Ventilatory and Orthostatic Challenges Reveal Biomarkers for Neurocognition in Children and Young Adults With Congenital Central Hypoventilation Syndrome.

BACKGROUND: Children and young adults with congenital central hypoventilation syndrome (CCHS) are at risk of cognitive deficits. They experience autonomic dysfunction and chemoreceptor insensitivity measured during ventilatory and orthostatic challenges, but relationships between these features are undefined. RESEARCH QUESTION: Can a biomarker be identified from physiologic responses to ventilatory and orthostatic challenges that is related to neurocognitive outcomes in CCHS? STUDY DESIGN AND METHODS: This retrospective study included 25 children and young adults with CCHS tested over an inpatient stay. Relationships between physiologic measurements during hypercarbic and hypoxic ventilatory challenges, hypoxic ventilatory challenges, and orthostatic challenges and neurocognitive outcomes (by Wechsler intelligence indexes) were examined. Independent variable inclusion was determined by significant associations in Pearson's analyses. Multivariate linear regressions were used to assess relationships between measured physiologic responses to challenges and neurocognitive scores. RESULTS: Significant relationships were identified between areas of fluid intelligence and measures of oxygen saturation (SpO2) and heart rate (HR) during challenges. Specifically, perceptual reasoning was related to HR (adjusted regression [ß] coefficient, -0.68; 95% CI, 1.24 to -0.12; P = .02) during orthostasis. Working memory was related to change in HR (ß, -1.33; 95% CI, -2.61 to -0.05; P = .042) during the hypoxic ventilatory challenge. Processing speed was related to HR (ß, -1.19; 95% CI, -1.93 to -0.46; P = .003) during orthostasis, to baseline SpO2 (hypercarbic and hypoxic ß, 8.57 [95% CI, 1.63-15.51]; hypoxic ß, 8.37 [95% CI, 3.65-13.11]; P = .002 for both) during the ventilatory challenges, and to intrachallenge SpO2 (ß, 5.89; 95% CI, 0.71-11.07; P = .028) during the hypoxic ventilatory challenge. INTERPRETATION: In children and young adults with CCHS, SpO2 and HR-or change in HR-at rest and as a response to hypoxia and orthostasis are related to cognitive outcomes in domains of known risk, particularly fluid reasoning. These findings can guide additional research on the usefulness of these as biomarkers in understanding the impact of daily physical stressors on neurodevelopment in this high-risk group.

Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.

PURPOSE: Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research. METHODS: We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP). RESULTS: Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development. CONCLUSION: Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD.

Neurocognitive monitoring in congenital central hypoventilation syndrome with the NIH Toolbox®.

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, caused by mutations in the paired-like homeobox gene PHOX2B, which alters control of breathing and autonomic nervous system regulation, necessitating artificial ventilation as life-support. A broad range of neurocognitive performance has been reported in CCHS, including an array of cognitive deficits. We administered the NIH Toolbox® Cognition Battery (NTCB), a novel technology comprised of seven tasks presented via an interactive computer tablet application, to a CCHS cohort and studied its convergent and divergent validity relative to traditional clinical neurocognitive measures. The NTCB was administered to 51 CCHS participants, including a subcohort of 24 who also received traditional clinical neurocognitive testing (Wechsler Intelligence Scales). Age-corrected NTCB scores from the overall sample and subcohort were compared to population norms. Associations between NTCB indices and Wechsler Intelligence scores were studied to determine the convergent and divergent validity of the NTCB. NTCB test results indicated reduced Fluid Cognition, which measures new learning and speeded information processing (p < 0.001), but intact Crystallized Cognition, which measures past learning, in CCHS relative to population norms. Moderate to strong associations (r > 0.60) were found between age-corrected NTCB Fluid and Crystallized indices and comparable Wechsler indices, supporting the convergent and discriminant validity of the NTCB. Results reveal deficits of Fluid Cognition in individuals with CCHS and indicate that the NTCB is a valid and sensitive measure of cognitive outcomes in this population. Our findings suggest that the NTCB may play a useful role in tracking neurocognition in CCHS.

Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare cause of syndromic obesity with risk of cardiorespiratory arrest and neural crest tumor. No ROHHAD-specific genetic test exists at present. Rapid weight gain of 20-30 pounds, typically between ages 2-7 years in an otherwise healthy child, followed by multiple endocrine abnormalities herald the ROHHAD phenotype. Vigilant monitoring for asleep hypoventilation (and later awake) is mandatory as hypoventilation and altered control of breathing can emerge rapidly, necessitating artificial ventilation as life support. Recurrent hypoxemia may lead to cor pulmonale and/or right ventricular hypertrophy. Autonomic dysregulation is variably manifest. Here we describe the disease onset with "unfolding" of the phenotype in a child with ROHHAD, demonstrating the presentation complexity, need for a well-synchronized team approach, and optimized management that led to notable improvement ("refolding") in many aspects of the child's ROHHAD phenotype over 10 years of care. CITATION: Khaytin I, Stewart TM, Zelko FA, et al. Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis. J Clin Sleep Med. 2022;18(3):937-944.

Congenital central hypoventilation syndrome: Broader cognitive deficits revealed by parent controls.

OBJECTIVE: To investigate neurocognitive deficits in children with Congenital Central Hypoventilation Syndrome (CCHS) by comparing them to their parents, since parents comprise a particularly suitable control group matched on disease-extrinsic factors that can influence neurocognitive functioning. We compared CCHS patients to their parents and to population norms, hypothesizing that they would obtain lower intelligence test scores than both groups. We also compared patient-parent differences against patient-normative differences, to determine whether the two analytic approaches would yield different results. METHODS: We administered an intelligence screening, the Shipley-2, to 21 school-aged patients (age 14.2 ± 5.5 years) with PHOX2B mutation-confirmed CCHS and their parents. Patients also received detailed clinical intellectual assessments using the Wechsler scales. RESULTS: CCHS patients scored significantly below parents on Shipley-2 indices of intelligence, vocabulary, and abstraction, with a trend for perceptual reasoning. The CCHS patients scored significantly below population norms on indices of abstraction and perceptual reasoning. Patient-parent differences were significantly larger than patient-normative differences for vocabulary scores. CCHS patients scored significantly below population norms on Wechsler indices of intelligence, perceptual reasoning, working memory, and processing speed. CONCLUSIONS: CCHS may affect a broader range of cognitive abilities than previous research based on comparisons to population norms has indicated. Comparisons of CCHS children to their parents reveal deficits of vocabulary and abstract reasoning which have not been previously identified. A full understanding of the neurocognitive impact of CCHS requires comparisons between patients and other individuals such as friends, parents, or siblings who closely resemble them on disease-extrinsic characteristics.

Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS: We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS: Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS: These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

The Postconcussion Symptom Scale: utility of a three-factor structure.

PURPOSE: This study aimed to determine the factor structure of a 19-item Postconcussion Symptom Scale and to examine associations between factor scores and sex, previous history of concussion, and length of time since injury. METHODS: This is a retrospective medical record review of pediatric patients with concussion seen in a sports medicine clinic from April 2008 to September 2012. We performed an exploratory factor analysis (EFA) followed by a confirmatory factor analysis (CFA). ANOVA and regression analysis were used to examine associations between factor scores and sex, previous history of concussion, mood disorder, anxiety disorder or attention-deficit disorder, and length of time since injury. RESULTS: EFA supported a three-factor solution for postconcussive symptoms employing 18 of the original 19 scale items. Factor 1 consisted of eight cognition-related items, factor 2 consisted of six somatic-related items, and factor 3 consisted of four emotional-related items. CFA results confirmed the unidimensionality of factors 1 (neurocognitive), 2 (somatic) and 3 (emotional), with factor 3 being considered borderline. Females and patients with anxiety disorders had significantly worse (higher) scores on all three factors. Patients seen >14 d after the concussive injury had worse (higher) factor 3 (emotional) scores than those seen <14 d after the injury. There was no significant difference in postconcussive symptom factor structures between those with and without a previous history of concussion. CONCLUSIONS: Our investigation demonstrates a consistent symptom 3-factor structure of the Postconcussion Symptom Scale in pediatric patients with concussions. Females and patients with anxiety disorders had higher scores than males for all three factors. Patients seen >14 d after concussive injury had higher scores for emotional symptoms, suggesting that prolonged concussion symptoms may affect emotional health.

