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Neurocognitive Dysfunction in Survivors of Childhood Brain Tumors
Neurocognitive Dysfunction in Survivors of Childhood Brain Tumors Nicole J. Ullrich, MD, PhD,*,† and Leanne Embry, PhD‡ Newer treatments have resulted in increasing numbers of survivors of childhood cancer, for whom neurological and neurocognitive toxicity directly impacts overall functioning and quality of life. There are multiple disease- and host-related factors that influence the development of cancer-related neurocognitive dysfunction, which can progress over time and lead to significant functional impairments. This article provides an overview of the types of neurocognitive deficits seen in survivors of childhood brain tumors, the tools used to assess neurocognitive function, and the factors that impact its severity. This provides a framework for consideration of potential areas for primary prevention by reducing treatment-related toxicity as well as interventions, using behavioral and pharmacologic treatments. Semin Pediatr Neurol 19:35-42 © 2012 Elsevier Inc. All rights reserved.
C
Which Major Cognitive Domains Are Affected?
*Department of Neurology, Children’s Hospital Boston, Boston, MA. †Pediatric Brain Tumor Program, Dana-Farber Cancer Institute, Boston, MA. ‡University of Texas Health Science Center, San Antonio, TX. Address reprint requests to: Nicole J. Ullrich, MD, PhD, Department of Neurology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]
Cancer-related neuropsychological dysfunction describes a complex of neurocognitive late effects that occur over time as a result of childhood cancer and its treatment. There are multiple neurocognitive, social, and psychological issues that emerge, as children are expected to master increasingly complex tasks. The pathogenesis is not well understood. Neurocognitive late effects can be defined as problems with thinking, learning, and remembering and may include permanent disruptions in brain development.4,5 Survivors of pediatric brain tumors are especially vulnerable to these late effects, given the aggressive CNS-directed therapies required for adequate treatment of these tumors. Research has consistently demonstrated that brain tumor survivors have higher rates of neurocognitive dysfunction than survivors of nonCNS malignancies. Cognitive impairment in brain tumor survivors may occur in many different areas of functioning. These deficits can be attributed to direct insult to the brain caused by tumor type, size, and location, surgical resection, impact of cranial radiation therapy (CRT), long-term effects of systemic chemotherapy, and treatment-related complications.2,5 Late effects can increase in severity over time and in direct relation to greater treatment intensity. The most commonly affected domains and modifiers include effects on overall cognitive ability, memory, attention, and executive functions, as well as deficits in motor skills, psychosocial functioning, adaptive behaviors, and social skills, but there is no specific pattern of
entral nervous system (CNS) tumors are the most common solid tumors in children, second only to leukemia in overall incidence. Importantly, in the modern treatment era, ⬎60% of children diagnosed with a brain tumor are expected to become long-term survivors; however, survival is not without serious long-term effects, and many individuals experience significant chronic medical complications.1 Neurotoxic effects, often referred to as “late effects,” are thought to fully manifest between 2 and 5 years after completion of treatment and are often associated with pronounced and chronic impairment. Late effects may occur in a variety of domains, including physical, medical, social, emotional, behavioral, and neurocognitive functioning. Importantly, it is estimated that 40%-100% of pediatric brain tumor survivors experience deficits in cognitive function related to the tumor and/or its treatment.1-3 Development of neurocognitive dysfunction is impacted by multiple host and treatment factors, and deficits often increase over time. Importantly, many survivors and their families are unaware of the risks. This chapter will focus on neurocognitive dysfunction in childhood cancer survivors, particularly survivors of CNS tumors.
