Assessing harmonized intelligence measures in a multinational study.

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to measure IQ across a five-site, multinational study and demonstrate the harmonized measure's cross-site validity. Culturally appropriate intelligence measures were selected: four short-form Wechsler intelligence tests (Brazil, Netherlands, South Africa, United States) and the Binet Kamat (India). Analyses included IQ scores from 255 healthy participants (age 18-50; 42% male). Regression analyses tested between-site differences in IQ scores, as well as expected associations with sociodemographic factors (sex, socioeconomic status, education) to assess validity. Harmonization (e.g., a priori selection of tests) yielded the compatibility of IQ measures. Higher IQ was associated with higher socioeconomic status, suggesting good convergent validity. No association was found between sex and IQ at any site, suggesting good discriminant validity. Associations between higher IQ and higher years of education were found at all sites except the United States. Harmonized IQ scores provide a measure of IQ with evidence of good validity that can be used in neurocognitive and circuit-based studies to control for intelligence across global sites.

Exploring associations between the gut microbiota and full-scale intelligence in preschool children.

The relationship between the gut microbiota and neurocognitive outcomes is becoming increasingly recognized; however, findings in humans are inconsistent. In addition, few studies have investigated the gut microbial metabolites that may mediate this relationship. The objective of this study was to investigate associations between full-scale intelligence (FSIQ) and the composition of the gut microbiota and metabolome in preschool children. Stool samples were collected from a community sample of 245 typically developing children (3-5 years) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. The faecal microbiome was assessed using 16S rRNA sequencing and the metabolome using LC-MS/MS. FSIQ and scores on the Verbal Comprehension, Visual Spatial, Working Memory indices of the Wechsler Preschool and Primary Scale of Intelligence-IV were used to assess neurocognition. Associations between the gut microbiota and FSIQ were determined using Pearson and Spearman correlations, which were corrected for multiple testing and relevant covariates. Verbal Comprehension correlated negatively with both Shannon alpha diversity (r = -0.14, p = 0.032) and the caffeine-derived metabolite paraxanthine (r = -0.22, p < 0.001). No other significant correlations were observed. Overall, the weak to modest correlations between Verbal Comprehension with alpha diversity and paraxanthine provide limited evidence of an association between the gut microbiota and neurocognitive outcomes in typically developing preschool children.

Long-term full-scale intelligent quotient outcomes following pediatric and childhood epilepsy surgery: A systematic review and meta-analysis.

OBJECTIVE: Cognitive measures are an important primary outcome of pediatric, adolescents, and childhood epilepsy surgery. The purpose of this systematic review and meta-analysis is to assess whether there are long-term alterations (≥ 5 years) in the Full-Scale Intelligence Quotient (FSIQ) of pediatric patients undergoing epilepsy surgery. METHODS: Electronic databases (EMBASE, MEDLINE, and Scopus) were searched for English articles from inception to October 2022 that examined intelligence outcomes in pediatric epilepsy surgery patients. Inclusion criteria were defined as the patient sample size of ≥ 5, average follow- up of ≥5 years, and surgeries performed on individuals ≤ 18 years old at the time of surgery. Exclusion criteria consisted of palliative surgery, animal studies, and studies not reporting surgical or FSIQ outcomes. Publication bias was assessed using a funnel plot and the Quality in Prognosis Studies (QUIPS) toolset was used for quality appraisal of the selected articles. A random-effects network meta-analysis was performed to compare FSIQ between surgical patients at baseline and follow-up and Mean Difference (MD) was used to calculate the effect size of each study. Point estimates for effects and 95% confidence intervals for moderation analysis were performed on variables putatively associated with the effect size. RESULTS: 21,408 studies were screened for abstract and title. Of these, 797 fit our inclusion and exclusion criteria and proceeded to full-text screening. Overall, seven studies met our requirements and were selected. Quantitative analysis was performed on these studies (N = 330). The mean long-term difference between pre- and post- operative FSIQ scores across all studies was noted at 3.36 [95% CI: (0.14, 6.57), p = 0.04, I2 = 0%] and heterogeneity was low. CONCLUSION: To our knowledge, this is the first meta-analysis to measure the long-term impacts of FSIQ in pediatric and adolescent epilepsy patients. Our overall results in this meta-analysis indicate that while most studies do not show long-term FSIQ deterioration in pediatric patients who underwent epilepsy surgery, there was an increase of 3.36 FSIQ points, however, the observed changes were not clinically significant. Moreover, at the individual patient level analysis, while most children did not show long-term FSIQ deterioration, few had significant decline. These findings indicate the importance of surgery as a viable option for pediatric patients with medically refractory epilepsy.

