The role of neuropsychology in UK pediatric HIV care: Relevance to clinical practice and research

There has been a dramatic improvement in the survival of children with perinatally-acquired HIV (PHIV) following the introduction of effective treatment in 1990s. The care for children living with PHIV is now focused on more accurately understanding the effects of both HIV and HIV treatment on the developing body and brain. An evaluation of current HIV neuroimaging, and neurocognitive research, when combined with clinical experience in the area of HIV, could help to inform United Kingdom (UK) PHIV service provision. This paper argues that an understanding from a neuropsychological perspective will help these young people to optimize their health, quality of life, and future functioning. The aim of the paper is to bring together research and clinical understanding of HIV and its treatment effects on the developing brain, together with an understanding of other potential neurological risk factors. It is argued here that there is a need for targeted neuropsychology assessment and preventative interventions, supported by clinical and preliminary research on the neurocognitive effects of HIV and its treatments.     

Neuropsychological complications of insulin dependent diabetes in children

Previous research suggests that children with insulin dependent diabetes (IDDM) show selective impairments on neuropsychological tests, with those developing IDDM before 5 years of age appearing to be the most affected. The effect of hypoglycaemia on the developing brain has been suggested as a possible risk factor as has the disruptive effect of chronic hyperglycaemia on myelinisation. A cohort of children (n = 124) with newly diagnosed IDDM, managed at The Royal Children's Hospital, Melbourne has been assembled and evaluated 3 months post diagnosis on standardised tests of general intelligence, attention, memory, new learning, executive functions, and educational achievement. The performance of the children with IDDM has been compared with that of a demographically representative control group (n = 129) of healthy children. At this baseline assessment, the findings strongly support the hypothesis that the neuropsychological and educational profiles of newly diagnosed children are not different from that of controls early in the course of the illness. Both groups will be reassessed 2 and 5 years after the initial evaluation when it is hypothesised that children with diabetes will perform more poorly. Parameters of the illness, such as age of onset, major metabolic crises, and history of glycaemic control will be related to the test performance of the children with IDDM to identify specific risk factors for neuropsychological and educational sequelae in that population.     

Neurological and developmental effects of HIV and AIDS in children and adolescents

HIV-related encephalopathy is an important problem in vertically infected children with HIV. Infected infants may manifest early, catastrophic encephalopathy, with loss of brain growth, motor abnormalities, and cognitive dysfunction. Even without evidence of AIDS, infected infants score lower than serorevertors on developmental measures, particularly language acquisition. Children with perinatal or later transfusion-related infection generally are roughly comparable developmentally to their peers until late in their course. Symptoms similar to adult AIDS dementia complex are occasionally seen in adolescents with advanced AIDS, including dementia, bradykinesia, and spasticity. Opportunistic CNS infections such as toxoplasmosis and progressive multifocal leukoencephalopathy are less common in children and adolescents than in adults. Increasing evidence suggests that aggressive antiretroviral treatment may halt or even reverse encephalopathy. Neuroimaging changes may precede or follow clinical manifestations, and include early lenticulostriate vessel echogenicity on cranial ultrasound, calcifying microangiopathy on CT scan, and/or white matter lesions and central atrophy on MRI. Differential diagnosis of neurological dysfunction in an HIV-infected infant includes the effects of maternal substance abuse, other CNS congenital infections, and other causes of early static encephalopathy. Initial entry of HIV into the nervous system occurs very early in infection. The risk of clinical HIV encephalopathy increases with very early age of infection and with high viral loads. Virus is found in microglia and brain derived macrophages, not neurons. The neuronal effect of HIV is probably indirect, with various cytokines implicated. Apoptosis is the presumed mechanism of damage to neurons by HIV.     

Neurocognitive outcomes in pediatric HIV

Cognitive impairment has long been associated with the natural history of HIV among vertically infected children. In children, HIV may have a direct or indirect impact on the developing brain, may lead to global or highly specific consequences, and may be responsible for minor cognitive consequences or, conversely, long-term and severe disability. This differential impact is related to multiple factors that influence the individual expression of the virus in any given child. This review provides an overview of the relevant literature on neurocognitive outcomes for infants, children, and youth vertically infected with HIV, with attention to those factors impacting neurocognitive outcome within a developmental framework. Research findings in both the era preceding and following the introduction of combined therapies are reviewed, since many of the issues identified prior to state-of-the-art treatment currently available in the United States and other developed countries still apply in much of the developing world. Intervention issues and directions for future research are also discussed.     

