A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

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.

Spatial attention in children with perinatal stroke.

Spatial neglect is a common feature of right hemisphere damage in adults, but less is known about spatial inattention following early brain damage. We used a Posner-based cueing task to examine hemispatial neglect and aspects of attention in children with perinatal stroke in either left (LH) or right hemisphere (RH) and controls. A visual perception task assessed the speed of visual perception. A spatial attention cueing task (the E-task) measured the ability to discriminate the direction of a target stimulus ("E"), when presented on the left or right side of the screen. This task provided indices of performance for attention orienting, disengagement and reorienting. Children with LH lesions had slowed visual perception compared to controls. Children with RH lesions did not demonstrate similar deficits. On the E-task, groups with both LH and RH lesions demonstrated lower accuracy on both left and right sides compared to controls. Children with LH lesions also showed impaired attention orienting and disengagement on left and right sides compared to controls, while children with RH lesions were most impaired in orienting and disengagement on their contralesional side. Children with LH lesions demonstrated more extensive attentional deficits than children with RH lesions. These results suggest that development of spatial attention may require different neural networks than maintenance of attention.

Longitudinal Stability of Spatial Inattention in Children With Perinatal Stroke.

BACKGROUND: Signs of contralateral hemispatial inattention may be witnessed in children following perinatal brain infarcts (lesions), and evidence shows a pattern distinct from that in adults. This study is a longitudinal analysis of children with perinatal infarcts, with the goals of determining the pattern of inattention found in children with left or right hemisphere lesions and whether this pattern shows signs of change over time. METHODS: Twenty-one children with left hemishpere lesions, nine children with right hemisphere lesions, and 80 neurologically healthy control children were given the Infant and Toddler Neglect Task at two different time points. At time 1, median age was 1.54 years (interquartile range [IQR] = 0.92 to 2.29). At time 2, median age was 3.25 years (IQR = 2.23 to 5.00). A standardized scoring system was developed to compare the children's preference for the left versus right side of space. RESULTS: Children with left hemisphere lesions showed a significantly increased preference for the left side of space and a slightly decreased preference for the right side of space at time 1 and a significantly decreased preference for the right side of space at time 2 compared with controls. Children with right hemisphere lesions showed a significantly decreased preference for the left side of space and a significantly increased preference for the right side of space compared with controls at time 1 and a significantly decreased preference for the left side of space and a significantly increased preference for the right side of space compared with controls at time 2. There were no significant within-subjects effects across time. CONCLUSIONS: These data suggest that mechanisms of hemispatial inattention affect children early in the developmental process and that hemispatial inattention in children with both left and right hemisphere perinatal lesions likely persists at least through the early elementary school years.

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.

Hierarchical processing of visual stimuli in nephropathic cystinosis.

Previous studies have shown that individuals with cystinosis may exhibit difficulty with visuospatial tasks. Global and local (hierarchical) processing are specific types of visuospatial tasks mediated by the right and left parietal lobes respectively. The study objective was to determine whether individuals with cystinosis and carriers of the cystinosin gene mutation show deficits in global and/or local processing. The study included 48 children (32 controls, 16 cystinosis) and 56 adults (25 controls, 25 carriers, and 6 cystinosis). Participants were instructed to replicate 10 hierarchical stimuli to assess global-local processing. The primary outcome measure was mean global and local performance on the hierarchical stimuli task between subgroups. Error subtypes were included to further assess each image. Compared to the control subgroups, adult and child cystinosis patients as well adult carriers demonstrated significant deficits in the global processing of a hierarchical stimulus against a background of unimpaired local processing. Child cystinosis patients performed significantly more poorly than controls on all error subtypes except local shape distortion. Adult cystinosis patients and carriers made significantly more global shape distortion errors than the controls. Our study shows that the cognitive profile documented in cystinosis patients and carriers includes significant difficulties with the global processing of an image. Results of the carrier population are important since they suggest that the cognitive impairments observed in patients cannot be attributed to symptomatic manifestations of the disease. Instead, the global processing deficits observed provide insight into the potential role of the cystinosin gene mutation on neurodevelopmental differences seen in these individuals.

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.

Comparison of Spontaneously Elicited Language Patterns in Specific Language Impairment and High-Functioning Autism.

