Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial.

BACKGROUND: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. METHODS: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. RESULTS: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. CONCLUSIONS: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.

Emotional functioning among children with neurofibromatosis type 1 or Noonan syndrome.

While neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are clinically distinct genetic syndromes, they have overlapping features because they are caused by pathogenic variants in genes encoding molecules within the Ras-mitogen-activated protein kinase signaling pathway. Increased risk for emotional and behavioral challenges has been reported in both children and adults with these syndromes. The current study examined parent-report and self-report measures of emotional functioning among children with NF1 and NS as compared to their unaffected siblings. Parents and children with NS (n = 39), NF1 (n = 39), and their siblings without a genetic condition (n = 32) completed well-validated clinical symptom rating scales. Results from parent questionnaires indicated greater symptomatology on scales measuring internalizing behaviors and symptoms of attention deficit hyperactivity disorder (ADHD) in both syndrome groups as compared with unaffected children. Frequency and severity of emotional and behavioral symptoms were remarkably similar across the two clinical groups. Symptoms of depression and anxiety were higher in children who were also rated as meeting symptom criteria for ADHD. While self-report ratings by children generally correlated with parent ratings, symptom severity was less pronounced. Among unaffected siblings, parent ratings indicated higher than expected levels of anxiety. Study findings may assist with guiding family-based interventions to address emotional challenges.

"I feel so bad but have nothing to do." Exploring Ugandan caregivers' experiences of parenting a child with severe malaria and subsequent repeated uncomplicated malaria.

BACKGROUND: Severe malaria in children is often associated with long-term behavioural and cognitive problems. A sizeable minority of children go on to experience repeated malaria due to the high transmission and infection rates in the region. The purpose of this study was to explore caregivers' experiences of parenting a child with a history of severe malaria followed by repeated episodes of uncomplicated malaria in comparison to healthy community children. METHODS: Thirty-one caregivers were enrolled in the study. These included caregivers of children previously exposed to severe malaria and who had experienced repeated uncomplicated malaria attacks (SM with RMA, n = 15), caregivers of children exposed to severe malaria who did not experience repeated episodes (SM, n = 10), and caregivers of healthy community children (CC, n = 6) were purposively selected. RESULTS: Thematic-content analysis generated eight areas of concern, six of which were noted only by caregivers of children with SM or SM with RMA: (1) a sense of helplessness; (2) challenges with changes in behaviour; (3) responses to a child's behaviour; (4) family life disruptions, including breakdown of relationships and inadequate male-spouse involvement in child care; (5) disagreements in seeking healthcare; (6) societal burden; and two by caregivers of children with SM, SM with RMA and also CC; (7) concern about academic achievement; and, (8) balancing work and family life. CONCLUSIONS: The study findings suggest that severe malaria, especially when followed by repeated malaria episodes, affects not only children who have the illness but also their caregivers. The effects on caregivers can decrease their social functioning and isolate them from other parents and may disrupt families. Interventions to support caregivers by counselling the ongoing problems that might be expected in children who have had severe malaria and repeated episodes of malaria, and how to manage these problems, may provide a way to improve behavioural and mental health outcomes for those children and their caregivers.

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure.

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.

Variability in clinical and neuropsychological features of individuals with MAP2K1 mutations.

Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature. Published studies have indicated that cognitive functioning of individuals with MAP2K1 mutations can range from severe intellectual disability to mildly below average. Neither of the individuals presented here had severe intellectual disability, and one had intellectual functioning within the average range. Neurodevelopmental concerns that were common among our two patients included fine motor difficulties, slow processing speed, reduced attention span, learning disabilities, and diminished energy/alertness. Taken together, our findings demonstrate that mutations in MAP2K1, which are frequently associated with neurological complications and intellectual disability, can be associated with a milder clinical and neurocognitive profile more typical of individuals with Noonan syndrome. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and obstetric factors, and environmental influences. © 2016 Wiley Periodicals, Inc.

Unique white matter microstructural patterns in ADHD presentations-a diffusion tensor imaging study.

