Case report: Exploring chemoradiotherapy-induced leukoencephalopathy with 7T imaging and quantitative susceptibility mapping.

Chemotherapy and radiotherapy are widely used in the treatment of central nervous system tumors and acute lymphocytic leukemia even in the pediatric population. However, such treatments run the risk of a broad spectrum of cognitive and neurological deficits. Even though the correlation with cognitive decline is still not clear, neuroradiological defects linked to white matter injury and vasculopathies may be identified. Thanks to the use of 7T MRI it is possible to better define the vascular pattern of the brain lesions with the added advantage of identifying their characteristics and anatomical localization, which, however, are not evident with a conventional brain scan. Moreover, the use of Quantitative Susceptibility Mapping (QSM) makes it possible to discriminate between calcium deposits on vessels (chemo-radiation-induced) and hemoglobin deposition in radio-induced cavernomas, speculating, as a result, about the pathophysiology of iatrogenic brain damage. We describe the case of a 9 year-old boy with a T-type acute lymphoid leukemia who had previously been treated with polychemotherapy and high-dose RT. To better define the child's neuroradiological pattern, 7T MRI and QSM were performed in addition to conventional imaging examinations. Our case report suggests the potential usefulness of a QSM study to distinguish radio-induced vascular malformations from mineralizing microangiopathy.

Case report: Clinical and neuroradiological longitudinal follow-up in Leukoencephalopathy with Calcifications and Cysts during treatment with bevacizumab.

Leukoencephalopathy with Calcifications and Cysts (LCC) is a rare genetic microangiopathy exclusively affecting the central nervous system caused by biallelic mutations in SNORD118. Brain magnetic resonance imaging (MRI) is often diagnostic due to the highly characteristic triad of leukoencephalopathy, intracranial calcifications, and brain cysts. Age at onset, presentation and disease evolution can all vary, ranging from pauci-symptomatic disease to rapid evolution of signs with loss of motor and cognitive abilities. No specific therapies for LCC are currently licensed. According to the literature, bevacizumab might represent an effective modality to improve the clinical and MRI features of the disease. However, uncertainty remains as to the true efficacy of this approach, when to begin therapy, appropriate dosing, and the consequences of drug withdrawal. According to CARE guidelines, we describe the long-term clinical and neuro-radiological follow-up of a 10-year-old child with LCC. We report disease evolution following repeated cycles of treatment with bevacizumab. Our case report suggests that repeated cycles of bevacizumab might effectively modify disease progression, possibly indicating a time-dependent effect.

Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?

There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5-17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.

Specific Learning Disabilities and Emotional-Behavioral Difficulties: Phenotypes and Role of the Cognitive Profile.

Specific Learning Disabilities (SLD) are often associated with emotional-behavioral problems. Many studies highlighted a greater psychopathological risk in SLD, describing both internalizing and externalizing problems. The aims of this study were to investigate the emotional-behavioral phenotype through the Child Behavior Checklist (CBCL), and evaluate the mediating role of background and cognitive characteristics on the relationship between CBCL profile and learning impairment in children and adolescents with SLD. One hundred and twenty-one SLD subjects (7-18 years) were recruited. Cognitive and academic skills were assessed, and parents completed the questionnaire CBCL 6-18. The results showed that about half of the subjects manifested emotional-behavioral problems with a prevalence of internalizing symptoms, such as anxiety and depression, over externalizing ones. Older children showed greater internalizing problems than younger ones. Males have greater externalizing problems compared to females. A mediation model analysis revealed that learning impairment is directly predicted by age and familiarity for neurodevelopmental disorders and indirectly via the mediation of the WISC-IV/WAIS-IV Working Memory Index (WMI) by the CBCL Rule-Breaking Behavior scale. This study stresses the need to combine the learning and neuropsychological assessment with a psychopathological evaluation of children and adolescents with SLD and provides new interpretative insights on the complex interaction between cognitive, learning, and emotional-behavioral phenotypes.

Sleep disturbances in specific learning disorders: a qualitative and quantitative investigation.