BACKGROUND: We aimed to characterize differences in the use of language in children with specific language impairment and high-functioning autism by analyzing verbal responses on standardized tests. The overall goal was to provide clinicians with additional tools with which to aid in distinguishing the two neurodevelopmental disorders. MATERIALS AND METHODS: This study included 16 children with specific language impairment, 28 children with high-functioning autism, and 52 typically developing participants between the ages of six and 14. Groups were matched for age, and specific language impairment and high-functioning autism groups were matched on verbal and performance IQ. Responses from standardized tests were examined for response length, grammatical errors, filler words, perseverations, revisions (repeated attempts to begin or continue a sentence), off-topic attention shifts (lapses in attention to the task), and rambling. Data were analyzed using parametric and nonparametric methods. RESULTS: Specific language impairment responses were longer and contained more filler words than did those of the other two groups, whereas high-functioning autism responses exhibited more grammatical errors, off-topic attention shifts, and rambling. Specific language impairment and high-functioning autism responses showed higher rates of perseveration compared with controls. There were no significant differences in revisions among the three groups. CONCLUSIONS: Differences in language patterns of participants with specific language impairment and high-functioning autism may be useful to the clinician in helping to differentiate isolated language impairment from high-functioning autism. The results also support the conclusion that the two conditions are separable, and each exhibits a different pattern of language dysfunction.

Neuroanatomical correlates of emotion-processing in children with unilateral brain lesion: A preliminary study of limbic system organization.

In this study, MRI and DTI were employed to examine subcortical volume and microstructural properties (FA, MD) of the limbic network, and their relationships with affect discrimination in 13 FL (6 right FL, M = 10.17 years; 7 left FL; M = 10.09) and 13 typically-developing children (TD; M = 10.16). Subcortical volume of the amygdala, hippocampus and thalamus and FA and MD of the fornix and anterior thalamic radiation (ATR) were examined. Results revealed no group differences across emotion-perception tasks or amygdalar volume. However, contrasting neuroanatomical patterns were observed in right versus left FL youth. Right FL participants showed increased left hippocampal and thalamic volume relative to left FL participants; whereas, the latter group showed increased right thalamic volume. DTI findings also indicated right FL children show greater MD of right fornix than other groups, whereas, left FL youth showed greater MD of left fornix. Right FL youth also showed lower FA of right fornix than left FL children, whereby the latter showed greater FA of left fornix and ATR. Differential associations between DTI indices and auditory/visual emotion-perception were observed across FL groups. Findings indicate diverging brain-behavioral relationships for emotion-perception among right and left FL children.

Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder.

Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD.

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.

Patterns of Sensitivity to Emotion in Children with Williams Syndrome and Autism: Relations Between Autonomic Nervous System Reactivity and Social Functioning.

Williams syndrome (WS) and autism spectrum disorder (ASD) are associated with atypical social-emotional functioning. Affective visual stimuli were used to assess autonomic reactivity and emotion identification, and the social responsiveness scale was used to determine the level social functioning in children with WS and ASD contrasted with typical development (TD), to examine syndrome-specific and syndrome-general features. Children with ASD exhibited the highest arousal in response to faces, with a lack of difference in autonomic sensitivity across different emotional expressions, unlike in WS and TD. The WS group demonstrated unique deficits in identifying neutral stimuli. While autonomic responsivity to neutral faces was associated with social functioning in all children, converging profiles characterized children with WS contrasted with TD and ASD.

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".

Nephropathic cystinosis: an international consensus document.

Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Face and location processing in children with early unilateral brain injury.

Human visuospatial functions are commonly divided into those dependent on the ventral visual stream (ventral occipitotemporal regions), which allows for processing the 'what' of an object, and the dorsal visual stream (dorsal occipitoparietal regions), which allows for processing 'where' an object is in space. Information about the development of each of the two streams has been accumulating, but very little is known about the effects of injury, particularly very early injury, on this developmental process. Using a set of computerized dorsal and ventral stream tasks matched for stimuli, required response, and difficulty (for typically-developing individuals), we sought to compare the differential effects of injury to the two systems by examining performance in individuals with perinatal brain injury (PBI), who present with selective deficits in visuospatial processing from a young age. Thirty participants (mean=15.1 years) with early unilateral brain injury (15 right hemisphere PBI, 15 left hemisphere PBI) and 16 matched controls participated. On our tasks children with PBI performed more poorly than controls (lower accuracy and longer response times), and this was particularly prominent for the ventral stream task. Lateralization of PBI was also a factor, as the dorsal stream task did not seem to be associated with lateralized deficits, with both PBI groups showing only subtle decrements in performance, while the ventral stream task elicited deficits from RPBI children that do not appear to improve with age. Our findings suggest that early injury results in lesion-specific visuospatial deficits that persist into adolescence. Further, as the stimuli used in our ventral stream task were faces, our findings are consistent with what is known about the neural systems for face processing, namely, that they are established relatively early, follow a comparatively rapid developmental trajectory (conferring a vulnerability to early insult), and are biased toward the right hemisphere.