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The aim of this study was to describe the phenotype of Leber hereditary optic neuropathy occurring in pediatric females. This disease generally affects young adult males, but it can occur also in females, and research data in this population is lacking. The very early onset can challenge the diagnosis and delay treatment. We searched PubMed through February 2021 and identified 226 pediatric females with genetically confirmed Leber hereditary optic neuropathy and added a new case of a 3-year-old female. The male-female ratio was 1.8:1; the mean onset age in females was 11 years with the onset at 3 years of age occurring in 3 females only. Acute onset with mild visual impairment was the most common presentation, associated with optic disc edema in 16%. Differential diagnoses are pseudotumor cerebri, optic nerve drusen and optic neuritis. The outcome is poor with partial recovery in 50%, despite some receiving Idebenone therapy.

Acute necrotizing encephalopathy (ANE) is a rare disease not yet described in children with Covid-19. RANBP2 gene variations are implicated in recurrences in the genetic form of ANE, the so called ANE1. We report the first case of pediatric ANE1 following Sars-CoV-2 infection. She had a first episode at 2 years of age following influenza type A with full recovery, many other respiratory and non-respiratory febrile viral infections without recurrences and a severe recurrence following Sars-CoV-2 infection, suggesting a potentiation effect on cytokine cascade. Her MRI showed the typical pattern of injury resembling that of mitochondrial disorders, and supported the role of RANBP2 in mitochondrial homeostasis. This case rises attention on diagnostic challenges and offers several interesting tips for discussion about new perspectives in pathogenesis and targeted treatments.

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These includebarriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs.The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations.A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided.(c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset have been also described. The etiopathogenesis is largely unknown, but it is likely to be multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering environmental stimulus are involved. CVS is characterized by acute, stereotyped and recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity and return to baseline health between episodes. A distinction with other differential diagnoses is a challenge for clinicians. Although extensive and invasive investigations should be avoided, baseline testing toward identifying organic causes is recommended in all children with CVS. The management of CVS requires an individually tailored therapy. Management of acute phase is mainly based on supportive and symptomatic care. Early intervention with abortive agents during the brief prodromal phase can be used to attempt to terminate the attack. During the interictal period, non-pharmacologic measures as lifestyle changes and the use of reassurance and anticipatory guidance seem to be effective as a preventive treatment. The indication for prophylactic pharmacotherapy depends on attack intensity and severity, the impairment of the QoL and if attack treatments are ineffective or cause side effects. When children remain refractory to acute or prophylactic treatment, or the episode differs from previous ones, the clinician should consider the possibility of an underlying disease and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities and specific sub-phenotype. This review was developed by a joint task force of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP) to identify relevant current issues and to propose future research directions on pediatric CVS.

To analyse the neuro-ophthalmological data of children referred for further work-up of infantile nystagmus where ophthalmological evaluation had not achieved a diagnosis.We retrospectively reviewed medical records of patients presenting with infantile nystagmus at our institution between 2007 and 2019. Inclusion criteria were onset before 6 months of age, availability of complete ophthalmic examination, visual electrophysiological tests, and neurological examination. Children with a previous definite ophthalmological diagnosis at onset and those with uncertain nystagmus onset age were not recruited.Out of 142 infants (mean age at nystagmus onset 3.6 mo, SD 1.7, range 0-6 mo; 56 females, 86 males), 23% had neurological nystagmus, 7% mixed neurological and sensory nystagmus, 48% sensory defect, and 22% idiopathic infantile nystagmus. The neurological diagnoses were inborn errors of metabolism, white matter genetic disorders, and brain malformations. The prevalent diagnosis in the sensory defect subgroup was retinal dystrophy.Infantile nystagmus without diagnostic ocular findings may be due to neurological, retinal, and optic nerve disorders or be a benign idiopathic condition. In infants with and without neurological abnormalities, the search for a sensory defect should include visual electrophysiology performed early in the diagnostic pathway.Infantile nystagmus without diagnostic ophthalmological signs has an underlying neurological cause in 30% of cases. Neurological diagnoses include congenital brain malformations, and metabolic and genetic disorders. Sensory defects are part of systemic neurological disorders in 23% of infants. Electrophysiology is useful when ophthalmological examination is uninformative.

Background Ocular paroxysmal events can accompany a variety of neurological disorders. Particularly in infants, ocular paroxysmal events often represent a diagnostic challenge. Distinguishing between epileptic and nonepileptic events or between physiological and pathologic paroxysmal events can be challenging at this age because the clinical evaluation and physical examination are often limited. Continuous polygraphic video-electroencephalography (EEG) monitoring can be helpful in these situations. Methods We review ocular paroxysmal events in newborns and infants. The aim is to improve clinical recognition of ocular paroxysmal events and provide a guide to further management. Using the PubMed database, we identified studies focused on all ocular motor paroxysmal events in neonates and infants. Results Fifty-eight articles were selected on the topic. We summarized and divided these studies into those describing nonepileptic and epileptic ocular paroxysmal events. Conclusions The diagnosis of ocular paroxysmal events can be difficult, but their recognition is important because of the variety of underlying etiologies. The distinction between epileptic versus nonepileptic ocular paroxysmal events often often requires polygraphic video-EEG to identify the epileptic events. For nonepileptic events, further testing can characterize pathologic ocular movements. To determine the etiology and prognosis of ocular paroxysmal events, a multimodal approach is required, including a thorough full history and clinical examination, polygraphic video-EEG monitoring, neuroimaging, and a careful follow-up plan.

