Assessment of Executive Functions after Treatment of Childhood Acute Lymphoid Leukemia: a Systematic Review

Neuropsychology Review - Individuals treated for childhood acute lymphoblastic leukemia (ALL) have a high survival rate. This fact, however, may lead to neurocognitive impairments in survivors, as...     

Characterizing neurocognitive late effects in childhood leukemia survivors using a combination of neuropsychological and cognitive neuroscience measures

Knowledge about cognitive late effects in survivors of childhood acute lymphoblastic leukemia (ALL) is largely based on standardized neuropsychological measures and parent reports. To examine whether cognitive neuroscience paradigms provided additional insights into neurocognitive and behavioral late effects in ALL survivors, we assessed cognition and behavior using a selection of cognitive neuroscience tasks and standardized measures probing domains previously demonstrated to be affected by chemotherapy.

130 ALL survivors and 158 control subjects, between 8 and 18 years old at time of testing, completed the n-back (working memory) and stop-signal (response inhibition) tasks. ALL survivors also completed standardized measures of intelligence (Wechsler Intelligence Scales [WISC-IV]), motor skills (Grooved Pegboard), math abilities (WIAT-III), and executive functions (Delis–Kaplan Executive Function System). Parents completed behavioral measures of executive functions (Behavior Rating Inventory of Executive Function [BRIEF]) and attention (Conners-3).

ALL survivors exhibited deficiencies in working memory and response inhibition compared with controls. ALL survivors also exhibited deficits on WISC-IV working memory and processing speed, Grooved Pegboard, WIAT-III addition and subtraction fluency, and numerical operations, as well as DKEFS number-letter switching. Parent reports suggested more attention deficits (Conners-3) and behavioral difficulties (BRIEF) in ALL survivors compared with referenced norms. Low correspondence between standardized and experimental measures of working memory and response inhibition was noted.

The use of cognitive neuroscience paradigms complements our understanding of the cognitive deficits evident after treatment of ALL. These measures could further delineate cognitive processes involved in neurocognitive late effects, providing opportunities to explore their underlying mechanisms.     

Neurocognitive Correlates of Type 1 Diabetes Mellitus in Childhood

Type 1 Diabetes Mellitus (T1DM) is one of the most prevalent chronic health conditions in children under the age of 18 years. Complications of the disease include hypo- and hyperglycemia, which can have an impact on children’s performance in assessment situations, in the clinic, and in school. Because there is no cure for this disease, there is a need to understand the cognitive deficits associated with some of its complications, as this knowledge will impact on the choice of treatment regimens as well as educational interventions. This paper provides a comprehensive review of the relevant literature on the neurocognitive outcome of T1DM. In particular, disease- and treatment-related variables that are associated with poor performance on cognitive domains will be reviewed. Specifically, age of onset, duration, pubertal effects, and presence of hypoglycemia or hyperglycemia will be examined. These findings are not without controversy, and limitations to conclusions will also be presented. Where relevant, recommendations for future research directions will be provided.     

Neurocognitive correlates of type 1 diabetes mellitus in childhood.

Type 1 Diabetes Mellitus (T1DM) is one of the most prevalent chronic health conditions in children under the age of 18 years. Complications of the disease include hypo- and hyperglycemia, which can have an impact on children's performance in assessment situations, in the clinic, and in school. Because there is no cure for this disease, there is a need to understand the cognitive deficits associated with some of its complications, as this knowledge will impact on the choice of treatment regimens as well as educational interventions. This paper provides a comprehensive review of the relevant literature on the neurocognitive outcome of T1DM. In particular, disease- and treatment-related variables that are associated with poor performance on cognitive domains will be reviewed. Specifically, age of onset, duration, pubertal effects, and presence of hypoglycemia or hyperglycemia will be examined. These findings are not without controversy, and limitations to conclusions will also be presented. Where relevant, recommendations for future research directions will be provided.     