A Two-Year Longitudinal Study of Neuropsychological and Cognitive Performance in Relation to Behavioral Problems and Competencies in Elementary School Children

Despite interest in early neuropsychological status as a possible contributor to children's behavioral development, prospective longitudinal investigations of neuropsychological measures in relation to later behavioral outcomes in childhood are few. A 2-year longitudinal study in a nonselected childhood sample is reported. The study tested the influence of early neuropsychological performance (verbal fluency, mental inhibitory control, and visual spatial ability) on later childhood behavioral problems and social competency. Regular education children (n = 235) were assessed at three time points 1 year apart. To control for autocorrelation of outcome measures, Time 1 behavior was partialed while testing the effects of Time 1 neuropsychological scores on Time 3 outcome. To control for autocorrelation of neuropsychological scores, Time 2 scores were partialed while testing the predictive effect of Time 1 scores on Time 3 outcome. Both sets of regression models suggested modest but statistically significant effects for inhibitory control and verbal fluency, but not IQ, reading, or visual spatial ability, on behavioral outcome. Study results are consistent with a modest causal effect of selected neuropsychological skills on later behavioral adjustment. The findings support theories that implicate subtle neuropsychological dysfunction in the development of behavioral problems in childhood.     

Executive functions in preschool children born preterm: application of cognitive neuroscience paradigms.

Although children born preterm are at risk for neuropsychological impairments at school age and adolescence, including difficulties with visual motor integration, spatial/constructional skills, attention, arithmetic, and nonverbal executive functions, specific neuropsychological outcome has not been investigated adequately in preschoolers. Application of cognitive neuroscience tasks offers the opportunity to characterize early executive functions in young children born preterm. In a preliminary sample of 29 preschool children born preterm (M birth gestational age = 32.4 weeks), executive function outcome was compared to that of fullterm controls by contrasting performance on two prototypic delayed-response-type paradigms, Delayed Alternation and Spatial Reversal. Preschoolers born preterm correctly retrieved the reward on fewer trials on Delayed Alternation than did matched controls. Furthermore, preschool children born preterm used problem-solving strategies that included more perseverative errors than controls. These preliminary findings highlight the utility of cognitive neuroscience paradigms to understand neuropsychological outcome in preschool children born preterm and suggest areas of developmental vulnerability that may include dorsolateral prefrontal circuits.     

Executive Functions in Preschool Children Born Preterm: Application of Cognitive Neuroscience Paradigms

Although children born preterm are at risk for neuropsychological impairments at school age and adolescence, including difficulties with visual motor integration, spatial/constructional skills, attention, arithmetic, and nonverbal executive functions, specific neuropsychological outcome has not been investigated adequately in preschoolers. Application of cognitive neuroscience tasks offers the opportunity to characterize early executive functions in young children born preterm. In a preliminary sample of 29 preschool children born preterm (M birth gestational age = 32.4 weeks), executive function outcome was compared to that of fullterm controls by contrasting performance on two prototypic delayed-response-type paradigms, Delayed Alternation and Spatial Reversal. Preschoolers born preterm correctly retrieved the reward on fewer trials on Delayed Alternation than did matched controls. Furthermore, preschool children born preterm used problem-solving strategies that included more perseverative errors than controls. These preliminary findings highlight the utility of cognitive neuroscience paradigms to understand neuropsychological outcome in preschool children born preterm and suggest areas of developmental vulnerability that may include dorsolateral prefrontal circuits.     