Summary The aim of this paper is to describe an uncommon physiological EEG artifact in newborns caused by tongue movements (TM), mimicking anterior slow dysrhythmia (ASD). The subjects are two full-term newborns (39 weeks gestational age (GA)), admitted to the Neonatal Intensive Care Unit for respiratory distress. Both underwent polygraphic video-EEG recording in order to better characterize tremor-like movements of all four limbs that appeared 48 hours after birth. Multichannel video-EEG polygraphy was performed using the 10–20 electrode montage modified for neonates. Ninety minutes of EEG was recorded for each subject, capturing different behavioral states. Background EEG activity was normal for both subjects. During active sleep (AS), synchronous and symmetric slow activity was recorded over bifrontal head regions. For subject 1, bursts of monomorphic 2 Hz delta waves, with an amplitude between 50–100 μV lasting two seconds, were recorded and identified as anterior slow dysrhythmia. For subject 2, polymorphic 1-2 Hz delta waves, 50–100 μV in amplitude and lasting for 20 seconds, were recorded only during suction. After thorough analysis of simultaneous digital video recording synchronized with the EEG trace, this activity was thought to be compatible with glossokinetic artifact. Interpretation of neonatal EEG can be challenging; the background activity is frequently intermixed with physiological artifacts, such as ocular, muscle and movement artifacts, complicating the interpretation. Even continuous video-recording might not make the diagnosis immediately obvious. Therefore, when a rhythmic monomorphic pattern without evolution in amplitude or frequency is seen, we suggest that tongue movement artifact should be considered.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Aim: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Method: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. Results: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo–18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2–4). Time to first relapse was median 31.5months (range 7–89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2–4, vs median mRS 5, range 3–5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046–0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0–1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14–137mo) than in monophasic patients (median 32mo, range 4–108mo; p=0.002). Interpretation: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. What this paper adds: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.

Background and objective Major deficits in the autonomic nervous system function, detected by measuring heart rate variability (HRV), are reported in neonatal hypoxic-ischemic encephalopathy (HIE)). However, it is unknown if they will recover in the long-term. Because of the possible implications for the neurological outcome, this study aimed to evaluate the HRV at school age, in a cohort of children who survived HIE managed with therapeutic hypothermia. Methods A cross-sectional study of HRV in 40 children: 20 HIE survivors and 20 healthy peers. All underwent 5-min plethysmography using the PPG Stress Flow device (BioTekna Italy). Absolute and normalized HRV spectral power in the very low frequency (VLF), low frequency (LF), and high frequency (HF) bands and total power were compared between patients and healthy children. The outcome evaluation included neurological, cognitive (WISC-IV), and psychosocial (Parent Stress Index-Short Form-PSI-SF and psychosocial interview) measures. Results All mean HRV values were significantly higher in survivors of HIE, compared to healthy peers, with the larger effect size for the HF band (Total Power 8.57 ± 0.59 vs 7.82 ± 0.77 ms2, p .003 ES 0.21; HF 7.82 + 0.77 vs 8.57 + 0.59 ms2, p .001 EF 0.24). None of the children had major health, neurological and psychosocial (PSI-SF/interview) problems. The IQ (WISC-IV) was normal in 17/20 patients, borderline in 2, and Conclusions HRV measures highlight autonomic dysfunction at school age in survivors of neonatal HIE, in the absence of major neurodevelopmental and psychosocial problems. The significance of this finding for children's future life needs further neuropsychiatric investigations and longer follow-up.

International audience; BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

According to the operational epilepsy definition adopted by the International League Against Epilepsy (ILAE) in 2014, in patients with one unprovoked seizure, clinicians must stratify the recurrence risk to determine if the criteria for diagnosis of epilepsy have been met and if antiseizure medications (ASM) are required. A remote symptomatic etiology was considered to be one of the best predictors for seizure recurrence, also according to the available prediction tools, but in children with a previously negative history and a normal neurological examination, estimating the probability of seizure relapse remains less obvious. This meta-analysis aimed to fill this gap of knowledge.The PubMed, Embase, and Scopus databases were searched from January 2000 to December 2020. We selected studies reporting children (1 month-18 years old) presenting a first unprovoked seizure. The absence of a known remote neurological pathology had to be clearly stated in the paper or the idiopathic/cryptogenic group data were used; the finding of epileptogenic structural brain MRI abnormalities during the diagnostic workup at the moment of the first unprovoked seizure was not an exclusion criterion. Factors analyzed, as possible predictors of recurrence, included: age at onset, sex, family history of epilepsy, type of seizure (focal or generalized), epileptiform abnormalities on EEG, and epileptogenic structural brain MRI abnormalities.Four studies met the inclusion criteria and the sample size consisted of 741 children. The estimated recurrence rate within 3 years was 50% (95%CI:33.9%-66.0%). Among the predictors of recurrence, focal seizure (OR = 1.52; 95%CI = 1.05-2.19), epileptiform abnormalities on EEG (OR = 1.97; 95%CI = 1.31-2.96), and positive family history for epilepsy (OR = 2.37; 95%CI = 1.56-3.59) were associated with a statistically significant increased risk.The analysis of data available until now cannot adequately assess the risk of recurrence after a first unprovoked seizure in neurotypical children. Prospective and multicenter cohort studies are expected.