Academic Underachievement in Children with Active Epilepsy.

Investigators from Lingfield, Surrey, UK; University of Gothenburg, Sweden; Great Ormond Street Hospital, London, UK, and other centers, conducted psychological assessment including measures of IQ, working memory and processing speed in 85 (74%) of 115 school aged children with active epilepsy (a seizure in the past year and/or on AEDs) from a population-based sample, without exclusion for intellectual deficiency.

Regional brain volumes and cognition in childhood epilepsy: does size really matter?

PURPOSE: Recent studies have correlated neurocognitive function and regional brain volumes in children with epilepsy. We tested whether brain volume differences between children with and without epilepsy explained differences in neurocognitive function. METHODS: The study sample included 108 individuals with uncomplicated non-syndromic epilepsy (NSE) and 36 healthy age- and gender-matched controls. Participants received a standardized cognitive battery. Whole brain T1-weighted MRI was obtained and volumes analyzed with FreeSurfer (TM). KEY FINDINGS: Total brain volume (TBV) was significantly smaller in cases. After adjustment for TBV, cases had significantly larger regional grey matter volumes for total, frontal, parietal, and precentral cortex. Cases had poorer performance on neurocognitive indices of intelligence and variability of sustained attention. In cases, TBV showed small associations with intellectual indices of verbal and perceptual ability, working memory, and overall IQ. In controls, TBV showed medium associations with working memory and variability of sustained attention. In both groups, small associations were seen between some TBV-adjusted regional brain volumes and neurocognitive indices, but not in a consistent pattern. Brain volume differences did not account for cognitive differences between the groups. SIGNIFICANCE: Patients with uncomplicated NSE have smaller brains than controls but areas of relative grey matter enlargement. That this relative regional enlargement occurs in the context of poorer overall neurocognitive functioning suggests that it is not adaptive. However, the lack of consistent associations between case-control differences in brain volumes and cognitive functioning suggests that brain volumes have limited explanatory value for cognitive functioning in childhood epilepsy.

Value of questionnaire-based screening as a proxy for neurocognitive testing in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To investigate the utility of questionnaire-based assessment of cognitive function and behavioral/emotional symptoms to screen for neurocognitive dysfunction in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Forty children with cSLE and 24 healthy controls ages 10­16 years were enrolled. Formal neurocognitive testing (FNCT) was done to determine cognitive performance in 4 key areas that appear to be sensitive to the adverse effects of cSLE: attention, working memory, psychomotor speed, and visuoconstructional ability. Paper and pencil questionnaires sampling cognitive functioning and behavioral/emotional symptoms were also completed: the Subjective Awareness of Neuropsychological Deficits for Children (SAND-C) questionnaire by patients, and the Child Behavioral Checklist and the Behavior Rating Inventory of Executive Function (BRIEF) by parents. RESULTS: Domain and summary scores of the BRIEF and SAND-C correlated modestly with participants' performance on FNCT. Questionnaire ratings did not discriminate subjects with different levels of cognitive ability as measured by FNCT. CONCLUSION: Contrary to some reports in adults with SLE, self-administered questionnaires of cognitive functioning and parent ratings of executive functioning do not appear well suited to replace FNCT in screening for neurocognitive impairment of children and adolescents with cSLE. However, they may provide information that is complementary to FNCT and therefore play a useful role in clinical followup.

Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study.