Cognitive outcomes of pediatric stroke

A limited number of longitudinal studies have investigated long-term neuropsychological development in the pediatric stroke population. This study retrospectively examines cognitive outcomes in 41 children with a history of stroke, with reference to age at stroke, laterality, region and mechanism of stroke. In the course of recovery, neuropsychological measures of intellectual functioning and memory were administered at two time points, whilst executive functioning, attention and academic skills were administered at one time point. As predicted, children with stroke performed significantly worse compared to normative expectations on all neuropsychological measures. Up to two thirds of children scored in the borderline impaired and impaired ranges on at least one domain of cognition. Performance on intellectual and memory assessment remained relatively stable over time. Younger age at stroke was found to be associated with poorer intellectual functioning. No effects of laterality of stroke on neuropsychological performance over time were found. Children with subcortical stroke demonstrated a greater improvement in immediate memory over time than children with cortical stroke. These findings reveal that children with stroke display long-term cognitive difficulties that typically remain stable over time. Attention and academic skills are particularly vulnerable to impairment. Further evidence that age at stroke is a significant factor in terms of cognitive outcome is provided, in support of the “early vulnerability” position.     

Functional Consequences of HIV-Associated Neuropsychological Impairment

This review focuses on the “real world” implications of infection with HIV/AIDS from a neuropsychological perspective. Relevant literature is reviewed which examines the relationships between HIV-associated neuropsychological impairment and employment, driving, medication adherence, mood, fatigue, and interpersonal functioning. Specifically, the relative contributions of medical, cognitive, psychosocial, and psychiatric issues on whether someone with HIV/AIDS will be able to return to work, adhere to a complicated medication regimen, or safely drive a vehicle will be discussed. Methodological issues that arise in the context of measuring medication adherence or driving capacity are also explored. Finally, the impact of HIV/AIDS on mood state, fatigue, and interpersonal relationships are addressed, with particular emphasis on how these variables interact with cognition and independent functioning. The purpose of this review is to integrate neuropsychological findings with their real world correlates of functional behavior in the HIV/AIDS population.     

Time of day affects episodic memory in older adults

The neuropsychological test scores of 2030 cognitively normal older adults were examined to evaluate performance patterns as they related to time of day (TOD) at which testing was initiated. Multiple regression analyses were used to examine the association of TOD with scores on seven neuropsychological tests used in the clinical evaluation of dementia. Episodic memory performance was significantly related to TOD, while memory span and verbal fluency were not. Best performance occurred during early morning hours and late afternoon; worst performance occurred mid-day (i.e., noon). These findings may have implications for clinical assessment, the design of research on dementia, and the daily functioning of older adults.     

An examination of risky sexual behavior and HIV in victims of child abuse and neglect: a 30-year follow-up.

OBJECTIVE: This article examined links between childhood maltreatment and risky sexual behavior (early sexual contact, promiscuity, prostitution) and HIV in adulthood. DESIGN: Using a prospective cohort design, physically and sexually abused and neglected children (ages 0-11) with documented cases during 1967-1971 were matched with nonmaltreated children and followed into adulthood. MAIN OUTCOME MEASURES: Early sexual contact, promiscuity, and prostitution were assessed through in-person interviews and official records (prostitution) at approximate age 29 (N=1196). HIV tests were conducted at approximate age 41 (N=631). RESULTS: Child maltreatment was associated with prostitution (OR=2.47, 95% CI=1.35-4.50) and early sexual contact (OR=1.73, 95% CI=1.24-2.40). Prevalence of HIV in the abuse/neglect group was twice that in controls (OR=2.35, 95% CI=.64-8.62), although this difference did not reach conventional levels of statistical significance. SEM provided significant support for a model linking child abuse and neglect to prostitution through early sexual contact and a marginal link to HIV through prostitution. CONCLUSION: These findings provide prospective evidence that maltreated children are more likely to report sexual contact before age 15, engage in prostitution by young adulthood, and test positive for HIV in middle adulthood.     

Time of Day Affects Episodic Memory in Older Adults*

ABSTRACT

The neuropsychological test scores of 2,030 cognitively normal older adults were examined to evaluate performance patterns as they related to time of day (TOD) at which testing was initiated. Multiple regression analyses were used to examine the association of TOD with scores on seven neuropsychological tests used in the clinical evaluation of dementia. Episodic memory performance was significantly related to TOD, while memory span and verbal fluency were not. Best performance occurred during early morning hours and late afternoon; worst performance occurred mid-day (i.e., noon). These findings may have implications for clinical assessment, the design of research on dementia, and the daily functioning of older adults.     

