Exome sequencing and electro-clinical features in pediatric patients with very early-onset retinal dystrophies: A cohort study.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abnormal heart rate variability at school age in survivors of neonatal hypoxic-ischemic encephalopathy managed with therapeutic hypothermia.

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 <70 in 1. 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.

Deciphering the natural history of SCA7 in children.

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.

Perinatal carotid artery ischemic stroke: Report of two cases.

The mechanisms of perinatal stroke are poorly understood but preclinical studies point to the crucial role of perinatal inflammation. Carotid artery occlusion represents a very rare and severe cause of perinatal stroke. We describe two cases diagnosed with extensive ischemic stroke due to carotid artery occlusion. In both cases, we demonstrated placental vasculopathy. High levels of C-reactive protein in mother and/or neonates suggested inflammatory mechanism as a potential trigger. Both cases underwent hypothermic treatment without complications because of initial diagnosis of perinatal asphyxia. The prognosis at the time of the last follow up was severe including cerebral palsy, epilepsy and cognitive impairment. Our cases contribute to the actual debate on pathogenic mechanisms and treatment options for this rare condition.

Clinical dissection of childhood occipital epilepsy of Gastaut and prognostic implication.

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.

Power spectral analysis of two-channel EEG in very premature infants undergoing heat loss prevention.

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 ß (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 ß 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.

Failure of hearing screening in high-risk neonates does not increase parental anxiety.

OBJECTIVE: The aim of this study was to determine whether a failure of neonatal hearing screening affected the anxiety level of parents of high-risk infants. METHODS: Two hundred and eighty-eight parents of infants included in the neonatal hearing screening protocol of our Institution were tested with the Spielberger State-Trait Anxiety Inventory and with an open-question questionnaire investigating parents' attitude to hearing problems in their child, done at the time of audiological follow-up. 105 were parents of high-risk infants who had been discharged from neonatal intensive care unit (NICU) and 183 of low-risk infants discharged from well-baby nursery. RESULTS: No differences in anxiety levels were seen between parents of high-risk infants passing and failing neonatal hearing screening using homogeneous case-control pairs. Additionally, no differences in the level of anxiety were found between parents of high- and low-risk infants failing neonatal auditory screening. CONCLUSIONS: Failure of neonatal auditory screening does not affect the anxiety levels of parents of high-risk infants at post discharge from NICU. This finding is a key factor to be considered when evaluating the costs and benefits of tests for universal neonatal hearing screening.

Bilateral loss of cortical somatosensory evoked potential at birth predicts cerebral palsy in term and near-term newborns.

Bilateral loss of cortical somatosensory evoked potential (SEP) is considered the single best indicator of adverse outcome in acute encephalopathy of adult patients and older children. This study determines whether the presence or absence of the neonatal cortical SEP can predict cerebral palsy at two years in survivors of neonatal encephalopathy scored according to Sarnat criteria. We also compare SEPs with visual evoked potentials (VEPs), the EEG and neonatal neurological status. Fifty-nine neonates admitted to the neonatal intensive care unit had SEP, VEP and EEG recordings analysed according to the presence (n=37, 63%) or absence (n=22, 37%) of neonatal encephalopathy (score >or=1). Cortical SEP was always present in the perinatal period in those surviving without major neurological disability, while it was bilaterally absent in all but one patient with a subsequent diagnosis of cerebral palsy. Multivariate analysis using the logistic regression model showed that bilateral loss of cortical SEP and Sarnat Score correctly classified the neurological outcome in all patients. Bilateral absence of cortical SEP indicates early identification of neonates at risk of cerebral palsy indicating that EPs have a clinical role in the workup of neonatal encephalopathy.

Tethered cord in patients with anorectal malformation: preliminary results.