Attention-deficit/hyperactivity disorder predominantly inattentive (ADHD-PI) and combined (ADHD-C) presentations are likely distinct disorders that differ neuroanatomically, neurochemically, and neuropsychologically. However, to date, little is known about specific white matter (WM) regions differentiating ADHD presentations. This study examined differences in WM microstructure using diffusion tensor imaging (DTI) data from 20 ADHD-PI, 18 ADHD-C, and 27 typically developed children. Voxel-wise analysis of DTI measurements in major fiber bundles was carried out using tract-based spatial statistics (TBSS). Clusters showing diffusivity abnormalities were used as regions of interest for regression analysis between fractional anisotropy (FA) and neuropsychological outcomes. Compared to neurotypicals, ADHD-PI children showed higher FA in the anterior thalamic radiations (ATR), bilateral inferior longitudinal fasciculus (ILF), and in the left corticospinal tract (CST). In contrast, the ADHD-C group exhibited higher FA in the bilateral cingulum bundle (CB). In the ADHD-PI group, differences in FA in the left ILF and ATR were accompanied by axial diffusivity (AD) abnormalities. In addition, the ADHD-PI group exhibited atypical mean diffusivity in the forceps minor (FMi) and left ATR and AD differences in right CB compared to healthy subjects. Direct comparison between ADHD presentations demonstrated radial diffusivity differences in FMi. WM clusters with FA irregularities in ADHD were associated with neurobehavioral performance across groups. In conclusion, differences in WM microstructure in ADHD presentations strengthen the theory that ADHD-PI and ADHD-C are two distinct disorders. Regions with WM irregularity seen in both ADHD presentations might serve as predictors of executive and behavioral functioning across groups. Hum Brain Mapp 37:3323-3336, 2016. © 2016 Wiley Periodicals, Inc.

Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort.

BACKGROUND: Cerebral malaria (CM) and severe malarial anaemia (SMA) are associated with neuro-developmental impairment in African children, but long-term mental health disorders in these children are not well defined. METHODS: A cohort of children previously exposed to CM (n = 173) or SMA (n = 99) had neurologic assessments performed and screening for behaviour difficulties using the Strengths and Difficulties Questionnaire (SDQ) a median of 21 months after the disease episode. These findings were compared to concurrently recruited community children (CC, n = 108). Participants with SDQ total difficulties score ≥ 17 had a mental health interview with the child and adolescent version of the Mini-International Neuropsychiatric Interview (MINI-KID) and a sample had brain magnetic resonance imaging (MRI). RESULTS: Fifty-five children had SDQ score ≥ 17. On the MINI-KID, these children were classified as having no difficulties (n = 18), behaviour difficulties only (n = 13) or a mental health disorder (n = 24). Behaviour difficulties were seen in similar frequencies in CM (3.5%), SMA (4.0%) and CC (2.8%). In contrast, mental health disorders were most frequent in CM (10.4%), followed by SMA (4.0%) and CC (1.8%). Externalizing disorders (conduct, oppositional defiance and attention deficit hyperactivity) were the most common mental health disorders. The median total coma duration was 72 (IQR 36.0-115.0) h in patients with mental health disorders compared to 48 (IQR 28.5-78.7) h in those without, p = 0.039. Independent risk factors for mental health disorder included neurologic deficit at discharge (OR 4.09 (95% CI 1.60, 10.5) and seizure recurrences during hospitalization, (OR 2.80, 95% CI 1.13, 6.97). Brain MRI findings consistent with small vessel ischaemic neural injury was seen in over half of these children. CONCLUSIONS: Cerebral malaria may predispose children to mental health disorders, possibly as a consequence of ischaemic neural injury. There is urgent need for programmes of follow-up, diagnosis and interventions for these children.

Severe Malaria and Academic Achievement.

BACKGROUND: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with neurocognitive impairment in childhood but their effects on long-term academic achievement are not known. METHODS: Ugandan children 5 to 12 years old who participated in a previous study evaluating cognitive outcomes after CM (n = 73) or SMA (n = 56), along with community children (CC, n = 100) from the same household or neighborhood, were on average enrolled 67.1 months (range, 19-101 months) after the severe malaria episode or previous study enrollment. Academic achievement in word reading, sentence comprehension, spelling, and math computation was evaluated using the Wide Range Achievement Test, Fourth Edition. Age-adjusted z-scores for academic achievement outcomes were calculated from CC scores. RESULTS: After adjustment for age and time from enrollment, reading scores were lower (mean difference from CC [95% confidence interval]) in children with CM (-0.15 [-0.27 to -0.03], P = .02) or SMA (-0.15 [-0.28 to -0.02], P = .02) than CC. Postdischarge malaria episodes were associated with worse spelling and reading scores in CM and worse spelling scores only in SMA. Pathway analysis showed that incidence of postdischarge uncomplicated malaria contributed significantly to the association of CM or SMA with poorer reading scores. CONCLUSION: Children with CM or SMA have poorer long-term reading skills. Postdischarge malaria episodes contribute significantly to this association. Postdischarge malaria chemoprevention should be assessed as an intervention to improve long-term academic achievement in children with severe malaria.

