Impact of COVID-19 Pandemic-Associated Social Changes on Boys with Moderate to Severe Autism.

Objectives: The COVID-19 pandemic and the resulting social changes have made unprecedented changes in our lifetime with unknown repercussions on children with autism spectrum disorders. We sought to assess the effect of the COVID-19 pandemic and resulting social changes on boys with autism spectrum disorder. Methods: We conducted a survey using the CRISIS-AFAR questionnaire of caregivers of a population of boys (n = 40) with moderate to severe autism spectrum disorder for changes in environment and behavior before and after the pandemic. Results: We found several interesting findings, including an increase in self-injurious behaviors after the start of the pandemic, but not in the level of hyperactivity, anxiety, or aggressive behavior, or amount and frequency of stereotypies/repetitive behaviors in the children before and after the start of the pandemic. There was an increased difficulty in adjusting to new daily routines after the pandemic, as well as increased difficulty falling asleep. Conclusions: The study showed that a majority of boys with moderate/severe autism in our study were negatively affected by the pandemic across several domains. Additionally, this study highlights the need for educational and mental health resources to be prepared for similar events in the future.

Visual and verbal learning and memory in cystinosis.

Cystinosis is a rare genetic lysosomal storage disorder characterized by the accumulation of cystine in lysosomes. Many organ systems are vulnerable to this cystine accumulation including the CNS. A past study demonstrated that children with cystinosis have deficits in visual learning and memory while their verbal learning and memory and global intellectual function are spared (Spilkin, Ballantyne, & Trauner, 2009). However, no related study has been performed to assess the dissociation between visual and verbal learning and memory in adults with cystinosis who have had the benefit of longterm treatment with the cystine-depleting agent, cysteamine. In this study we assessed visual and verbal learning and memory in 15 adults with cystinosis, with a mean age of 30.2 years. The results indicate that adults with cystinosis have no significant deficits in either verbal or visual learning and memory. However, the individuals did perform better on the verbal assessment. The results suggest that if early and continued treatment is given to individuals with cystinosis there is a relative sparing of visual learning and memory that might have otherwise declined. This emphasizes the essential nature of the proper clinical management of cystinosis.

Auditory neglect in children following perinatal stroke.

Auditory neglect has been found in adults with right hemisphere focal brain lesions following strokes. Visual and tactile neglect has been found in children following both left and right hemisphere lesions resulting from perinatal strokes. The present cross-sectional study assessed auditory neglect in children with early unilateral brain damage from perinatal stroke. Twenty-six children with perinatal stroke and matched controls participated. All were asked to identify the location of a pure tone presented in left or right auditory fields. We found that children who had experienced left hemisphere perinatal strokes were significantly better at localizing sounds on the left side of space than the right side of space, and that response times improved with age on a normal trajectory relative to controls in left hemispace, while they did not improve normally in right hemispace. Children with right hemisphere perinatal strokes were significantly worse at localizing sounds on the right side of space relative to typically developing controls, and did not follow control trajectories for improvement in response times on the left or the right sides of space. Our preliminary results suggest that left hemisphere perinatal strokes may result in contralateral auditory neglect, while right hemisphere perinatal strokes may result in bilateral auditory neglect. Neglect was more severe in children with parietal lobe involvement, suggesting that the parietal lobe may play a dominant role in auditory attention in the developing brain.

Chiari I Malformation in Nephropathic Cystinosis.

OBJECTIVE: To determine the relative incidence of Chiari I malformations in children with cystinosis compared with those in the general population. STUDY DESIGN: Magnetic resonance imaging scans were performed on 53 patients with nephropathic cystinosis and 120 controls, age range 3-18 years. RESULTS: Ten of 53 (18.9%) patients with cystinosis had Chiari I or tonsillar ectopia, and only 2 of 120 controls (1.6%) had a similar finding. At least 2 of the patients had symptoms or signs thought to be related to the malformation, and one had surgical decompression. Two had an associated cervical syrinx. CONCLUSIONS: Children with cystinosis have a 12-fold higher prevalence of Chiari I malformations than the general pediatric population. Chiari I malformations should be high on the differential diagnosis when individuals with cystinosis develop neurologic signs and symptoms, and magnetic resonance imaging scans should be performed on children with cystinosis who present with new-onset headache, ataxia, incontinence, or other unexplained neurologic symptoms.

Clock drawing in children with perinatal stroke.