BACKGROUND: A tethered cord (TC) has been reported in as much as 50% of the patients affected by anorectal malformation (ARM). No guidelines for timing and modality of diagnosis and treatment have been established. We present the preliminary results of a multidisciplinary protocol carried out at our center. METHODS: Seventy-four ARM patients underwent spinal magnetic resonance imaging (MRI). All TC patients underwent videourodynamic (UD), somatosensory-evoked potentials (SEPs), and neurological examination at baseline and, if normal, at 5 and 10 years of age. Conversely, when UD or SEP abnormalities were detected the follow-up was individually tailored at shorter time. RESULTS: 25/74 patients had a neuroradiological TC (33.7%). Based on the results of UD, SEP, and neurological status, four patients were untethered, eight are possible candidates, nine are stable, and four were excluded because of incomplete data. DISCUSSION: Tethered cord is frequent in ARM patients. Because neurological deficits secondary to TC can contribute to neurological disability, we recommend routine MRI examination and a multidisciplinary program of follow-up in cases of TC. Preliminary results suggest the combined use of SEPs and UD could represent a useful adjunct to clinical examination in patients in whom a "wait and see" approach is preferred to the prophylactic surgery.

Prognostic role of somatosensory and auditory evoked potentials in paediatric hypoxic-ischemic encephalopathy managed with hypothermia: an illustrative case.

INTRODUCTION: The contribution of clinical neurophysiology in the neurological prognosis of hypoxic-ischemic coma has been well established in adults: the bilateral absence of cortical somatosensory evoked potentials (SEP) is considered the single best indicator of adverse outcome, while the presence of the auditory mismatch negativity (MMN) is thought to herald arousal. STUDY AIM: To use MMN combined with serial EEG recordings, somatosensory and brainstem auditory evoked potentials (BAEP) in a paediatric case of postanoxic coma managed with hypothermia, since they have not yet been described in children. METHODS: We report the case of a nine-year-old boy with hypoxic-ischemic encephalopathy due to cardiorespiratory arrest after accidental burial in sand, who was treated with therapeutic hypothermia for 72 hours. Serial EEG recordings, evoked potentials, brain CT scan and brain MRI were performed in the first few days after the event. RESULTS: SEP to median nerve stimulation showed bilateral absence of the N20 component, while the N13 and P14 peaks were preserved; BAEP showed normal I-V interpeak latency and normal hearing threshold. At the same time, the MMN component of auditory event related potentials, recorded in the classical oddball paradigm, was absent. Seventeen months after the accident, the patient is alive in persistent vegetative state. CONCLUSIONS: This case illustrates the particular significance of SEP and MMN together with EEG in gaining prognostic information, even in sedated and hypothermic patients, and encourages systematic study of these prognostic tools in paediatric postanoxic coma.

Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study.

OBJECTIVE: The purpose of the study was to compare and contrast the initial presenting demographic, clinical, neuroimaging, and laboratory features in a cohort of children affected from multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). METHODS: A 12-year prospective study was conducted in 68 pediatric patients (age

Reliability of hearing screening in high-risk neonates: comparative study of otoacoustic emission, automated and conventional auditory brainstem response.

OBJECTIVE: To compare the diagnostic reliability of automated transient evoked otoacoustic emissions (a-TEOAE), automated auditory brainstem response (a-ABR) and conventional brainstem auditory evoked potential (BAEP/ABR) for identification of hearing loss in high-risk neonates. METHODS: Two hundred and six neonatal intensive care unit (NICU) admitted neonates were tested pre-discharge. Follow-up included a-TEOAE in all children, repetition of a-ABR or BAEP if failed in NICU. Sensitivity and specificity were compared and correlated with auditory risk factors. RESULTS: BAEP had the highest sensitivity (100%) and specificity (90.8%), a-ABR the lowest (88.9% and 70.6%). A statistically significant difference in risk factors for temporary hearing loss was observed between normal and false positive a-TEOAE and BAEP, but not a-ABR outcome. Differences in specificity between a-ABR and a-TEOAE explain the pattern of "absent a-ABR/present a-TEOAE" in 13.8% of ears. CONCLUSIONS: The BAEP appears the more reliable test for hearing screening of high-risk neonates because of highest sensitivity and specificity and should be used to confirm the diagnosis of "auditory neuropathy" in high-risk neonates. The reliability of a-ABR devices in critically ill neonates needs further investigation. SIGNIFICANCE: This is, to our knowledge, the first attempt to compare the diagnostic reliability of a-TEOAE, a-ABR and BAEP in high-risk neonates.

Brain auditory activation measured by near-infrared spectroscopy (NIRS) in neonates.