Neurodevelopment and chronic illness: Mechanisms of disease and treatment

Successful treatment of many childhood diseases once considered terminal has resulted in the emergence of long-term effects of the disease or consequences of treatment that were previously unrecognized. Many of these long-term effects involve the central nervous system (CNS) and are developmental in the way that they emerge over time. Because we are now able to observe the natural history of childhood diseases such as sickle cell anemia or HIV, or the consequences of treatment of disease such as leukemia, brain tumors, or kidney disease, we are also able to study a number of biological mechanisms that result in long-term neurocognitive impairment. While some of the neurodevelopmental outcomes can be directly linked to structural damage of the CNS, other systems (e.g., hematologic, immunologic, pulmonary) appear to play crucial indirect roles in the development of the CNS and neurocognitive abilities because of the way that they affect the course of brain development and activity of the brain across time. Important interactions between acute disease factors, biological mechanisms, age at the time of disease or treatment effect, and disruptions in patterns of development after successful treatment or management all provide support for a neurodevelopmental model of childhood chronic illness. Testing this model may make it possible to more accurately predict the timing and degree of severity of long-term neurodevelopmental consequences, provide guidance for improved treatment and prevention, and offer better understanding of neurodevelopmental disruptions that occur in other non-chronic illness related disabilities.     

Neurocognitive impairment does not predict treatment outcome in obsessive-compulsive disorder

There is conflicting evidence pertaining to whether or not neurocognitive task performance at baseline predicts treatment response in obsessive-compulsive disorder (OCD). In the present study, we administered a set of executive neurocognitive tests with a putative sensitivity for treatment outcome to a sample of 138 OCD patients. Additionally, subjective neurocognitive dysfunction was determined via a questionnaire. All patients participated in a cognitive-behavioural treatment program (CBT). Results showed that responders (n = 73) did not differ from non-responders (n = 65) on any of the parameters except for decreased performance on the delayed alternation test (p < .1, effect size: .61). A subsidiary analysis revealed that slowing on the Trail-Making Test A and an enhanced rate of perserveration errors on the Wisconsin Card Sorting Test predicted poor outcome for the treatment of compulsions. It is concluded that neurocognitive impairment does not represent a reliable early warning sign for non-response to CBT.     

Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review

This article presents a review of studies that have investigated the neuropsychological effects of antiretroviral treatment (ART) for HIV-1 infection. It provides a brief overview of the era of monotherapy, dual-therapy, and an extended overview of the current era of combination antiretroviral therapy (CART). This review highlights that while CART has had a dramatic effect on the incidence and the severity of HIV-associated neurocognitive disorders (HAND), HAND, in its mild form, still remains prevalent. New causes of this sustained prevalence are poor CNS penetration of some antiretroviral agents, drug resistance, poor adherence, potential neurotoxicity, co-morbidities such as the long-term CART side effects in relation to cardio-vascular disease, and chronic HIV brain infection that may facilitate the expression of new forms of neurodegenerative processes. The review emphasizes the need to address methodological limitations of published studies and the need for large and representative cross-disciplinary longitudinal investigations across the HIV illness span.     

Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.     

Obstructive Sleep Apnea Syndrome in Prader-Willi Syndrome: An Unrecognized and Untreated Cause of Cognitive and Behavioral Deficits?

Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by a range of physical, psychological, and physiological abnormalities. It is also distinguished by the high prevalence of obstructive sleep apnea syndrome (OSAS), i.e., repetitive upper airway collapse during sleep resulting in hypoxia and sleep fragmentation. In non-PWS populations, OSAS is associated with a range of neurocognitive and psychosocial deficits. Importantly, these deficits are at least partly reversible following treatment. Given the findings in non-PWS populations, it is possible that OSAS may contribute to neurocognitive and psychosocial deficits in PWS. The present review examines this possibility. While acknowledging a primary contribution from the primary genetic abnormality to central neural dysfunction in PWS, we conclude that OSAS may be an important secondary contributing factor to reduced neurocognitive and psychosocial performance. Treatment of OSAS may have potential benefits in improving neurocognitive performance and behavior in PWS, but this awaits confirmatory investigation.     

Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls

With more children surviving a brain tumor, insight into the late effects of the disease and treatment is of high importance. This study focused on profiling the neurocognitive functions that might be affected after treatment for a pediatric brain tumor, using a broad battery of computerized tests. Predictors that may influence neurocognitive functioning were also investigated. A total of 82 pediatric brain tumor survivors (PBTSs) aged 8–18 years (M = 13.85, SD = 3.15, 49% males) with parent-reported neurocognitive complaints were compared to a control group of 43 siblings (age M = 14.27, SD = 2.44, 40% males) using linear mixed models. Neurocognitive performance was assessed using measures of attention, processing speed, memory, executive functioning, visuomotor integration (VMI), and intelligence. Tumor type, treatment, tumor location, hydrocephalus, gender, age at diagnosis, and time since diagnosis were entered into regression analyzes as predictors for neurocognitive functioning. The PBTSs showed slower processing speeds and lower intelligence (range effect sizes .71–.82, p < .001), as well as deficits in executive attention, short-term memory, executive functioning, and VMI (range effect sizes .40–.57, p < .05). Older age at assessment was associated with better neurocognitive functioning (B = .450, p < .001) and younger age at diagnosis was associated with lower intelligence (B = .328, p < .05). Medical risk factors, e.g., hydrocephalus, did not show an association with neurocognitive functioning. Late effects in PBTSs include a broad range of neurocognitive deficits. The results suggest that even PBTSs that were traditionally viewed as low risk for neurocognitive problems (e.g., surgery only, no hydrocephalus) may suffer from decreased neurocognitive functioning.     

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.     

HIV Infection and the Central Nervous System: A Primer

The purpose of this brief review is to prepare readers who may be unfamiliar with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) and the rapidly accumulating changes in the epidemic by providing an introduction to HIV disease and its treatment. The general concepts presented here will facilitate understanding of the papers in this issue on HIV-associated neurocognitive disorders (HAND). Toward that end, we briefly review the biology of HIV and how it causes disease in its human host, its epidemiology, and how antiretroviral treatments are targeted to interfere with the molecular biology that allows the virus to reproduce. Finally, we describe what is known about how HIV injures the nervous system, leading to HAND, and discuss potential strategies for preventing or treating the effects of HIV on the nervous system.     

Neurocognitive dysfunction in children with sleep disorders

It is well known that adults with sleep disturbances frequently exhibit a wide range of neurocognitive decrements, and that these deficits are potentially reversible with effective treatment. However, the consequences of respiratory sleep disturbances on neurocognitive function in children have only recently been evaluated, and suggest a strong causal association between the episodic hypoxia and sleep fragmentation that characterize the disease and the emergence of reduced memory, attention and intelligence as well as a link to problematic and hyperactive behaviours and mood disturbances. This article takes a critical look at the current literature on these issues, reviews the major findings and discusses such findings in conjunction with those derived from pertinent animal models.     

Modeling the Ecological Validity of Neurocognitive Assessment in Adults with Acquired Brain Injury

Neuropsychologists are increasingly asked to make judgments regarding treatment options and rehabilitation strategies in addition to evaluating the degree and scope of neuropsychological impairment following acquired brain injuries. The capacity to make informed clinical decisions relies upon research investigating the relationships between neuropsychological and psychosocial status (i.e., ecological validity). Unfortunately, much of this research employs exploratory analyses, an approach that can lead to theoretical ambiguity and ad-hoc interpretations. The current availability and accessibility of analytical tools, like structural equation modeling (SEM), however, permits the testing of specific hypotheses regarding ecological validity and promotes a-priori theory development. In the current study, a theory-driven model of the ecological validity of a neurocognitive assessment was tested against data obtained from individuals with acquired brain injury using SEM. The results provide confirmatory evidence for the ecological validity of neurocognitive constructs and empirical support for a theory-driven analytical approach to ecological validity research.     

Elevated outcome-anticipation and outcome-evaluation ERPs associated with a greater preference for larger-but-delayed rewards

Although waiting for a reward reduces or discounts its value, some people have a stronger tendency to wait for larger rewards and forgo smaller-but-immediate rewards. This ability to delay gratification is captured by individual differences in so-called intertemporal choices in which individuals are asked to choose between larger-but-delayed versus smaller-but-immediate rewards. The current study used event-related potentials (ERPs) to examine whether enhancement in two neurocognitive processes, outcome anticipation and outcome evaluation, modulate individual variability in intertemporal responses. After completing a behavioral intertemporal choice task, 34 participants performed an ERP gambling task. From this ERP task, we separately examined individual differences in outcome anticipation (stimulus-preceding negativity; SPN), early outcome valuation (feedback-related negativity; FRN), and late outcome evaluation (P3). We observed that both elevated outcome-anticipation (SPN) and late outcome-evaluation (P3) neural processes predicted a stronger preference toward larger-but-delayed rewards. No relationship was observed between intertemporal responses and early outcome evaluation (FRN), indicating that the relationship between outcome evaluation and intertemporal responses was specific to the late outcome-evaluation processing stream. Moreover, multiple regression analyses indicated that the SPN and P3 independently modulate individual differences in intertemporal responses, suggesting separate mechanisms underlie the relationship between these two neurocognitive processes and intertemporal responses. Accordingly, we identify two potential neurocognitive modulators of individual variability in intertemporal responses. We discuss the mechanisms underlying these modulators in terms of anticipation-related processing (SPN) and a saliency bias toward gain (compared to loss) outcomes (P3).     

