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Background: Nicolaides-Baraitser and Coffin-Siris syndromes are emerging conditions with overlapping clinical features including intellectual disability and typical somatic characteristics, especially sparse hair, low frontal hairline, large mouth with thick and everted lips, and hands and feet anomalies. Since 2012, mutations in genes encoding six proteins of the BAF complex were identified in both conditions., Methods and Results: We have clinically evaluated a cohort of 1161 patients with intellectual disability from three different Italian centers. A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1. Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex., Conclusions: These results prove that the frequency of these conditions may be as high as the most common syndromes with intellectual deficit (about 1%). Clinical geneticists should be well aware of this group of disorders in the clinical setting when ascertaining patients with intellectual deficit, the specific facial features being the major diagnostic handle. Finally, this work adds information on the clinical differences of the two conditions and presents a fast and sensitive test for the molecular diagnosis., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Within the group of muscular dystrophies, dystroglycanopathies represent an important subgroup of recessively inherited disorders. Their severity varies from the relatively mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies (CMD) with cerebral and ocular involvement. We describe 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation c.367G>A (p.Gly123Arg) in the ISPD gene. Mutations in this gene have been recently reported as a common cause of congenital and limb-girdle muscular dystrophy. Patient 1 is an 8-year-old female with an intermediate phenotype between CMD and early LGMD; patient 2 is a 20-month-old male and second cousin of patient 1, showing a CMD phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both patients. To our knowledge, this is the first report on the co-occurrence of both a CMD/early LGMD intermediate phenotype and a CMD within the same family carrying a homozygous ISPD mutation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Epileptic syndromes with continuous spikes-waves during sleep (CSWS) represent a wide spectrum of epileptic disorders having CSWS as a common EEG-feature. Defined therapeutic strategies are still lacking. We evaluated the efficacy of lacosamide add-on therapy on the EEG, behavior, and cognition in children with CSWS., Material and Methods: Eight children with CSWS refractory to other conventional antiepileptic drugs were included in the study. A 24-h EEG recording was performed at 6-month-interval in all patients. The spike-wave index (SWI) was obtained in each 24-h EEG recording. Neuropsychological data were obtained before lacosamide introduction and after a minimum of 12 months of therapy., Results: After a 6-month period of therapy, 75% of patients was defined as responder, 12.5% as partial responder and another 12.5% as non-responder. In particular, 24-h EEG normalized in 3 cases (37%). After a minimum of 12 months, 24-h EEG normalized in another patient while two patients showed electroclinical relapses. A total of 62.5% of patients was therefore defined as responder. Neuropsychological functions slightly improved in 25% of patients., Conclusion: Although further studies are needed to validate our observations, this study suggests that lacosamide add-on therapy may be safe and effective in children affected by CSWS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Optic perineuritis is a rare form of orbital inflammatory pseudotumor in which the specific target tissue is the optic nerve sheath. Patients are mainly represented by adult women. Differential diagnosis with demyelinating optic neuritis is essential in terms of prognosis and treatment., Case Presentation: An 8-year-old Caucasian girl presented with bilateral loss of vision, disc edema, eye movement impairment, and diplopia. Brain MRI findings were suggestive of optic perineuritis. The patient received steroid pulse therapy followed by prolonged course of oral steroid therapy. The visual acuity recovered dramatically within 2 days. Two months later, a new MRI investigation was normal. No clinical relapse was observed at the follow-up., Discussion: We first report on a child affected by optic perineuritis. Our observation suggests that optic perineurits should be considered in the differential diagnosis of children presenting with visual loss and disc edema. An early and correct diagnosis may lead to an appropriate therapeutic approach with very good outcome., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Studies on the efficacy and tolerability of rufinamide in infants and young children are scarce. Here we report on an open, retrospective, and pragmatic study about safety and efficacy of rufinamide in children aged less than four years, in terms of seizures types and epilepsy syndromes., Methods: Forty children (mean age 39.5 months; range 22-48) were enrolled in the study. The mean follow-up period was 12.2 months (range 5-21). Rufinamide was initiated at a mean age of 26.7 months (range 12-42). Final rufinamide mean dosage was 31.5 mg/kg/day if associated with valproic acid and 44.2 mg/kg/day if not., Results: The highest seizure reduction rate was observed in the epileptic spasms (46%) and drop attacks (42%) groups. Seizure reduction was also observed in tonic seizures (35%) and in the focal seizure (30%) groups. In terms of epilepsy syndrome, rufinamide was effective in Lennox-Gastaut syndrome. Results were very poor for those affected by Dravet's syndrome. Globally, responder rate was 27.5%, including two (5%) patients seizure-free. Adverse reactions occurred in 37.5% of children and were mainly represented by vomiting, drowsiness, irritability, and anorexia. Discontinuation rate due to treatment-emergent adverse events was 15%., Conclusion: The present study concludes that rufinamide may be a safe and effective drug for a broad range of seizures and epilepsy syndromes in infants and young children and represents a valid therapeutic option in this population., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Human Parvovirus B19 (B19V) infection usually causes erythema infectiosum (EI). In recent decades, several uncommon exanthems have been described in association with B19V. Recently, haemorrhagic manifestations such as purpuric-petechial rash have been reported. We describe an unusual paediatric case of B19V associated with generalized petechial eruption, and a review of the recent literature.