This study presents a new measure of the hemodynamic changes to an auditory stimulus in newborns. Nineteen newborns born at 28-41 wk and aged 1 to 49 d were studied in waking and/or sleeping state, for a median time of 4 min 40 s before, 2 min 40 s during, and 3 min 5 s after an acustic stimulus (tonal sweep of frequency increasing from 2 to 4 kHz, intensity 90 dB SPL) originating 5 cm from the external auditory meatus. The emitter and detector optodes were placed over the left or right temporal region, corresponding to T3 or T4 EEG electrodes. The concentration changes in cerebral chromophores Delta[HbO2], Delta[Hb] and Deltaoxidized-reduced cytochrome aa(3) were recorded every 5 s. Changes in cerebral blood volume were calculated from the changes in total Hb x 0.89/large vessel Hb concentration. Increased oxyhemoglobin, Delta[HbO2], total Hb, Delta[Hb (sum)], and cerebral blood volume, DeltaCBV, were found in 13/19 neonates, with the exception of a neonate who only had increased in Delta[Hb], Delta[Hb (sum)] and DeltaCBV. During the stimulation phase there was a significant increase in DeltaCBV (t test, p = 0.00006) in the responsive newborns from a mean value of 0.006 (+/-0.02) mL/100 g in the pretest phase to 0.09 (+/-0.06) mL/100 g during the auditory stimulus. After the test DeltaCBV decreased to 0.04 (+/-0.07) mL/100 g (t test, p = 0.01), so did Delta[Hb (sum)] (p = 0.02). Hemodynamic responses of the subjects who showed increases in Delta[Hb (sum)] and Delta[HbO(2)] were analyzed to study the Delta[Hb]. The responder subjects could be classified into two groups according to Delta[Hb] changes: 8/13 (61.5%) showed an increase of Delta[Hb] (pattern A), while 5/13 (38.4%) showed a decrease (pattern B) (t test, p = 0.03). These two patterns did not show differences related to Delta[HbO(2)] and Delta[Hb (sum)]. The DeltaCBV changes in nonresponders presented a decrease during the test phase (t test, p = 0.04). CBV did not return to pretest values, suggesting a fronto-temporal brain pathway for storing unusual sounds. The increase in CBV followed the local increase in oxyhemoglobin and total Hb concentrations due to a greater use of oxygen in the homolateral temporal cortex of the newborns.

[Role of evoked potentials in neonatal hypoxic-ischemic encephalopathy: review of the literature]. / Ruolo dei potenziali evocati nell'encefalopatia ipossico-ischemica neonatale: revisione della letteratura.

Results of the studies on evoked potentials (EP) in neonates with hypoxic-ischaemic encephalopathy and their technical feasibility support extensive application in neonatal intensive care units. The combined application of visual evoked potentials (VEP) and somestesic evoked potentials (SEP) is the method of choice for neurodevelopmental prognostication in full-term neonate; especially useful in cases with moderate encephalopathy; in preterm neonates EP are complementary to head ultrasound scans, particularly early on when the findings are in the process of evolution. Brainstem auditory evoked potentials (BAEP) are the technique of choice for early identification of sensorineural hearing loss necessitating intervention. Long term prognosis on vision and audition is based on VEP and BAEP. Studies devoted to definition of the role of EP in selection of babies and monitoring neuroprotective intervention are warranted.

Neuropsychological evaluation of neurologically asymptomatic HIV-infected children.

Forty-two children born to HIV positive mothers (29 infected at different stages of the disease, according to the Disease Control Classification Centers, and 13 noninfected) underwent evaluation using a battery of neuropsychological tests. Executive function impairments were present in all infected children, whereas memory and visuo-prassic deficits were evident only in those with full-blown AIDS. Language abilities and overall intelligence were spared. Performance of seroreverters was in the normal range. These findings suggest that even in neurologically asymptomatic children, neuropsychological evaluation can identify early impairment of specific cognitive functions. The findings are discussed in the light of the prognostic power of neuropsychological assessment for early signs of HIV neurological involvement.

Optic atrophy as the first symptom in Hallervorden-Spatz syndrome.

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.

Evoked potentials in pediatrics: economic audit.

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.