Affective and neuropsychological correlates of children's rituals and compulsive-like behaviors: continuities and discontinuities with obsessive-compulsive disorder

This study explored the relations among ritualistic and compulsive-like behavior, fears, and neuropsychological performance in typically developing children between the ages of four and eight years. Forty-two children were administered a battery of neuropsychological tasks assessing response inhibition and set-shifting. Two parent-report questionnaires assessed the intensity of children's fears and compulsive-like behaviors ("just right" perceptions and repetitive behaviors). For younger children (72 months), set-shifting and response inhibition accounted for significant variance in their ritualistic, compulsive-like behaviors. For older children (>72 months), a combination of neuropsychological (response inhibition) and affective (animal fears and social anxiety) factors predicted compulsive-like behaviors. These findings suggest that common neuropsychological mechanisms underlie compulsive, ritualistic behavior exhibited in normal development and in obsessive-compulsive disorder.     

Perinatally acquired HIV infection: Long-term neuropsychological consequences and challenges ahead

Over the past three decades, perinatal HIV infection in the United States has evolved from a fatal disease to a manageable chronic illness. As the majority of youth with perinatal HIV infection age into adolescence and adulthood, management of this stigmatizing, transmittable disease in the backdrop of a cadre of environmental stressors presents challenges beyond those of other chronic illnesses. The neurologic and neuropsychological consequences of this neurotropic virus have important implications for the successful navigation of responsibilities related to increasingly independent living of this aging population. This article will review the neurologic and neuropsychological consequences of perinatal HIV infection and concomitant factors in the era of highly active antiretroviral therapy and will provide an overview of the neuropathology, pathogenesis, neuroimaging findings, and treatment of perinatal HIV infection, as well as recommendations for service provision and future research.     

Characterization and sociocultural predictors of neuropsychological test performance in HIV+ Hispanic individuals

Hispanic individuals in the U.S. have been disproportionately impacted by HIV/AIDS, yet little is known regarding the neuropsychological sequelae of HIV within the Hispanic population. This study characterized neuropsychological (NP) test performance of HIV+ English-speaking Hispanic participants (n = 51) and investigated the combined roles of sociocultural factors (e.g., ethnicity, socioeconomic status [SES] proxy, and reading level) on NP test performance among our HIV+ Hispanic and non-Hispanic White participants (n = 49). Results revealed that the pattern of NP impairment in HIV+ Hispanic participants is consistent with the frontal-striatal pattern observed in HIV-associated CNS sequelae, and the overall prevalence of global NP impairment was high compared to previous reports with more ethnically homogeneous, non-Hispanic White cohorts. Multivariate prediction models that considered both sociocultural factors and CD4 count revealed that reading level was the only unique predictor of global NP functioning, learning, and attention/working memory. In contrast, ethnicity was the only unique predictor of abstraction/executive functioning. This study provides support for the use of neuropsychological evaluation in detecting HIV-associated NP impairment among HIV+ Hispanic participants and adds to the growing literature regarding the importance of considering sociocultural factors in the interpretation of NP test performance.     

Lateralized brain injury and behavior problems in children

This study investigated the types of behavior problems found in children with lateralized brain lesions. Children referred for neuropsychological assessment were assigned to dominant (DH) or nondominant (NDH) groups on the basis of history of neurological disease or injury, findings on neurological examination, functional and structural laboratory findings, and neuropsychological assessment. Over two-thirds fell into the clinical range of behavior problems by parental report on the Achenbach Child Behavior Checklist. Degrees of pathology were nearly equal. DH children showed more externalizing than internalizing symptomatology. NDH children showed more internalizing than externalizing behavior problems. Results are discussed in terms of symptom formation based on lateralization of lesion.     