Objective: Status epilepticus (SE) is considered a life-threatening medical emergency. First-line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs. Scarce evidence is available to support specific guidelines for the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE., Method: Children with RSE who were treated with ivLCM were included in the study. Efficacy was defined as the cessation of seizures after administration of ivLCM, with no need for any further antiepileptic drug. All patients had been unsuccessfully treated following standard protocols before ivLCM was administered., Results: Eleven children entered the study (mean age: 9.4 years). Etiology was symptomatic in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported., Conclusions: LCM might be an effective and well-tolerated AED in children with RSE., (Copyright © 2014. Published by Elsevier Ltd.)

Background: The outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations., Aim: To assess the long-term neurological outcome of a large sample of children presenting with CwG., Methods: We reviewed clinical features of 81 subjects presenting with CwG (1994-2010) from three different Italian centers with a follow-up period of at least 3 years., Results: Follow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7%). Fourteen children (17.3%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7%), and a transient photosensitivity in one (1.2%). No recurrence of CwG was observed. Three patients (3.7%) presented with a febrile seizure and two (2.5%) with an unprovoked seizure, but none developed epilepsy., Conclusions: The long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

By way of whole-exome sequencing, we identified a homozygous missense mutation in VARS2 in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I and compound heterozygous mutations in TARS2 in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in Single Nucleotide Polymorphism (SNP) databases and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl-tRNA and threonyl-tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wild-type transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl-tRNA synthetases, as causes of clinically distinct, early-onset mitochondrial encephalopathies., (© 2014 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Objective: Available data on the efficacy of lacosamide in children with Lennox-Gastaut syndrome (LGS) are scarce and controversial. We present our experience with lacosamide therapy in children affected by LGS., Material and Methods: Medical charts of all children affected by LGS receiving oral lacosamide adjunctive therapy in six paediatric neurology centres were retrospectively evaluated. Efficacy was determined according to the frequency of countable seizures during the 4 weeks prior to treatment and the frequency in the last 4 weeks of observation. Patients whose seizure frequency was reduced by at least 50% were defined as responders., Results: Eighteen children (mean age 12.3 years) were identified. After a mean follow-up period of 9 months, 33% of patients were responders. None of them was seizure-free during the study period. The overall seizure reduction rate was 29%. The percentage reductions from baseline in tonic seizures and drop-attacks rates were 31% and 20%, respectively. Adverse reactions occurred in 44% of patients. The drug was discontinued in four (22%) patients because of increased seizure frequency (three cases) and walking instability (another patient)., Conclusions: A third of children with LGS were responders after lacosamide adjunctive therapy. Although caution is still necessary when the drug is used in children with LGS, our preliminary observations suggest that lacosamide might be effective and represent a possible therapeutic option in children affected by LGS., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions., (Crown Copyright © 2014. Published by Elsevier Masson SAS. All rights reserved.)