Anorexia and the hippocampus: A case report.

Eating disorders have been shown to be associated with epilepsy, typically associated with the temporal lobe and usually of non-dominant hemisphere origin. We report the case of a 56-year-old woman with drug resistant epilepsy, localized to the dominant left hippocampus. She experienced an increasing frequency of seizures over a two-year period associated with loss of appetite and substantial weight loss independent of antiseizure medication changes. Extensive workup eliminated gastrointestinal and paraneoplastic etiologies. There was no history of psychiatric illness, including anorexia nervosa. Pre-surgical workup showed mesial temporal sclerosis on MRI and video-EEG was consistent with ipsilateral medial temporal seizure onset. The patient underwent laser interstitial ablation of the left amygdala and hippocampus, which resulted in a cessation of seizures. Within 24 h of the laser ablation, her appetite returned to normal and, within 8 months she regained 26 lbs. To our knowledge, this is the first case report of a patient with dominant temporal lobe epilepsy with anorexia that was temporally associated with escalating seizure frequency and stopped with treatment and cessation of seizures, suggesting a causal and pathogenic relationship.

Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL® DINCH biomarkers. The relation between phthalates/HEXAMOLL® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 ± 11 (NAC-II), 98 ± 12 (OCC), and 81 ± 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (ß = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (ß = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (ß = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value ≥ 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.

Long-term psychiatric outcomes in youth with enterovirus A71 central nervous system involvement.

Long-term neurological and neurodevelopmental sequelae are a concerning issue for people with Enterovirus A71 (EV-A71) central nervous system (CNS) infection. Unfortunately, no longitudinal prospective clinical study has systematically investigated the consequences of EV-A71 CNS infection during early life on the later development of other psychiatric disorders. In this naturalistic longitudinal follow-up design, we followed forty-three youth, who got EV-A71 CNS involvement 6-18 years ago and were enrolled in other EV-A71 clinical studies then. Their psychiatric presentation, emotional/behavioral problems, and cognitive issues were examined using a psychiatrist-conducted diagnostic interview, parent- and self-rated questionnaires, and neuropsychological tests, respectively. We compared the prevalence of psychiatric disorders in youth with EV-A71 CNS involvement to a nationally representative cohort. Emotion/behavior and cognition in EV-A71-CNS-infected youth were compared to those in a matched community-based sample of healthy controls and youth with attention-deficit/hyperactivity disorder (ADHD). Compared to a national sample (absolute ADHD prevalence 10.1%), youth with EV-A71 CNS involvement had three times the odds of receiving an ADHD diagnosis (standardized prevalence ratio, 95% CI = 1.8, 4.2; absolute ADHD prevalence 34.9%). No other psychiatric diagnoses were more common in EV-A71-CNS-infected youth. Compared to community-based ADHD youth, EV-A71-CNS-infected youth with psychiatric disorders showed comparable core ADHD symptoms, opposition/defiance, autistic features, and suboptimal sustained attention performance (based on the Conners' Continuous Performance Test), all of which were more severe than healthy controls. EV-A71-CNS-infected youth without psychiatric disorders showed comparable autistic features to EV-A71-CNS-infected youth with psychiatric disorders and ADHD youth. EV-A71 CNS involvement may cause long-term, adverse psychiatric outcomes that develop into an ADHD diagnosis alongside social/communication/emotion problems and autistic features. We recommend earlier identification and intervention of these problems among these children.

