Early Childhood Diarrhea Predicts Cognitive Delays in Later Childhood Independently of Malnutrition.

Understanding the complex relationship between early childhood infectious diseases, nutritional status, poverty, and cognitive development is significantly hindered by the lack of studies that adequately address confounding between these variables. This study assesses the independent contributions of early childhood diarrhea (ECD) and malnutrition on cognitive impairment in later childhood. A cohort of 131 children from a shantytown community in northeast Brazil was monitored from birth to 24 months for diarrhea and anthropometric status. Cognitive assessments including Test of Nonverbal Intelligence (TONI), coding tasks (WISC-III), and verbal fluency (NEPSY) were completed when children were an average of 8.4 years of age (range = 5.6-12.7 years). Multivariate analysis of variance models were used to assess the individual as well as combined effects of ECD and stunting on later childhood cognitive performance. ECD, height for age (HAZ) at 24 months, and weight for age (WAZ) at 24 months were significant univariate predictors of the studies three cognitive outcomes: TONI, coding, and verbal performance (P < 0.05). Multivariate models showed that ECD remained a significant predictor, after adjusting for the effect of 24 months HAZ and WAZ, for both TONI (HAZ, P = 0.029 and WAZ, P = 0.006) and coding (HAZ, P = 0.025 and WAZ, P = 0.036) scores. WAZ and HAZ were also significant predictors after adjusting for ECD. ECD remained a significant predictor of coding (WISC III) after number of household income was considered (P = 0.006). This study provides evidence that ECD and stunting may have independent effects on children's intellectual function well into later childhood.

Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: a preliminary study.

OBJECTIVE: To compare neurocognition and quality-of-life (QoL) in a group of children and adolescents with or without growth hormone deficiency (GHD) following moderate-to-severe traumatic brain injury (TBI). STUDY DESIGNS: Thirty-two children and adolescents were recruited from the TBI clinic at a children's hospital. Growth hormone (GH) was measured by both spontaneous overnight testing and following arginine/glucagon stimulation administration. Twenty-nine subjects participated in extensive neuropsychological assessment. RESULTS: GHD as measured on overnight testing was significantly associated with a variety of neurocognitive and QoL measures. Specifically, subjects with GHD had significantly (p < 0.05) lower scores on measures of visual memory and health-related quality-of-life. These scores were not explained by severity of injury or IQ (p > 0.05). GHD noted in response to provocative testing was not associated with any neurocognitive or QoL measures. CONCLUSIONS: GHD following TBI is common in children and adolescents. Deficits in neurocognition and QoL impact recovery after TBI. It is important to assess potential neurocognitive and QoL changes that may occur as a result of GHD. It is also important to consider the potential added benefit of overnight GH testing as compared to stimulation testing in predicting changes in neurocognition or QoL.

Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil.

OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-for-height z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes.

Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-forheight z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9 percent. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes.

Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction.

BACKGROUND: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation. OBJECTIVE: To determine the prevalence of GHD and associated features following TBI among children and adolescents. STUDY DESIGN: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration. RESULTS: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels. CONCLUSIONS: GHD following TBI is common in children and adolescents, underscoring the importance of assessing for GHD, including evaluating height and weight velocities after TBI. Children and adolescents with GHD may further exhibit absence or intermediate function for other pituitary hormones.

Semantic fluency: a sensitive marker for cognitive impairment in children with heavy diarrhea burdens?

One of the most affected cognitive impairments in children who experienced heavy burdens of diarrhea is semantic fluency, the same impairment that is most affected in Alzheimer's dementia. These findings are leading us into provocative genetic studies that may elucidate the evolution of such genetic polymorphisms as the APOE alleles. Alternatively, diarrhea could launch the cognitive deficits that might later progress in neurodegenerative diseases. In addition, they suggest that semantic fluency could provide a simple mean to assess cognitive impairment in impoverished settings so as to determine preventive measures.

Assessing the relationship between the WNSSP and therapeutic participation in adolescents in low response states following severe traumatic brain injury.