Gender differences in brain activation on a mental rotation task.

Few neuroimaging studies have explored gender differences on mental rotation tasks. Most studies have utilized samples with both genders, samples mainly consisting of men, or samples with six or fewer females. Graduate students in science fields or liberal arts programs (20 males, 20 females) completed a mental rotation task during functional magnetic resonance imaging (fMRI). When a pair of cube figures was shown, the participant made a keypad response based on whether the pair is the same/similar or different. Regardless of gender, the bilateral middle frontal gyrus, bilateral intraparietal sulcus (IPS), and the left precuneus were activated when a subject tried to solve the mental rotation task. Increased activation in the right inferior frontal gyrus/middle frontal gyrus, the left precuneus/posterior cingulate cortex/cuneus region, and the left middle occipital gyrus was found for men as compared to women. Better accuracy and shorter response times were correlated with an increased activation in the bilateral intraparietal sulcus. No significant brain activity differences related to mental rotation were found between academic majors. These findings suggest that networks involved in visual attention appear to be more strongly activated in the mental rotation tasks in men as compared to women. It also suggests that men use a more automatic process when analyzing complex visual reasoning tasks while women use a more top-down process.

Do comorbid symptoms discriminate between autism spectrum disorder, ADHD and nonverbal learning disability?

Characterizing the functioning of individuals with neurodevelopmental disorders is crucial to their diagnosis. Research has found that children with different neurodevelopmental disorders, including autism spectrum disorders (ASD), attention deficit and hyperactivity disorder (ADHD), and nonverbal learning disability (NLD), may have comorbid symptoms of anxiety and depression, and problems with pragmatic language. The main aim of the present study was to identify any differences in the above-mentioned comorbid symptoms associated with these clinical profiles. A second aim was to establish how well signs of pragmatic language difficulties could discriminate between the three clinical profiles, in terms of their diagnostic power. For this purpose, 107 participants from 8 to 16 years old with a diagnosis of ASD, ADHD or NLD were compared with a group of typically-developing children. Self-reports on symptoms of anxiety and depression, and parents' reports on social and communication problems were analyzed. Our findings confirmed that symptoms of anxiety and depression, and problems with pragmatic language are associated with different neurodevelopmental disorders, but not in the same way. In terms of diagnostic power, we found that pragmatic language difficulties clearly discriminated children with ASD, ADHD or NLD from typically-developing children. Importantly, pragmatic language difficulties also discriminated adequately between ASD and NLD. Our findings are discussed in terms of the value of considering comorbid symptoms to obtain a more accurate diagnosis of neurodevelopmental disorders.

Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria.

OBJECTIVE: To assess children with retinopathy-positive cerebral malaria (CM) for neurocognitive sequelae. METHODS: Participants were selected from an ongoing exposure-control study. Eighty-three Malawian children averaging 4.4 years of age and diagnosed with retinopathy-positive CM were compared to 95 controls. Each child was classified as delayed or not using age-based norms for the Malawi Developmental Assessment Tool (MDAT) for developmental delay on the total scale and for the domains of gross motor, fine motor, language and social skills. Groups were also compared on the Achenbach Child Behaviour Checklist (CBCL) (1.5-5 years). RESULTS: Children with retinopathy-positive CM were delayed, relative to the comparison group, on MDAT total development (P = 0.028; odds ratio or OR = 2.13), with the greatest effects on language development (P = 0.003; OR = 4.93). The two groups did not differ significantly on the Achenbach CBCL internalizing and externalizing symptoms total scores. Stepwise regression demonstrated that coma duration, seizures while in hospital, platelet count and lactate level on admission were predictive of assessment outcomes for the children with retinopathy-positive CM. CONCLUSIONS: Children who suffer retinopathy-positive CM at preschool age are at greater risk of developmental delay, particularly with respect to language development. This confirms previous retrospective study findings with school-age children evaluated years after acute illness. The MDAT and the Achenbach CBCL proved sensitive to clinical indicators of severity of malarial illness.