Background The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics. Objectives To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented. Methods PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population. Results PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%. Conclusion PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research.

Inherited retinal dystrophies (IRDs) are a major cause of childhood blindness. Timely diagnosis requires a high level of clinical suspicion from both neurologists and ophthalmologists and is increasingly important given recent advancements in gene therapy. We focused our study on genotype-phenotype associations in very early-onset forms of retinal dystrophy, the least well characterized and most challenging diagnostic subgroup.From January 12, 2015 to March 31, 2017, we prospectively performed whole exome sequencing targeted on the phenotype of non-syndromic IRDs and phenotype characterization in a cohort of 68 children affected by very early-onset inherited retinal dystrophies, defined by the onset before five years of age. Phenotype parameters included age at onset, clinical presentation, ophthalmic evaluation, electrophysiological patterns and clinical course.A genetically confirmed diagnosis was achieved in 50 out of 60 (83%) families. The median age at onset was 4 months (6 m in 70%,2 y in 82% of the cases). Clinical presentation was associated with visual loss and nystagmus in the majority of patients. Three (CNGB3, CNGA3 and CACNA1F) out of 22 genes considered pathogenic in the cohort, accounted for 51% of all IRD's, all within the class of stationary IRDs.This study reports on the largest cohort of very early-onset retinal dystrophies, including a description of electroretinography patterns. The electro-clinical phenotype coupled with genetic diagnosis provided additional clues for child neurologists dealing with low vision and nystagmus in infancy. A high level of clinical suspicion improves the diagnosis with important implications for the future of the affected child.

Background A targeted treatment approach is increasingly promoted in epilepsy management. Aim To investigate if etiology (both established or initially presumed) influences antiepileptic drug choice of experts in neonatal seizures. Methods An invitation to participate to a web-based questionnaire was sent to Italian pediatric neurologists affiliated to the Italian Society of Pediatric Neurology (SINP). Results 19 pediatric neurologists from different centers, all consultants of third level Neonatal Intensive Care Units (NICUs) answered. As first-line drug phenobarbital was the most common choice, it was used in 79% of cases of acute symptomatic seizures, in 63% of structural epilepsy, in 42% of genetic epilepsies. As second-line drug phenytoin was used by 58% in acute symptomatic seizures, 37% in structural epilepsy, 5% in genetic epilepsy. Pyridoxine/pyridoxalphosphate was much more used in genetic epilepsy (as first-line in 26%, as second-line in 37%) than in the other two conditions. Long-term conventional EEG monitoring was suggested as important to verify efficacy of drugs in controlling seizures by 84% of interviewed neurologists, but EEG was available around the clock in only 53% of their centers. 1 to 3-channel aEEG/EEG (commonly named CFM) was often used instead of conventional EEG monitoring. Conclusion This is the first survey looking at a targeted approach in treatment of neonatal seizures by pediatric neurologists consulted by NICUs. The treatment approach is similar to previous surveys in case of acute symptomatic seizures, but in case of other etiologies the choices are different, especially for the second-line option. Larger studies should address this topic.

In the first days after birth, a major focus of research is to identify infants with hypoxic ischemic encephalopathy at highest risk of death or severe neurological impairment. This is especially crucial in view of the discussion of redirection of care. We aimed to seek associations between some neonatal routinely recorded parameters and the development of severe outcomes. The study group included 83 neonates recruited for TH because of perinatal asphyxia, who underwent continuous EEG/aEEG monitoring. Severe outcome was defined as death or major neurological sequelae at one-year of age. 17% had seizures, mean age at seizure onset was 22.29 h (range 5–35), mean total period with seizures 21.71 h (range 1–73), seizure burden (%of time seizuring/hour) mean 5.39% (range 0.92%-12.17%), seizure frequency mean 1.8 seizure/hours (range 1–4.25). Severe outcome was significantly associated with pH and base excess measured in the first hour of life, mode of delivery, Apgar score, Sarnat & Sarnat score, EEG-confirmed neonatal epileptic seizures, antiepileptic therapy. Seizures with electro-clinical dissociation increased 6-fold the chance of having a severe outcome (OR CI 95%: 1.02–38.87). We suggest a multi-parametric protocol which can be useful to identify neonates at high neurological risk, available before rewarming from TH.

Background Acute diplopia (AD) is an uncommon and distressing symptom of numerous ocular and neurological conditions, with potentially serious sequelaes. No data are present in pediatrics on the presentation and management of AD. Aim This study investigated characteristics, etiology and health care utilization of the pediatric population with AD accessed to pediatric Emergency Departments (ED), trying to identify “red flags” associated with potentially life -threatening (LT) conditions. Methods We conducted a cohort multicenter study on children with AD in ten Italian hospitals. Patients were classified into diagnostic categories, comparing children with and without LT disease. Results 621 children presented AD at a rate of 3.6 per 10.000. The most frequent diagnosis among no-LT conditions (81.2%) were headache, ocular disorders and minor post-traumatic disease, while LT conditions (18.8%) were represented by brain tumors, demyelinating conditions, idiopathic intracranial hypertension and major post-traumatic diseases. The LT group showed a significantly higher age, with the odds increased by 1% for each month of age. Monocular diplopia occurred in 16.1%, but unlike adult one-fifth presented LT conditions. Binocular diplopia, associated ocular manifestations or extraocular neurological signs were significantly more common in the LT group. At regression logistic analysis strabismus and ptosis were associated with LT conditions. Conclusion The majority of children presented no-LT conditions and more than one-fourth of patients had headache. Monocular diplopia in the LT group was never isolated but associated with other signs or symptoms. Our study was able to identify some specific ocular disturbances or neurologic signs potentially useful for ED physician to recognize patients with serious pathologies.