Neurological and Cognitive Performance After Childhood Encephalitis.

Background: Children with encephalitis have increased risk for long-term neurological sequelae. We investigated minor neurological dysfunction (MND) and cognitive performance as a measurement for long-term outcome of encephalitis in childhood. Materials and Methods: Children with encephalitis (n = 98) treated in Turku University Hospital during the years 1995-2016 were retrospectively identified. We included the patients without severe developmental delay before the encephalitis and without recorded neurological disability caused by encephalitis. MND was assessed using the Touwen examination. Age-appropriate Wechsler Intelligence Scale was used to determine the full-scale intelligence quotient (IQ). Residual symptoms in everyday life were evaluated using a questionnaire. Results: Forty-two subjects participated in the study and returned the questionnaire regarding residual symptoms. The median age was 4.3 years at the time of encephalitis, and 11.3 years at the time of the Touwen examination (n = 41) and the cognitive assessment (n = 38). The Touwen examination indicated MND in 29 of 41 participants (71%; simple MND in 16 and complex MND in 13 patients). The median full-scale IQ was lower in participants with MND compared with participants without MND (98 vs. 110, p = 0.02). Participants with IQ < 85 (n = 5) had lower median age at acute encephalitis compared to participants with IQ ≥ 85 (n = 33) (1.8 vs. 5.3 years, p = 0.03). Problems in daily performance were reported in participant with MND (p = 0.2) and low full-scale IQ (p = 0.008). Conclusions: The prevalence of MND was high and it was related to lower cognitive performance after childhood encephalitis. Younger age at acute encephalitis was a risk factor for lower cognitive performance.

Auditory processing disorder evaluations and cognitive profiles of children with specific learning disorder.

OBJECTIVE: This study investigated the auditory sensory-perceptual level of specific learning disorder (SLD) and explored relationships among neuropsychological assessments for SLD, auditory processing, and short and long latencies of auditory event-related potentials (ERPs). METHODS: Fifteen children (7-14 years old) comprised the control group; 34 children comprised the SLD group. Audiologic assessments included tone audiometry, acoustic immittance measurements, acoustic reflex, central auditory processing, brainstem evoked response audiometry, and long latency potentials (P3 and N2). Children's intelligence levels were assessed with 2 intelligence batteries, 1 verbal and 1 non-verbal, as well as with visuomotor skills. RESULTS: Multiple regression showed a significant interaction effect of APE tests and P3/N2 over Wechsler Scale performance in freedom of distractibility indexes and multiple subtests. Errors in the Bender Visual Motor Gestalt Test were predicted by lower parental education, lower performance in APE tests: dichotic digits and pediatric/synthetic sentence identification-ipsilateral, and longer P3/N2 latencies, particularly regarding integration and rotation distortions. CONCLUSIONS: Children with altered auditory processing exhibit a specific cognitive profile, including lower verbal and spatial reasoning performance, that is sensitive to parental education level. SIGNIFICANCE: Children with SLD should undergo a complete multimodal examination to identify their specific difficulties and needs.

Growth in early life and physical and intellectual development at school age: a cohort study.

