Three different scenarios for epileptic spasms.

Epileptic Spasms (ES) is a type of seizure usually occurring in the context of a severe childhood epileptic syndrome associated to significant Electroencephalogram (EEG) abnormalities. There are three scenarios in which ES may occur. The first one is represented by West Syndrome (WS): ES occur in a previously non encephalopathic infant in association with the development of a hypsarrhythmic EEG pattern. In most cases, standard treatment with Adrenocorticotropic Hormone (ACTH), steroids or vigabatrin leads to a reversal of the electroclinical picture. The second scenario is represented by Developmental and Epileptic Encephalopathies (DEEs): ES are documented, often along other seizures types, in an infant who often shows developmental delay since birth; the EEG pattern is pathological both in wakefulness and in sleep, without typical features of hypsarrhythmia; therapies (with the exception of few potentially treatable syndromes) are poorly effective. The last scenario is represented by ES in the context of Focal Epilepsies (FEs): ES, sometimes showing focal signs or closely related to focal seizures, are associated with focal brain lesions. Treatment with ACTH, steroids or vigabatrin may not be effective as well as antiepileptic drugs for focal epilepsies. In drug-resistant patients, surgery should be considered. Although there are some gaps in our current scientific knowledge concerning the peculiar electroclinical and physiopathological features of ES, we nowadays possess the necessary tools to correctly frame this unique seizure type into one of these scenarios and therefore properly manage the diagnostic and therapeutic workup.

Oxygen exchange and energy metabolism in erythrocytes of Rett syndrome and their relationships with respiratory alterations.

Rett syndrome (RTT) is a neurodevelopmental disorder, mainly affecting females, which is associated to a mutation on the methyl-CpG-binding protein 2 gene. In the pathogenesis and progression of classic RTT, red blood cell (RBC) morphology has been shown to be an important biosensor for redox imbalance and chronic hypoxemia. Here we have evaluated the impact of oxidation and redox imbalance on several functional properties of RTT erythrocytes. In particular, we report for the first time a stopped-flow measurement of the kinetics of oxygen release by RBCs and the analysis of the intrinsic affinity of the hemoglobin (Hb). According to our experimental approach, RBCs from RTT patients do not show any intrinsic difference with respect to those from healthy controls neither in Hb's oxygen-binding affinity nor in O2 exchange processes at 37 °C. Therefore, these factors do not contribute to the observed alteration of the respiratory function in RTT patients. Moreover, the energy metabolism of RBCs, from both RTT patients and controls, was evaluated by ion-pairing HPLC method and related to the level of malondialdehyde and to the oxidative radical scavenging capacity of red cells. Results have clearly confirmed significant alterations in antioxidant defense capability, adding important informations concerning the high-energy compound levels in RBCs of RTT subjects, underlying possible correlations with inflammatory tissue alterations.

Donepezil modulates the endogenous immune response: implications for Alzheimer's disease.

OBJECTIVE: Donepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Aß). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC). METHODS: Fifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n = 25) or not (DNPZ-, n = 25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for Aß and NAb determination. RESULTS: Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-Aß NAb with respect to DNPZ- patients and Aß 1-42 with respect to normal controls. CONCLUSIONS: Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aß may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd.

Use of the DISCERN tool for evaluating web searches in childhood epilepsy.

Epilepsy is an important cause of neurological disability in children. Nowadays, an increasing number of parents or caregivers use the Internet as a source of health information concerning symptoms, therapy, and prognosis of epilepsy occurring during childhood. Therefore, high-quality websites are necessary to satisfy this request. Using the DISCERN tool, we evaluated online information on childhood epilepsy provided by the first 50 links displayed on the Google search engine. The same links were evaluated by a team of pediatric neurologists (PNs) and by a lay subject (LS). The evaluation performed by the PNs found out that only 9.6% of the websites showed good reliability, that only 7.2% of the websites had a good quality of information on treatment choices, and that only 21.5% of the websites showed good overall quality of the content. With regard to the evaluation performed by the neutral subject, it was found that 21.4% of the websites showed good reliability, that 59.5% of the websites showed poor quality of information on treatment choices, and that only 2% of the websites showed good overall quality of the content. Our conclusion is that online information about childhood epilepsy still lacks reliability, accuracy, and relevance as well as fails to provide a thorough review of treatment choices.