BACKGROUND: Children with perinatal stroke may show evidence of contralateral spatial neglect. The goal of this study was to determine whether the Clock Drawing Test commonly used in adults to identify neglect would be effective in detecting neglect in children with perinatal stroke. METHODS: Thirty-eight individuals (age range 6-21 years) with left hemisphere or right hemisphere perinatal onset unilateral lesions and 179 age-matched controls were given a free-drawn Clock Drawing Test in a cross-sectional design. An adapted scoring system that evaluated right- and left-sided errors separately was developed as part of the investigation. RESULTS: Children with right hemisphere lesions made a greater number of errors on both the right and left sides of the clock drawings in all age subgroups (6-8 years, 9-14 years, and 15-21 years) compared with controls. Children with right hemisphere lesions showed greater left and right errors in the younger groups compared with controls, with significantly poorer performance on the left at 6-8 years, suggestive of contralateral neglect. However, by ages 15-21 years, the right hemisphere lesion subjects no longer differed from controls. CONCLUSIONS: Clock drawing can identify spatial neglect in children with early hemispheric damage. However, brain development is a dynamic process, and as children age, spatial neglect may no longer be evident. These findings demonstrate the limitations of predicting long-term outcome after perinatal stroke from early neurocognitive data. Children with perinatal stroke may require different neural pathways to accomplish specific skills or to overcome deficits, but ultimately they may have "typical" outcomes.

Behavioral correlates of epileptiform abnormalities in autism.

There is a high incidence of epileptiform abnormalities in children with autism even in the absence of clinical seizures. These findings are most prominent during sleep recordings. The significance of these abnormalities is unclear. Although studies do not all agree, there may be some association between cognitive function, behavior, and the presence or absence of epileptiform discharges. Small studies of anticonvulsant treatment mostly suggest an improvement in certain aspects of cognitive or behavioral functioning in these children, but larger and more comprehensive studies are needed to determine the potential relationship between epileptiform discharges on EEG, cognitive and behavioral functioning, and treatment effects in the population with autism. This article is part of a Special Issue entitled "Autism and Epilepsy".

Hippocampal volume and memory performance in children with perinatal stroke.

BACKGROUND: Pediatric neurologists and neonatologists often are asked to predict cognitive outcome after perinatal brain injury (including likely memory and learning outcomes). However, relatively few data exist on how accurate predictions can be made. Furthermore, although the consequences of brain injury on hippocampal volume and memory performance have been studied extensively in adults, little work has been done in children. METHODS: We measured the volume of the hippocampus in 27 children with perinatal stroke and 19 controls, and measured their performance on standardized verbal and non-verbal memory tests. RESULTS: We discovered the following: (1) As a group, children with perinatal stroke had smaller left and right hippocampi compared with control children. (2) Individually, children with perinatal stroke demonstrated 1 of 3 findings: no hippocampal loss, unilateral hippocampal loss, or bilateral hippocampal volume loss compared with control children. (3) Hippocampal volume inversely correlated with memory test performance in the perinatal stroke group, with smaller left and right hippocampal volumes related to poorer verbal and non-verbal memory test performance, respectively. (4) Seizures played a significant role in determining memory deficit and extent of hippocampal volume reduction in patients with perinatal stroke. CONCLUSIONS: These findings support the view that, in the developing brain, the left and right hippocampi preferentially support verbal and nonverbal memory respectively, a consistent finding in the adult literature but a subject of debate in the pediatric literature. This is the first work to report that children with focal brain injury incurred from perinatal stroke have volume reduction in the hippocampus and impairments in certain aspects of declarative memory.

Incidence and behavioral correlates of epileptiform abnormalities in autism spectrum disorders.

Autism spectrum disorders (ASD) are associated with an increased incidence of epilepsy and of epileptiform discharges on electroencephalograms. It is unknown whether epileptiform discharges correlate with symptoms of ASD. We completed a retrospective chart review of 101 patients with ASD who had overnight electroencephalograms. We looked for a relationship between epileptiform abnormalities and diagnosis, history of regression, communication skills, and other features associated with ASD. There was a higher incidence of epileptiform activity in children with stereotypies and aggressive behavior. The incidence of epileptiform abnormalities was significantly lower in Asperger's compared with more severe forms of autism. Results suggest that increasing severity of autistic symptoms may be associated with higher likelihood of epileptiform abnormalities. Whether treatment alters outcome is unknown.

Early language development after peri-natal stroke.

