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Purpose: Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern., Methods: Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed., Key Findings: We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature., Significance: Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Ethical, legal, and social issues related to the collection, storage, and use of biospecimens and data derived from children raise critical concerns in the international debate. So far, a number of studies have considered a variety of the individual issues crucial to pediatric biobanking such as decision making, privacy protection, minor recontact, and research withdrawal by focusing on theoretical or empirical perspectives. Our research attempted to analyze such issues in a comprehensive manner by exploring practices, rules, and researcher opinions regarding proxy consent, minor assent, specimens and data handling, and return of results as faced in 10 European countries. Because of the lack of comparative analyses of these topics, a pilot study was designed. Following a qualitative methodology, a questionnaire draft mostly including open-ended queries was developed, tested, and sent by e-mail to a selected group of researchers dealing with pediatric biobanking (n=57). Returned questionnaires (n=31) highlighted that the collection, storage, distribution, and use of biospecimens and data from children were widely practiced in the contacted laboratories. In most cases, pediatric biobanking was subjected to national or local regulations covering adult biobanks (n=26). Informed consent was generally given by parents or legal representatives (n=17). Children's opinions were frequently sought and taken into account (n=16). However, minors were usually not recontacted at the age of maturity to express their own choices (n=26). Based on the collected data, dedicated recommendations are needed to govern unique ethical and regulatory issues surrounding pediatric biobanking.

The dynamics of a neuron are influenced by the connections with the network where it lies. Recorded spike trains exhibit patterns due to the interactions between neurons. However, the structure of the network is not known. A challenging task is to investigate it from the analysis of simultaneously recorded spike trains. We develop a non-parametric method based on copulas, that we apply to simulated data according to different bivariate Leaky Integrate and Fire models. The method discerns dependencies determined by the surrounding network, from those determined by direct interactions between the two neurons. Furthermore, the method recognizes the presence of delays in the spike propagation. This article is part of a Special Issue entitled "Neural Coding"., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS., Competing Interests: The authors have declared that no competing interests exist.

A splice site variation (c.603-91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603-91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug-resistant and 401 patients with drug-responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603-91G>A genotypes was similar among drug-resistant and drug-responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603-91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

We describe the detailed clinical and molecular characterization of three patients (aged 7, 8(4/12) and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

Purpose: To study neuropsychological functions in children with idiopathic epilepsy at onset of treatment and after 1 year of therapy and to identify factors associated with cognitive impairment., Methods: 43 Subjects aged 5.2-16.9 years with newly diagnosed idiopathic epilepsy were enrolled and started treatment with valproate or carbamazepine. At admission and after 12 months, all patients underwent clinical examinations, the Child Behavioural Checklist, EEG and a neuropsychological test battery. The results of each test were correlated to demographic, clinical, electrophysiological and therapeutic variables., Results: Except for attention, all neuropsychological functions were normal at admission and after 12 months. An improvement with time was noted for memory (p<0.05) and logical-executive functions (p<0.01). Attentive deficit was worse at 12 months (53.5% vs. 32.6%). Low socio-economic level and emotional and behavioural disturbances were the only factors negatively correlated to intelligence, memory and attention. Compared to valproate, carbamazepine was most commonly implicated., Discussion: Idiopathic epilepsy can affect attention, even before starting treatment. Emotional and behavioural difficulties and a low socio-economical status are associated with cognitive impairment., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6)., Objective: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation., Patients and Methods: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects., Results: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed., Conclusions: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.

Purpose: Ring chromosome 20 [r(20)] syndrome is a well-defined chromosomal disorder characterized by epilepsy, mild-to-moderate mental retardation, and lack of recognizable dysmorphic features. Epilepsy is often the most important clinical manifestation of the syndrome, even if its appearance is not constantly precocious. Seizures are frequently drug resistant., Methods: We describe three children with [r(20)] syndrome in whom the onset of epilepsy (age at onset range: 4 years and 6 months to 9 years and 4 months) determined a kind of epileptic status (age at onset range: 6 years and 10 months to 9 years and 8 months) with dramatic neuropsychological deterioration. This epileptic status lasted for several months because of refractoriness to most antiepileptic drugs (AEDs), but it was treated successfully with a combination of valproate and lamotrigine in two children., Results: As soon as seizures stopped, the children showed prompt recovery with partial restoration of the neuropsychological impairment., Conclusion: This clinical picture can be described as abrupt epileptic encephalopathy.

