year-old and epilepsy evolution was 20 years. Eighteen were pharmacorresistant at baseline. At 12 months, the mean dose was 850mg/day, the retention rate 69%, the responder rate 62% and 24.1% were seizure-free. At 12 months, 16 patients (55.2%) had ≥1 adverse effect (AE), that led to discontinuation in 7 patients. Dizziness, nausea and ataxia were the most common AEs. The tolerability profile improved in 4/5 patients who switched from carbamazepine (CBZ) or oxcarbazepine (OXC) to ESL due to AEs. CONCLUSIONS: ESL was well-tolerated and effective in elderly patients in a real-life setting over 1year, with a dose around 800mg/day. AE effects improved in most of who switched from CBZ or OXC to ESL.

Arrangement and mobility of water in vermiculite hydrates followed by 1H NMR spectroscopy.

The arrangement of water molecules in one- and two-layer hydrates of high-charged vermiculites, saturated with alkaline (Li(+), Na(+)) and alkali-earth (Mg(2+), Ca(2+), Ba(2+)) cations, has been analyzed with (1)H NMR spectroscopy. Two different orientations for water molecules have been found, depending on the hydration state and the sites occupied by interlayer cations. As the amount of water increases, hydrogen bond interactions between water molecules increase at expenses of water-silicate interactions. This interaction favors water mobility in vermiculites. A comparison of the temperature dependence of relaxation times T(1) and T(2) for one and two-layer hydrates of Na-vermiculite shows that the rotations of water molecules around C(2)-axes and that of cation hydration shells around the c-axis is favored in the two-layer hydrate. In both hydrates, the anisotropic diffusion of water takes place at room temperature, preserving the orientation of water molecules relative to the silicate layers. Information obtained by NMR spectroscopy is compatible with that deduced by infrared spectroscopy and with structural studies carried out with X-ray and neutron diffraction techniques on single-crystals of vermiculite.

Effect of lamotrigine on sexual function in patients with epilepsy.

OBJECTIVE: To assess the course of sexual function in epilepsy patients treated with lamotrigine. MATERIAL AND METHODS: This open study included 141 patients treated with lamotrigine for a period of 8 months: 79 patients initiated treatment with lamotrigine monotherapy, and 62 were switched to lamotrigine because of lack of efficacy or adverse events to a previous antiepileptic drug (AED). Patients were assessed at baseline and after 4 and 8 months of treatment. In the baseline and final visits the Changes in Sexual Functioning Questionnaire (CSFQ) was applied. Analysis was performed in an intent-to-treat population. RESULTS: In women who started treatment with lamotrigine, a significant improvement was observed, both in total CSFQ score (increase of 5.39 +/- 6.95 points; p < 0.05), and in the five dimensions of the scale (desire/frequency, desire/interest, pleasure, arousal/excitement and orgasm). In men, a significant improvement was only observed in the pleasure dimension. In the group of patients in whom a previous AED was substituted by lamotrigine, significant improvement was recorded in the dimensions of pleasure and orgasm in men and desire/frequency in women, whilst in women the desire/interest dimension showed a decrease. CONCLUSIONS: In this observational study, an improvement in sexual dysfunction was observed in association with lamotrigine. This could have been the result of improvement of the epilepsy, changes in quality of life, elimination of side effects from other AEDs, or a mood-stabilizing effect of lamotrigine.

The Ca2+/calmodulin signaling system in the neural response to excitability. Involvement of neuronal and glial cells.

Ca2+ plays a critical role in the normal function of the central nervous system. However, it can also be involved in the development of different neuropathological and neurotoxicological processes. The processing of a Ca2+ signal requires its union with specific intracellular proteins. Calmodulin is a major Ca(2+)-binding protein in the brain, where it modulates numerous Ca(2+)-dependent enzymes and participates in relevant cellular functions. Among the different calmodulin-binding proteins, the Ca2+/calmodulin-dependent protein kinase II and the phosphatase calcineurin are especially important in the brain because of their abundance and their participation in numerous neuronal functions. We present an overview on different works aimed at the study of the Ca2+/calmodulin signalling system in the neural response to convulsant agents. Ca2+ and calmodulin antagonists inhibit the seizures induced by different convulsant agents, showing that the Ca2+/calmodulin signalling system plays a role in the development of the seizures induced by these agents. Processes occurring in association with seizures, such as activation of c-fos, are not always sensitive to calmodulin, but depend on the convulsant agent considered. We characterized the pattern of expression of the three calmodulin genes in the brain of control mice and detected alterations in specific areas after inducing seizures. The results obtained are in favour of a differential regulation of these genes. We also observed alterations in the expression of the Ca2+/calmodulin-dependent protein kinase II and calcineurin after inducing seizures. In addition, we found that reactive microglial cells increase the expression of calmodulin and Ca2+/calmodulin-dependent protein kinase II in the brain after seizures.

Residues from veterinary medicinal products, growth promoters and performance enhancers in food-producing animals: a European Union perspective.

The authors present an overview of the presence of residues from veterinary medicinal products, growth-promoting agents and performance enhancers in food-producing animals, as a result of administering these substances--legally or illegally--on farms. The current situation in the European Union (EU) is represented by an analysis of the 2004 results from the national residue monitoring plans of EU Member States. Aspects of ante-mortem and postmortem inspection are also considered, as well as the practical challenges facing veterinary inspectors attempting to uncover illegal uses and prevent public health risks. Substances which are considered illegal because their risks have not yet been assessed, such as those employed in minority species or for minor uses, are also discussed.

Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study.

BACKGROUND: Real-world data of current antiepileptic drugs (AEDs) used to treat focal seizures is of importance to understand the efficacy and safety outside of the clinical trial setting. Here we report real-world data from a large series of patients treated with perampanel for 1year. METHODS: FYDATA was a multicentre, retrospective, 1-year observational study assessing the efficacy and safety of adjuvant perampanel in patients ≥12 years of age with focal epilepsy in a real-world setting. At 12 months, the proportion of patients who were seizure free, median percentage seizure reduction, proportion of responders, retention rate and proportion of patients with adverse events (AEs) were assessed. Analyses were also performed to identify any patient-, medication- and disease-related factors associated with a large clinical response or carry a risk for AEs. RESULTS: A total of 464 patients were included in the study with a retention rate of 60.6% at 1year. The mean number of prior AEDs was 7.8. The median percentage reduction in overall seizures was 33.3% (75% for secondary generalised seizures) after 1year, with 7.2% of patients achieving seizure freedom. Furthermore, patients on non-enzyme-inducing AEDs were more likely to achieve seizure freedom, and logistic regression revealed that patients aged ≥65 years, those with epilepsy due to a vascular aetiology and those who had received fewer prior AEDs showed a better clinical response to perampanel. A total of 62.9% of the patients experienced AEs at 12 months; dizziness, somnolence and irritability were the most frequent AEs. Patients with prior psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs with perampanel, and slower titration schedules were associated with less AEs overall. CONCLUSION: Perampanel, for the treatment of focal epilepsy in a real-world setting in a refractory population, over 1year, demonstrates a similar efficacy and safety profile to that observed in clinical trials. Our results have implications for the optimisation of perampanel use in a clinical setting.

Changes in sinusoidal plasma membrane enzyme activities during the pre-replicative phase of liver regeneration.

Changes in a range of plasma membrane enzyme activities during the early period of liver regeneration are thought to be related to the initiation of DNA synthesis and the triggering of cellular activation. The sinusoidal plasma membrane was isolated from control and partially hepatectomized animals at various intervals during the pre-replicative phase. The specific activities of 5'-nucleotidase, (Na+ + K+)-ATPase, Ca2+-ATPase, Mg2+-ATPase showed that after partial hepatectomy changes in the enzyme activities at the sinusoidal plasma membrane region occur. These changes are probably related to the remodeling of the cell-surface that occurs before the division of hepatocytes.

Isolation of rat liver spectrin and identification of functional domains.

Immunohistochemical studies carried out with liver sections show that spectrin is uniformly distributed along the whole plasma membrane of hepatocytes. The bilecanalicular spectrin is released during the purification of liver subplasma membrane fractions, whereas most of the basolateral spectrin remains tightly bound to the membrane. Spectrin associated with the basolateral membranes has been purified and its subunits isolated. The alpha-subunit retains the ability to bind both calmodulin and actin. Fragments have been obtained either by chemical or by proteolytical digestion of the 240 kDa alpha-subunit. Treatment with CNBr yields fragments of about 30 kDa which bind actin and calmodulin. Digestion with Staphylococcus aureus V-8 proteinase yields a calmodulin-binding fragment of 27 kDa and an actin-binding fragment of 31 kDa.

Biotechnology, animal health and animal welfare within the framework of European Union legislation.

Experimental and farm animals are used in biomedical research and in biotechnology studies that are designed to improve agricultural productivity. European legislation governing such research, which is modelled on existing National Laws regarding animal health and welfare, is agreed after several preliminary sessions in which contributions and opinions from large sections of European society are sought. Special attention is paid to opinions expressed by ethical and animal rights associations, which emphasise that animals should be considered as 'sentient beings' and not mere 'goods' or 'property'. A statement to this effect is included in the Treaty establishing a Constitution for Europe, which was signed in Rome in 2004 by the 25 European Union member states.

[Breath-holding spell or epileptic seizure? A description of three girls with epileptic seizures triggered by anoxia]. / ¿Espasmo del sollozo prolongado o crisis epiléptica?: descripción de tres niñas con crisis epilépticas desencadenadas por anoxia.

TITLE: ¿Espasmo del sollozo prolongado o crisis epiléptica?: descripción de tres niñas con crisis epilépticas desencadenadas por anoxia.

New nuclear functions for calmodulin.

The data reported here summarize a series of results which reveal new functions for nuclear calmodulin (CaM). The addition of CaM inhibitors to cultures of proliferating NRK cells blocked the activity of the cyclin-dependent protein kinases 4 (cdk4) and 2 (cdk2), which are enzymes implicated in the progression of G1 and in the onset of DNA replication, respectively. CaM modulates the activity of cdk4 by regulating the nuclear location of both cdk4 and cyclin D, its associated regulatory subunit. By using CaM-affinity chromatography, we have recently identified two new nuclear CaM-binding proteins: (i) the protein La/SSB, which is an autoantigen implicated in several autoimmune diseases such as lupus erythematosus and Sjögren's syndrome (since La/SSB participates in the process of transcription mediated by RNA polymerase III, CaM could be involved in the regulation of this process); and (ii) the protein SAP145, a member of the spliceosome-associated proteins (SAPs) which is a subunit of the splicing factor SF3(b). This finding suggests the involvement of CaM in pre-mRNA splicing. Finally, a screening for new CaM-binding proteins in the fission yeast performed by using the phage display analysis, revealed that several nucleolar-ribosomal proteins associate to CaM, suggesting that CaM modulates ribosomal assembly and/or function.