OBJECTIVES: Increasing evidence suggests that uncontrolled seizures have deleterious effects on cognition and behavior, particularly in the developing brain. METHODS: In a community-based cohort, 198 children, aged <8 years with new-onset epilepsy were followed prospectively and reassessed with the Wechsler Intelligence Scales for Children, Third Edition (WISC-III) 8-9 years later. Linear regression analyses with interactions between age at onset (age) and pharmacoresistance (PR) were used to test whether earlier onset conveyed greater vulnerability to the effects of uncontrolled seizures. Full-scale IQ (FSIQ) and the 4 subdomain scores were examined. Adjustment for adaptive behavior scores in a subset was performed. A dichotomous indicator for IQ <80 or ≥80 was used to permit inclusion of children who were not tested, particularly those who were untestable. RESULTS: FSIQ was not correlated with age. PR was associated with an 11.4 point lower FSIQ (p = 0.002) and similar decrements in each WISC-III domain. There were substantial age-PR interactions for FSIQ (p = 0.003) and 3 domain scores, indicating a lessening impact of PR with increasing age. The dichotomous IQ indicator was strongly correlated with age at onset in the pharmacoresistant group (p < 0.0001) and not in the non-pharmacoresistant group (p = 0.61). Adjustment for adaptive behavior measured near onset did not alter the conclusions. CONCLUSIONS: Uncontrolled seizures impair cognitive function with effects being most severe in infancy and lessening with increasing age at onset. These findings further emphasize the need for early aggressive treatment and seizure control in infants and young children.

Cognitive proficiency in pediatric epilepsy.

Cognitive proficiency (CP) is a sensitive gauge of neurological status, but it is not typically viewed in relation to focal cerebral function. We examined CP and its relationship to general intellectual ability and seizure focus in 90 patients with pediatric epilepsy. CP was significantly lower than general ability (GA) in the overall sample. In particular, it was more deficient than GA in patients with right- than left-lateralized epilepsy onset, and in patients with frontal- than temporal-onset epilepsy. The discrepancy between CP and GA varied with participants' overall intelligence, being more pronounced (i.e., GA-CP difference larger) in individuals of lower overall ability. Deficits in CP are a defining characteristic of pediatric epilepsy and serve as an important marker of neurocognitive status, especially when seizures originate from a primary epileptogenic focus within the right hemisphere or the frontal lobe.

Special education participation in children with epilepsy: what does it reflect?

Epilepsy is associated with academic and neurocognitive disorders, with the latter often assumed to explain the former. We examined utilization of special education services (SpES) in relation to neurocognitive test scores in a case-matched sibling control study. In a follow-up assessment 8-9 years after entry into a prospective study of childhood-onset epilepsy, cases and siblings participated in an interview and standardized neurocognitive testing. Analyses included 142 pairs in which both had Full Scale IQ ≥ 80 and the case had normal examination and imaging. Sixty-four (45%) cases and 25 (17.6%) controls reported SpES utilization, (matched odds ratio [mOR]=5.3, P<0.0001). Adjustment for neurocognitive test scores resulted in a mOR of 4.6 (P<0.0001). Types and duration of services were similar in cases and controls. Twenty-four percent of school-aged cases were already receiving services at the time of initial epilepsy diagnosis. Young people with epilepsy have academic difficulties that are not explained simply by cognitive test scores.

Congenital central hypoventilation syndrome: neurocognitive functioning in school age children.

OBJECTIVE: Examine indices of neurocognitive functioning in children with PHOX2B mutation-confirmed neonatal onset congenital central hypoventilation syndrome (CCHS) and relate them to indices of PHOX2B genotype, demographics, and disease severity. METHODS: Subjects were 20 patients with PHOX2B mutation-confirmed CCHS diagnosed as neonates who had undergone neurocognitive assessment in the course of clinical care at the Rush Children's Hospital CCHS Center between 1990 and 2006. Neurocognitive variables of interest included Full Scale IQ (FSIQ) and Wechsler-derived marker indices (subtests) of verbal comprehension (Vocabulary), visuoperceptual reasoning (Block Design), working memory (Digit Span), and clerical/processing speed (Coding). RESULTS: Single sample t-tests revealed participants' general intelligence index (FSIQ; mean 84.9, SD 23.6) to be lower than the general population, though the range of FSIQ observed was broad. Visuoperceptual reasoning and clerical/visuographic speed marker indices were similarly depressed. These deficits were related to special education participation but not to PHOX2B genotype status or other demographic and clinical risk factors. CONCLUSIONS: PHOX2B mutation-confirmed CCHS confers risk for adverse neurocognitive outcome, though the range of functioning observed raises questions about factors that may contribute to neurocognitive variability. Visuoperceptual reasoning and clerical/visuographic speed appear particularly vulnerable. PHOX2B genotype and disease severity indicators were unrelated to neurocognitive indices, possibly due to our modest sample. Future research should employ comprehensive neurocognitive assessment emphasizing visuoperceptual ability, mental speed, attention, and information processing efficiency. Increased recognition and expedited diagnosis with PHOX2B testing should allow larger studies of the relationship between neurocognitive functioning, PHOX2B genotype/mutation, and disease severity and management.

Surgically restoring portal blood flow to the liver in children with primary extrahepatic portal vein thrombosis improves fluid neurocognitive ability.

OBJECTIVES: Children with primary extrahepatic portal vein thrombosis (EHPVT) have portal-systemic shunting, which may lead to disturbed neurocognitive function similar to portal-systemic encephalopathy (PSE) seen with chronic liver disease and cirrhosis. The functions most affected are those involving fluid cognitive ability, which comprise neurocognitive domains such as attention, processing speed, and short-term memory, that are particularly vulnerable to systemic illness or diffuse neurologic insult. We determined the fluid cognitive ability of children with EHPVT and whether surgically restoring portal blood flow by mesenteric left portal vein bypass (MLPVB) improved it. DESIGN: Twelve children with EHPVT and no overt PSE underwent comprehensive neurocognitive testing before and 1 year after undergoing surgery with intent to perform MLPVB. The evaluations sampled 4 functional domains at both time points: (1) neurobehavioral (behavior, emotional, executive functioning); (2) broad cognitive (intelligence, achievement); (3) fluid ability (attention, mental speed, working memory, memory encoding); and (4) visual motor (drawing, fine motor). Tasks in the fluid-ability and visual-motor domains were expected to be especially sensitive to adverse effects of EHPVT and to be most likely to show improvement with MLPVB. The test group consisted of 8 subjects who underwent successful MLPVB, and the comparison group was composed of 3 patients who received distal splenorenal shunts and one whose MLPVB failed. RESULTS: Both groups demonstrated similar fluid cognitive ability at initial evaluation. Successful MLPVB resulted in significantly improved fluid cognitive function: in the fluid cognitive domain, significant improvements were seen for the hit reaction time variability in the Conner's Continuous Performance Test, the attention scale of the Cognitive Assessment System, and immediate verbal memory in the Children's Memory Scale. In the visual-motor domain, z scores on the Grooved Pegboard Test improved. No improvement was observed in the comparison group. DISCUSSION: The results show that surgically restoring portal flow to the liver in children with primary EHPVT results in improved fluid cognitive ability. Subjects showed some neurocognitive abnormalities involving mainly fluid cognitive ability consistent with minimal PSE seen in adults with chronic liver disease. Cognitive defects in patients with minimal PSE seem to relate primarily to attention and fine motor skill, and although affected patients can function in everyday life, they are at risk for performance deficits in educational and vocational situations requiring the ability to pay close attention and react quickly (eg, driving, employment in manufacturing). The tests we administered in these domains are pediatric equivalents to measures used to detect minimal PSE in adults and should detect abnormalities in the same functional domains. Our results suggest that a narrow battery of tests could be used to detect minimal PSE in children in a manner similar to the 5-test battery used in adults, eliminating the need for the comprehensive and broad testing we performed. Our findings suggest that shunting of portal blood from the liver in primary EHPVT can result in PSE and question whether it is as benign a disease as previously thought. The importance of our findings is twofold. For understanding the pathophysiology of PSE, we have shown that restoring blood flow to the liver improves cognitive function in children with EHPVT. For therapy for EHPVT, it becomes clear that MLPVB is an excellent treatment option. It is effective for treating the complications of portal hypertension and provides effective portal blood flow that other medical and surgical therapies do not. The findings provide additional evidence that primary EHPVT should be considered curable by MLPVB. However, comparison of overall risks and benefits of MLPVB with those of other therapeutic options and longer-term outcome studies must be completed before MLPVB can be fully endorsed as the best treatment for EHPVT in children. CONCLUSIONS: Surgical restoration of portal venous flow to the liver in children with primary EHPVT by MLPVB improves fluid cognitive ability. MLPVB should be considered in treating primary EHPVT, because it corrects portal blood flow and could optimize learning potential.