EEG Features in Autism Spectrum Disorder: A Retrospective Analysis in a Cohort of Preschool Children.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG recordings in children with these clinical pictures are abnormal, however the precise frequency of these abnormalities and their relationship with the pathogenic mechanisms and in particular with epileptic seizures are still unknown. We retrospectively reviewed 292 routine polysomnographic EEG tracings of preschool children (age < 6 years) who had received a first multidisciplinary diagnosis of ASD according to DSM-5 clinical criteria. Children (mean age: 34.6 months) were diagnosed at IRCCS E. Medea (Bosisio Parini, Italy). We evaluated: the background activity during wakefulness and sleep, the presence and the characteristics (focal or diffuse) of the slow-waves abnormalities and the interictal epileptiform discharges. In 78.0% of cases the EEG recordings were found to be abnormal, particularly during sleep. Paroxysmal slowing and epileptiform abnormalities were found in the 28.4% of the subjects, confirming the high percentage of abnormal polysomnographic EEG recordings in children with ASD. These alterations seem to be more correlated with the characteristics of the underlying pathology than with intellectual disability and epilepsy. In particular, we underline the possible significance of the prevalence of EEG abnormalities during sleep. Moreover, we analyzed the possibility that EEG data reduces the ASD clinical heterogeneity and suggests the exams to be carried out to clarify the etiology of the disorder.

Super-refractory status epilepticus (SRSE): A case series of 22 pediatric patients.

BACKGROUND: Super-refractory Status Epilepticus (SRSE) is a rare condition in which SE persists or recurs ≥24 h after the onset of anesthesia. Although its characteristics are well defined in adulthood, only few studies on children are available. METHODS: we retrospectively analyzed the population of patients with SRSE aged <18 years treated in the Pediatric Intensive Care Unit of the Bambino Gesù Pediatric Hospital. We assessed clinical history, etiology, neuroimaging, electro-clinical features of SRSE, treatments and neurological status after SRSE cessation. RESULTS: We identified 22 children with median age at SRSE onset of 3.1 years (IQR 1.3-7.3) and SRSE duration of 22.0 days (IQR 11.2-30.5) Before SRSE, 17 patients (77.3%) had an abnormal neurological examination, 18 (81.8%) had a diagnosis of epilepsy, 8 of which already presented an episode of SE. Only 4 patients (18.2%) had New Onset SRSE. Eleven patients had a progressive etiology (PE), 9 had a remote etiology (RE) and 2 patients had an acute etiology (AE). Amongst PE the most frequent etiologies were mitochondrial diseases, while among RE they were Developmental Epileptic Encephalopathies of genetic origin. Time to SRSE cessation was significantly longer in PE (p = 0.04). After SRSE, 8 patients, (7 with PE) showed a significant worsening of neurological status. In this group, mean time at SE cessation was significantly longer (p = 0.05). CONCLUSIONS: pediatric SRSE is mostly associated with progressive diseases and remote etiologies. Underlying etiology seems to impact both on SRSE duration and subsequent neurological evolution, however more studies are needed to confirm these findings.

KETASER01 protocol: What went right and what went wrong.

OBJECTIVE: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies. METHODS: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children. RESULTS: During the 5-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s). SIGNIFICANCE: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.

Transient infant movements (TIM): frequent infant non-pathological developmental motor phenomena.

Lombroso and Fejerman, in 1977, described non-epileptic movements in normal infants and named them "benign myoclonus of early infancy", which were recently relabelled by Fernandez-Alvarez as "benign polymorphous movement disorder of infancy" (BPMDI). The focus of our study was to describe, categorize and point out the peculiar clinical representations of these heterogeneous phenomena through our video footage, particularly to those less experienced in paediatric neurology. We included all infants with a video-EEG performed at our unit or a home video recording of "Fejerman-Lombroso", "benign myoclonus of early infancy", "shuddering attacks" or "paroxysmal non-epileptic movements". Twenty-one children were selected. Age at onset ranged between two and 13 months, age at disappearance ranged between seven and 16 months, age at recording ranged between four and 16 months, and duration of the phenomena ranged between two weeks and 19 months. In total, 85% infants had normal neurodevelopment at onset and follow-up (mean follow-up: 31.47 months) and 15% presented with neuropsychological or neurosensory deficits. We distinguished four different patterns of movements: movement of the head in 50%, shuddering attacks in 30%, tonic brief contractions of the trunk and limbs in 10%, and elevation of the shoulders in 10%. These motor phenomena do not affect neurological status and are not associated with developmental delay. Considering that clinical interpretation may be challenging, especially relative to epileptic seizures, we present an explanatory video of these characteristic events. We also propose a new definition that is simple to remember: "transient infant movements" (TIM).