BACKGROUND: The literature reports a significant association between sleep disorders and learning disabilities. Nevertheless, not all children with learning disorders have sleep alterations, and which sleep characteristics are associated with which learning difficulty is still unknown. The study aimed at acquiring new information on the relation between sleep disturbances or habits and the learning profiles of children with a specific learning disorder (SLD). METHODS: The Sleep Disturbance Scale for Children (SDSC) and an actigraph (the FitBit-Flex, FB-F) were used in 26 and 16 SLD children respectively; all children were also assessed for learning skills. RESULTS: Although parents' reports at the SDSC did not differentiate SLD from typical readers, the awakening, respiratory and arousal disturbances at the SDSC correlated with sleep duration at the FB-F. Sleep alterations at the FB-F actigraph characterize SLD with literacy difficulties: children with reading decoding difficulties showed shorter minimum amount of sleep than typical children, and severe SLDs showed shorter maximum sleep duration and a higher number of awakenings in comparison to SLDs with mild learning deficits. CONCLUSIONS: Mild alterations in the amount, duration and quality of sleep may characterize children with learning disorders and actigraphy proves to be a useful tool in starting the individual monitoring of sleep in these populations.

Further characterization of NFIB-associated phenotypes: Report of two new individuals.

Nuclear Factor I B (NFIB) haploinsufficiency has recently been identified as a cause of intellectual disability (ID) and macrocephaly. Here we report on two new individuals carrying a microdeletion in the chromosomal region 9p23-p22.3 containing NFIB. The first is a 7-year 9-month old boy with developmental delays, ID, definite facial anomalies, and brain and spinal cord magnetic resonance imaging findings including periventricular nodular heterotopia, hypoplasia of the corpus callosum, arachnoid cyst in the left middle cranial fossa, syringomyelia in the thoracic spinal cord and distal tract of the conus medullaris, and a stretched appearance of the filum terminale. The second is a 32-year-old lady (the proband' mother) with dysmorphic features, and a history of learning disability, hypothyroidism, poor growth, left inguinal hernia, and panic attacks. Her brain magnetic resonance imaging findings include a dysmorphic corpus callosum, and a small cyst in the left choroidal fissure that marks the hippocampal head. Array-based comparative genomic hybridization identified, in both, a 232 Kb interstitial deletion at 9p23p22.3 including several exons of NFIB and no other known genes. Our two individuals add to the knowledge of this rare disorder through the addition of new brain and spinal cord MRI findings and dysmorphic features. We propose that NFIB haploinsufficiency causes a clinically recognizable malformation-ID syndrome.

Enhancing DLG2 Implications in Neuropsychiatric Disorders: Analysis of a Cohort of Eight Patients with 11q14.1 Imbalances.

Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory-inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs.

Neural substrates of neuropsychological profiles in dystrophynopathies: A pilot study of diffusion tractography imaging.

INTRODUCTION: Cognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures. MATERIALS AND METHODS: This pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract. RESULTS: Regarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949). DISCUSSION AND CONCLUSION: In this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.

Autism Spectrum Disorder and Disruptive Behavior Disorders Comorbidities Delineate Clinical Phenotypes in Attention-Deficit Hyperactivity Disorder: Novel Insights from the Assessment of Psychopathological and Neuropsychological Profiles.

Although childhood-onset psychiatric disorders are often considered as distinct and separate from each other, they frequently co-occur, with partial overlapping symptomatology. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) commonly co-occur with each other and with other mental disorders, particularly disruptive behavior disorders, oppositional defiant disorder/conduct disorder (ODD/CD). Whether these associated comorbidities represent a spectrum of distinct clinical phenotypes is matter of research. The aim of our study was to describe the clinical phenotypes of youths with ADHD with and without ASD and/or ODD/CD, based on neuropsychological and psychopathological variables. One-hundred fifty-one participants with ADHD were prospectively recruited and assigned to four clinical groups, and assessed by means of parent-reported questionnaires, the child behavior checklist and the behavior rating inventory of executive functions. The ADHD alone group presented a greater impairment in metacognitive executive functions, ADHD+ASD patients presented higher internalizing problems and deficits in Shifting tasks, and ADHD+ODD/CD subjects presented emotional-behavioral dysregulation. Moreover, ADHD+ASD+ODD/CD individuals exhibited greater internalizing and externalizing problems, and specific neuropsychological impairments in the domains of emotional regulation. Our study supports the need to implement the evaluation of the psychopathological and neuropsychological functioning profiles, and to characterize specific endophenotypes for a finely customized establishment of treatment strategies.