Background: Miller Fisher syndrome is usually a monophasic disorder. Recurrent Miller Fisher syndrome is extremely rare, and all patients with recurrences have been adults. Although the optimal treatment for Miller Fisher syndrome has yet to be established, the typical therapy includes intravenous immunoglobulin or plasma exchange. The efficacy of steroids is still debated., Patients: We describe two children with recurrent Miller Fisher syndrome. Episodes occurred at the age of 11.5 and 13 years in patient 1 and at the age of 8 and 13 years in patient 2., Results: Clinical patterns of the first and recurrent episodes of Miller Fisher syndrome were overlapping. In both patients, steroids were effective in controlling clinical deterioration of Miller Fisher syndrome recurrences., Conclusions: Recurrent Miller Fisher syndrome is a rare disorder that may occur in children. Our observations and a review of the literature suggest that there may be a small group of patients in whom steroids may be a therapeutic option when intravenous immunoglobulin fails to control clinical symptoms., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Lacosamide is effective and well-tolerated antiepileptic drug (AED) in both children and adults., Aim: This multicentric, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in children aged less than four years presenting with refractory focal seizures., Methods: Lacosamide was added to the baseline therapy at a starting dose of 1-2 mg/kg/day and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after a three-month period of therapy. When possible, we compared the initial efficacy and the retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy (defined as the return to the baseline seizure frequency)., Results: Twenty-four children were enrolled in the study. Mean age was 2.7 years. After a minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group of 18 patients. In the latter group, eight patients (44%) were initial responders (three of whom seizure free). After 12 months of follow-up, four of them (22%) maintained the improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4 of the initial responders (50%). Adverse events were seen in 8 (33%) patients., Conclusion: We conclude that lacosamide is an effective and a well-tolerated antiepileptic drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent a possible therapeutic option in infants and young children affected by uncontrolled focal epilepsy., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Reports of childhood epilepsies in temporal association with vaccination have had a great impact on the acceptance of vaccination programs by health care providers, but little is known about this possible temporal association and about the types of seizures following vaccinations. For these reasons the Italian League Against Epilepsy (LICE), in collaboration with other Italian scientific societies, has decided to generate Guidelines on Vaccinations and Epilepsy. The aim of Guidelines on Vaccinations and Epilepsy is to present recent unequivocal evidence from published reports on the possible relationship between vaccines and epilepsy in order to provide information about contraindications and risks of vaccinations in patients with epilepsy. The following main issues have been addressed: (1) whether contraindications to vaccinations exist in patients with febrile convulsions, epilepsy, and/or epileptic encephalopathies; and (2) whether any vaccinations can cause febrile seizures, epilepsy, and/or epileptic encephalopathies. Diphtheria-tetanus-pertussis (DTP) vaccination and measles, mumps, and rubella vaccination (MMR) increase significantly the risk of febrile seizures. Recent observations and data about the relationships between vaccination and epileptic encephalopathy show that some cases of apparent vaccine-induced encephalopathy could in fact be caused by an inherent genetic defect with no causal relationship with vaccination., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Globoid cell leukodystrophy or Krabbe disease is an inherited autosomal recessive disorder caused by mutations in the galactosylceramidase (GALC) gene. Deficiency of GALC results in the accumulation of a highly cytotoxic metabolite galactosylsphingosine (psychosine). In the present study, we describe the development and validation of a sensitive and specific LC-ESI-tandem-MS method for the determination of psychosine in the serum of twitcher mice, the naturally occurring animal model of this disease. The method was validated in terms of accuracy, precision, specificity, linearity and sensitivity. Calibration plots were linear over the concentration range of 2.5-50ng/mL. Recovery of psychosine from serum was in the range 94.20-98.02%. The results of this study show that in the affected mice the concentration of psychosine (ranging from 2.53 to 33.27ng/mL) increased significantly with the progression of the disease. The maximum level (33.27ng/mL) was detected in the serum of one of the twitcher mice sacrificed at 40PND. Psychosine was not detected at significant levels in wild type mice. These results clearly demonstrate that this noninvasive, rapid, and highly sensitive LC-ESI-tandem-MS method is a very useful approach for the detection of psychosine in serum., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome., Methods and Results: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations., Conclusions: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Status dystonicus (SD) is a medical emergency weighed by a relevant morbidity and mortality. It mainly affects patients with primary or secondary dystonia and is often triggered by events such as fever, infections, exposure medications or their abrupt cessation. We report on three patients presenting with SD. Two of them were affected by a static encephalopathy and the other one by a neurodegenerative disorder such as megalencephalic leukoencephalopathy with subcortical cysts (MLC). To our knowledge this is the first patient affected by MLC presenting with SD. All our patients underwent continuous infusion of midazolam, in association with pimozide and trihexyphenidyl, which led to complete resolution of muscular spasms in two patients. In the other one a complete cessation of dystonic spasms was obtained after intrathecal baclofen. From a therapeutic point of view there are no evidence-based management guidelines in SD. The approach is empiric and based on very limited anecdotal reports. On the basis of our observations and an extensive review of the literature we delineated a possible therapeutic strategy of SD in children., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: celiac disease (CD) is an immune-mediated chronic inflammatory disease associated with HLA-DQ2 and DQ8 molecules. We evaluated the role of HLA in the CD diagnostic algorithm in order to contribute to the development of practical indications for the use of HLA typing., Material and Methods: we selected 317 subjects typed for DR-DQ genes. CD was present in 123 patients, and 89 were included in the study; a control sample of 70 healthy individuals was recruited., Results: 64% of patients with CD carried DQ2 heterodimer (α5β2), 13.5% carried DQ8 heterodimer without DQ2, 21.4% only showed β2 chain and 1.1% were positive for DQ2 α5 chain. The only presence of α5 chain did not predispose to CD, while DQB1*02 allele resulted more frequent than in other reports, pointing out the intrinsic correlation between β2 chain and CD. In the case-control study we observed a progression of increased risk, ranging from 1:7 for HLA-DQ2 homozygous to 1:85 for DQ8 heterozygous subjects. Overall, 8,6% of first degree family members were affected, exclusively in presence of HLA-DQ2, -DQ8 or DQB1*02, and CD was significantly more frequent among siblings than parents. Finally, considering the different patterns of clinical presentation among the HLA-DQ risk classes identified we found no relationship between CD clinical presentation and HLA-DQ risk categories., Conclusions: our results strengthen the evidence that HLA-DQ status strongly influences the development of CD and demonstrate that knowledge of a patient's HLA-DQ genotype allows to establish clinically relevant genetic risk profiles.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies which is related to the deletion of tandem repeats on chromosome 4q35. Extramuscular features such as hearing loss, retinopathy, mental retardation, and epilepsy, may be observed in patients carrying large 4q35 deletions resulting in fragment sizes less than 12 kilobases (kb) (normal >35 kb). We report on a family affected by FSHD carrying a small 4q35 deletion and residual fragments length of 17 kb, presenting with epilepsy (three patients), speech delay (two), and mental retardation (one). In all patients semeiology of seizures and interictal EEG anomalies were congruent with a localization-related epilepsy possibly involving the temporal lobe. In conclusion, we provide further evidences that extramuscular findings such as epilepsy, speech delay, and mental retardation may occur in those patients carrying smaller 4q35 deletions, suggesting that a close correlation between 4q35 fragment size and clinical severity in FSHD is therefore not constant. Moreover, a review of the literature and our observations seem to suggest that focal epilepsies, likely related to the temporal lobe in the present family, represent the main type of epilepsy occurring in children with FSHD., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: To assess the clinical characteristics and the outcome of benign convulsions associated with mild gastroenteritis (CwG) in Italian children., Methods: We studied clinical and EEG features of 128 children with CwG who were hospitalized between January 2004 and February 2008 and then followed for at least 12 months in 14 Italian centers., Results: Age at onset ranged from 6 to 60 months. The seizures were generalized in 73 cases (57%), only focal in 16 (12.5%), and secondarily generalized in 39 (30.5%). The duration of the seizures was under 5 min in 97 patients (75.8%), between 5 and 30 min in 26 (20.3%), and longer than 30 min in 5 (3.9%). Seventy-three participants (57%) had 2 or more seizures, which recurred within 24-48 h. In the acute phase, antiepileptic drugs were used in 72 patients (56.3%). Although interictal abnormalities were present in EEG of 28 children (21.9%), these reverted to normal. During the follow up period, only 6 patients (4.7%) suffered from recurrence of CwG, 7 (5.5%) suffered from simple febrile seizures, and 3 (2.3%) developed epilepsy., Conclusions: Recognition of CwG in children allows pediatricians to avoid extensive evaluations and continuous antiepileptic therapy and to reassure parents regarding the lack of long-term complications., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Oxidative stress may lead to abnormal peroxidation of membrane lipids, oxidation of sulfhydryl groups and disruption of nucleic acids. Experimental and clinical studies suggested that free radicals may be involved in the pathogenesis of epilepsy. Three groups of patients were considered in the study. Group 1 (N=34) included patients affected by epileptic encephalopathy; Group 2 (N=31) included those affected by idiopathic epilepsy syndromes and under valproic acid (VPA) monotherapy, and Group 3 (N=22) represented by healthy controls. All patients and healthy children underwent blood withdrawals to evaluate redox status by measuring levels of F2-isoprostanes (F2-iso), advanced oxidative protein products (AOPP), non-protein binding iron (NPBI), thiols (-SH groups), and total hydroperoxides (TH). In comparison to the controls, Group 1 patients showed significantly higher plasma levels of F2-iso, AOPP, and TH. By contrast, no differences there were in the plasma NPBI concentrations. Again, no statistical differences there were in the plasma levels of the oxidative stress markers between patients from Group 2 and normal subjects. Our study showed that patients with epileptic encephalopathy have increased levels of oxidative stress markers. By contrast, normal redox status was observed in patients with idiopathic epilepsy syndromes under long-term VPA monotherapy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPA-associated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors., (Copyright © 2010 S. Karger AG, Basel.)