Neonatal seizures: When semiology points to etiology.

OBJECTIVE: The aim of our study was to evaluate the relationship between seizure semiology and etiological factors in our population of neonates, in pointing out that specific kinds of clinical presentation are strictly related to specific etiologies. METHODS: We selected neonates which presented clinical seizures during video-EEG monitoring performed in Neonatal and Neurological Units between 2010 and 2017. We excluded patients with electrographic seizures only or video-EEGs of poor quality. Seizures were divided into the main subgroups "motor" (focal clonic, focal tonic and myoclonic) and "non motor". For each patient we evaluated etiology, considering two major categories: acute and remote symptomatic. RESULTS: The study included 65 patients, including 44 with an acute symptomatic cause and 21 with remote symptomatic etiology. Focal motor clonic seizures were almost exclusively associated to acute symptomatic etiology (p < 0.05), mainly to stroke and infective causes. Focal motor tonic seizures were the prevalent type of seizures in remote symptomatic etiologies (p < 0.05). They were observed mainly in patients with Developmental Epileptic Encephalopathy. Focal non motor seizures were more represented in acute symptomatic causes (p = 0.01) and were the main type of seizure in HIE. CONCLUSIONS: Seizure semiology in neonates may help physicians in the early recognition of specific etiologies. In particular, focal clonic seizures are strongly suggestive of acute symptomatic causes, allowing an early diagnosis and treatment.

GRIA3 missense mutation is cause of an x-linked developmental and epileptic encephalopathy.

PURPOSE: GRIA3, encoding subunit 3 of glutamate ionotropic AMPA receptor, is associated with X-linked intellectual disability (ID), dysmorphic features, and non-syndromic epilepsy. We aimed to characterize electro-clinical features of patients with GRIA3 variants. METHODS: We report a patient carrying a hemizygous missense variant c.2359 G > A (p.Glu787Lys) inGRIA3 gene. Following a literature search, we also reviewed clinical, electrophysiological, radiological, and genetic features of 19 patients with GRIA3 mutations. RESULTS: This 26-month-old boy had developmental delay, early onset refractory myoclonic epilepsy, and non-convulsive refractory status epilepticus. In published reports, epilepsy was in 6 of 19 patients carrying different genotypes, though epilepsy and electroencephalogram features were not completely defined. Out of the 6 patients, one presented with generalized tonic-clonic seizures, two with myoclonic and clonic events (one also presented with epileptic spasms), and one with atypical absences and myoclonic jerks. Information on type of epilepsy was unavailable for 3 cases. Epilepsy onset was early in life and there was potential tendency for myoclonic/clonic events. The epilepsy was difficult to treat and prognosis is poor. Severity of ID ranged from mild to severe and was variably associated with bipolar affective disorder and autistic spectrum disorders. Other neurological features included hypotonia, asthenic body habitus with poor muscle bulk, and hyporeflexia. CONCLUSION: Our report expands knowledge on the electro-clinical and molecular spectrum of GRIA3 variants. Larger investigations will better define the prevalence of epilepsy, the epileptic phenotype, and syndromic features underlying GRIA3 variants.

Treatment of infantile spasms: why do we know so little?