The associations between growth during early life and subsequent cognitive development and physical outcomes are not widely known in low-resource settings. We examined postnatal weight and height gain through early life and related these measurements to the nutritional status and intellectual development of the same children when they were between 7 and 9 years old. Mothers had enrolled in an randomised controlled trial to evaluate the effect of prenatal micronutrient supplementation on birth weight. Their children were born in 2004, their height and weight were measured at 6, 12, 18 and 24 months of age and were followed up between October 2012 and September 2013 (at ages 7-9 years, n 650). Height-for-age, weight-for-age and BMI-for-age were used to describe the nutritional status, and the Wechsler Intelligence Scale for Children fourth edition was used to measure the intellectual function. Multilevel linear and logistic modelling was used to estimate the association between early growth and subsequent growth and intellectual function. After adjustment, weight gain from 6 to 12 months of age was associated with Full-scale Intelligence Quotient, Verbal Comprehension Index, Working Memory Index and Perceptual Reasoning Index. Weight gain during early life was associated with subsequent nutritional status. For every 1 kg increase in weight during the 0- to 6-month period, the OR for underweight, thinness and stunting at 7-9 years of age were 0·19 (95 % CI 0·09, 0·37), 0·34 (95 % CI 0·19, 0·59) and 0·40 (95 % CI 0·19, 0·83), respectively. Weight gain during the periods of 6-12 months of age and 18-24 months of age was also associated with a lower risk of being underweight. Weight gain during early life was associated with better growth outcomes and improved intellectual development in young school-aged children.

Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels.

AIM: This study examined the impact of fluctuations in metabolic control on the intelligence quotient (IQ) of children and adolescents with early, continuously treated phenylketonuria (PKU). METHODS: This was a clinic-based study carried out at University Hospital Munster, Germany, from 2015 to 2017. We investigated 49 patients (28 boys) with early treated PKU, who were aged 6-18 years with a mean age of 11.2 ± 4.1 years. All the patients were on a continuous phenylalanine-restricted diet. Of the 49 patients, 29 (18 boys) had classic PKU and 21 patients (11 girls) had mild PKU. The patients' blood phenylalanine levels were assessed every week for 26 weeks and analysed for fluctuations, indicated by the standard deviation of the individual blood phenylalanine levels. We also assessed the concurrent Full Scale IQ (FSIQ) of the patients. RESULTS: In patients with classic PKU, FSIQ was negatively correlated with blood phenylalanine levels, but not with level fluctuations. In patients with mild PKU, FSIQ was not correlated with blood phenylalanine levels, but was negatively correlated with level fluctuations. CONCLUSION: The blood phenylalanine levels of patients with mild PKU showed minor interindividual differences, which may have allowed fluctuations to exert a negative effect on the FSIQ.

Neurocognitive changes in pituitary adenoma patients after Gamma Knife radiosurgery.

OBJECTIVEPituitary adenomas and the treatment required for the underlying neuropathology have frequently been associated with cognitive dysfunction. However, the mechanisms for these impairments remain the subject of much debate. The authors evaluated cognitive outcomes in patients treated with or without Gamma Knife radiosurgery (GKRS) for an underlying pituitary adenoma.METHODSThis was a retrospective, institutional review board-approved, single-institution study. A total of 51 patients (23 male, 28 female) treated for pituitary adenoma were included in this neurocognitive study. Twenty-one patients underwent GKRS following transsphenoidal surgery, 22 patients were treated with transsphenoidal surgery alone, and eight patients were conservatively managed or were treated with medical management alone. Comparisons using psychometric tests of general intellectual abilities, memory, and executive functions were made between the treatment groups, between male and female patients, and between patients with Cushing's disease and those with nonfunctioning adenoma (NFA).RESULTSThe entire patient sample, the NFA group, and the GKRS group scored significantly below expected on measures of both immediate and delayed memory, particularly for visually presented information (p ≤ 0.05); however, there were no significant differences between the patients with Cushing's disease and those with NFA (t ≤ 0.56, p ≥ 0.52). In those who underwent GKRS, memory scores were not significantly different from those in the patients who did not undergo GKRS (t ≤ 1.32, p ≥ 0.19). Male patients across the sample were more likely to demonstrate impairments in both immediate memory (t = -3.41, p = 0.003) and delayed memory (t = -3.80, p = 0.001) than were female patients (t ≤ 1.09, p ≥ 0.29). There were no impairments on measures of general intellectual functioning or executive functions in any patient group. The potential contributions of tumor size and hormone levels are discussed.CONCLUSIONSOverall, pituitary adenoma patients demonstrated relative impairment in anterograde memory. However, GKRS did not lead to adverse effects for immediate or delayed memory in pituitary adenoma patients. Cognitive assessment of pituitary adenoma patients is important in their longitudinal care.