Early unilateral brain damage has different implications for language development than does similar damage in adults, given the plasticity of the developing brain. The goal of this study was to examine early markers of language and gesture at 12 and 24months in children who had peri-natal right hemisphere (RH) or left hemisphere (LH) stroke (n=71), compared with typically developing controls (n=126). Parents completed the MacArthur-Bates Communicative Development Inventory (CDI): Words & Gestures (12month data point), or the CDI: Words & Sentences (24month data point). Statistical analyses were performed on percentile scores using analysis of variance techniques. At 12months, there were no differences among groups for Words Understood, Phrases Understood or Words Produced. At 24months, both lesion groups scored significantly lower than controls on Word Production, Irregular Words, and Mean Length of Sentences, but lesion groups did not differ from each other. In a longitudinal subset of participants, expressive vocabulary failed to progress as expected from 12 to 24months in the stroke group, with no differences based on lesion side. Gesture and word production were dissociated in the left hemisphere subjects. Findings suggest that early language development after peri-natal stroke takes a different course from that of typical language development, perhaps reflecting brain reorganization secondary to plasticity in the developing brain.

Effect of age at treatment on cognitive performance in patients with cystinosis.

OBJECTIVE: To determine whether early treatment with cysteamine affects cognitive functioning in patients with nephropathic cystinosis. STUDY DESIGN: Forty-six subjects aged 3-18 years with cystinosis underwent cognitive testing to determine intelligence, visual-spatial abilities, and visual-motor skills. An age-matched control group (n = 85; age 2-22 years) underwent the same tests. Age at diagnosis and age at initiation of treatment with cysteamine were recorded at the time of testing. RESULTS: Patients with cystinosis treated at or after age 2 years (late-treatment group) scored significantly lower on verbal, performance, and full-scale IQ measures, as well as on a test of visual-spatial skills, compared with patients treated before age 2 years (early-treatment group) and controls. Both groups of subjects with cystinosis demonstrated impaired visual-motor skills compared with controls, with no difference between the early-treatment and late-treatment groups. CONCLUSION: Early treatment with cysteamine appears to improve intellectual function in patients with nephropathic cystinosis. However, the lack of improvement in visual-motor function with early cysteamine treatment suggests possibly different mechanisms underlying visual-motor performance compared with other areas of cognition in this disorder.

Executive function in nephropathic cystinosis.

OBJECTIVE: We studied executive function (EF) in children and adolescents with cystinosis. BACKGROUND: Cystinosis is a genetic metabolic disorder in which the amino acid cystine accumulates in all organs of the body, including the brain. Previous research has shown that individuals with cystinosis have visuospatial deficits, but normal intelligence and intact verbal abilities. Better understanding of the behavioral phenotype associated with cystinosis could have important implications for treatment. METHODS: Twenty-eight children with cystinosis and 24 control participants (age range 8 to 17 years) underwent selected Delis-Kaplan executive function system tests for neuropsychological assessment of EF, and the participants' parents completed the behavior rating inventory of executive function. RESULTS: Participants with cystinosis performed significantly more poorly than controls on all Delis-Kaplan Executive Function System indices examined and on the behavior rating inventory of executive function metacognition index and global executive composite. CONCLUSIONS: EF is an area of potential risk in cystinosis. Our data have implications not only for the function of affected children and adolescents in school and daily life, but also for disease management and treatment adherence. Our findings can aid in the design and implementation of interventions and lead to a greater understanding of brain-behavior relationships in cystinosis.

Cognition in nephropathic cystinosis: pattern of expression in heterozygous carriers.

Individuals with cystinosis exhibit specific cognitive deficits in visual spatial function. The purpose of the current study was to examine if obligate heterozygotes of the CTNS mutation have the same pattern of cognitive functioning seen in homozygotes, namely aberrant visual-spatial functioning against a background of relatively intact visual-perceptual functioning and overall cognitive ability. Study participants were 254 adults (100 heterozygotes and 154 controls), ages 17 years 10 months through 74 years 9 months. Tests of intelligence, visual perceptual, and visual spatial functioning were administered. Our results showed that cystinosis heterozygotes demonstrated intelligence within the normal range, and performed similarly to controls on tests of visual-perceptual ability. In contrast, the heterozygotes performed significantly more poorly on each of the visual-spatial tests when compared to controls. Obligate heterozygotes for the CTNS mutation display a similar pattern of visual processing decrements as do individuals with cystinosis. Namely, carriers demonstrate relative weaknesses in visual-spatial processing, while maintaining normal visual perceptual ability and intelligence in the normal range. The visual spatial decrements in heterozygotes were not as marked as those found in individuals with cystinosis, suggesting a gene dosing effect. This study provides an impetus for other studies of gene-behavior relationships in recessive disorders, and may stimulate further interest in the role of aberrant genes on "individual differences" in behavior.