INTRODUCTION: Infantile spasm (IS) is an epileptic syndrome with typical onset within the first 2 years of life. This condition might be caused by several etiologies. IS is associated with pathological neuronal networks; however, definite hypotheses on neurobiological processes are awaited. AREAS COVERED: Changes in NMDA and GABAB receptors and increase of Ca2+ conductance are some of the possible pathophysiological mechanisms. Animal models can help, but most have only some features of IS. Outcome is strongly affected by etiology and the timing of treatment, which relies still on ACTH, oral steroids, and vigabatrin. No significant differences in terms of efficacy have been documented, though a combination of ACTH and vigabatrin seems to be associated with better long-term outcomes. Despite the increasing knowledge about the etiology and pathophysiology of IS, in the last years, no new treatment approaches have been recognized to be able to modify the neurobiological process underlying IS. Precision medicine has far to come in IS. EXPERT OPINION: Recently, no new therapeutic options for IS have emerged, probably due to the lack of reliable animal models and to the extreme variability in etiologies. Consequently, the outlook for patients and families is poor and early recognition and intervention remain research priorities.

Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies.

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy with a yet undefined etiology, affecting healthy children. It is characterized by acute manifestation of recurrent seizures or refractory status epilepticus preceded by febrile illness, but without evidence of infectious encephalitis. To date, the absence of specific biomarkers poses a significant diagnostic challenge; nonetheless, early diagnosis is very important for optimal management. FIRES is mostly irreversible and its sequelae include drug-resistant epilepsy and neuropsychological impairments. The treatment of FIRES represents a significant challenge for clinicians and is associated with low success rates. Early introduction of ketogenic diet seems to represent the most effective and promising treatment. This review aims to highlight the most recent insights on clinical features, terminology, epidemiology, pathogenesis, diagnostic challenges and therapeutic options.

Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy.

BACKGROUND: In pediatric epilepsy, neurodevelopmental comorbidities could be sometimes even more disabling than seizures themselves, therefore it is crucial for the clinicians to understand how to benefit these children, and to choose the proper antiepileptic drug for the treatment of epilepsy associated to a specific neurodevelopmental disorder. Aim of this paper is to discuss the potential impact on cognition and behavior of new and newest AEDs and to guide the choice of the clinicians for a targeted use in epilepsy associated with specific neurodevelopmental disorders. METHODS: Information in this review is mainly based on peer-reviewed medical publications from 2002 until October 2016 (PubMed). We choose to include in our review only the AEDs of second and third generation approved for pediatric population. RESULTS: Vigabatrin, lamotrigine, topiramate, levetiracetam, oxcarbazepine, zonisamide, rufinamide, lacosamide, eslicarbazepine, and perampanel have been included in this review. The most tolerated AEDs from a cognitive and behavioral point of view are lamotrigine and rufinamide, thus representing optimal drugs for children with cognitive and/or attention problems. DISCUSSION: Most of the new AEDs are initially licensed for adult patients. Data on children are usually very limited, both in terms of efficacy and safety, and the use standardized cognitive and behavioral outcome measures are very limited in pediatric clinical trials. CONCLUSION: Several factors including polytherapy, administration of AEDs with the same mechanism of action and the dose and titration of the drug, should be considered as important in the development of cognitive and behavioral side effects.

Retention of Mitochondria in Mature Human Red Blood Cells as the Result of Autophagy Impairment in Rett Syndrome.

Rett Syndrome (RTT), which affects approximately 1:10.000 live births, is a X-linked pervasive neuro-developmental disorder which is caused, in the vast majority of cases, by a sporadic mutation in the Methyl-CpG-binding protein-2 (MeCP2) gene. This is a transcriptional activator/repressor with presumed pleiotropic activities. The broad tissue expression of MeCP2 suggests that it may be involved in several metabolic pathways, but the molecular mechanisms which provoke the onset and progression of the syndrome are largely unknown. In this paper, we report that primary fibroblasts that have been isolated from RTT patients display a defective formation of autophagosomes under conditions of nutrient starvation and that the mature Red Blood Cells of some RTT patients retain mitochondria. Moreover, we provide evidence regarding the accumulation of the p62/SQSTM1 protein and ubiquitin-aggregated structures in the cerebellum of Mecp2 knockout mouse model (Mecp2 -/y ) during transition from the non-symptomatic to the symptomatic stage of the disease. Hence, we propose that a defective autophagy could be involved in the RTT clinical phenotype, which introduces new molecular perspectives in the pathogenesis of the syndrome.