Background and Objectives: Central muscle relaxants are a clinical option in patients with spastic palsy. Eperisone is a central muscle relaxant used in several conditions, but its therapeutic potential in spastic palsy needs to be verified. This dose-ranging trial compares two doses of eperisone in patients with spastic palsy associated to cerebral or spinal diseases., Patients and Methods: In this randomized, placebo-controlled, double-blind, three-way cross-over study, patients (18-75 years) with spastic palsy received eperisone 150 mg/day, eperisone 300 mg/day, or placebo for 8 weeks. Treatment periods lasted for 14 days. Objective clinical parameters (intensity of spasticity and physiological reflexes) and functional parameters (walking capability, capability to climb stairs, rigidity) were measured. Tolerability was also evaluated., Results: Eighteen patients were enrolled. The reduction in the intensity of spasticity versus the beginning of each treatment cycle was significant with eperisone 300 mg/day (p = 0.004). Similar findings were observed in the evaluation of patellar reflex (p = 0.01), while the other reflexes were not significantly different. Walking capability was significantly improved with eperisone 300 mg/day (p < 0.05). No significant differences were observed in the capability to climb stairs and in rigidity. A trend towards a reduction in pain was noted with eperisone 300 mg/day versus placebo. The incidence of adverse events was similar in all groups., Discussion: Eperisone 300 mg/day might be an effective and well-tolerated treatment for spastic palsy. Larger studies are required to further characterize the efficacy of eperisone in this therapeutic area.

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Introduction: Few trials have compared different central muscle relaxants in the treatment of spastic palsy. This head-to-head phase 3 trial compares oral eperisone, a central muscle relaxant with a promising activity in spasticity therapy, and oral baclofen., Methods: Patients (>18 years) with moderate to severe spastic palsy were eligible in this double-blind, randomized study; they received eperisone 300 mg/ day or baclofen 60 mg/day for 6 weeks. The efficacy evaluations included: functional analysis (Pedersen's scale, muscular tone, joint range of motion, 10-meter walking time); physiological and pathological reflexes; and electromyography (Hmax/Mmax amplitude ratio and the Wartenberg test). Physicians and patients globally assessed treatment efficacy., Results: Both eperisone (n=40) and baclofen (n=40) significantly improved functionality of lower limbs versus baseline (eperisone: -9.1%, P<0.01; baclofen: -8.3%, P<0.05), but only eperisone improved this parameter in the upper limbs (-7.8%, P<0.01 vs. -6.3%, P=NS). Both drugs reduced muscular tone from week 2. Only eperisone improved the joint range of motion (-32.5%, P<0.01 vs. -14.6%, P=NS). Both treatments reduced the 10-meter walking time (eperisone: -20.2%, P<0.01; baclofen: -24.0%, P<0.01); this effect was evident at week 2 with eperisone only. Both drugs improved reflexes. Eperisone and baclofen decreased the Hmax/Mmax amplitude ratio (eperisone: -30.0%, baclofen: -18.6%; P<0.01 for both). Eperisone increased the number of leg oscillations at the Wartenberg test (P<0.05) while baclofen increased the velocity of leg falling (P<0.01). For tolerability, no differences were observed between eperisone and baclofen in any parameters. Eperisone was judged as "good" by a higher number of physicians and patients than baclofen. Eighteen adverse events, most of mild intensity, were reported with eperisone and 27 with baclofen., Conclusion: Eperisone 300 mg/day and baclofen 60 mg/day, administered orally, are effective and well-tolerated drugs in the treatment of spastic palsy. However, eperisone might be associated with some additional clinical benefits when compared with baclofen.

Purpose: To examine the functioning of patients with alternating hemiplegia of childhood (AHC), a very rare clinical condition manifesting with recurrent episodes of hemiplegia lasting from few minutes to several days, paroxysmal occurrence of tonic/dystonic attacks and other autonomic disturbances. Furthermore, patients exhibit chronic disabilities as well as mental retardation, epilepsy and motor disorders that affect the patients' everyday functioning to a considerable extent., Method: Data about 25 patients with AHC (F = 13) aged 3-34 years were collected with International Classification of Functioning Disability and Health (ICF) questionnaires. Data analysis was carried out on four age groups: 3-6, 7-12, 13-18 and >18 years, using only the ICF questionnaires' cross-age items., Results: In the body functions component, paying attention, seeing, muscle tones were common problems for all age groups. In the activity and participation component, all participants showed problems in basic interpersonal interactions. Finally, in the environmental factors component, barriers concern the climate and health services. On the other hand, families reported adequate support from social services., Conclusions: Although these findings must be validated, they appear to be promising and can contribute to understanding the daily functioning features of patients with AHC.

