Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) - a target for clinical trials.

Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.

[Timely consideration of future care; advance care planning for people with intellectual disabilities]. / Tijdig nadenken over toekomstige zorg.

People with intellectual disabilities (IDs) are often unable to decide for themselves regarding complex medical decisions, and need assistance from representatives, often next-of-kin. People with IDs are often frail. This frailty is characterized on the one hand by health problems, on the other hand by significant limitations in both intellectual functioning and in adaptive behaviour. In this group of people, when compared to the general population, the principles of palliative care are applicable more often and over a longer period. Advance care planning should be considered not only at the end of life, but at each stage where decisions have to be made that may affect quality of life. In this article, we present three patient cases to illustrate the complexity of the process and the commitment of representatives and other key stakeholders.

Attention training modulates resting-state neurophysiological abnormalities in posttraumatic stress disorder.

Recent research indicates the relative benefits of computerized attention control treatment (ACT) and attention bias modification treatment (ABMT) for posttraumatic stress disorder (PTSD); however, neural changes underlying these therapeutic effects remain unknown. This study examines how these two types of attention training modulate neurological dysfunction in veterans with PTSD. A community sample of 46 combat veterans with PTSD participated in a randomized double-blinded clinical trial of ACT versus ABMT and 32 of those veterans also agreed to undergo resting-state magnetoencephalography (MEG) recordings. Twenty-four veterans completed psychological and MEG assessments at pre- and post-training to evaluate treatment effects. MEG data were imaged using an advanced Bayesian reconstruction method and examined using statistical parametric mapping. In this report, we focus on the neural correlates and the differential treatment effects observed using MEG; the results of the full clinical trial have been described elsewhere. Our results indicated that ACT modulated occipital and ABMT modulated medial temporal activity more strongly than the comparative treatment. PTSD symptoms decreased significantly from pre- to post-test. These initial neurophysiological outcome data suggest that ACT modulates visual pathways, while ABMT modulates threat-processing regions, but that both are associated with normalizing aberrant neural activity in veterans with PTSD.

Accentuate the Negative: Grammatical Errors During Narrative Production as a Clinical Marker of Central Nervous System Abnormality in School-Aged Children With Fetal Alcohol Spectrum Disorders.

Purpose: The purpose of this study was to examine (a) whether increased grammatical error rates during a standardized narrative task are a more clinically useful marker of central nervous system abnormality in Fetal Alcohol Spectrum Disorders (FASD) than common measures of productivity or grammatical complexity and (b) whether combining the rate of grammatical errors with the rate of cohesive referencing errors can improve utility of a standardized narrative assessment task for FASD diagnosis. Method: The method used was retrospective analysis of narrative and clinical data from 138 children (aged 7-12 years; 69 with FASD, 69 typically developing). Narrative analysis was conducted blind to diagnosis. Measures of grammatical error, productivity and complexity, and cohesion were used independently and in combination to predict whether a story was told by a child with an FASD diagnosis. Results: Elevated grammatical error rates were more common in children with FASD, and this difference facilitated a more accurate prediction of FASD status than measures of productivity and grammatical complexity and, when combined with an accounting of cohesive referencing errors, significantly improved sensitivity to FASD over standard practice. Conclusion: Grammatical error rates during a narrative are a viable behavioral marker of the kinds of central nervous system abnormality associated with prenatal alcohol exposure, having significant potential to contribute to the FASD diagnostic process.

Imaging of Congenital Malformations.

PURPOSE OF REVIEW: Intracranial congenital malformations are anomalies of brain development caused by genetic and environmental influences. This article discusses common intracranial congenital malformations, presents the associated neuroimaging findings, and discusses how appropriate identification of intracranial anomalies can impact diagnosis and treatment. RECENT FINDINGS: Advances in neuroimaging techniques and genetic research have led to a better understanding of the pathogenesis of many congenital malformations, adding insight into their clinical relevance and the intricate relationship between critical periods of development, genetic predisposition, and environmental insults. When one malformation is discovered, a high likelihood of more malformations exists. In some instances, the intracranial anomalies will lead to the diagnosis of a particular neurologic syndrome, which may, in turn, lead to modification of a plan of care. SUMMARY: Knowledge of congenital malformations and their appearance on imaging sequences is essential to improve clinical outcomes and quality of life for patients.