We describe the case of a 13-year-old male with ù aciduria. Conventional magnetic resonance imaging and diffusion weighted imaging disclosed some previously unreported findings. In particular, we observed an almost total sparing of early myelinated regions, and a restricted diffusion pattern in the dentate nuclei. Magnetization transfer contrast showed a normal range of values in early myelinated regions, and revealed abnormal values in the subcortical temporal white matter, internal capsule and globi palladi.

We report a patient with mental retardation, epilepsy, overgrowth, delayed bone age, peculiar facial features, corpus callosum hypoplasia, enlarged cisterna magna and right cerebellar hypoplasia. Array-CGH analysis revealed the presence of a de novo 3.2 Mb interstitial deletion of the long arm of chromosome 7 involving bands q22.2-q22.3. The rearrangement includes 15 genes and encompasses a genomic region that represents a site of frequent loss of heterozygosity in myeloid malignancies. Four genes are implicated in the control of cell cycle: SRPK2, MLL5, RINT1 and LHFPL3. Haploinsufficiency of these genes might therefore be associated with overgrowth and could confer susceptibility to cancers or other tumours, so that attention to this possibility would be appropriate during regular medical review. In conclusion, array-CGH analysis should be performed in patients with overgrowth where the known causes have already been excluded, because some still unclassified overgrowth syndromes may be caused by subtle genomic imbalances., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Bathing epilepsy, also known as water-immersion epilepsy, refers to a rare form of benign reflex epilepsy in which seizures are precipitated by the normal process of domestic bathing. This condition has been confused with true hot water epilepsy, even though bathing in water at normal temperature is the trigger. Focal seizures predominate with a staring gaze, pallor and generalised features followed by prolonged postictal somnolence. A variable percentage of patients may also show unprovoked seizures. The prognosis is usually favourable, and modifying bathing habits may prevent further seizures. We report two Caucasian patients with bathing epilepsy. In one, seizures were provoked by water immersion. In the other, we noted an unusual triggering factor; pouring of lukewarm water over the genitalia.