In clinical routine, the evaluation of sustained attention is often performed by analyzing the behavioral data collected during specific tests. Such analyses are rarely accompanied by a detailed examination of the subject's simultaneous electroencephalographic (EEG) activity, and particularly its frequency content. In this study, a group of healthy volunteers and a group of patients affected by diffuse axonal injury (DAI) were tested while performing a modified version of the Conners' continuous performance test. A comparative study was carried out between the behavioral and neuropsychological data obtained during the task, to investigate neural activation. Spectral power was calculated for each of the recorded EEG signals, taking account of the frequency bands traditionally considered in literature. Then a compressed spectral array sequence of spectra was plotted to put into evidence the temporal modifications in the signal power spectral density, and, finally, the analysis of the rhythm variability was carried out. Evaluation of the results thus obtained shows that the two groups registered very different cerebral activation dynamics during the ongoing attentional task. Moreover, DAI patients showed mild cortical activation in the prefrontal region, spread equally throughout both brain hemispheres, while controls showed strong predominant activation of the right prefrontal area. Our findings encourage further investigations of the combined employment of tests and EEG recordings during the clinical assessment of sustained attention performance.

Background: Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel alpha 1 subunit (Na(v)1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy., Objective: To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause)., Design: Clinical characterization and molecular genetic analysis of a cohort of patients., Setting: University hospitals, rehabilitation centers, and molecular biology laboratories., Patients: Sixty unrelated patients with cryptogenic epileptic syndromes., Main Outcome Measures: Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening., Results: No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative., Conclusions: These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.

An optimum signal in the Ornstein-Uhlenbeck neuronal model is determined on the basis of interspike interval data. Two criteria are proposed for this purpose. The first, the classical one, is based on searching for maxima of the slope of the frequency transfer function. The second one uses maximum of the Fisher information, which is, under certain conditions, the inverse variance of the best possible estimator. The Fisher information is further normalized with respect to the time required to make the observation on which the signal estimation is performed. Three variants of the model are investigated. Beside the basic one, we use the version obtained by inclusion of the refractory period. Finally, we investigate such a version of the model in which signal and the input parameter of the model are in a nonlinear relationship. The results show that despite qualitative similarity between the criteria, there is substantial quantitative difference. As a common feature, we found that in the Ornstein-Uhlenbeck model with increasing noise the optimum signal decreases and the coding range gets broader.

Normalized entropy as a measure of randomness is explored. It is employed to characterize those properties of neuronal firing that cannot be described by the first two statistical moments. We analyze randomness of firing of the Ornstein-Uhlenbeck (OU) neuronal model with respect either to the variability of interspike intervals (coefficient of variation) or the model parameters. A new form of the Siegert's equation for first-passage time of the OU process is given. The parametric space of the model is divided into two parts (sub-and supra-threshold) depending upon the neuron activity in the absence of noise. In the supra-threshold regime there are many similarities of the model with the Wiener process model. The sub-threshold behavior differs qualitatively both from the Wiener model and from the supra-threshold regime. For very low input the firing regularity increases (due to increase of noise) cannot be observed by employing the entropy, while it is clearly observable by employing the coefficient of variation. Finally, we introduce and quantify the converse effect of firing regularity decrease by employing the normalized entropy.

In clinical routine, the evaluation of sustained attention is often performed analyzing behavioral data collected during specific tests. It is not common to match such analyses with a detailed examination of the subject's simultaneous electroencephalographic (EEG) activity, and particularly its frequency content. In this study, 9 healthy volunteers underwent a modified Conners' CPT test, while their EEG were contemporarily recorded. Spectral power was calculated for each of the recorded EEG signals, with particular attention to frequency bands that are traditionally reported in literature. Then Compressed Spectral Array (CSA) sequence of spectra was plotted, and the analysis of the variability of the rhythms was carried out. Evaluation of the obtained results shows that the nine subjects shared a progressive backshift of alpha rhythm during the accomplishment of the CPT test. Moreover, beta and gamma activities were stronger in the right than in the left hemisphere. An intense and widespread decrease in EEG spectral power during test performing became visible in many subjects. Statistical analysis provided evidence that EEG activity correlates with the test behavioral results in many cerebral areas. For this reason, we encourage further investigations of the combined employment of tests and EEG recording during the clinical assessment of sustained attention performance.