Brief Report: Syndromes in Autistic Children in a Finnish Birth Cohort.

We studied the association between specific congenital syndromes and autism spectrum disorders (ASD) in the large Finnish Register material. Our data include all children diagnosed with ASD (n = 4441) according to Finnish Hospital Discharge Register in 1987-2000. Four controls per each case were matched to sex, birthplace, date of birth (±30 days) and residence in Finland (n = 17,695). The prevalence of specific congenital syndromes in the Finnish Register of Congenital Malformations was evaluated among the ASD group and the controls by sex. The results of this study suggest that there is an association between several etiologically different syndromes and ASD when compared to controls without ASD. Statistically significant associations were observed with 47,XYY, Sotos syndrome, neurofibromatosis I, and syndrome not otherwise specified. Syndromes were more common among males with ASD compared to controls. These results support the previous studies of etiological heterogeneity of ASD and have importance in clinical examination, management and rehabilitation.

[Neurological appraisal of children and adolescents with psychotic symptoms]. / Valoracion neurologica de niños y adolescentes con sintomas psicoticos.

INTRODUCTION: Psychotic manifestations in childhood are not infrequent, yet the existing literature dealing with the neurological appraisal of children and adolescents with a clinical picture of psychosis is very scant. AIM: To conduct a non-systematic review of the literature that provides an answer to these three questions: When must a neurological appraisal be performed in a child with psychotic traits? What medical conditions can include signs and symptoms of psychosis in their development? And, what diagnostic procedure should be followed? DEVELOPMENT: The diseases that can present psychotic symptoms at onset or during their course are reviewed and grouped by pathologies: inborn errors of metabolism, genetic diseases, autoimmune and infectious diseases, malformations of the central nervous system, epilepsy, vascular pathology, rheumatologic processes, brain tumours, and psychoactive substances and drugs. A diagnostic regimen is proposed in which both the information obtained from the anamnesis and examination and the findings from each of the diagnostic tests are evaluated. CONCLUSIONS: A huge number of processes can display psychotic symptoms during their course and the key information offered by the anamnesis and examination must be taken into account. This review can help neuropaediatricians and other specialists perform a more systematised appraisal of children and adolescents with psychotic signs and symptoms.

TITLE: Valoracion neurologica de niños y adolescentes con sintomas psicoticos.Introduccion. Las manifestaciones psicoticas en la infancia no son infrecuentes; sin embargo, la bibliografia existente acerca de la valoracion neurologica de niños y adolescentes con cuadros psicoticos es muy escasa. Objetivo. Realizar una revision bibliografica no sistematica que permita responder a estas tres cuestiones: cuando debe llevarse a cabo una valoracion neurologica en un niño con rasgos psicoticos?, cuales son las condiciones medicas que pueden incluir un cuadro psicotico en su evolucion? y cual debe ser el procedimiento diagnostico? Desarrollo. Se revisan las enfermedades que pueden presentar sintomatologia psicotica al inicio o durante la evolucion, y se agrupan por patologias: errores congenitos del metabolismo, enfermedades geneticas, enfermedades autoinmunes e infecciosas, malformaciones del sistema nervioso central, epilepsia, patologia vascular, procesos reumatologicos, tumores cerebrales, y farmacos y sustancias psicoactivas. Se propone una pauta diagnostica en la que se valora la informacion obtenida a partir de la anamnesis y la exploracion y la aportacion de cada prueba diagnostica. Conclusiones. El numero de procesos que pueden manifestar sintomatologia psicotica a lo largo de su evolucion es muy elevado, y hay que considerar las claves que ofrecen la anamnesis y la exploracion. Esta revision puede ayudar a neuropediatras y otros especialistas a realizar una valoracion mas sistematizada de niños y adolescentes con cuadros psicoticos.

Fragile X syndrome: a review of associated medical problems.

Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.

Neuroembryology and brain malformations: an overview.