1071-9091/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2012.02.014
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36 neurocognitive dysfunction that is pathognomonic for pediatric brain tumor survivors. A recent meta-analysis comprising 39 empiric studies estimated the magnitude of general and specific neurocognitive late effects for survivors of pediatric brain tumors.5 By extracting information across 10 neurocognitive domains, the authors discovered that these children exhibited significant and pervasive impairments in multiple domains, and that survivors’ scores on measures of global cognitive ability, both verbal and nonverbal, fell nearly one standard deviation below normative means. Survivors were also found to perform poorly on measures of attention, memory, executive function, processing speed, psychomotor skills, visual-spatial skills, and language. Examination of effect sizes across studies revealed more severe deficits in attention, verbal memory, and language compared with the other domains assessed. Attention and memory are critical skills by which new knowledge is acquired.6 Impairment in these areas has significant implications for intellectual growth and development and academic performance over time, as expectations and developmental demands increase with age. In fact, recent research has suggested that many learning problems are likely the result of difficulties in attending to and retaining new information rather than the decay of previously learned material.5 The resulting level of impairment can range from mild learning problems to severely limited capabilities and overall poor quality of life.2,7-12 Brain tumor survivors treated with CRT have consistently shown evidence of greater neurocognitive dysfunction than those treated without CRT. The risk of impairment increases with higher doses of CRT, and there is a continuing pattern of decline over time.6,13 In a heterogeneous sample of 133 longterm survivors of pediatric brain tumors, 5% of individuals had such severe cognitive impairment that they were unable to complete intelligence quotient (IQ) testing.9 For those completing the assessment, the authors found several important predictors of adverse outcomes. CRT was the single most important risk factor for subsequent adverse neurocognitive functioning, accounting for an average loss of 18 fullscale IQ points (normative mean IQ score ⫽ 100; standard deviation ⫽ 15). However, other risk factors included shunt insertion because of hydrocephalus (effect estimate of 11 fullscale IQ points) and cerebral hemisphere tumor location (effect estimate of 10-15 full-scale IQ points). These authors found no association between long-term cognitive functioning and tumor grade, disease relapse, or chemotherapy.
Factors That Influence Neurocognitive Outcome There are multiple disease and host factors that influence the development of cancer-related neurocognitive dysfunction. These can be divided into tumor- and treatment-related factors, host- related factors, and environmental/psychosocial (Table 1). One way to conceptualize the impact of a brain tumor is to envision that tumor diagnosis, treatment, and follow-up occur along the spectrum of neurodevelopment.
Table 1 Risk Factors for Neurocognitive Dysfunction Tumor-Related Factors
Host Factors
Presence/absence of hydrocephalus Tumor location Tumor size Weakness/sensory deficits Cranial nerve deficits Duration of symptoms Presence/absence of seizures Need for anticonvulsants Steroid use
Age at diagnosis Age at treatment Gender Genetic polymorphisms Presence/absence of neurogenetic syndrome Pretreatment/baseline level of functioning Socioeconomic status Other medical complications/illnesses Sleep disorders Fatigue Hypertension Sensorineural hearing loss Visual impairment Endocrine dysfunction
Treatment factors Surgery Neurologic injury Motor/sensory deficits Ataxia Perioperative infarction Hemorrhage Posterior fossa syndrome Chemotherapy Neuropathy Hearing deficit Headaches Fatigue Encephalopathy Leukoencephalopathy Intrathecal chemotherapy Steroid use “Chemobrain” Radiation therapy Radiation dose Radiation field Use of radiosensitizer Radiation tissue injury White matter injury Radiation necrosis Stroke or vasculopathy Vision changes (cataracts)
Environmental/ Psychosocial factors School absences Adequacy of educational supports Access to neuropsychological assessments Hospital-based school consultation Educational/vocational supports Technical support Books on tape Assistive devices Computers Loss of socialization/peer experiences Emotional distress (patient/ sibling/family) Changes to physical appearance Psychological adjustment Self-image/psychological distress Depression/anxiety
Overall neurologic and neurocognitive function is directly impacted at each time point.