The diagnosis of a subtelomeric rearrangement has immediate impact on counseling, particularly in the case of familial rearrangements. However, the existence of subtelomeric imbalances with absent phenotypic effects may hamper genetic counseling, particularly when the rearrangement has not been previously described. We report on a new subtelomeric polymorphism, consisting of a familial subtelomeric rearrangement of chromosome 19 resulting in distal trisomy for 21q, detected in a child with Angelman Syndrome (AS) due to an UBE3A mutation. This report shows that new, previously unknown, benign subtelomeric variants may complicate the correct clinical diagnosis.

We report the case of a 32-month-old female patient presenting with cerebellar pilocytic astrocytoma with epileptic seizures, psychomotor delay, and severe language delay. Usually, the typical onset of cerebellar tumor is characterized by raised intracranial pressure and cerebellar incoordination. A review of the few cases reported in the literature evidencing epileptic seizures symptomatic of a focal, nondegenerative mass limited to the cerebellum is included. Moreover, a discussion about the cerebellar contribution to nonmotor functions in children is presented, in particular following tumor resection.

We present a computational algorithm aimed to classify single unit spike trains on the basis of observed interspikes intervals (ISI). The neuronal activity is modeled with a stochastic leaky integrate and fire model and the inverse first passage time method is extended to the Ornstein-Uhlenbeck (OU) process. Differences between spike trains are detected in terms of the boundary shape. The proposed classification method is applied to the analysis of multiple single units recorded simultaneously in the thalamus and in the cerebral cortex of unanesthetized rats during spontaneous activity. We show the existence of at least three different firing patterns that could not be classified using the usual statistical indices.

Objective: To investigate the relevance of serum topiramate (TPM) levels (SL) monitoring in the clinical management of epileptic patients., Methods: Twenty-seven patients with different epileptic syndromes on TPM therapy were studied. TPM was used as add-on in 26 patients, only in one as monotherapy de novo; one case changed from TPM as add-on to TPM monotherapy. The mean follow-up time was 11 months. TPM SL were measured by fluorescence polarization immunoassay., Results: We analyzed the TPM SL in 43 samples from 27 patients. Mean TPM dose was 3.9mg/kg, mean TPM SL 13.43mumol/l. The mean level to dose ratio (LDR) was 3.63mumol/l/mg/kg. Four patients became seizure-free, all with TPM dosages lower than the mean. Eleven patients had at least 50% seizure reduction. The comedication with enzyme-inducing AED significantly reduced TPM SL and LDR. On the other hand, the influence of valproic acid (VPA) on TPM LDR was not univocal. Indeed, patients younger than 15 years showed SL values lower than the adults did, although not significant., Conclusion: We could not detect a direct relationship between high TPM SL and efficacy neither between high TPM SL and tolerability. However, the data we collected seem to favour the hypothesis that high TPM dosage and SL might be associated to a greater probability to reduce seizure severity.

The aim of this work is to describe, using functional imaging techniques, the spatial and temporal distribution of neural activations ensuing from execution of cognitive functions and to find correlation in data coming from analysis modalities related to different physical properties. A 10-mm continuous performance test (CPT) was administered to a group of healthy subjects as measure of sustained attention. Images of electroencephalography (EEG) and of near infrared spectroscopy (NIRS) were recorded during the task. cerebral activation's measure is obtained from the recording of quantities linked with electrical neural activity for the EEG and with change in blood oxygenation for the NIRS system. Good agreement was found between the two modalities, both showing higher activation in the middle upper frontal region and similar temporal trend. A further understanding of the superior central nervous system behavior can be achieved from combined use of both imaging modalities.

The level of agreement in the interpretation of EEG records by different experienced readers working in three child neurology tertiary centers has been evaluated. EEG recordings randomly chosen from patients with idiopathic epilepsy were included. Optimal or suboptimal agreement was found for presence of ictal and interictal discharges. Contrary to ictal discharges, the distribution and location of interictal discharges was not unanimously interpreted and agreement was unsatisfactory when assessing the background activity.