The role of the right hemisphere for processing of social interactions in normal adults using functional magnetic resonance imaging.

OBJECTIVE: The main purpose of this study was to evaluate whole-brain and hemispheric activation in normal adult volunteers to videos depicting positive and negative social encounters. There are few studies that have utilized dynamic social stimuli to evaluate brain activation. METHOD: Twenty young adults viewed videotaped vignettes during an functional magnetic resonance imaging procedure. The vignettes included positive and negative interaction scenes of social encounters. RESULTS: Significant right greater than left activation for positive and negative conditions was found for the social interaction videos in the amygdaloid complex, the inferior frontal gyrus, the fusiform gyrus, and the temporal gyri (p < 0.0001). CONCLUSION: These findings support the hypothesis that the regions of the right hemisphere are more active in the interpretation of social information processing than those regions in the left hemisphere. This study is a first step in understanding processing of dynamic stimuli using ecologically appropriate stimuli that approximate the real-time social processing that is appropriate for use with populations who experience significant social problems.

Updates on attention-deficit/hyperactivity disorder and learning disorders.

The relationship of attention-deficit/hyperactivity disorder (ADHD) to learning disorders was reviewed and included reading disability, mathematics learning disability, and nonverbal learning disability. Genetic, neuroimaging, and neuropsychological functioning were examined for each disorder, along with a discussion of any existing literature when ADHD co-occurred with the disorder. All the disorders were found to frequently co-occur with ADHD. A review of the underlying neuroanatomic and neurofunctional data found specific structures that frequently co-occur in these disorders with others that are specific to the individual diagnosis. Aberrations in structure and/or function were found for the caudate, corpus callosum, and cerebellum, making these structures sensitive for the disorder but not specific. Suggestions for future research, particularly in relation to intervention, are provided.

Supporting Acquisition of Spelling Skills in Different Orthographies Using an Empirically Validated Digital Learning Environment.

This paper discusses how the association learning principle works for supporting acquisition of basic spelling and reading skills using digital game-based learning environment with the Finland-based GraphoLearn (GL) technology. This program has been designed and validated to work with early readers of different alphabetic writing systems using repetition and reinforcing connections between spoken and written units. Initially GL was developed and found effective in training children at risk of reading disorders in Finland. Today GL training has been shown to support learning decoding skills among children independent of whether they face difficulties resulting from educational, social, or biological reasons.

Evidence for specificity of ERP abnormalities during response inhibition in ADHD children: a comparison with reading disorder children without ADHD.

Executive function and working memory deficits are not only present in ADHD, but also in reading disorder (RD). Here, high-density ERPs were recorded during the Stop Signal Task in 53 children and adolescents: An ADHD-combined type group, a group with RD, and a healthy control group. The ADHD-C group displayed unique abnormalities of the frontal N200. Both healthy controls and RD groups showed a success-related right frontal N200 modulation, which was absent in the ADHD group. Second, for Success Inhibition trials, the ADHD-C had smaller right frontal N200 waves relative to healthy controls, while the RD group did not. In contrast, NoGo-P3 abnormalities were present both in the ADHD-C and RD groups. Impaired early response inhibition mechanisms, indexed by the frontal N200, appear to be limited to ADHD-C. In contrast, deficits in later cognitive control and error monitoring mechanisms, indexed by the NoGo-P3, appear to be present in both conditions.

Pediatric traumatic brain injury: rehabilitation and transition to home and school.