Reduced areal bone mineral density (aBMD) is a common feature of neurofibromatosis type 1 (NF1). Moreover, in recent years there has been a growing interest in using quantitative ultrasound (QUS) for the evaluation of bone status. In 55 NF1 subjects (mean age: 9.3+/-5.4yr) and in 51 age- and sex-matched controls we measured aBMD at lumbar spine, at femoral neck (aBMD-FN), and at total femur (aBMD-T). Apparent volumetric bone mineral density (BMAD) was also calculated. In all subjects, QUS parameters at phalanges were evaluated. In NF1 subjects, the values of aBMD and BMAD were lower than in controls at all skeletal sites, but the difference reached statistical significance only at femoral sites (p<0.05). Both aBMD and QUS parameters were lower in those NF1 subjects with skeletal abnormalities than in those without abnormalities, but the difference was statistically significant (p<0.05) only for aBMD-FN and aBMD-T. Multiple regression analysis showed that the subjects with skeletal abnormalities had a higher risk of having bone transmission time (BTT) Z-score and aBMD Z-score at femoral sites less than -1. In conclusion, our results suggest that aBMD and QUS represent useful tools in evaluating the impairment of bone status in NF1 subjects., (Copyright (c) 2010 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this open label pilot study was to evaluate the efficacy and tolerability of levetiracetam (LEV) as 'de novo' monotherapy in children and adolescents with late onset childhood occipital epilepsy-Gastaut type (COE-G)., Material and Methods: Twelve patients suffering from COE-G were enrolled in this prospective study. The age of seizures onset ranged from 6.1 to 16.2 years with a peak of frequency at mean (+/-SD) 10.54 +/- 2.77 years. Therapy with LEV was started at 10 mg/kg/day and, after titration, the final dose was generally achieved within 4 weeks and ranged from 20.7 to 45.2 mg/kg/day., Results: At the 6 month evaluation, 11 (91.6%) of the 12 patients studied were seizure free, and one (8.3%) showed four additional episodes. Electroencephalography (EEG) activity was normal in six (54.5%) patients, unchanged in two (18.1%) children, and in four (33.3%) patients sporadic occipital abnormalities persisted. At the 12-month evaluation all patients were completely seizure free. Four patients (33.3%) continued to show some EEG abnormalities, while eight (72.8%) patients had normal EEG. At the 18-month evaluation all patients were seizure free and 10 patients (83.3%) showed a complete normalization of EEG abnormalities., Discussion: Monotherapy with LEV was effective and well tolerated in patients with COE-G. Nevertheless, prospective, large, long-term double-blind studies are needed to confirm these findings.

A retrospective multicentre study was performed to analyse psychogenic non-epileptic seizures (PNES) in prepubertal and pubertal patients with idiopathic epilepsy and to determine whether have different clinical characteristics. In this study, we reviewed 36 patients from six neurological referral centres: Department of Pediatrics, Chieti (3 patients); Department of Child Neuropsychiatry, Naples (9 patients); Department of Child Neuropsychiatry, Bologna (8 patients); Department of Neuroscience, Tor Vergata University, Rome (3 patients); Department of Pediatrics, La Sapienza University, Rome (5 patients); and Department of Pediatrics, Siena (8 patients). The population was divided according to Tanner'stages into 14 prepubertal (group I) and 22 pubertal (group II) patients. The two groups were compared on several variables examining the differences between them. The most frequent clinical manifestations in group I were unresponsive events, whereas in group II, motor events were exhibited more significantly. Mood disorders, including major depression, appeared more frequently in pubertal group, but this did not reach a significant difference. Among the psychosocial stressors, fear of rejection and need for attention were the predominant types in the prepubertal patients. The findings of this study reveal some similarities and differences between prepubertal and pubertal patients, which might help to identify predictive factors in patients affected by idiopathic epilepsy who can develop PNES.

We describe a de novo 3q27.3q29 deletion in a 2.5-year-old female patient with developmental and growth delay, dysmorphic facial features, mild tricuspid valve dysplasia, bifid thumb, clinodactyly of the 2nd toe bilaterally and scoliosis. The deletion overlaps for about 1Mb with the 1.6Mb region commonly deleted in patients with 3q29 microdeletion syndrome. The phenotype of the two syndromes is not completely overlapping, though the most important clinical features, such as mental retardation and microcephaly, occur in both. This suggests that the deletion in our patient causes a distinct clinical phenotype, not described previously. In the deleted region there are 47 annotated genes. Among them, seven are of particular interest for correlation with clinical features of the patient. Two genes, OPA1 and CCDC50, responsible for autosomal dominant optic atrophy and deafness, respectively, may be important for the correct follow-up of the patient.

Adenosine, a potent anticonvulsant, can be produced in the body by the hydrolysis of adenine nucleotides through the action of ecto- or soluble nucleotidases. Changes in nucleotide hydrolysis occur after pentylenetetrazol-induced epileptic events. We evaluated serum ATP, ADP and AMP hydrolysis rates and soluble nucleotide phosphodiesterase (PDEase) activity at 5, 10, 15, 30 and 60 min, and 12h following an epileptic event. Fifteen patients (seven female, eight male; mean age 15.5 years) were included in the study. The type of seizure was generalized in four patients and was localization related in the remaining 11. There were no differences in adenine nucleotide hydrolysis rates between patients and healthy subjects in the interictal stage. In comparison with controls, ATP, ADP and AMP hydrolysis rates were significantly increased at 5 min (53+/-1.4%, 79.2+/-2.8% and 37.0+/-2.6%, respectively) and up to 30 min following the epileptic event. In contrast to ADP and AMP, ATP hydrolysis remained significantly increased at 60 min (71.4+/-1.6%), returning to the basal level after 12h. Serum PDEase activity was also significantly higher in the patients than in healthy subjects, peaking at 15 min (61+/-2.9%) and remaining significantly increased up to 60 min (4.6+/-1.2%) following the epileptic episode. Globally, the variations in the postictal serum ADP hydrolysis rate almost overlapped those of AMP hydrolysis, whereas changes in the ATP hydrolysis rate overlapped those of PDEase activity. The clinical significance of this elevation in postictal soluble serum nucleotidase activity remains to be clarified. However, it is possible to hypothesize that the higher nucleotidase activity might play a role in the modulation of epileptic events.