发展性障碍儿童的脑发育特点及干预

随着发展认知神经科学的兴起, 研究者借助脑成像等技术探讨了发展性障碍儿童的脑结构发育特点, 发展缺陷与脑功能损伤的关系以及障碍干预和脑功能改善的机制等, 这为揭示发展性障碍儿童异常神经机制的共性和特异性, 进而为早期诊断和干预提供了重要的生物学标记。针对儿童期常见的发展性障碍, 从脑结构损伤、脑激活异常、脑网络连接和脑功能康复等方面对相关研究进行了总结, 指出未来研究应拓展角度, 注重揭示各发展性障碍之间异常脑发育特点的共性和特异性的具体表现、病理机制及基因基础等; 临床工作者应注重将脑发育的异常和功能改善用于辅助各类障碍的早期识别和干预效果评估。     

Cognitive and behavioral functioning in Coffin-Siris syndrome and epilepsy: a case presentation

The authors characterized the cognitive, adaptive, and behavioral sequelae of Coffin-Siris (CS) syndrome and epilepsy in a 7.5-year-old child. Little is known about the early neurobehavioral presentation of CS. Clinical features consistent with this genetic anomaly include underdeveloped tips and nails of the fifth fingers, extended infranasal depression, and craniofacial abnormalities. MRI findings often reveal callosal agenesis. The authors conducted a neuropsychological evaluation and obtained parental ratings of behavioral and adaptive functioning. Attentional abilities were limited. As assessed by the Mullen Scales of Early Learning, receptive language abilities (age equivalent [AE]: 3-3) were relatively stronger than expressive skills (AE: 1-4). Adaptive functioning was low across all domains (Vineland Adaptive Behavior Composite AE: 1-9). On the Behavior Assessment for Children (BASC-2), social skills dysfunction, stereotyped and self-stimulatory behaviors, restricted interests, ritualistic play, and inappropriate object usage were noted. No significant mood disturbances were endorsed. Study findings indicate a diffuse pattern of neurobehavioral deficits in a child with CS and epilepsy. Further clinical assessment and research should include multidimensional assessment techniques, including evaluation of adaptive behavior, in an effort to capture the full range developmental sequelae in children with CS.     

AIDS and pediatric HIV infection: the problem of the infected mother and her newborn

The number or pediatric AIDS cases in the US was around 2000 in 1990, and children under 13 accounted for about 2% of reported cases. Pediatric cases are increasing as the number of infected women increases. Such cases are concentrated in poor urban populations, aggravating the lack of resources of already overtaxed health services. Ethnic minorities are overrepresented among AIDS cases. In the US, 52% of AIDS cases in adult women are in blacks, 27% in non-Hispanic whites, and 20% in women of Hispanic origin. Among children under 13, 53% are in blacks, 25% in Hispanics, and 22% in whites. The majority of children with AIDS were 5 and were probably infected by vertical transmission. Over 80% were born to mothers with AIDS or at risk of HIV infection, 11% received transfusions of contaminated blood, and 5% received contaminated blood products. Through December 1989, 53% of white, 91% of black, and 85% of Hispanic children with AIDS were infected vertically by their mothers. In the US, over 1/2 of cases of vertical AIDS transmission are due to maternal IV drug abuse and 1/5 to mothers who have sexual relations with IV drug abusers. The rate of infection in children born to seropositive mothers has not been established. Estimates of rates of transmission range from 20% to 50%. The factors causing HIV transmission in 1/3 of infants and protecting the other 2/3 have not been identified. Transmission to the infant may occur during pregnancy or delivery or through breast feeding. There is no evidence that cesarean delivery can protect against infection. The risk of intrauterine infection is probably much greater than that of infection during delivery. Diagnosis of HIV infection in young infants is difficult. There are no physical characteristics distinguishing infected newborns, and laboratory diagnosis is unhelpful because maternal HIV antibodies cross the placental barrier to the fetus. There is as yet no vaccine or curative treatment for HIV infection. Prevention of pediatric HIV infection requires prevention of the infection and the disease in pregnant women. Primary prevention in women depends on their being adequately informed about risks and able to change risk behaviors. Secondary prevention is achieved through use of AZT, which slows the progression of the disease, and prevention or treatment of complications. There is no conclusive evidence as yet that pregnancy hastens the progression of maternal HIV infection. Seropositive mothers should avoid breast feeding if adequate substitute foods are available. The average age at appearance of symptoms in infected children is 8 months. Mortality is higher among children manifesting the disease in the 1st year, with a median survival of 38 months. Full information about HIV infection and voluntary and confidential screening should be available to all women contemplating pregnancy.