The purpose of this review is to provide a summary of the empirical research on rehabilitation in pediatric traumatic brain injury (TBI). Studies of the effectiveness of interventions with children with TBI are hampered by difficulty with combining subjects with various levels of TBI, problems with random assignment to treatment groups, and varying age levels at injury. While these are areas of concern, there are emerging studies that indicate both applied behavioral analysis (ABA) and positive behavioral interventions are helpful to many children. For some children, ABA is not successful, and a shift to positive behavioral interventions has been found to be helpful. Transitions to home and school can be difficult particularly if there are family issues that predated the injury. This review provides additional information for the pediatric neuropsychologist to assist with transition to school and home. Studies utilizing the Internet for family interventions have revealed promising results. This review suggests that additional studies as to the efficacy of interventions following TBI are needed particularly to evaluate outcomes after initial recovery and at follow-up. In addition, this review suggests that an important role for pediatric neuropsychologists is to provide support for schools and families through therapy and inservices for school personnel on TBI.

Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment.

Objective: Common methods for clinical diagnosis include clinical interview, behavioral questionnaires, and neuropsychological assessment. These methods rely on clinical interpretation and have variable reliability, sensitivity, and specificity. The goal of this study was to evaluate the utility of machine learning in the prediction and classification of children with ADHD-Combined presentation (ADHD-C) using brief neuropsychological measures (d2 Test of Attention, Children with ADHD-C and typically developing control children completed semi-structured clinical interviews and measures of attention/concentration and parents completed symptom severity questionnaires. Method: We used a forward feature selection method to identify the most informative neuropsychological features for support vector machine (SVM) classification and a decision tree model to derive a rule-based model. Results: The SVM model yielded excellent classification accuracy (100%) of individual children with and without ADHD (1.0). Decision tree algorithms identified individuals with and without ADHD-C with 100% sensitivity and specificity. Conclusion:This study observed highly accurate statistical diagnostic classification, at the individual level, in a sample of children with ADHD-C. The findings suggest data-driven behavioral algorithms based on brief neuropsychological data may present an efficient and accurate diagnostic tool for clinicians.

Neurodevelopmental Impairments 1 Year After Cerebral Malaria.

: media-1vid110.1542/5972295739001PEDS-VA_2018-1026Video Abstract BACKGROUND AND OBJECTIVES: Cerebral malaria (CM) causes significant mortality and morbidity in sub-Saharan African children. Reliable morbidity estimates are scarce because of methodological variability across studies. We describe the incidence, course, and severity of neurodevelopmental impairments in survivors of CM and the associated patient characteristics to inform epidemiologic estimates of malaria morbidity rates and prevention and treatment efforts. METHODS: We conducted an exposure-control study of 85 survivors of CM and 100 age-matched patients in a control group who were enrolled at hospital discharge and assessed after 1, 6, and 12 months using caregiver interviews and standardized developmental, cognitive, and behavioral measures. RESULTS: Developmental or cognitive impairment (<10th percentile of the control distribution) and/or new onset of caregiver-reported behavior problems occurred in 53% of case patients compared with 20% of the patients in the control group (odds ratio 4.5; 95% CI: 2.4 to 8.6; P < .001). In case patients, developmental or cognitive impairment at the 12-month assessment was associated with HIV-positive status and short stature at presentation, more prolonged fever and coma during admission, and severe atrophy or multifocal abnormalities being found on MRI at the 1-month assessment. CONCLUSIONS: One-half of survivors of CM were neurodevelopmentally impaired at the 1-year assessment. With these results, we support prevention trials of acute, neuroprotective interventions and the allocation of resources to evaluation, education, and rehabilitation efforts to reduce the significant long-term burden of CM-associated impairments on families and their communities.

Executive functioning in children with attention-deficit/hyperactivity disorder: combined type with and without a stimulant medication history.

Behavioral and neuropsychological functioning in unmedicated children with attention-deficit/hyperactivity disorder (ADHD) who have a history of medication treatment (Rx) versus those who are treatment naïve (TN) has, to our knowledge, not been previously studied. Ninety-four children in four groups (ADHD/Rx, ADHD/TN, learning disabilities [LD], and controls) were evaluated, while unmedicated, on measures of achievement, neuropsychological functioning, and behavior. The ADHD/Rx group performed significantly better than the TN group on writing, Stroop interference, and measures of attention, and performed as well as the control group on executive functioning, verbal working memory, and academics. Behaviorally, the ADHD groups showed more difficulty with mood and externalizing behaviors compared with the LD and control groups, with the ADHD/TN performing the most poorly. Findings suggest that the ADHD/Rx group shows better executive and academic functioning even when unmedicated.