Deletions in the azoospermia factor region AZFa on the human Y chromosome and, more specifically, in the region that encompasses the ubiquitin-specific peptidase 9, Y-linked gene USP9Y have been implicated in infertility associated with oligospermia and azoospermia. We have characterized in detail a deletion in AZFa that results in an absence of USP9Y in a normospermic man and his brother and father. The association of this large deletion with normal fertility shows that USP9Y, hitherto considered a candidate gene for infertility and azoospermia, does not have a key role in male reproduction. These results suggest that it may not be necessary to consider USP9Y when screening the Y chromosome of infertile or subfertile men for microdeletions., (2009 Massachusetts Medical Society)

Purpose: To report on the first multicenter Italian experience with zonisamide as an add-on drug for refractory generalised or partial epilepsy in children, adolescents and young adults., Methods: The patients were enrolled in a prospective, add-on, open-label treatment study from eight Italian centres for children and adolescent epilepsy care. Eighty-two young patients (45 males, 37 females), aged between 3 and 34 years (mean 13.1 years), all affected by partial (47) or generalised (35) refractory epilepsy, were enrolled in the study. ZNS was added to the baseline therapy at a starting dose of 1 mg/kg/day twice daily. This dose was increased by 2 mg/kg every 1-2 weeks over a period of up 3 months, according to the patient's response and tolerability, up to a maximum dose of 12 mg/kg. ZNS was given at the mean daily dose of 5.7/mg/kg/24 h (range 1-12 mg/kg)., Results: After a mean follow-up period of 11.9 months (range 2-64 months), 9 patients (10.9%) were seizure-free. The number of seizures decreased by 50-99% in 31 cases (37.8%), by 25-49% in 5 cases (6.1%), remained the same in 29 cases (35.4%) and increased in 8 cases (9.7%). After 15 months of follow-up, 61 patients (74.4%) were still taking ZNS, while the remaining 21 (25.6%) had stopped. Twenty-two patients (26.8%) reported adverse effects while taking ZNS. They generally appeared during the first weeks of treatment, and were mild to moderate. The most frequent adverse effects were irritability and a reduced appetite., Conclusion: ZNS effectively reduced seizure frequency in this pediatric population with both partial and generalised crypto/symptomatic refractory epilepsy. Its overall tolerability was good.

Background: Valproic acid is the drug of choice for a wide variety of epileptic seizures and syndromes because of its broad spectrum of activity and because, in most patients, it is well tolerated. Although weight gain is a well-known adverse effect of valproic acid therapy, only a few studies have addressed weight gain associated with it in children aged 2-8 years., Objective: To evaluate valproic acid-associated changes in the body mass index (BMI) z-scores and to assess changes in serum triglyceride, cholesterol, and fasting glucose levels in young children receiving valproic acid treatment., Methods: Eighty-seven patients (39 females, 48 males) receiving valproic acid therapy for at least 3 months were included in the retrospective longitudinal study. Mean +/- SD age at initiation of therapy was 4.8 +/- 0.8 years. Changes in BMI z-scores as well as serum triglyceride, total cholesterol, and fasting glucose levels were evaluated as continuous variables and analyzed by longitudinal methods for all patients., Results: The average change from baseline in BMI z-scores was 0.80 (p = 0.001) at 3.1 years of follow-up. No significant change in triglyceride, cholesterol, and serum fasting glucose levels was observed over the same period. The percentage of overweight children at baseline was 6.9% and rose to 16% by the final visit (p = 0.081)., Conclusions: Valproic acid-associated weight gain may occur in young children. However, only 16% of patients were categorized as overweight at the end of the study; this percentage overlaps the percentage of overweight healthy young Italian children. The BMI z-scores significantly increased during the first 16 months of therapy, then appeared to level off. These observations may influence clinical practice and decision-making regarding suspending the drug due to weight gain in children in whom seizure control has been achieved.

Topiramate (TPM) is a new, effective and safe antiepileptic drug. TPM is also effective in treating a wide spectrum of conditions such as eating disorders and related anomalies, bulimia nervosa and other conditions in which serotonin (5-hydroxytryptamine, 5-HT) is involved pathogenetically. Plasma serotonin mainly derives from blood platelets, which represent a valid model of serotoninergic neurons. We measured plasma 5-HT levels in 12 children affected by epilepsy who underwent TPM therapy. Inclusion criteria were (i) age range 2-12 years, (ii) weight greater than 12 kg, (iii) no more than one antiepileptic drug used when TPM therapy was instituted, and (iv) a minimum study period of 3 months. After a mean period of 3 months of TPM treatment, a significant increase in mean plasma serotonin levels was observed with respect to the basal levels and those of a control group. There were no significant correlations between the changes in serotonin concentrations and the antiepileptic efficacy or doses of TPM used. TPM may influence serotonin metabolism in children affected by epilepsy. Further studies are needed to establish whether these serotonin plasma changes represent an epiphenomenon or indicate direct effects of TPM on the serotoninergic system.