Perinatal risk factors and later social, thought, and attention problems after perinatal stroke.

Objective. Survivors of perinatal stroke may be at risk for behavioral problems. Perinatal risk factors that might increase the likelihood of later behavior problems have not been identified. The goal of this study was to explore whether perinatal factors might contribute to behavior problems after perinatal stroke. Methods. 79 children with unilateral perinatal stroke were studied. Perinatal factors included gender, gestational age, neonatal seizures, instrumented delivery, fetal distress, acute birth problems, birth weight, and time of diagnosis. Subjects with evidence of hypoxic ischemic encephalopathy were excluded. Parents completed the Achenbach Child Behavior Checklist (CBCL) (Achenbach 1985). The CBCL yields T-scores in several symptom scales. We focused on Social, Thought, and Attention Problems scates. Results. Gestational age and the presence of uteroplacental insufficiency were associated with significant differences on the Thought Problems scale; Attention Problems scores approached significance for these variables. Fetal distress, neonatal seizures, or neonatal diagnosis was associated with 25-30% incidence of clinically significant T-scores on Social, Thought, and Attention Problems scales. Conclusions. Several perinatal factors were associated with a high incidence of social, thought, and behavior problems in children with perinatal stroke. These findings may be useful in anticipatory guidance to parents and physicians caring for these children.

Spatial analysis after perinatal stroke: patterns of neglect and exploration in extra-personal space.

This study was conducted to determine whether school-aged children who had experienced a perinatal stroke demonstrate evidence of persistent spatial neglect, and if such neglect was specific to the visual domain or was more generalized. Two studies were carried out. In the first, 38 children with either left hemisphere (LH) or right hemisphere (RH) damage and 50 age-matched controls were given visual cancellation tasks varying in two factors: target stimuli and stimulus array. In the second study, tactile neglect was evaluated in 41 children with LH or RH damage and 72 age-matched controls using a blindfolded manual exploration task. On the visual cancellation task, LH subjects omitted more target stimuli on the right, but also on the left, compared with controls. Children with RH lesions also produced a larger number of omissions on both the left and right sides than controls, but with poorer performance on the left. On the manual exploration task, LH children required significantly longer times to locate the target on both sides of the board than did controls. RH children had significantly prolonged search times on the left side, but not on the right, compared with controls. In both tasks, LH subjects employed unsystematic search strategies more often than both control and RH children. The search strategy of RH children also tended to be erratic when compared to controls, but only in the random arrays of the visual cancellation tasks; structure of the target stimuli improved their organization. These results demonstrate that children with early LH brain damage display bilateral difficulties in visual and tactile modalities; a pattern that is in contrast to that seen in adults with LH damage. This may result from disorganized search strategies or other subtle spatial or attentional deficits. Results of performance of RH children suggests the presence of contralateral neglect in both the visual and tactile modalities; a finding that is similar to the neglect in adult stroke patients with RH lesions. The fact that deficits in spatial attention and organizational strategies are present after very early focal damage to either the LH or the RH broadens our understanding of the differences in functional lateralization between the immature and mature brain. These results also add to evidence for limitations to plasticity in the developing brain. Our findings may have therapeutic and rehabilitative implications for the management of children with early focal brain lesions.

Neurological impairment in nephropathic cystinosis: motor coordination deficits.

Nephropathic cystinosis is a rare genetic metabolic disorder that results in accumulation of the amino acid cystine in lysosomes due to lack of a cystine-specific transporter protein. Cystine accumulates in cells throughout the body and causes progressive damage to multiple organs, including the brain. Neuromotor deficits have been qualitatively described in individuals with cystinosis. This study quantitatively examined fine-motor coordination in individuals with cystinosis. Brain magnetic resonance imaging (MRI) scans were also performed to determine whether structural changes were associated with motor deficits. Participants were 52 children and adolescents with infantile nephropathic cystinosis and 49 controls, ages 2-17 years, divided into preacademic and school-age groups. Results indicated that both the preacademic and school-age cystinosis groups performed significantly more poorly than their matched control groups on the Motor Coordination Test. Further, the level of performance was not significantly different between the preacademic and school-age groups. There were no significant differences in motor coordination scores based on MRI findings. This is the first study to document a persistent, nonprogressive, fine-motor coordination deficit in children and adolescents with cystinosis. The fact that these difficulties are present in the preschool years lends further support to the theory that cystinosis adversely affects neurological functioning early in development. The absence of a relationship between brain structural changes and motor function suggests that an alternative cause for motor dysfunction must be at work in this disorder.