Improved electron energy confinement in tokamak plasmas, related to internal transport barriers, has been linked to nonmonotonic current density profiles. This is difficult to prove experimentally since usually the current profiles evolve continuously and current injection generally requires significant input power. New experiments are presented, in which the inductive current is used to generate positive and negative current density perturbations in the plasma center, with negligible input power. These results demonstrate unambiguously for the first time that the electron confinement can be modified significantly solely by perturbing the current density profile.

The clock errors are modeled by stochastic differential equations (SDE) and the relationships between the diffusion coefficients used in SDE and the Allan variance, a typical tool used to estimate clock noise, are derived. This relationship is fundamental when a mathematical clock model is used, for example in Kalman filter, noise estimation, and clock prediction activities.

Objective: To investigate whether Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles., Methods: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated., Results: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency "giant" SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD., Conclusions: Patients with Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

Background: Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation., Methods: The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation., Results: All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression., Conclusion: The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.

Before starting antiepilepsy therapy (T1) and after 1 year (T2), 19 children (7 female) affected by focal or generalized idiopathic epilepsy were considered with the aim of studying attention performance. All of the children received a neurological examination and clinical interview, electroencephalography (EEG) in wakefulness or sleep, and a standardized computerized measure of attention (Conners' Continuous Performance Test). At T1, 21% of the patients showed a specific attention disorder, and their percentage rose to 42% after 1 year, despite complete control of seizures. The prognosis was strongly correlated with (1) the presence of active seizures for a period of over 6 months, (2) the persistence of specific interictal abnormalities on an electroencephalogram at T2, and (3) the presence of emotional and behavioral disorders at the diagnosis of epilepsy. Our results confirm that attention disorders are frequent in children with idiopathic epilepsy. The Conners' Continuous Performance Test has proven useful both for diagnosis and follow-up over time.

Congenital cytomegalovirus (CMV) infection can cause malformations of cortical development (MCD). It is difficult to establish CMV as a cause of MCD several months postpartum. This can now be done by detection of CMV DNA in dried blood spots (DBS test) on Guthrie cards. The authors used DBS tests to assess 10 patients with MCD of unknown cause. Four of the 10 patients were positive for CMV.

A 17-year-old boy with polymorphic simple and complex partial seizures is described. Magnetic resonance imaging revealed a unilateral periventricular nodular heterotopia near the occipital ventricular right horn. Interictal and ictal electroencephalographic recordings showed bilateral specific epileptiform anomalies in the occipital region and asynchronous slow waves in frontal areas. Single photon emission computed tomography documented a reduction in regional cerebral blood flow in an area of the left occipital cortex and a symmetric increase in tracer uptake in the frontal lobes. The neuropsychologic assessment revealed a dysfunction of the frontal associative areas. Data collected led the authors to suspect a more diffuse cortical dysfunction than the nodular heterotopia revealed on magnetic resonance imaging.

Two familial X-linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X-linked transmission. On the other hand, the pedigrees of 2 families ruled out X-linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X-linked syndrome of cortical maldevelopment.

A family is described in which bilateral perisylvian polymicrogyria was present in 6 members of 3 consecutive generations. Typical anatomic and clinical findings of the syndrome, with a mild phenotype, were present in the 5 affected women from all 3 generations. More severe impairment was observed in the only affected male individual, a boy, in the third generation. Analysis of the pedigree and severity of the phenotype in the affected boy are consistent with transmission of an X-linked dominant trait, although other patterns of inheritance cannot be ruled out with certainty.

The polypeptide diazepam binding inhibitor (DBI) displays epileptogenic activity by binding to benzodiazepine receptors. We analyzed DBI concentrations in the plasma of pediatric and adult epileptic patients, as a possible peripheral marker in epilepsy. DBI plasma concentrations are significantly higher (+ 62%, P < 0.001) in adult patients and slightly but significantly higher (+15%, P < 0.01) in pediatric patients, compared to age-related controls. Strikingly, plasma DBI is much higher (+81%, P < 0.001) in generalized epilepsy in adults and in drug-resistant pediatric and adult patients. Based on these findings, plasma DBI may be considered as a peripheral biological marker of epilepsy and, in association with lymphocyte benzodiazepine receptor density, of anticonvulsant drug responsiveness.