Long-term follow-up for patients with infantile hydrocephalus treated by choroid plexus coagulation.

OBJECTIVEShunt surgery is the most common treatment for hydrocephalus, but it is associated with several long-term complications. Endoscopic choroid plexus coagulation (CPC) and endoscopic third ventriculostomy (ETV) are alternative surgeries that may avoid the need for shunt surgery. Although the short-term efficacy and safety of CPC have been reported in previous studies, long-term outcome, including not only avoiding shunt placement but also intellectual development, remains to be elucidated. The purpose of the present study was to investigate the long-term outcome of CPC.METHODSThe study population comprised patients who had infantile hydrocephalus treated by endoscopic CPC before the age of 24 months and who were followed until at least 5 years of age. Retrospective review was performed using the medical charts. The authors assessed educational status and the full-scale intelligence quotient (FSIQ) using the Wechsler Intelligence Scale for Children (WISC) IV as the means to evaluate the intellectual development.RESULTSFourteen patients with infantile hydrocephalus underwent CPC with or without ETV as a primary surgery. There were no intraoperative complications. In 7 patients (50%), hydrocephalus was successfully controlled without shunt placement. Six patients (43%) eventually required shunt placement. In one patient hydrocephalus was controlled by additional ETV. In the shunt-independent group, 4 patients went to age-appropriate school or achieved age-appropriate development according to intelligence quotient (IQ), 1 patient went to specialized school, and 2 patients had disabilities. In the shunt-dependent group, 4 patients went to an age-appropriate school or achieved age-appropriate development by IQ, 1 patient went to specialized school, and 1 patient had disabilities. The mean FSIQ score in 3 patients without shunts was 90 (range 89-91) and the mean FSIQ score in 4 patients with shunts was 80 (range 48-107). There was no significant difference in the rate of normal development between the shunt-independent group and the shunt-dependent group (p = 0.72).CONCLUSIONSThe CPC with or without ETV can be a safe and effective treatment in children with infantile hydrocephalus. Long-term control of hydrocephalus and normal intellectual development can be achieved in successful cases. Further prospective studies should be required to elucidate appropriate indications.

Altered perspective-dependent brain activation while viewing hands and associated imitation difficulties in individuals with autism spectrum disorder.

Background: Individuals with autism spectrum disorder (ASD) appear to have a unique awareness of their own body, which may be associated with difficulties of gestural interaction. In typically developing (TD) individuals, the perception of body parts is processed in various brain regions. For instance, activation of the lateral occipito-temporal cortex (LOTC) is known to depend on perspective (i.e., first- or third-person perspective) and identity (i.e., own vs. another person's body). In the present study, we examined how perspective and identity affect brain activation in individuals with ASD, and how perspective- and identity-dependent brain activation is associated with gestural imitation abilities. Methods: Eighteen young adults with ASD and 18 TD individuals participated in an fMRI study in which the participants observed their own or another person's hands from the first- and third-person perspectives. We examined whether the brain activation associated with perspective and identity was altered in individuals with ASD. Furthermore, we identified the brain regions the activity of which correlated with gestural imitation difficulties in individuals with ASD. Results: In the TD group, the left LOTC was more strongly activated by viewing a hand from the third-person perspective compared with the first-person perspective. This perspective effect in the left LOTC was significantly attenuated in the ASD group. We also observed significant group differences in the perspective effect in the medial prefrontal cortex (mPFC). Correlation analysis revealed that the perspective effect in the inferior parietal lobule (IPL) and cerebellum was associated with the gestural imitation ability in individuals with ASD. Conclusions: Our study suggests that atypical visual self-body recognition in individuals with ASD is associated with an altered perspective effect in the LOTC and mPFC, which are thought to be involved in the physical and core selves, respectively. Furthermore, the gestural imitation difficulty in individuals with ASD might be associated with the altered activation in the IPL and cerebellum, but not in the LOTC. These findings shed light on common and divergent neural mechanisms underlying atypical visual self-body awareness and gestural interaction in ASD.