Tumor- and Treatment-related Factors The location and size of the initial tumor can impact many factors, such as symptoms at presentation, resectability, and presence/absence of neurologic deficits. These deficits can be focal, with specific relationship to the tumor location and brain regions affected, or diffuse/poorly localizable, likely
Neurocognitive dysfunction in childhood cancer survivors related to raised intracranial pressure and hydrocephalus. The impact of hydrocephalus, both in terms of degree and duration before correction, is poorly accounted.14 As many as 25% of children with a primary brain tumor experience seizures at tumor presentation.15-17 Seizure onset can occur at the time of diagnosis, can be the first sign to herald relapse of tumor, or may occur/recur many years after completion of therapy. There are several proposed causes of seizures, which include the tumor itself, surrounding areas of dysplasia, altered levels of neurotransmitters, peritumor blood products/edema, and/or scar formation.17,18 The use of necessary anticonvulsants can further contribute to cognitive dysfunction in patients who are already at risk.19 Treatment for a primary brain tumor may involve a combination of surgery, chemotherapy, radiation therapy, and stem cell transplant; specific tumor-directed therapy is tailored to the underlying tumor type and location in children. Surgical resection remains the mainstay of therapy for most primary brain tumors, both to provide histologic diagnosis and to reduce tumor burden, and is often the most important factor in overall prognosis. Deficits and long-term effects of surgery are multifactorial and depend on tumor location. Direct sequelae from surgical removal can impact neurocognitive function in a variety of ways, including development of focal weakness, sensory deficits, new cranial nerve deficits, or truncal/appendicular ataxia. Surgery may also produce local damage related to development of hemorrhage or vascular injury. Recent studies suggest that even patients treated with surgery alone are at risk for long-term effects, including ataxia, hemiparesis, and persistent neurosensory and neurocognitive deficits.2,20 One prime example of surgical toxicity is cerebellar mutism, or posterior fossa syndrome, which occurs postoperatively in 15%-25% of patients with tumors in the posterior fossa, most commonly after medulloblastoma resection.21 There is thought to be a delay of 12-48 hours after surgery, followed by a loss of verbal expression, pseudobulbar dysfunction, irritability, and ataxia. In addition, poor attention and eye contact, vomiting, incontinence, and emotional lability are common. Speech recovery ranges from days to many months. These emotional, motor, and neurocognitive effects may last months to years, and are often confounded by other aspects of cancer treatment.22 Chemotherapy, both systemic and intrathecal, can have an important impact on neurologic function; the neurologic effects of chemotherapy are seen with increasing frequency as a result of more aggressive therapy and prolonged survival. Side effects may result from direct neurotoxicity or indirect effects from metabolic encephalopathies, seizures, infections, transient ischemic attacks, ataxia, and myelopathy, as well as movement disorders. Because standard therapy often relies on combinations of chemotherapy, it is often difficult to isolate the offending agent. Drug-induced encephalopathy can be seen with chemotherapy, immunosuppressive agents, or supportive treatments, such as steroids, and the effects are often dose dependent and drug specific. Many patients now receive intrathecal therapy or high-dose chemotherapy with autologous stem cell rescue. There are a variety of experimental approaches that are being evaluated to enhance the effi-
37 cacy of conventional chemotherapy. Newer techniques are also being designed to improve access to the CNS across the blood– brain barrier and to provide more molecularly directed approaches. Neurologic effects of these new molecularly targeted agents are only beginning to be recognized in adults, but the impact on the developing nervous system is far from clear. As neurocognitive assessments are incorporated into upcoming clinical trials as important outcome measures, the effects from these specific treatments will be better documented and appreciated. Radiation therapy remains an important component of cancer treatment in children. Individuals may experience different effects depending on age, disease status, concomitant therapies, length of survival, and radiation features, such as dose, size of the field, and fractionation schema. Radiation injury can affect each level of the nervous system and can occur at the time of therapy or months or even years after completion of treatment. The most common neurologic complications related to radiation are neurocognitive dysfunction and neuroendocrine damage. Several studies have shown a progressive deterioration in IQ among children who receive whole-brain radiotherapy. For example, a craniospinal axis dose of 3600 centigray (cGy) resulted in a 20- to 30-point decline in IQ score when administered to children between the ages of 3 and 7 years.23 Cognitive deficits are typically progressive in nature, and younger children are more likely to suffer the severest damage; however, no patient, regardless of age, is free of the risk of damage.6,10,24 These long-term effects on cognitive function and growth and development emphasize the importance of examining the efficacy of reduced overall dose of therapy for diseases with high cure rates.
Host-related Factors Overall, neurologic and neurocognitive function is also directly impacted by characteristics of the child or host. Neurodevelopment occurs over a prolonged period, during which the central nervous system is susceptible to a variety of insults. Critical features such as gender and age at diagnosis and treatment, therefore, often dictate susceptibility to treatment-related morbidities. Younger age at time of tumor diagnosis and treatment is likely the most important host factor that impacts the development and severity of neurocognitive dysfunction. However, sex of the child is also a significant variable in some treatment protocols, where girls are known to be at higher risk than boys for neurocognitive impairment.13 Comorbid conditions, such as inherited genetic syndromes, may also impact the timing and development of neurocognitive dysfunction. For example, children with neurofibromatosis type 1 may have baseline neurological and neurodevelopmental issues, which can be difficult to distinguish from tumor- and treatment-related side effects and can increase susceptibility to neurocognitive impairment resulting from treatment.25 A child’s premorbid level of cognitive, developmental, or neurological functioning may also be a significant predictor
N.J. Ullrich and L. Embry
38 of subsequent neurocognitive dysfunction. Children with a history of neurodevelopmental disorders, such as Down syndrome, mental retardation, low birth weight, or learning disabilities, may have an even greater risk of functional impairment after cancer treatment.