A mortality cohort study (1951-1988) was conducted on 526 female workers in two lead and zinc mines in southwestern Sardinia (Italy), 310 of whom had been exposed to silica. Women exposed to silica showed a nonsignificant 38% increase in the standardized mortality ratio (SMR) for nonmalignant respiratory diseases, which was highest and statistically significant among women at the mine with the highest exposure to silica (SMR = 217; 95% confidence interval [CI] = 104, 400; based on 10 observed and 4.6 expected deaths). Five deaths from lung cancer also occurred among those exposed to silica (SMR = 283; 95% CI = 91,660), but the excess was not related to the level or duration of exposure. No information was available concerning lifestyle risk factors in this cohort. However, smoking was quite rare among Sardinian women at the time cohort members worked, so it may be presumed that very few of them were smokers.

We describe three female patients (aged 10, 11 and 21 years) with a Magnetic Resonance appearance of band heterotopia, a diffuse neuronal migration disorder, also known as double cortex syndrome. The clinical picture was characterized by the association of epilepsy and mental retardation in all three cases, as has been previously described in patients with double cortex syndrome. The epileptic syndrome (Lennox-Gastaut syndrome in one case, and symptomatic partial epilepsy in the other two), the response to medical treatment, and the severity of mental retardation were markedly different in the three patients. No clear-cut relationship was found between the clinical picture and the severity of the neuronal migration disorder, as revealed by magnetic resonance imaging. In the three cases, EEG shares some common features: multifocal epileptic activity with frequent bilateral diffusion, and high-amplitude anterior fast activity, intermingled in two patients with bursts of repetitive spikes.

Ten patients with dystrophia myotonica (8 adults and 2 prepubertal children), from three unrelated families, were investigated for diurnal sleepiness, using a sleep questionnaire and multiple sleep latency test (MSLT). Immunogenetic study was also carried out to assess the involvement of HLA region genes in modulating susceptibility to excessive diurnal sleepiness (EDS). EDS was reported by 5 patients and confirmed in each case by MSLT. In the whole patients group, mean daytime sleep latency was significantly shorter than in healthy controls matched for age and sex. At clinical or neurophysiological evaluation, EDS did not show the features associated with the narcoleptic type. In only one case hypersomnolence could be explained by underlying sleep-disordered breathing. HLA patterns were different from those frequently observed in the narcoleptic or non-narcoleptic types of hypersomnia. In patients with EDS, the frequency of the DQW1 and particularly of the DRW6-DQW1 haplotype appeared to be over-represented.

1. The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2. Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P less than 0.01) in patients taking enzyme-inducing anticonvulsants and increased by about 50% (P less than 0.05) in patients taking sodium valproate. 3. Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 +/- 2.0 h vs 9.1 +/- 3.4 h, means +/- s.d., P less than 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 +/- 1.8 h) were similar to those found in controls.

A multiparametric investigation of daytime sleepiness was performed in 18 healthy young university students. After undergoing a standard polysomnographic recording at home the night before, all subjects were evaluated by Multiple sleep latency test (MSLT) at 10.00, 12.00, 14.00, 16.00, 18.00. Subjective sleepiness (by using Visual Analogue Rating Scale) and performance tasks (Cancellation Test, Digit Symbol Substitution, Choice Reaction Time, Critical Flicker Fusion Threshold) were also assessed at the same times. Mean daily sleep latency was found to be about 10 minutes, with several individual values in the borderline range (greater than 5 less than 10 minutes). Subjects did not rate themselves as excessively sleepy and there was no correlation between subjective and objective estimates of sleepiness. No consistent correlation was found between subjective-objective sleepiness and results of performance tests. Anxiety trait (Spielberg State Anxiety Trait) did not correlate with sleepiness, but higher anxiety scores were significantly associated with poor performance. These results confirm the occurrence of fairly marked objective drowsiness in healthy young subjects which, however, was not associated with subjective sleepiness and did not adversely affect performance on a variety of tests of CNS function.

A long-term, clinical and polygraphic investigation of nocturnal sleep was performed in nine non-ambulatory Duchenne muscular dystrophy patients (mean age 16.2 years, range 10-20) with normal daytime blood gas tensions. The data show that nocturnal sleep has some adverse influence on oxygen balance in these patients as suggested by the occurrence of arterial oxyhaemoglobin desaturation occurring mainly during REM stages. This adverse effect tended to worsen significantly within a 2-year period in the absence of any sleep-related symptoms. A significant correlation between the degree of oxygen imbalance during sleep and the degree of restrictive thoracic syndrome during wakefulness was shown.