Differences in the intellectual profile of children with intellectual vs. learning disability.

The WISC-IV was used to compare the intellectual profile of two groups of children, one with specific learning disorders (SLDs), the other with intellectual disabilities (ID), with a view to identifying which of the four main factor indexes and two additional indexes can distinguish between the groups. We collected information on WISC-IV scores for 267 children (Mage=10.61 [SD=2.51], range 6-16 years, females=99) with a diagnosis of either SLD or ID. Children with SLD performed better than those with ID in all measures. Only the SLD children, not the ID children, revealed significant differences in the four main factor indexes, and their scores for the additional General Ability Index (GAI) were higher than for the Cognitive Proficiency Index (CPI). Children with a diagnosis of SLD whose Full-Scale Intelligence Quotient (FSIQ) was <85 showed a similar pattern. Our findings confirm the hypothesis that children with SLD generally obtain high GAI scores, but have specific deficiencies relating to working memory and processing speed, whereas children with ID have a general intellectual impairment. These findings have important diagnostic and clinical implications and should be considered when making diagnostic decisions in borderline cognitive cases.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Early childhood outcomes of infants born with gastroschisis.

PURPOSE: To describe neonatal and childhood outcomes of a contemporary cohort of infants with gastroschisis. METHODS: Observational, single center, inception cohort of children born with gastroschisis from January 2005 to December 2008. RESULTS: Of 63 infants, 61 survived to hospital discharge and 39 were seen for follow-up. Complications included sepsis (37%), necrotizing enterocolitis (10%), parenteral nutrition related cholestasis (25%), and short bowel syndrome (13%). Of survivors, 5% had visual impairment and 10% had hearing loss. No child tested had mental delay or cerebral palsy. Early gestational age predicted death or disability (OR 0.60, 95% CI 0.38, 0.96; p=0.033). There was a high incidence of prescription medications for presumed gastroesophageal reflux (90%). Some infants continued to require tube feeds (15%). There were improvements in longitudinal growth reflected in increasing z-scores. CONCLUSIONS: Although children with gastroschisis are at risk for disability, childhood outcomes are encouraging.

Cognitive and psychosocial function post hematopoietic stem cell transplantation in children with hemophagocytic lymphohistiocytosis.

OBJECTIVES: This study investigated the cognitive and psychosocial outcomes in childhood survivors of hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation. METHODS: Twenty-one children were assessed on standardized measures of cognitive and psychosocial functioning and compared with an unaffected sibling control group (n = 14). Parent and teacher reports were obtained to provide additional information. RESULTS: The average full-scale intelligence quotient for the patient cohort was 81 (95% CI, 72-90), which was significantly lower than both the population average of 100 (P = .001) and the average for the unaffected sibling control group (99.2, P = .002). Fifty-six percent of school-aged children were receiving additional support at school, with the majority needing high levels of support. These children also experienced significant psychosocial difficulties. Lower socioeconomic status was associated with poorer cognitive outcomes, but age at transplantation, time to transplantation, type of conditioning, and presence of mixed chimerism were not. Ten (48%) of 21 children had evidence of neurologic involvement at diagnosis, but surprisingly, this was not significantly associated with adverse neurologic outcomes, and some children who did not have any apparent neurologic involvement at diagnosis had severe learning difficulties at follow-up. CONCLUSIONS: In summary, childhood survivors of hemophagocytic lymphohistiocytosis are at risk of long-term cognitive and psychosocial difficulties. Prospective and systematic long-term follow-up of these patients is essential for early identification and effective management of these problems.