PRIMARY OBJECTIVE: This study examines the relationship between scores on the Western Neuro Sensory Stimulation Profile (WNSSP) and therapeutic participation as it relates to rehabilitation readiness (RR) in adolescents with low response following severe traumatic brain injury (TBI). RESEARCH DESIGN: This is a serial observational design using multiple measures of clinical status and participation. METHODS AND PROCEDURES: Ten children, mean age 16.7 years, who remained in a low response state (30 days or more) were assessed with the WNSSP and videotaped during physical and occupational therapy sessions. Associations were evaluated between WNSSP scores and participation scores related to arousal, awareness and communication. MAIN OUTCOMES AND RESULTS: The WNSSP was only associated with the communication score (p < 0.0001). The arousal and awareness scores had no significant impact on the WNSSP score. CONCLUSIONS: These results suggest that scores on the WNSSP may be related to the return of communication skills in adolescents in low response states as one part of assessing their therapeutic participation and ultimate rehabilitation readiness. This ability may assist in making decisions regarding care planning.

MRI patterns in prolonged low response states following traumatic brain injury in children and adolescents.

OBJECTIVES: To explore the relationship between location and pattern of brain injury identified on MRI and prolonged low response state in children post-traumatic brain injury (TBI). METHODS: This observational study compared 15 children who spontaneously recovered within 30 days post-TBI to 17 who remained in a prolonged low response state. RESULTS: 92.9% of children with brain stem injury were in the low response group. The predicted probability was 0.81 for brain stem injury alone, increasing to 0.95 with a regional pattern of injury to the brain stem, basal ganglia, and thalamus. CONCLUSIONS: Low response state in children post-TBI is strongly correlated with two distinctive regions of injury: the brain stem alone, and an injury pattern to the brain stem, basal ganglia, and thalamus. This study demonstrates the need for large-scale clinical studies using MRI as a tool for outcome assessment in children and adolescents following severe TBI.

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development.

Our group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood. Despite being a marker for cognitive decline with Alzheimer's and cardiovascular diseases later in life, APOE4 appears to be important for cognitive development under the stress of heavy diarrhea. The reviewed findings provide a potential explanation for the survival advantage in evolution of the thrifty APOE4 allele and raise questions about its implications for human development under life-style changes and environmental challenges.

Dopamine agonist therapy in low-response children following traumatic brain injury.

The objective of this study was to determine whether a dopamine agonist could improve mental status among children in a low-response state following traumatic brain injury. In an 8-week, prospective, double-blind, randomized trial, 10 children and adolescents ages 8 to 21 years (X = 16.7 years) with traumatic brain injury sustained at least 1 month previously and remaining in a low-response state (Rancho Los Amigos Scale level pound 3) received pramipexole or amantadine. Medication dosage was increased over 4 weeks, weaned over 2 weeks, and then discontinued. At baseline and weekly during the study, subjects were evaluated with the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale. Scores improved significantly from baseline to the medication phase on the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale (P < .005). The weekly rate of change was significantly better for all three measures on medication than off medication (P < .05). Rancho Los Amigos Scale levels improved significantly on medication as well (P < .05). There was no difference in efficacy between amantadine and pramipexole. No unexpected or significant side effects were observed with either drug. This clinical trial supports the benefit of two dopamine agonists in the restoration of functional arousal, awareness, and communication. These drugs can be helpful in accelerating eligibility for acute rehabilitation among children and adolescents who have sustained significant brain injuries.

Global impact of diarrheal diseases that are sampled by travelers: the rest of the hippopotamus.

Travelers who experience diarrhea (i.e., "turista") are exposed to the same pathogens and illnesses that pose some of the greatest threats to life and development among malnourished children in developing areas around the world, where inadequate water and poor sanitation remain. This article focuses on new findings about the impact, diagnosis, and control of these illnesses and the genetic predispositions of persons who acquire them. Despite the reductions in mortality due to dehydrating diarrhea, the morbidity associated with diarrheal illnesses continues unabated. Furthermore, we increasingly recognize the lasting detrimental effects of enteric infections that occur during early childhood on later physical and cognitive development and, in patients with acquired immunodeficiency syndrome, on the absorption of antiretroviral drugs. Genetic predispositions to inflammation and potential protection associated with such alleles as ApoE4, which are not suspected of being involved in diarrhea, remind us of how much we have to learn about the effect and interactions of enteric tropical infectious diseases with regard to our host genome. New diagnostic methods hold promise for improved recognition and, hopefully, control of enteric infections worldwide.

Limitations in verbal fluency following heavy burdens of early childhood diarrhea in Brazilian shantytown children.

The effects of heavy burdens of diarrhea in the first 2 years of life on specific executive control function like verbal fluency are not well understood. In previous studies, we have shown associations of early childhood diarrhea (ECD) with nonverbal intelligence and school functioning. Therefore, we postulated that ECD might affect early neuropsychological development leading to long-term deficits in normal cognitive development. Based on our extensive 14-year prospective cohort studies of early childhood diarrheal illnesses in a Brazilian shantytown community, we examined ECD correlations between specific impairments of higher mental function and executive skills in shantytown children 5-10 years later (now at 6-12) years of age. Specifically we examined whether heavy diarrheal illnesses correlate with reduced performance on selected tests of executive function. Our study, for the first time, suggests a disproportional impairment in semantic but not phonetic fluency in a subset of children with heavy burdens of diarrhea in their first 2 years of life even when controlling for maternal education, breastfeeding, and child schooling. Similar semantic decrements have been associated with impaired recovery from brain injury. These exploratory studies suggest the importance of verbal fluency tests to assess executive functioning in children challenged by poor nutrition and diarrhea in early life. In addition, our unique findings show the potential influences of early childhood diarrhea on language development that is so critical to productive adulthood and potentially set a foundation for new neuropsychological approaches, which assess early burdens of enteric illnesses on childhood development.

APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil.

Polymorphisms in the apolipoprotein E (APOE) have constituted the major rationale to identify potential risk groups for developing late-onset Alzheimer's disease and help to predict recovery of cognitive function after brain injury. However, the APOE impact on cognitive development in children living in poor areas of the developing world, where we have discovered profound significant associations of early childhood diarrhea (at 0-2 y) with lasting impairments of growth, cognition, and school performance, is not known. Therefore, we conducted APOE genotyping in 72 Brazilian shantytown children under active surveillance since birth, using purified DNA extracted from buccal cell samples. We found a high frequency of APOE4 alleles (18% versus 9-11% expected) in children with lower diarrhea burdens. When we examined the children who experienced the heavier diarrhea burdens (greater than or equal to the median of seven illnesses in the first 2 y of life), those with APOE4 did significantly better in the coding subtest (p=0.01) when compared with APOE4-negative children with similar diarrhea burdens. Positive correlations between the APOE4 occurrence and coding scores remained, even after adjusting for family income, maternal education, and breast-feeding. Moreover, the APOE4-positive group, under heavy burdens of diarrhea, had preserved semantic fluency and the mean difference in fluency scores, p=0.025, a standardized coefficient for disproportional verbal fluency impairment. Our findings show that APOE4 is relatively common in favela children and suggest a protective role of the APOE4 allele in children with a history of heavy burdens of diarrhea in their first 2 y of life.

Paroxysmal autonomic instability with dystonia after brain injury.

A complication of severe brain injury is a syndrome of intermittent agitation, diaphoresis, hyperthermia, hypertension, tachycardia, tachypnea, and extensor posturing. To capture the main features of this syndrome, derived through literature review and our own case series, we propose the term paroxysmal autonomic instability with dystonia. We reviewed reports of autonomic dysregulation after brain injury and extracted essential features. From the clinical features, consistent themes emerge regarding signs and symptoms, differential diagnosis, and pharmacological therapies. We used these findings to make recommendations regarding diagnosis and treatment. Paroxysmal autonomic instability with dystonia appears to be a distinctive syndrome after brain injury that can mimic other life-threatening conditions. Early recognition may lead to fewer diagnostic tests and a rational approach to management. Prospective trials of specific drugs are needed to determine optimal efficacy.

Brain imaging as a predictor of early functional outcome following traumatic brain injury in children, adolescents, and young adults.

OBJECTIVES: A depth of lesion (DOL) model using brain imaging has been proposed to aid in medical decision-making and planning for rehabilitation resource needs. The purpose of this study was to determine the early prognostic value of a DOL classification system for children and young adults following severe traumatic brain injury. METHODS AND OUTCOME MEASURES: CT/MRI brain imaging studies on 92 patients, aged 3 to 21, admitted to the Kluge Children's Rehabilitation Center, University of Virginia, were evaluated to determine DOL. Images were classified according to 5 DOL levels (cortical to brainstem). Functional outcomes in mobility, self-care, and cognition, as rated on the WeeFIM instrument, were compared by DOL levels. RESULTS: Admission WeeFIM scores were significantly different for the DOL levels with the highest score for frontal and/or temporal lesions and the lowest for lesions including the brainstem or cerebellum (P<.001). However, the deeper the lesion, the greater the functional gains (P=.05), resulting in discharge WeeFIM scores that were not significantly different across DOL levels. Patients with deeper lesions tended to have longer lengths of stay in rehabilitation but were able to "catch up" with patients who had more superficial lesions. CONCLUSIONS: While relatively simple and convenient, the DOL classification system is limited in its usefulness as an early prognostic tool. It may not be possible to predict outcome in the early acute phase in the intensive care unit on the basis of standard brain imaging alone. Patients with deeper lesions may enter rehabilitation at a more impaired level but can make remarkable progress, though it may take longer than for less severely injured individuals.

Quality of life in children with traumatic brain injury--basic issues, assessment, and recommendations.

An international Task Force was convened under the guidance of BMBF Conference so as to review the "State of the art" for measuring quality of life (QoL) in children who have suffered traumatic brain injury (TBI). After expert review of instruments and evaluation of two independent literature reviews this work group established "inclusion criteria" for the review of current tools that could contribute to the measurement of QoL in children with TBI. Six instruments were determined to meet all or most of the criteria required to be used in current clinical practice and research for children with TBI.

Neuropsychological sequelae of adolescent infectious diseases.

This article discusses the neuropsychological sequelae of adolescent infectious diseases. Primary care physicians are encouraged to extend their clinical activities beyond the primary medical care aspects of the infectious disease process to encompass a comprehensive, multidisciplinary, continuum of health care approach. Patient, disease, and socioecologic parameters are the foundation of this approach. This article is designed to help primary care physicians appreciate the complexity of neuropsychological infectious disease issues in the adolescent. Human immunodeficiency virus 1 (HIV-1) is emphasized because the legion of related sequelae demands a comprehensive health care approach and serves as a model for discussing other principal infectious diseases such as encephalitis (particularly Lyme disease) and bacterial meningitis.

Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown.

Diarrhea is well recognized as a leading cause of childhood mortality and morbidity in developing countries; however, possible long-term cognitive deficits from heavy diarrhea burdens in early childhood remain poorly defined. To assess the potential long-term impact of early childhood diarrhea (in the first 2 years of life) on cognitive function in later childhood, we studied the cognitive function of a cohort of children in an urban Brazilian shantytown with a high incidence of early childhood diarrhea. Forty-six children (age range, 6-10 years) with complete diarrhea surveillance during their first 2 years of life were given a battery of five cognitive tests. Test of Non-Verbal Intelligence-III (TONI) scores were inversely correlated with early childhood diarrhea (P = .01), even when controlling for maternal education, duration of breast-feeding, and early childhood helminthiasis (Ascaris or Trichuris). Furthermore, Wechsler Intelligence Scale for Children (WISC-III) Coding Tasks and WISC-III Digit Span (reverse and total) scores were also significantly lower in the 17 children with a history of early childhood persistent diarrhea (PD; P < .05), even when controlling for helminths and maternal education. No correlations were seen between diarrhea rates and Wide Range Assessment of Memory and Learning subtests or WISC-III Mazes. This report (with larger numbers of participants and new tests) confirms and substantially extends previous pilot studies, showing that long-term cognitive deficits are associated with early childhood diarrhea. These findings have important implications for the importance of interventions that may reduce early childhood diarrheal illnesses or their consequences.