Modern neuroembryology integrates descriptive morphogenesis with more recent insight into molecular genetic programing and data enabled by cell-specific tissue markers that further define histogenesis. Maturation of individual neurons involves the development of energy pumps to maintain membrane excitability, ion channels, and membrane receptors. Most malformations of the nervous system are best understood in the context of aberrations of normal developmental processes that result in abnormal structure and function. Early malformations usually are disorders of genetic expression along gradients of the three axes of the neural tube, defective segmentation, or mixed lineages of individual cells. Later disorders mainly involve cellular migrations, axonal pathfinding, synaptogenesis, and myelination. Advances in neuroimaging now enable the diagnosis of many malformations in utero, at birth, or in early infancy in the living patient by abnormal macroscopic form of the brain. These images are complimented by modern neuropathological methods that disclose microscopic, immunocytochemical, and subcellular details beyond the resolution of MRI. Correlations may be made of both normal and abnormal ontogenesis with clinical neurological and EEG maturation in the preterm or term neonate for a better understanding of perinatal neurological disease. Precision in terminology is a key to scientific communication.

Cognitive outcome in children with rhombencephalosynapsis.

PURPOSE: Rhombencephalosynapsis is a rare congenital cerebellar malformation increasingly recognized by prenatal and neonatal neuroimaging. Cognitive outcome seems to be variable but is not well documented. AIMS AND METHODS: To study neurological, behavioural, and cognitive functions of patients with non-syndromic rhombencephalosynapsis, five patients (three female and two male, mean age at the time of this study 8.9 years, range 4.3-17.3 years) were assessed by neurological examination and several tests of behaviour and cognitive functions. RESULTS: Ataxia was present in all patients, but daily life activities were partly restricted in only one. Other symptoms were muscular hypotonia, abnormal eye movements, and head stereotypies. Three patients had pathological scores on both attention and hyperactivity/impulsivity scales. Only two patients had normal full-scale IQ (IQ value of 109 and 114, respectively). Verbal and/or performance IQ were impaired in three. CONCLUSION: In non-syndromic rhombencephalosynapsis the clinical presentation is variable. Attention deficit and hyperactivity disorders are frequent behavioural problems. Cognitive functions are mostly impaired, as mild intellectual impairment without a typical cognitive profile. However, rhombencephalosynapsis is compatible with normal cognitive functions. No definitive correlation between cognitive impairment and additional supratentorial abnormalities could be established.

[Passage from childhood to adulthood and craniovertebral malformations]. / Passage de l'enfant à l'adulte et malformations de la charnière crâniorachidienne.

Craniovertebral malformations are infrequent in children. Their causes are numerous (Chiari, congenital bone diseases, metabolic diseases, and genetic anomalies). When symptomatic (seldom), these malformations require surgical decompression and fixation. Progress in therapy probably will postpone the occurrence of these signs and require cooperation between pediatric and adult physicians.

Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.

Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as d-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor d-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.

Clinical-psychological characteristics of children with dysgenesis of the cerebellar vermis.

This report addresses behavioral abnormalities in children with cerebellar anomalies demonstrated on MRI scans. Published data are presented showing an interaction between cerebellar pathology and early childhood autism. The cerebellum is involved not only in movement coordination, but also in social adaptation and verbal communication. The genes expressed in the cerebellum during childhood are identical to those expressed in the hippocampus. We have observed 20 children with MRI-identified agenesis of the cerebellar vermis and behavioral abnormalities; children were aged 3-15 (mean 7.05) years and there were 12 males and eight females. A variety of autistic characteristics were identified in these children.

Verbal and gestural communication in children with bilateral perisylvian polymicrogyria.

We assessed intelligence and receptive and expressive language skills in 6 children, ages 7 years 9 months to 12 years 4 months, with bilateral perisylvian polymicrogyria of variable extent and with dysarthria of different severity. In view of the recent findings of a close relationship between word and gesture, we also examined the communicative use of gesture. We found that mental retardation was related to the extent of cortical malformation; lexical comprehension, but not morphosyntactic comprehension, and verbal production were more compromised than expected from nonverbal intellectual abilities; lack of verbal language was not compensated by the use of referential gestures. Results are discussed suggesting that compromised verbal and gestural communication in bilateral perisylvian polymicrogyria are not due simply to mental retardation and/or dysarthria but also to dysfunction of Sylvian fissure areas concerned with the totality of language processing.