The Role of Executive Functions in the Development of Empathy and Its Association with Externalizing Behaviors in Children with Neurodevelopmental Disorders and Other Psychiatric Comorbidities.

Executive functions have been previously shown to correlate with empathic attitudes and prosocial behaviors. People with higher levels of executive functions, as a whole, may better regulate their emotions and reduce perceived distress during the empathetic processes. Our goal was to explore the relationship between empathy and executive functioning in a sample of children and adolescents diagnosed with Attention Deficit and Hyperactivity Disorder alone or associated with comorbid Disruptive Behavior Disorders and/or Autism Spectrum Disorder. We also aimed to examine the role of empathic dimensions and executive skills in regulating externalizing behaviors. The 151 participants with ADHD were assigned to four groups according to their psychiatric comorbidity (either "pure" or with ASD and/or ODD/CD) and assessed by means of either parent- or self-reported questionnaires, namely the BRIEF-2, the BES, and the IRI. No questionnaire was found to discriminate between the four groups. Affective Empathy was found to positively correlate with Emotional and Behavioral Regulation competences. Furthermore, Aggressiveness and Oppositional Defiant Problems were positively associated with Executive Emotional and Behavioral Regulation competences. On the other hand, Rule-Breaking Behaviors and Conduct Problems were negatively associated with Affective Empathy and with Behavioral skills. Our study provides an additional contribution for a better understanding of the complex relationship between empathic competence and executive functions, showing that executive functioning and empathic attitudes interact with each other to regulate aggressive behaviors. This study further corroborates developmental models of empathy and their clinical implications, for which externalizing behaviors could be attenuated by enhancing executive functioning skills.

Training RAN or reading? A telerehabilitation study on developmental dyslexia.

Rehabilitation procedures recommended for developmental dyslexia (DD) are still not fully defined, and only few studies directly compare different types of training. This study compared a training (Reading Trainer) working on the reading impairment with one (Run the RAN) working on the rapid automatized naming (RAN) impairment, one of the main cognitive deficits associated with DD. Two groups of DD children (N = 45) equivalent for age, sex, full IQ, and reading speed were trained either by Reading Trainer (n = 21) or by Run the RAN (n = 24); both trainings required an intensive home exercise, lasting 3 months. Both trainings showed significant improvements in reading speed and accuracy of passages and words. Bypassing the use of alphanumeric stimuli, but empowering the cognitive processes underlying reading, training RAN may be a valid tool in children with reading difficulties opening new perspectives for children with severe impairments or, even, at risk of reading difficulties.

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI.

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions.

Telerehabilitation in developmental dyslexia: methods of implementation and expected results.

BACKGROUND: Developmental Dyslexia is a disorder, highly frequent in the school population, for which the recommended rehabilitation procedures are not well defined. This study aimed to automatize reading decoding skills by using an innovative system for rehabilitation, based on a telerehabilitation method. It requires an intensive home-exercise with the supervision, by web, of the clinician. The study had three main aims: to diffuse knowledge on new methods for rehabilitation of reading difficulties; to verify whether an intensive and simplified exercise, targeted to the automation of reading, is suitable for different subgroups of dyslexic children; to define the treatment effects on basic cognitive functions underlying reading. METHODS: Twenty-five children, grouped according to the neuropsychological and anamnestic profiles, took part to the treatment by the software Reading Trainer®. RESULTS: Both speed and accuracy of reading decoding increased significantly after treatment, independently from the functional neuropsychological profile or the history of oral language delay. These changes were specific to decoding and not associated with improvements in reading comprehension or spelling skills. However, there was a "cascade effect" of the treatment efficacy on those basic cognitive functions considered precursors of the ability to read, with significant improvements in rapid lexical access, phonological processing and visual attention. CONCLUSIONS: This study provides information on the efficacy of new tools for telerehabilitation of specific reading disorders.