The comparative pharmacokinetics and pharmacodynamics of single oral doses of eterobarbital (N,N'-dimethoxymethylphenobarbital, DMMP, 400 mg) and phenobarbital (200 mg) were evaluated in a double-blind study in 8 normal volunteers. Following administration of DMMP, no unchanged drug could be detected in serum. The active monomethoxymethyl metabolite (MMP) appeared rapidly in the circulation but its concentration remained generally low and declined below the limit of detection (0.5 micrograms/ml) usually before 9.5 h. Serum levels of DMMP-derived PB increased slowly and reached a peak between 24 and 48 h in most cases. One subject showed an atypical pharmacokinetic profile, characterized by relatively high levels of MMP and a delayed appearance of low levels of PB. After administration of PB, serum drug levels peaked within 1.5 h and remained, at all sampling times, higher than those observed after intake of DMMP. Compared with DMMP, PB induced greater sedative effects as assessed by visual analogue rating scale, critical flicker fusion frequency and multiple sleep latency tests.

A night-time polygraphic sleep recording was performed in 14 patients with late onset partial epilepsy receiving chronic carbamazepine monotherapy. All patients had unstable nocturnal sleep patterns as indicated by significantly altered sleep continuity parameters compared with normal controls. Patients with poor seizure control tended to show greater alterations of sleep stability compared to patients in complete clinical remission but the difference failed to reach statistical significance. Epileptic patients also showed less REM sleep and longer REM latencies compared with normal controls, the most altered REM values being observed in patients with poor seizure control. These data confirm that polygraphic sleep alterations are seen in patients with symptomatic focal epilepsy and indicate that these abnormalities occur irrespective of seizure recurrence.

The relationship between the serum concentration of phenobarbital and its pharmacodynamic effects was assessed in a double-blind controlled study in eight normal volunteers who were given single oral doses of phenobarbital (200 mg) and placebo according to a randomized cross-over design. Compared with the placebo session, phenobarbital was found to induced CNS-depressing effects as assessed by visual analogue rating scales (VARS) and critical flicker fusion tests (CFF), whereas no significant effects were detected on choice reaction times, tappings, and digit symbol substitutions. There was a clear-cut dissociation between the time course of serum phenobarbital levels, which remained at a plateau throughout most of the period of observation (up to 72 h) and its subjective (VARS) and objective (CFF) effects, which could be documented only for up to 9 h after administration. These data suggest that pharmacodynamic tolerance develops rapidly even after a single oral dose of the drug. Multiple Sleep Latency Tests (MSLTs) were also performed in the same subjects and showed that phenobarbital increases diurnal drowsiness and attenuates the circadian variation in drowsy state that is seen under control conditions. MLSTs appeared to be superior to other tests in documenting the sedative effects of the barbiturate.

The non-penalization envisaged by the new law concerning the use and possession of drugs, will not cause the population of drug addicts to disappear from the prisons; it is however to be expected a qualitative modification of them, with the drug addicts clinically in most serious and persistent conditions and more involved with the criminal subculture, gradually increasing in number. Such individuals will represent a group of potential customers much different from that found up to now, and their more meaningful features will concern their age (higher), polytoxicomania (almost always resulting in heroinism), the abandonment of all family ties, of the pristine social and cultural status, of work, to acquire a new role, where identity is extremely ambiguous and uncertain. As concerns the treatment hypotheses, the less involved users being no longer dealth with--upon whom the attention of operators had been chiefly centered, and on whom the prospects of a psychotherapeutic success had been founded--only two solutions are regarded as implementable in the future: either to give up all intramural treatments, with the exception of those having a medical character, and, extramurally, to provide for the supply (controlled and through dispensaries) of heroin or substitute drugs, so as to reduce as much as possible the danger drug addicts represent for society; or to establish therapeutic or intramural communities, forming the one instrument capable of suggesting or conditioning new identity patterns, as an initial stage of an analogous institutional treatment to be continued when the convict leaves the prison.

Research was conducted in 39 cases of urinary infections caused by Pseudomonas Aeruginosa in patients in various hospital wards. The aim was to assess the onset of such opportunistic infections in the hospital environment as reported earlier by other authors. A comparison was then made between the most commonly used antibacterial drugs used to combat such infections assessing their percentage efficacy on the basis of the germs' resistance to the drug.