To assess the prognostic role of evoked potentials (EP) in neonates with normal magnetic resonance imaging (MRI) after therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy (HIE).Thirty-five neonates recruited for TH because of HIE, having normal neonatal MRI, performed neonatal somatosensory (SEP), visual (VEP) evoked potentials and electroencephalogram (EEG). The effect of SEP, VEP or EEG abnormalities on Griffith's developmental scales at 12 and 24 months was measured; positive (PPV) and negative (NPV) predictive value, sensitivity, specificity and accuracy were calculated.At 24 months, 28% had global psychomotor impairment and 57% had isolated impairments. VEP abnormality was associated with impaired hearing-language score (p = 0.002) and performance score (p 0.0001). VEP achieved best PPV (0.91, 95% C.I. 0.62-0.99) and specificity (0.93, 95% C.I. 0.70-0.99). The combination of neurophysiological tests achieved the best NPV (0.85, 95% C.I. 0.58-0.96), sensitivity (0.90, 95% C.I. 0.70-0.97), overall accuracy (0.83, 95% C.I. 0.67-0.92).Psychomotor sequelae may occur in survivors of neonatal HIE with normal MRI. VEP is the single best neurophysiological prognostic marker but the combination of neurophysiological tests has a better value.When facing the challenge of neurodevelopmental prognosis in infants with normal MRI after TH, EPs are useful prognostic tools, complementary to EEG.

The introduction of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy call for reevaluation of the prognostic role of SEPs. This study aimed to test the prognostic value of SEPs using as outcome measure MRI severity and patterns of injury. Neonates eligible for hypothermia were recruited from four Italian Centers if they performed SEP and MRI at 4–15 days of life. SEPs were scored as: normal (bilaterally recorded/unilaterally absent N20) or altered (bilaterally absent N20). The severity of brain injury was measured using a validated MRI scoring system for acute and sub-acute signal abnormalities. 58 neonates were included in the analysis. Bilaterally absent N20 was observed in 10/58 (17%); all had moderate/severe MRI abnormalities. Furthermore, 37 infants (62%) had normal MRI all with normal N20. The positive predictive value of SEP on MRI outcome was of 100%, while the negative predictive value 72%, sensitivity 43%, specificity 100%, with an accuracy of 78% (p Bilateral absence of cortical SEPs is associated with a moderate/severe MRI pattern of injury, as previously reported in non-cooled infants. The prognostic value of SEPs is not (or minimally) affected by hypothermia.

Flash steady state visual evoked potentials (fSSVEPs) were introduced over 80 years ago. In infancy, fSSVEPs may be useful because of their rapid acquisition time and small variability. Few studies proved their utility in clinical setting.1,2. The aim of this study was to evaluate 33 Hz fSSVEPs in children with optic atrophy using standardized visual inspection analysis. Twenty-seven children (mean age 3.9 ± 3.2 years) diagnosed with optic nerve atrophy underwent transient and fSSVEPs in Robert Hollman Foundation. Stimuli consisted of white light flash at 1–33 Hz. Analysis: N1 and P2 waves of TVEP and visual inspection of fSSVEPs for presence/absence of the fundamental response or other harmonics. 3 subjects were excluded because of artifacts. 16/24 patients with abnormal TPEV had absence of fundamental frequency but presence of a subharmonic; 5 patients had an absent or markedly reduced response. All subjects with normal TPEV had absent or markedly reduced fundamental harmonic and presence of a subharmonic. According to Shpak2 fSSVEPs can be useful in differential diagnosis of optic atrophy in children. These preliminary results suggest that the implementation of flash TVEPs methodology with fSSVEPs can provide further diagnostic information and encourage further studies in optic nerve and visual pathways disorders.

PURPOSE Cortical auditory evoked potentials may serve as an early indicator of developmental problems in the auditory cortex. The aim of the study was to determine the effect on neonatal cortical auditory processing of clinical conditions occurring in early prematurity. METHODS Sixty-seven preterm infants born at 29 weeks mean gestational age (range, 23-34 weeks) were recorded at a mean postconception age of 35 weeks, before discharge from the third level neonatal intensive care unit. The average of 330 responses to standard 1000 Hz pure tones delivered in an oddball paradigm was recorded at frontal location. Data of 45 of 67 recruited premature infants were available for analysis. Mean amplitudes calculated from the data points of 30 milliseconds centered on P1 and N2 peaks in the waveforms of each subject were measured. The effect of perinatal clinical factors on cortical auditory evoked responses was evaluated. RESULTS The amplitude of P1 component was significantly lower in infants with bronco-pulmonary dysplasia (P = 0.004) and retinopathy of prematurity (P = 0.03). The multivariate analysis, done to evaluate the relative weight of gestational age and bronco-pulmonary dysplasia and/or retinopathy of prematurity on cortical auditory evoked potentials components, showed an effect of clinical factors on P1 (P = 0.005) and of gestational age on N2 (P = 0.02). CONCLUSIONS Cortical auditory processing seems to be influenced by clinical conditions complicating extremely preterm birth.