The contribution of discrete-trial naming and visual recognition to rapid automatized naming deficits of dyslexic children with and without a history of language delay.

Children with Developmental Dyslexia (DD) are impaired in Rapid Automatized Naming (RAN) tasks, where subjects are asked to name arrays of high frequency items as quickly as possible. However the reasons why RAN speed discriminates DD from typical readers are not yet fully understood. Our study was aimed to identify some of the cognitive mechanisms underlying RAN-reading relationship by comparing one group of 32 children with DD with an age-matched control group of typical readers on a naming and a visual recognition task both using a discrete-trial methodology, in addition to a serial RAN task, all using the same stimuli (digits and colors). Results showed a significant slowness of DD children in both serial and discrete-trial naming (DN) tasks regardless of type of stimulus, but no difference between the two groups on the discrete-trial recognition task. Significant differences between DD and control participants in the RAN task disappeared when performance in the DN task was partialled out by covariance analysis for colors, but not for digits. The same pattern held in a subgroup of DD subjects with a history of early language delay (LD). By contrast, in a subsample of DD children without LD the RAN deficit was specific for digits and disappeared after slowness in DN was partialled out. Slowness in DN was more evident for LD than for noLD DD children. Overall, our results confirm previous evidence indicating a name-retrieval deficit as a cognitive impairment underlying RAN slowness in DD children. This deficit seems to be more marked in DD children with previous LD. Moreover, additional cognitive deficits specifically associated with serial RAN tasks have to be taken into account when explaining deficient RAN speed of these latter children. We suggest that partially different cognitive dysfunctions underpin superficially similar RAN impairments in different subgroups of DD subjects.

Cerebral lateralization for language in deaf children with cochlear implantation.

Functional Transcranial Doppler ultrasonography (fTCD) was used to investigate the effects of early acoustic deprivation and subsequent reafferentation on cerebral dominance for language in deaf children provided with Cochlear Implantation (CI). Twenty children with CI (13 in right ear and 7 in left ear) and 20 controls matched for age, sex and handedness were administered a fTCD animation description task. Left hemisphere dominance for language with comparable mean Laterality Indexes (LIs) was found in children with CI and controls; right-ear implanted subjects showed cerebral activation controlateral to implanted ear more frequently than left-ear implanted ones. Linguistic proficiency of CI recipients was below age expectation in comparison to controls; language scores did not significantly differ between children with left and right LI, whereas both age and side of implantation were significantly related to language outcome. Theoretical implication and potential clinical application of fTCD in CI management are discussed.

Long-term reading and spelling outcome in Italian adolescents with a history of specific language impairment.

Specific language impairment (SLI) diagnosed in the pre-school years is frequently associated with reading and writing difficulties at school age. The nature of this relationship is unclear, despite the availability of a large number of studies, mostly on English speaking children. Phonological processing deficits have been considered the prominent cause of both difficulties. However recent findings in both children with SLI and in children with reading difficulties are not easily accommodated within a single dimensional model explaining the relationship between oral and written language deficits. Our study focuses on the long-term reading and spelling outcome in relation to preschool oral language skills in a group of Italian adolescents with a documented history of SLI. Sixteen Italian adolescents diagnosed as SLI at our Hospital in the pre-school years and 32 normal controls were submitted to an extensive assessment of oral and written language skills. At a group level SLI adolescents had weak oral and written language skills in almost all tests. Results show that reading difficulties have some features in common with those of Italian developmental dyslexics but also have distinct characteristics, since reading accuracy and written comprehension, usually relatively spared in Italian developmental dyslexics, were impaired in adolescents with SLI. Longitudinal analyses showed that expressive morpho-syntactic and lexical abilities at pre-school age were the oral language skills that best predicted reading and spelling outcomes in adolescents with SLI. However, also children with severe phonological impairment in the absence of other oral language deficits showed later literacy difficulties, although less severe and mainly limited to reading accuracy. Our study supports the notion that there is a complex relationship between oral and written language difficulties which may change at different developmental time points, not captured by a single deficit model, but best conceptualized considering multiple interactions between language skills and literacy abilities.