Background In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. Methods In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. Findings Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99•08 (SD 18•35) in the awake-regional anaesthesia group and 98•97 (19•66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0•23 (95% CI-2•59 to 3•06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. Interpretation Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia ...

Cerebral visual impairment is a visual function deficit caused by damage to the retrogeniculate visual pathways in the absence of any major ocular disease. It is the main visual deficit in children in the developed world. Preperinatal hypoxic-ischemic damage is the most frequent cause of cerebral visual impairment, but the etiology is variable. The authors set out to evaluate the presence of visual disorders not attributable to any major ocular pathology in a sample of children with central nervous system disease and to describe the clinical picture of cerebral visual impairment in this cohort. One hundred twenty-one patients with central nervous system damage and visual impairment underwent a protocol developed at the authors' center that included neurologic, neurophthalmologic, and neuroradiologic assessments (brain magnetic resonance imaging). Reduced visual acuity was found in 105 of 121 patients, reduced contrast sensitivity in 58, abnormal optokinetic nystagmus in 88, and visual field deficit in 7. Fixation was altered in 58 patients, smooth pursuit in 95, and saccadic movements in 41. Strabismus was present in 88 patients, and abnormal ocular movements were found in 43 patients. Of the 27 patients in whom they could be assessed, visual-perceptual abilities were found to be impaired in 24. Fundus oculi abnormalities and refractive errors were frequently associated findings. This study confirms that the clinical expression of cerebral visual impairment can be variable and that, in addition to already well-documented symptoms (such as reduced visual acuity, visual field deficits, reduced contrast sensitivity), the clinical picture can also be characterized by oculomotor or visual-cognitive disorders. Cerebral visual impairment is often associated with ophthalmologic abnormalities, and these should be carefully sought. Early and careful assessment, taking into account both the neurophthalmologic and the ophthalmologic aspects, is essential for a correct diagnosis and the development of personalized rehabilitation programs.

Aim  Cognitive visual dysfunctions (CVDs) reflect an impairment of the capacity to process visual information. The question of whether CVDs might be classifiable according to the nature and distribution of the underlying brain damage is an intriguing one in child neuropsychology. Method  We studied 22 children born preterm (12 males, 10 females; mean age at examination 8y, range 6–15y; mean gestational age 30wks, range 28–36wks) with periventricular leukomalacia, spastic diplegia, normal intelligence (mean Full‐scale IQ 84; mean Verbal IQ 97; mean Performance IQ 74), and normal visual acuity, focusing on higher visual functions. Brain magnetic resonance images (MRI) were analysed to establish the presence of lesions along the primary optic pathway, in the occipitoparietal and occipitotemporal regions. Results  Most children displayed an uneven cognitive profile, with deficits in visual object recognition, visual imagery, visual–spatial skills, and visual memory, and sparing of visual associative abilities, non‐verbal intelligence, and face and letter recognition. Conventional brain MRI did not document major alterations of parietal and temporal white matter, or cortical alteration of areas involved in visual associative functions. Interpretation  We suggest a widespread involvement of higher visual processing systems, involving both the ventral and dorsal streams, in preterm children with periventricular leukomalacia. The lack of major alterations on conventional MRI does not exclude the possibility of malfunctioning of higher visual processing systems, expressing itself through discrete CVDs. Possible mechanisms underlying these neuropsychological deficits are discussed.

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Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3’ end ribonucleases with mostly unknown substrate specificity1. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration with ambiguous genitalia2 (MIM%614969). We studied 12 human families with PCH7, uncovering biallelic, loss of function mutations in TOE1 (NC_000001.11), which encodes an unconventional deadenylase3,4. Toe1-morphant zebrafish displayed mid- and hind-brain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found TOE1 associated with incompletely processed small nuclear (sn)RNAs of the spliceosome, which is responsible for pre-mRNA splicing. These pre-snRNAs contained 3’ genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3’ end-extended pre-snRNAs, and immuno-isolated TOE1 complex was sufficient for 3’ end maturation of snRNAs. Our findings reveal the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in processing of snRNA 3’ ends.

Joubert Syndrome Related Disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the "molar tooth sign" (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and MeckelGruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in two out of 16 families with cerebello-renal presentation (~12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%).

Summary Objective PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors. Methods We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. Results At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). Significance We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Our results underline that preterm birth could be a risk factor for the co-construction of interactive exchanges between mother and premature baby. This study could help practitioners to better consider parental roles and to carry out specific supportive interventions for both parents and children.