Background and purpose: Our aim was to describe the clinical and electrical features and the long-term evolution of childhood occipital epilepsy of Gastaut (COE-G) in a cohort of patients and to compare long-term prognosis between patients with and without other epileptic syndromes. Methods: This was a retrospective analysis of the long-term outcome of epilepsy in 129 patients with COE-G who were referred to 23 Italian epilepsy centres and one in Austria between 1991 and 2004. Patients were evaluated clinically and with electroencephalograms for 10.1-23.0 years. The following clinical characteristics were evaluated: gender, patient age at seizure onset, history of febrile seizures and migraine, family history of epilepsy, duration and seizure manifestations, circadian distribution and frequency of seizures, history of medications including the number of drugs, therapeutic response and final outcome. Results: Visual hallucinations were the first symptom in 62% and the only manifestation in 38.8% of patients. Patients were subdivided into two groups: group A with isolated COE-G; group B with other epileptic syndromes associated with COE-G. The most significant (P < 0.05) difference concerned antiepileptic therapy: in group A, 45 children responded to monotherapy; in group B only 15 children responded to monotherapy. At the end of follow-up, the percentage of seizure-free patients was significantly higher in group A than in group B. Conclusions: Childhood occipital epilepsy of Gastaut has an overall favourable prognosis and a good response to antiepileptic therapy with resolution of seizures and of electroencephalogram abnormalities. The association of typical COE-G symptoms with other types of seizure could be related to a poor epilepsy outcome.

Objective: To clarify the most frequent modalities of use of plasma exchange (PE) in pediatric anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis and to establish the most effective association with other immunotherapies. Methods: Systematic literature review on PE in pediatric anti-NMDAR encephalitis (2007-2015). Results: Seventy-one articles were included (mostly retrospective), reporting a total of 242 subjects (73.2%, 93/127 females; median age at onset 12 years, range 1-18). Median time to immunotherapy was 21 days (range 0-190). In most cases, PE was given with steroids and IVIG (69.5%, 89/128), or steroids only (18%, 23/128); in a minority, it was associated with IVIG only (7%, 9/128), or was the only first-line treatment (5.5%, 7/128). In 54.5% (65/119), PE was the third treatment after steroids and IVIG, in 31.1% (37/119) the second after steroids or IVIG; only in 14.3% (17/119) was it the first treatment. Second-line immunotherapies were administered in 71.9% (100/139). Higher rates of full/substantial recovery at follow-up were observed with immunotherapy given

The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a "burst suppression" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease.

To contribute to characterize electroencephalographic (EEG) activity in pediatric anti- N-methyl-d-aspartate (anti-NMDA) receptor encephalitis, we reviewed electroclinical data of 5 children with anti-NMDA receptor encephalitis diagnosed in our department. We identified 4 longitudinal electroencephalographic phases: in the early phase, background activity was normal, with intermixed nonreactive slow waves; in the florid phase, background activity deteriorated with appearance of sequences of peculiar rhythmic theta and/or delta activity unrelated to clinical changes, unresponsive to stimuli and antiepileptic medications; in the recovery phase, these sequences decreased and reactive posterior rhythm re-emerged; electroencephalogram normalized 2 to 5 months after onset. In conclusion, in the presence of evocative clinical history, recognizing a characteristic longitudinal electroencephalographic activity could provide ancillary aspects addressing the diagnosis and the overall management of children with anti- N-methyl-d-aspartate receptor encephalitis; in particular, knowing that peculiar and recurrent paroxysmal nonepileptic rhythmic theta-delta patterns can occur in these patients could help distinguish paroxysmal epileptic and nonepileptic electroencephalographic activity.

Electroretinography can be performed early in life by non-invasive methodology, using skin electrodes. It provides unique insight into retinal function. 1 The aim of this study was to evaluate patterns of rods and cones dysfunction in early onset retinal dystrophies (EORD), using ERG. Forty-eight patients (mean age 17.6 ± 15.4 months) presenting with sensory nystagmus and electro-clinical diagnosis of isolated retinal dystrophy, were reviewed. ERGs were recorded with skin electrodes, without pupillary dilatation and sedation, under photopic and scotopic conditions. Thirteen cases with Leber’s Congenital Amaurosis had severely depressed or flat ERG early in life. Nineteen children with Achromatopsia had stationary cone involvement confirmed by at least one follow up ERG, 8/19 had also a mild stationary reduction of the amplitude of scotopic ERG. Nine cases with rod-cone dystrophy had progressive abnormality with earlier and prevalent scotopic involvement. Seven patients with cone-rod dystrophy had progressive photopic ERG involvement exceeding scotopic ERG involvement. The ERG represents a valid diagnostic tool, particularly in infancy when other diagnostic tests are more challenging. Specific ERG phenotypes support EORD diagnosis allowing timely genetic testing.

Autonomic function can be measured assessing heart rate variability (HRV). The analysis by frequency domains allows to study sympathetic and parasympathetic activity (Shaffer et al., 2014). This methodology showed to be sensitive in discrimination of high-risk subjects in pathological conditions, such children born prematurely (Fyfe et al., 2015). However, data on physiological maturation of HRV in healthy children is lacking. The aim of this study was to evaluate the development of HRV in healthy children aged (5–10 years). We recorded the HRV in 25 infants, for 5 min, during awake state. The following parameters were calculated: total power, reflecting the global ANS activity; low frequency, reflecting a combination of sympathetic and parasympathetic nervous; high frequency, predominantly reflecting parasympathetic activity. We found total power (range 5.8–9.9, mean 8.16 ds 0.9), low (range 5.12–8.7, mean 7.07 ds0.9) and high (range 4.05–8.97, mean 7.03 ds1.22) frequency power, low and high frequency power ratio (range 0.4–3.2, mean 1.21 ds0.74), and sympathetic (range 28.2–76.4, mean 50.75 ds12.88) and parasympathetic (range 23.6–71.8, mean 49.26 ds12.88) activity percentages. We did not find an effect of age on HRV parameters.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

Background Neonatal seizures are a risk factor for later epilepsy and their etiology is known to be implicated in the outcome but, little is known about this issue in the subgroup of seizures symptomatic of perinatal arterial ischemic stroke. The aim of this study was to describe the long term risk of epilepsy after electroencephalographic confirmed neonatal seizures symptomatic of perinatal arterial ischemic stroke. Design/subject Fifty-five patients with electroclinical ictal data, vascular territory confirmed by neuroimaging and a minimum follow up of 3.5years were identified from a multi-centre prospective neonatal seizures registry. Primary outcome was occurrence of post-neonatal epilepsy. The association of outcome with family history of epilepsy, gender, location of the infarct, neonatal clinical and electroencephalogram data were also studied. Results During a mean follow up of 8years and 5months, 16.4% of the patients developed post neonatal epilepsy. The mean age at first post neonatal seizure was 4years and 2months (range 1–10years and 6months). Location of the infarct was the only statistically significant risk factor ( p =0.001); epilepsy was more represented in males but the difference was not statistically significant. Conclusions Neonatal seizures symptomatic of perinatal arterial ischemic stroke had lower risk and later onset of post-neonatal epilepsy, compared to seizures described in the setting of other perinatal brain insults. Our data have implications for counseling to the family at discharge from neonatal intensive care unit.

Background Moyamoya syndrome represents an etiologically heterogeneous cerebral evolutive angiopathy. It can be associated with both well-characterized and recently described genetic conditions with mendelian inheritance. Case report We report the case of a moyamoya angiopathy in a prematurely born girl affected by congenital heart defect, mild facial dysmorphism, mild neurodevelopmental delay and borderline cognitive profile, associated to a de novo complex rearrangement involving the terminal segment of the short arm of chromosome 6. Conclusion To the best of our knowledge, this is the second case described of pediatric moyamoya syndrome associated with a 6p complex rearrangement. Adding this case to the pertinent literature, we discuss the pathogenic role of rearrangements in 6p region in moyamoya syndrome and suggest to investigate in this region potential genes involved in angiogenesis or vascular homeostasis.

Somatosensory evoked potentials (SEPs) are considered a useful exam for the prognosis of newborns with hypoxic-ischemic encephalopathy (HIE) treated with hypothermia. We examined our data in respect to the MRI, considering the repetitivity of the abnormalities of the SEPs in the time. Of a large number of newborns evaluated with HIE treated with hypothermia in both centers we considered a group of patients with SEPs and MRI just after the completion of hypothermia. 10 patients with abnormal SEPs have repeated the exam after a period ranging from 4 days to 7 months: in 7 cases the SEPs were normalized (in 3 newborns just after few weeks). In conclusion, we think that SEPs abnormalities in neonatal HIE have to be confirmed for a possible role in the prognosis.

Background Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders. Case We report the case of two monozygotic twins who came for the first time to our attention at the age of 20 months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients’ phenotype. Conclusions This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.

Background 14q12 deletions, including the Forkhead Box G1 (FOXG1) gene and point mutations of this gene, are associated with a complex encephalopathy described as a congenital variant of Rett syndrome. A mixture of jerks, athetosis, chorea, and dystonia is observed early in life in many patients. The aim of this article is to report on the spectrum of movement disorders associated with FOXG1 haploinsufficiency, as described in the literature. Patients and Methods We provide a review of the cases reported in the literature, adding two new patients. We searched for a comprehensive set of clinical features, including age at onset and semiology of the movement disorder, occurrence and type of stereotypies, and neurological outcome. Results A total of 51 cases were included in our study. Nonepileptic abnormal movements occurred in 33 cases, often variably combined and presenting during the first year of life. Conclusion The neurological phenotype of FOXG1 haploinsufficiency shows the features of a dyskinetic encephalopathy of infancy.