Environmental Factors Lastly, there are environmental factors in the life of a child that affect neurocognitive functioning. These include socioeconomic status (SES), loss of schooling and socialization, and alterations in family psychosocial functioning. Lower SES is associated with greater cognitive decline in acute leukemia and can impact the neurocognitive outcome in brain tumor survivors.12,26 Children from families of higher SES tend to score better on measures of IQ, achievement, and adaptive functioning.27 Academic performance may also be impacted by other sociodemographic factors, such as ethnicity and parental education.13 It is likely that many children from higher SES families benefit from greater parental support, more cognitively stimulating home environments, and increased ability of parents to advocate for the unique needs of their children. Furthermore, more affluent schools may have greater resources to provide specialized services for children experiencing treatment-related neurocognitive dysfunction. A number of family characteristics are associated with the behavioral and psychological adjustment of children with chronic illnesses, including childhood cancer. For example, stress and family conflict have been consistently linked to child maladaptive behaviors. One study found that children from 2-parent households and children who had experienced fewer negative life events tended to be more emotionally well adjusted and performed better on measures of intellectual functioning.27 Although they are not directly related to disease or treatment severity, all of these factors may have differential impact on long-term neurocognitive outcomes of childhood cancer survivors.13
How/When Do We Evaluate for Cognitive Impact? Longitudinal evaluation of neurocognitive functioning for childhood cancer survivors is not yet considered standard of care,5 although many pediatric oncology programs emphasize neurocognitive assessment for high-risk patients, including those diagnosed with brain tumors. These assessments are essential in facilitating access to needed special education services and in tracking each child’s developmental trajectory over time. Estimates of the need for special education services vary by diagnosis. In one study, 25% of a heterogeneous sample of childhood cancer survivors qualified for special education in school compared with only 8% of a sibling control group.28 Other research has estimated that 40%-50% of acute lymphoblastic leukemia survivors and up to 70%80% of brain tumor survivors will require special education services at some point during their school years.13 A comprehensive neurocognitive assessment should target global intellectual functioning and academic achievement as well as the specific high-risk domains described previously. The assessment battery should be modified as needed to accommodate for other late effects of therapy, such as chronic fatigue or hearing loss. The Children’s Oncology Group consensus recommendations suggest that, at a minimum, all high-risk survivors be evaluated when they transition into a survivorship or long-term follow-up program. This should be performed regardless of patient/parent report of concern, both to detect subtle impacts on overall functioning and to serve as a baseline for future assessments, as it is known that cognitive late effects can progress over time.6 Reevaluation should factor in academic performance, any acute changes or emergence of new difficulties, and the individual child’s specific risk factors. Table 2 includes relevant domains of neurocognitive functioning that may be part of these assessments along with commonly used measurement tools. These tools include both traditional instruments that are administered to
Table 2 Neurocognitive Assessment in Children Neurocognitive Domain
Commonly Used Assessment Tools
Global cognitive functioning (IQ)
WISC-IV; WPPSI-III; WJ-III; SB-5; KABC-II; BSID-III Mental Scale
Attention
CPT-II; NEPSY-II; Trail Making Test Part A; Conners Rating Scales, Third Edition
Memory
CMS; WRAML-2; CVLT-C; Rey-O
Processing speed
WISC-IV Coding/Symbol Search; WJ-III Achievement Fluency; D-KEFS Fluency
Executive functioning
BRIEF; D-KEFS; WCST; NEPSY-II; Trail Making Test Part B; Tower of London Test
Psychomotor skills
VMI; Finger Tapping test; Grooved Pegboard; Rey-O; BSID-III Motor Scale
Academic achievement
WIAT-III; WRAT-IV; WJ-III
BSID-III, Bayley Scales of Infant Development, Third Edition; BRIEF, Behavior Rating Inventory of Executive Function; CMS, