Peter D. Patrick

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 Alzheimers 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.

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 ( = 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 ≤ 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. (J Child Neurol 2006;21:879—885; DOI 10.2310/ 7010.2006.00203).

Fluconazole Prophylaxis in Extremely Low Birth Weight Infants and Neurodevelopmental Outcomes and Quality of Life at 8 to 10 Years of Age

OBJECTIVE To examine the long-term effects of fluconazole prophylaxis in extremely low birth weight infants. STUDY DESIGN Neurodevelopmental status and quality of life of survivors from a randomized, placebo-controlled trial of fluconazole prophylaxis were evaluated at 8 to 10 years of life using the Vineland Adaptive Behavior Scales-II (VABS-II) and the Child Health Questionnaire Parent-Completed Form 28 (CHQ-PF28), respectively. RESULTS VABS-II Domain Scores for the fluconazole-treated (n = 21; 9.1 ± 0.7 years) compared with the placebo group (n = 17; 9.3 ± 0.8 years) were similar for communication [94.6 (±14.8) versus 92.6 (±12.6), P = .65], daily living skills [87.9 (±10.6) versus 87.4 (±9.3), P = .89], socialization [97.2 (±9.2) versus 94.4 (±7.9), P = .31], and motor skills [92.1 (±17.8) versus 95.1 (±14.6), P = .57]. Internalizing and externalizing behaviors and maladaptive behavior index were also similar. The CHQ-PF28 revealed no differences between the two groups regarding quality of life. Survivors were also happy or satisfied with school (90% versus 100%, P = .49), friendships (90% versus 88%, P = 1.00), and life (95% versus 100%, P = 1.00). Self esteem scores were 87.3 ± 15.7 versus 89.7 ± 10.4 (P = .59). There were also no differences between groups regarding emotional difficulties or behavior problems. CONCLUSIONS Fluconazole prophylaxis for the prevention of invasive Candida infections is safe in extremely low birth weight infants and does not appear to be associated with any long-term adverse effects on neurodevelopment and quality of life at 8 to 10 years of life.

The use of dopamine enhancing medications with children in low response states following brain injury

Primary objective : The study examines the possible relationship between dopamine-enhancing medications and improvement of arousal and awareness in children during persistent low response states (Rancho Los Amigos Levels I, II and III). Research design : A retrospective review was conducted of 10 children enrolled in an existing clinical protocol. The Kluge Childrens Rehabilitation Center (KCRC) low response protocol provides a double baseline serial measure (A, A, B, B, B) design. Scores on the Western NeuroSensory Stimulation Profile (WNSSP) are the dependent variable. Methods and procedures : Ten children, mean age of 13.7 years low response state (30 days or more) who were treated with dopamine agonists. Co-morbid or iatrogenic influences were addressed or ruled out. Seven children had traumatic brain injury, one cerebral vascular accident, one anoxia and one encephalitis. Experimental intervention : On average, dopamine medications were started 52.9 days post-event. Main outcomes and results : Paired t -test of WNSSP scores before medications and on medications were significant at p = 0.03 (paired t -test). Also, the distributions of the slopes (rates of change of WNSSP scores over time) were significantly different in the pre-medication and medication phases (Paired T -test, p = 0.02). Random coefficient model comparison of individuals during pre- and medication phase response variability on WNSSP yielded F -test at p = 0.02. Conclusions : These results suggest a promising relationship between acceleration of recovery for some children in a low response state and administration of dopamine-enhancing medications.

ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children

A series of studies have shown that the heavy burdens of diarrheal diseases in the first 2 formative years of life in children living in urban shanty towns have negative effects on physical and cognitive development lasting into later childhood. We have shown that APOE4 is relatively common in shanty town children living in Brazil (13.4%) and suggest that APOE4 has a protective role in cognitive development as well as weight-for-height in children with heavy burdens of diarrhea in early childhood (64/123; 52%), despite being a marker for cognitive decline with Alzheimers and cardiovascular diseases later in life. APOE2 frequency was higher among children with heaviest diarrhea burdens during the first 2 years of life, as detected by PCR using the restriction fragment length polymorphism method, raising the possibility that ApoE-cholesterol balance might be critical for growth and cognitive development under the stress of heavy diarrhea burdens and when an enriched fat diet is insufficient. These findings provide a potential explanation for the survival advantage in evolution of genes, which might raise cholesterol levels during heavy stress of diarrhea burdens and malnutrition early in life.

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.

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 Childrens 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.

International study of emergency department care for pediatric traumatic brain injury and the role of CT scanning.

Abstract Objects: Our objective was to investigate the use of CT and its relationship to head injury severity and age. Method: The multi-center group International Study of Head Injury Project (ISHIP) serves as the administrative body for research design, data collection and analysis. This is a nonrandomized prospective study of longitudinal outcomes following examination and care in emergency department in five different countries. The subjects of our study were 4,690 children from birth to 15 years of age, all of whom were systematically evaluated. Each child was medically evaluated and categorized as to injury severity, mechanism of injury and findings on X-ray and CT scan. Follow-up interview and assessment was completed for comparison with the presenting clinical state. Results: CT scans were performed for674 (14.3%) of the children: 438 scans were normal and 236 were abnormal (P<0.001). Of the children with abnormal CT scans, 23.3% had mild head injuries, 42.7% had moderate injuries, and 33.8% had severe injuries, as determined by the GCS. By age, 10.5% of the positive CTs were in children aged 0–2 years, 56.3% in 3- to 9-year-olds, and 33% in 10- to 15-year-olds; only in 2% of cases were both CT and X-ray positive. Conclusions: The majority of children did not need significant medical intervention. Physicians ordered X-ray investigations more frequently than CT scanning. The use of X-ray to decide whether or not CT is ne- cessary is not warranted. The implications of positive CTs in mild or moderate injuries were most noteworthy, as were age-related interactions with positive CT findings.

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, thereby 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.

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 Alzheimers 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.