The introduction of array-CGH analysis is allowing the identification of novel genomic disorders. However, this new high-resolution technique is also opening novel diagnostic challenges when inherited private CNVs of unclear clinical significance are found. Oligo array-CGH analysis of 84 patients with mild to severe mental retardation associated with multiple congenital anomalies revealed 10 private CNVs inherited from a healthy parent. Three were deletions (7q31, 14q21.1, Xq25) and seven duplications (12p11.22, 12q21.31, 13q31.1, 17q12, Xp22.31, Xq28) ranging between 0.1 and 3.8Mb. Six rearrangements were not polymorphic. Four overlapped polymorphic regions to the extent of 10-61%. In one case the size was different between the proband and the healthy relative. Three small rearrangements were gene deserts. The remaining seven had a mean gene content of five (ranging from 1 to 18). None of the rearranged genes is known to be imprinted. Three disease-genes were found in three different cases: KAL1 in dupXp22.31, STS in another dupXp22.31 and TCF2 in dup17q12. The patient carrying the last duplication presents sex reversal, Peters' anomaly and renal cysts and the duplication is located 4Mb away from the HSD17B1 gene, coding a key enzyme of testosterone biosynthesis. Considering the overlap with polymorphic regions, size-identity within the family, gene content, kind of rearrangement and size of rearrangement we suggest that at least in five cases the relationship to the phenotype has not to be excluded. We recommend to maintain caution when asserting that chromosomal abnormalities inherited from a healthy parent are benign. A more complex mechanism may in fact be involved, such as a concurrent variation in the other allele or in another chromosome that influences the phenotype.

Steroids are commonly used for the treatment of intractable epilepsy. Deflazacort has shown similar effects to prednisone, but with a less worrying adverse-effect profile. In this study, we first compared the efficacy, safety, and seizure relapse rate of deflazacort versus hydrocortisone in children affected by drug-resistant epilepsies. This was an open, non-blinded, randomized clinical study of 35 children affected by drug-resistant epilepsies. The study lasted 12 months. Group 1 (16 patients) received hydrocortisone for 6 months; group 2 (19 patients) was treated with deflazacort for the entire study period. Drug efficacy and tolerability were evaluated after 6 months of therapy. Seizure relapse rates were evaluated 12 months after the start of the study. After 6 months of therapy, hydrocortisone was effective in 44% of patients (responders, with a decrease in seizure frequency of >50%). Deflazacort was effective in 47% of patients (P=0.9). Adverse events occurred in 37% of patients using hydrocortisone and in none of those using deflazacort (P=0.002). At the end of the study, seizure relapse rate resulted significantly higher in group 1 than in group 2 (P=0.04). Hydrocortisone may be useful in the treatment of severely drug-resistant childhood epilepsies. However, its effects may be transient. Deflazacort should be considered in the therapeutic armamentarium for epileptic encephalopathies. The drug is as effective as hydrocortisone and may be used in therapy for a long period, with a less worrying adverse-effect profile.

Background and Purpose: To review our experience of the efficacy and tolerability of felbamate in children younger than 4 years., Methods: We used a retrospective chart review to identify 53 children with seizures who were younger than 4 years. Efficacy was evaluated based on the occurrence of responsiveness, defined as seizure frequency reduction of more than 50% for a minimum period of 4 months. Tolerability was based on parent-reported side effects., Results: Twenty-two (41%) patients resulted to be responders and 31 (59%) did not. By univariate analysis, those achieving seizure remission were probably much older, to have a shorter history of epilepsy and a lower frequency of seizures before felbamate therapy. The number of antiepileptic drugs (AEDs) used before felbamate therapy was the only significant predictor of the duration of response to felbamate, with a longer responsiveness to the drug seen in those who were placed under fewer than three AEDs before felbamate compared with those who had taken more than three (median, 16 months vs. 7 months; P < 0.0084). Side effects occurred in 30% of the subjects, but these did not require discontinuation of the drug., Discussion: Felbamate is an effective medication for a wide range of epilepsy syndromes in children younger than 4 years. Although caution is necessary when the drug is used in children, felbamate might represent a possible option for the treatment of epilepsy in this age group.

Late onset childhood occipital epilepsy-Gastaut type (LOCOE) is a rare idiopathic epilepsy syndrome with an uncertain long-term prognosis. Elementary visual hallucinations and interictal spike-and-wave complexes in the occipital areas represent the main electroclinical findings of the syndrome. The functional nature of LOCOE has been emphasized together with the presence of genetic predisposition in the affected patients. Here, we report on two families in which two patients, respectively, showed electroclinical features compatible with LOCOE. Although further studies are needed to validate our observations, the involvement of two generations in one of the families we studied may corroborate the previously formulated hypothesis of an autosomal dominant model of inheritance in LOCOE. Of course, the identification of larger families is propaedeutic to linkage analysis studies.

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation., (Copyright 2008 Wiley-Liss, Inc.)