Development of the self-concept during adolescence

Adolescence is a period of life in which the sense of 'self' changes profoundly. Here, we review recent behavioural and neuroimaging studies on adolescent development of the self-concept. These studies have shown that adolescence is an important developmental period for the self and its supporting neural structures. Recent neuroimaging research has demonstrated that activity in brain regions associated with self-processing, including the medial prefrontal cortex, changes between early adolescence and adulthood. These studies indicate that neurocognitive development might contribute to behavioural phenomena characteristic of adolescence, such as heightened self-consciousness and susceptibility to peer influence. We attempt to integrate this recent neurocognitive research on adolescence with findings from developmental and social psychology.     

Cognitive training programs for childhood cancer patients and survivors: A critical review and future directions

A robust literature has developed documenting neurocognitive late effects in survivors of leukemia and central nervous system (CNS) tumors, the most frequent cancer diagnoses of childhood. Patterns of late effects include deficits in attention and concentration, working memory, processing speed, and executive function, as well as other domains. As childhood cancer survivors are living longer, ameliorating deficits both in broad and specific neurocognitive domains has been increasingly recognized as an endeavor of paramount importance. Interventions to improve cognitive functioning were first applied to the field of pediatric oncology in the 1990s, based on strategies used effectively with adults who had sustained a traumatic brain injury (TBI). Compilation and modification of these techniques has led to the development of structured cognitive training programs, with the effectiveness and feasibility of such interventions currently an active area of research. Consequently, the purpose of this critical review is to: (1) review cognitive training programs intended to remediate or prevent neurocognitive deficits in pediatric cancer patients and survivors, (2) critically analyze training program strengths and weaknesses to inform practice, and (3) provide recommendations for future directions of clinical care and research.     

Math weaknesses in survivors of acute lymphoblastic leukemia compared to healthy children.

Difficulties in math are the most frequently reported area of academic deficit in survivors of acute lymphoblastic leukemia (ALL) and the most frequent academic complaint among parents of ALL survivors. However, previous studies that included measures of math skills have been limited by the use of only a single measure of math skills, most often a measure of written calculations, without any assessment of math reasoning or math application skills. Further, the nature of these math difficulties has not been adequately investigated. The purpose of this study was to examine the performance of ALL survivors using multiple measures of math skills. Performance was compared to a group of healthy controls matched for age and sex as well as to normative levels. Other measures of neuropsychological function were also administered, and the relationships between these measures and the math measures were explored. Converging evidence for math difficulties in ALL survivors compared to healthy controls and normative levels was found. While ALL survivors generally performed within the average range on measures of math skills, math performance was mostly related to memory function and dominant-hand psychomotor speed. By contrast, math performance of healthy children was mostly related to basic reading skills and visual-motor integration. These findings shed light on the nature of math difficulties in ALL survivors and have implications for intervention.     

CNS prophylaxis of childhood leukemia: What are the long-term neurological,neuropsychological, and behavioral effects?

Current medical treatments for childhood acute lymphoblastic leukemia (ALL) have improved the outlook to where more than 50% can be expected to survive five years or more. The use of CNS prophylaxis has contributed in a significant way to these improved survival statistics by reducing the likelihood of CNS relapses. The literature relating to the potential adverse psychological consequences of CNS prophylaxis, which include cranial radiation therapy (CRT), is reviewed and analyzed. The majority of published papers of children in first remission report that CNS prophylaxis, which include both CRT and intrathecal methotrexate, results in a variety of learning problems in many children who were younger than age 5 when treated. The available literature on the social, emotional, and educational sequelae of childhood ALL is also reviewed.Contributing Childrens Cancer Study Group investigators, institutions, and grant numbers are given in the Appendix. Address reprint requests to the Childrens Cancer Study Group, 440 East Huntington Drive, Suite 300, P.O. Box 60012, Arcadia, California 91066-6012.