Background: Breath-holding spells (BHS) are benign non-epileptic paroxysmal events of infancy, rarely occurring with high frequency and complicated by prolonged syncope, convulsions and even status epilepticus. In these cases response to medical treatment is often unsatisfactory. Pacemaker implantation is a possible therapeutic option, but its indications, efficacy and complications have not been clarified yet. Objective: To report a new case of BHS treated with pacemaker and to review its indications and efficacy in patients with severe BHS. Methods: We extensively searched the literature in PubMed on cardiac pacing in patients with BHS and we described a new case. Results: A previously healthy boy presented at the age of 4 months with frequent BHS inconstantly associated to prolonged syncope and post-anoxic non-epileptic and epileptic seizures. Parental reassurance, iron supplementation and piracetam were ineffective. After cardiac pacing at the age of 16 months, BHS and their complications disappeared. We identified 47 patients with BHS treated with pacemaker in the literature. Based on the available data, in all patients asystole or marked bradycardia were documented during BHS or stimulating maneuvers; syncope complicated BHS in 100% of cases and post-anoxic convulsions in 78.3%. Medical treatment before pacing, when administered, was ineffective or poorly tolerated. After pacing, BHS complications disappeared in 86.4% of cases, and decreased in 13.6%. Technical problems with the device were reported in 25.7% of patients and mild medical complications in 11.4%. Conclusions: Pacemaker could be reasonably considered in subjects with frequent and severe BHS, poor response to medications, and demonstration of cardioinhibition during spells.

Convulsive epileptic seizures in children represent a common cause of admission to pediatric emergency department. Data about incidence, etiology, and outcome are still lacking in literature. We retrospectively reviewed medical records of children presenting to our pediatric emergency department with convulsive seizures during a 12-month period and collected their diagnoses over the following year. In all, 182 children met the inclusion criteria, for a total of 214 visits (1.2% of all attendances, n = 24 864). Seizures lasted less than 5 minutes in 76%, 5 to 30 minutes in 20%, 30 to 60 minutes in 2%, and over 60 minutes in 2% visits (“early,” “established,” “refractory,” convulsive status epilepticus, respectively). Incidence of “early” (seizure lasting 5-30 minutes) and “established” (seizure lasting 30-60 minutes) status epilepticus was 52/100 000/year and 7/100 000/year respectively. Most common causes were febrile seizures (56%) and remote symptomatic seizures (19%). Knowing the epidemiology of convulsive seizures in children is important to guide appropriate management and individualized follow-up.

Background Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. Methods To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. Results Mean age at onset was 8 years (range 3–17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12–18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5–82), 85% patients had mRS 0–1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. Conclusions Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.

Background Acute disseminated encephalomyelitis is an inflammatory-demyelinating disorder of the central nervous system usually with a monophasic course and a favorable neurological outcome. Long-term neurocognitive sequelae and quality of life have not yet been fully investigated. Aim To examine neurocognitive outcome and quality of life in pediatric monophasic acute disseminated encephalomyelitis. Methods Of the 36 patients diagnosed with acute disseminated encephalomyelitis at our institution, six were lost to follow-up and eight relapsed (two with multiphasic forms and six with multiple sclerosis). The outcome of the 22 remaining patients was evaluated using four subscales of the Wechsler Intelligence Scales for estimation of IQ, a battery of neuropsychological tests, and semistructured and PedsQL questionnaires for quality of life. The effect of age at onset, neuroradiological recovery, and time elapsed from the acute event on outcome was also investigated. Results Estimated IQ, neuropsychological mean group scores, and quality of life at follow-up were within the normal range, but 23% of the patients had pathological scores in various neuropsychological functions, among which attention was the most clearly affected. The neuroradiological recovery was not correlated with the result of the neuropsychological tests. Age at onset correlated with linguistic skills, whereas the time elapsed from the acute event had a significant effect on attention tasks: scores were worse in the group of patients with a follow-up shorter than 7 years. Conclusion Our results suggest that pediatric monophasic acute disseminated encephalomyelitis has a favorable neurocognitive outcome. Patients with longer follow-up had a better outcome, suggesting a neurocognitive course that is different from that of multiple sclerosis and a potential for long-term recovery of affected functions.

Summary Objective To evaluate whether wearing a wool cap, a routine practice used to prevent heat loss in premature infants, affects interpretation of electroencephalogram spectral analysis. Methods Eighteen premature infants (median gestational age 28 weeks, range 23–32) without neurological complications were randomized to two channel (C3, C4 referred to Cz) digital electroencephalogram recordings with (90 min) and without (90 min) wearing wool cap, at 4 days of life. Electroencephalogram was analyzed automatically by measurement of burst suppression ratio and asymmetry index and by Fast Fourier Transform to calculate total absolute spectral power; relative spectral power in the δ (0.5–3.5 Hz), θ (4–7.5 Hz), α (8–12.5 Hz), and β (13–30 Hz) frequency bands; spectral edge frequency; and mean dominant frequency. Results The use of wool cap had no effect on all electroencephalogram parameters considered. Gestational age showed an effect on relative spectral power of all considered bands, spectral edge frequency and mean dominant frequency, while no effect was seen on burst suppression ratio and asymmetry index. Neonates born at gestational weeks lower than 28 had significantly higher relative power in the δ band and lower relative power in the α and β bands. Conclusions Heat loss prevention using wool cap does not affect interpretation of spectral electroencephalogram. Spectral values in our group of very premature infants without neurological complications correspond to normal data reported in the literature. Maturation changes consist of reduction of relative power of the δ band, spectral edge frequency and mean dominant frequency.

Introduction: Allan–Herndon–Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. Case report: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17 months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14 months, were normal. Discussion: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan–Herndon–Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.