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are degenerative disorders of muscle. Although the mechanisms underlying muscle degeneration are still uncertain, oxidative-damage has been proposed to play a key role. Isoprostanes are markers of free radical-catalyzed lipid peroxidation; the aim of our study was to evaluate plasma isoprostane levels in group of patients affected by Duchenne and Becker muscular dystrophies. PF(2)-isoprostane levels were measured by colorimetric enzyme immunoassay in the plasma of 17 patients with DMD and 24 with BMD. When compared to a group of healthy controls, affected patients showed significantly higher plasma levels of isoprostanes (p=0.001). When patients were stratified according to the clinical diagnosis, isoprostane levels were not statistically different between DMD and BMD patients. In conclusion whether the condition of oxidative stress found in plasma depends on the degenerative process occurring in muscles or on different mechanisms, such as the release of myoglobin in the blood, should be ascertained. However, our study confirms that oxidative stress findings in DMD/BMD patients are effectively present at the plasma levels. The condition of oxidative stress might act as an adjunctive cause of extra-muscular cell damage to which these patients are exposed for their entire life.

Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene (LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3-->pter and partial trisomy of 12q24.3-->qter. No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3.

Unlabelled: Epilepsy and electroencephalographic (EEG) anomalies are common in subjects carrying chromosomal aberrations. We report clinical and EEG investigations on 13 patients carrying chromosome 2 anomalies, including two patients with inversions, six with translocations, two with partial duplications and three with interstitial deletion syndromes. Epilepsy and/or EEG anomalies were found in one patient with a chromosome 2 translocation, in both of those carrying partial duplications and in all three with interstitial deletion syndromes. No epilepsy or EEG anomalies were detected in the remaining patients., Conclusions: Epilepsy may be associated with chromosome 2 aberrations. Gross rearrangements involving the long arm of chromosome 2 might be more often associated with epilepsy than those involving the short arm. The association of epilepsy with chromosome 2 duplications is less clear. In particular, our observations and a review of the literature appear to suggest that a strict relationship between epilepsy and interstitial deletions involving the 2q24-q31 region. In the latter disorder tonic and focal seizures occur early in life. Generalized and focal myoclonic jerks tend to appear in infancy and are subsequently followed by seizures mixed in type. Seizures usually persist up to late childhood and are drug resistant. Further studies are necessary to better define the electroclinical patterns of patients carrying deletions in 2q24-q31. These may help to direct systematic study of this--probably underestimated--cause of severe epilepsy.

Aicardi syndrome is a congenital disorder characterized by severe psychomotor retardation, corpus callosum agenesis, chorioretinal lacunae, and early-onset infantile spasms. The prognosis is generally poor for children with the classical form. We report a peculiar case of Aicardi syndrome characterized by corpus callosum hypoplasia, brain malformations with subependymal heterotopias, extensive chorioretinal lacunae, seizures, and normal cognitive functions. Therefore, the clinical picture of the syndrome is broader than originally described. Cognitive disorders should not be considered inevitable and the prognosis not ineludibly poor.

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.

Aicardi syndrome (AS) is a rare disorder which includes the triad of total or partial agenesis of the corpus callosum, infantile spasms, and chorioretinal anomalies. Seizures and electroencephalogram findings observed in AS are polymorphic with both focal and generalized seizures. We first report on a patient affected by AS who presented with reflex audiogenic seizures specifically triggered by the starting tune of a popular television news. No other type of stimuli, either simple or complex, were able to precipitate the seizures in the patient. The severe cortical-subcortical lesions commonly observed in AS are associated with hyperexcitability of the cortices and may well account for the broad electroclinical patterns noted in this group of patients. From our report, the context of these patterns should be extended to include reflex audiogenic seizures.

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been detected in patients presenting with seizures in the first few months of life and Rett syndrome features. Twenty-seven cases have been detected to date. Generalized intractable seizures, as infantile spasms, and generalized tonic-clonic seizures and myoclonic seizures characterize the clinical picture of CDKL5 mutations. Here we report on a patient who presented with sleep-related hyperkinetic seizures. Our observation and review of the literature suggest that a broader polymorphic electroclinical pattern with both generalized and focal seizures may occur in patients with CDKL5 mutations. A screen for CDKL5 mutations is useful in patients, mainly females, with a history of early onset intractable seizures and becomes mandatory when idiopathic infantile spasms and/or atypical Rett syndrome features are also present.

To assess the efficacy, tolerability and safety of Levetiracetam (LEV) therapy, we identified 21 (15 male; 6 female) patients with a history of benign epilepsy with centrotemporal spikes (BECTS), with and without secondarily generalization in children and adolescents aged between 5.0 and 12.1 years. LEV was administered as a first drug (number of patients=9) or converted after previous treatment with other AEDs (number of patients=12). The patients were subdivided into two groups: "newly diagnosed" patients and "converted" patients. Patients were followed up for 12 months and all patients were able to continue on LEV treatment. At the end of follow-up (12 months), all patients were seizure free or showed a reduction of seizures >50%. LEV dosage ranged from 1000 to 2500mg/daily. Overall, 100% of patients completed the 12 months study, without any important side effect. Somnolence and irritability occurred in two (9.5%) patients. Our results support findings that LEV monotherapy is effective and well tolerated in children with BECTS. Prospective, large, long-term double-blind studies are needed to confirm these findings.