Developmental changes in cerebral white matter microstructure in a disorder of lysosomal storage.

The goal of this work was to study white matter (WM) integrity in children with cystinosis, a rare lysosomal storage disorder resulting in cystine accumulation in peripheral and central nervous system tissue. Based on previous reports of cystine crystal formation in myelin precursors as well as evidence for specific cognitive deficits in visuospatial functioning, diffusion tensor imaging (DTI) was applied to 24 children with cystinosis (age 3-7 years) and to 24 typically developing age-matched controls. Scalar diffusion indices, fractional anisotropy (FA) and mean diffusivity (MD), were examined in manually defined regions of interest within the parietal and inferior temporal lobes. Diffusion indices were correlated with performance on measures of visuospatial cognition and with white blood cell cystine levels. Bilaterally decreased FA and increased MD were evident in the inferior and superior parietal lobules in children with cystinosis, with comparable FA and MD to controls in inferior temporal WM, and implicate a dissociation of the dorsal and ventral visual pathways. In older cystinosis children (age>5), diminutions in visuospatial performance were associated with reduced FA in the right inferior parietal lobule. In addition, increased MD was found in the presence of high cystine levels in all children with cystinosis. This study provides new information that the average diffusion properties in children with cystinosis deviate from typically developing children. Findings suggest the presence of early microstructural WM changes in addition to a secondary effect of cystine accumulation. These alterations may impact the development of efficient fiber networks important for visuospatial cognition.

Visual and verbal learning in a genetic metabolic disorder.

Visual and verbal learning in a genetic metabolic disorder (cystinosis) were examined in the following three studies. The goal of Study I was to provide a normative database and establish the reliability and validity of a new test of visual learning and memory (Visual Learning and Memory Test; VLMT) that was modeled after a widely used test of verbal learning and memory (California Verbal Learning Test; CVLT). One hundred seventy-two neurologically intact individuals ages 5 years through 50 years were administered the VLMT and the CVLT. Normative data were collected and the results suggested that the VLMT is a reliable and valid new measure of visual learning and memory. The aim of Study II was to examine possible dissociations between verbal and visual learning and memory performances in individuals with cystinosis as well as to assess changes in performance as individuals with the disorder age. Thirty-seven individuals with cystinosis and 37 matched controls were administered a new test of visual learning and memory (Visual Learning and Memory Test; VLMT) and the California Verbal Learning Test (CVLT). Individuals with cystinosis performed at a lower level than controls on almost all indices of visual learning and memory while no differences were found between the groups on the verbal measure. Examination of the results on the VLMT indicated that the visual learning and memory impairment in cystinosis may result from difficulty with processing visual information quickly. Study III aimed to remediate the observed visual learning and memory deficit by implementing an intervention that increased the exposure time for visual stimuli. Fifteen individuals with cystinosis were administered a version of the VLMT in which the stimuli were exposed for 3s rather than 1s. Fifteen matched controls were administered the 1-s version of the VLMT. The results of Study III indicated that by increasing the exposure time for each visual stimulus, individuals with cystinosis were able to perform at the same level as control subjects. This is the first study to demonstrate impaired visual learning and spared verbal learning in individuals with cystinosis. These results may provide the foundation for designing cognitive interventions, may lead to further hypotheses regarding the underlying mechanism of the observed visual learning and memory deficit, and have implications for a greater understanding of gene-behavior relationships.

Weight gain in children treated with valproate.

Weight gain in children due to valproate is a major concern in the treatment of epilepsy. Previous studies have yielded conflicting results both as to how common this problem is in children and as to whether there are clinical predictors of weight gain. The authors perform a chart review of 94 pediatric patients treated with valproate to investigate weight gain and potential predictors. The slope of the regression line for the body mass index z scores for each patient at each available visit was calculated, (Deltaz-score). Relationships between Deltaz scores and predictors of interest were assessed via univariate analyses. Twenty-three of 94 patients had Deltaz score >0.25 SD/year. Twelve of 94 patients had Deltaz score >0.5 SD/year. Pediatric participants appear to be less prone to weight gain on valproate than adults. A negative correlation was found between duration on treatment and Deltaz score. No other significant correlations were found between potential clinical predictors and Deltaz score.