Objective To present a case carrying a chromosomal rearrangement of the 6p25.3 locus and diagnosed with Moyamoya syndrome. Methods A Caucasian 4 years-and-9-months-old girl was admitted to a peripheral hospital for vomiting and acute left hemiparesis, followed by left arm clonic seizures, aphasia and confusion. Phenytoin stopped the crisis, but hemiparesis persisted. EEG documented widespread slow waves, mainly on the right hemisphere. Computed tomography (third day) showed hypodensity of the entire right hemisphere. Past history was characterized by prematurity (born at 32 g.w.), cardiac defects (atrial septal defect, patent ductus arteriosus), surgically corrected at 3 years old. High resolution karyotype showed this rearrangement: 46, XX, der(6)dup(6) (p24p23)del(6)(p25). Cognitive level was borderline. On day 4 the girl was transferred to our Child Neurology Unit where she underwent a complete workup. Results Echocardiogram: normal; carotid doppler ultrasound: bilateral stenosis of internal carotid arteries; brain magnetic resonance imaging (MRI): ischemic areas in territories supplied by right middle and anterior cerebral arteries; brain angio-MRI: bilateral multiple stenosis of anterior and posterior cerebral arteries and collateral circulation consistent with Moyamoya syndrome. Therefore, after a digital angiography, the patient underwent an encephalo-duro-arterial-myo-sinangiosis. The post-operative period was uneventful. Conclusion Moyamoya syndrome is known to be associated to some genetic conditions (such as Neurofibromatosis type 1, Alagille syndrome and Trisomy 21). To date, only one pediatric case with Moyamoya syndrome and chromosomal rearrangement of 6p25.3 has been reported, similar to our patient. Therefore, all patients presenting with a chromosomal rearrangement involving the 6p25.3 locus should be studied with brain angio-MRI; moreover this genetic region should be investigated to identify possible disease-specific genes for Moyamoya syndrome.

Objective To present a case of congenital gluteal muscles absence associated with renal ectopia, without spina bifida occulta. Methods A 3-years-old child was referred to our child Neurology Unit for motor delay and walking difficulties. Familial and pregnancy history were unremarkable except for right renal ectopia diagnosed with antenatal ultrasound. At birth, he presented flexed hips and lower limbs rigidity. He started walking at 19 months. Neurological examination (28 months) showed waddling gait, gluteal muscles hypoplasia and lumbar hyperlordosis. Laboratory findings, imaging and electrophysiological exams were performed. Results At 28 months of age the child underwent electromyography (with needle of 50 mm) that showed absence of voluntary activity in the territory of gluteal muscles, with normal response in the regions of vastus medialis and sural triceps and normal nerve conduction studies. Laboratory findings (creatine phosphokinase and transaminases) were normal. Musculoskeletal and pelvis magnetic resonance imaging (MRI) revealed a complete, symmetrical fibroadipose replacement of gluteus, gracilis, semitendinosus, semimembranosus and biceps femoris muscles, anterior legs muscles were normal. Spinal magnetic resonance excluded spina bifida occulta. Right kidney was ectopic. Conclusion Bilateral symmetrical congenital absence of muscles is rare, other than Eagle-Barrett syndrome. So far, only three cases of congenital absence of gluteal muscles have been reported and they all had spina bifida occulta. To the best of our knowledge, our case is the first report of congenital absence of gluteal muscles without spinal dysraphism. The only remarkable finding was the kidney ectopia, never described in association with gluteus' agenesis by previous Literature. This association could be explained by a disruption of normal embryologic migration of mesodermal cells during gestational age. Muscular MRI and extensive electromyography should be considered in the diagnostic work-up of children with motor delay and walking difficulties and with clinical suspicion of neuromuscular disorders.

A 16-year-old boy with the classic or postinfantile type of Hallervorden-Spatz syndrome is described. Bilateral optic atrophy with visual loss but without retinal changes was the only presenting symptom. Mild cognitive impairment, behavioural disturbances and insidious extrapyramidal involvement appeared later. MRI showed marked symmetrical hypointensity of the globi pallidi and substantia nigra. This new observation suggests that the occurrence of optic atrophy in a patient with Hallervorden-Spatz syndrome should be regarded as noncoincidental and stresses the importance of an accurate neurological work-up in all adolescents with any unusual form of progressive optic atrophy.

In the present era of resource management, there is increasing emphasis on the need to make the best possible use of available resources. We therefore measured the productive factors directly involved in performance of 59 evoked potential examinations (brainstem auditory evoked potentials, BAEPs; flash visual evoked potentials, F-VEPs; and electroretinograms, ERGs) in different pediatric age groups. In order to ascertain the gap between the costs of instrumental examinations performed in our service on children and the fees reimbursed by the Italian national health service (NHS) a breakdown was made of the costs of tests and their scheduling in relation to the different age variables involved. It was found that the fees reimbursed do not cover the real costs, because they underestimate the actual consumption of resources. The findings recorded indicate that for pediatric tests the economic audit should be graded according to the ages of the children examined and should include an analysis of different test phases. The economic audit should also be considered a preliminary step in clinical audit. It is concluded that it is financially punitive to reimburse a pediatric service with a fee based on the examination of adults, because in pediatrics the variable ``age'' influences the duration and complexity of tests and also their interpretation.