Rhombencephalosynapsis diagnosed in childhood: clinical and MRI findings.

Rhombencephalosynapsis (RES) is a rare cerebellar malformation of unknown etiology characterized by vermal agenesis or hypogenesis, fusion of hemispheres and the dentate nuclei. Clinical presentation and prognosis are extremely variable and generally depends one the associated supratentorial anomalies. We report the first Tunisian case of RES diagnosed by magnetic resonance imaging (MRI) in a 3.5-year-old boy born to consanguineous parents. The child had spastic diplegia, facial dysmorphia, skeletal anomalies and normal intellectual development. Additional supratentorial anomalies were agenesis of septum pellucidum, moderate hydrocephalus and hypogenesis of corpus callosum. In this paper, the clinical and MRI findings and possible pathogenesis of this disorder are discussed.

Parents' experiences of sharing neonatal information and decisions: consent, cost and risk.

This paper is about the care of babies with confirmed or potential neurological problems in neonatal intensive care units. Drawing on recent ethnographic research, the paper considers parents' experiences of sharing information and decisions with neonatal staff, and approaches that support or restrict parents' involvement. There are growing medico-legal pressures on practitioners to inform parents and involve them in their babies' care. Data are drawn from observations in four neonatal units in southern England, and interviews with the parents of 80 babies and with 40 senior staff. The paper compares standards set by recent guidance, with parents' views about their share in decision-making, their first meetings with their babies, 'minor' decision-making, the different neonatal units, being a helpless observer and missed opportunities. Parents' standards for informed decisions are summarised, with their reported views about two-way decision-making, and their practical need to know. Whereas doctors emphasise distancing aspects of the consent process, parents tend to value 'drawing together' aspects.

Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia.

OBJECTIVE: To define the behavioral profile of periventricular nodular heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. METHODS: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. RESULTS: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. CONCLUSION: The neuronal migration disorder of periventricular nodular heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence.

Preserved episodic memory in subcortical band heterotopia.

PURPOSE: Neuropsychological profiles of four patients with subcortical band heterotopia (SBH) are presented to delineate further the phenotype of this disorder. METHODS: Standardized, norm-referenced measures of cognitive functioning, including intelligence, processing speed, attention, language, visuomotor skills, memory, and fine motor ability were administered to four patients with magnetic resonance imaging evidence of SBH. RESULTS: Despite intellectual impairment and other severe cognitive deficits, all four patients displayed relatively intact episodic memory. CONCLUSIONS: This selective sparing of memory functions has not been previously reported in individuals with SBH and suggests that doublecortin does not play a role in the development of memory systems in the mesial temporal region, which tend to be spared in SBH.

Prenatal diagnosis of cerebral malformation with an uncertain prognosis: a study concerning couple's information and consequences on pregnancy.

UNLABELLED: Fetal ultrasound (FU) is used during almost all pregnancies and makes a large contribution to the identification of fetal malformation. It is particularly difficult to announce a malformation, particularly those affecting the brain, because there are often doubts concerning both the diagnosis and the prognosis. AIM: The aim of this study was to analyze how imaging for prenatal screening is organized and how couples are managed and supported. We concentrated on the procedures used to inform couples: content, method of delivery and consequences. METHOD: Study amongst large multidisciplinary centers in Paris and the Paris region, by semi-directed interviews using a questionnaire. RESULTS: We showed that it is difficult to standardize the way in which information is supplied before and after the examination, and that doctors tend to recommend abortion when the prognosis is uncertain. DISCUSSION: These results provide information that will help decision-making concerning a standardized procedure allowing couples to benefit from all the capacities of prenatal screening, particularly when the diagnosis and prognosis are uncertain. There is a need for multidisciplinary teams to support and to accompany the decision concerning whether to have an abortion or to continue the pregnancy.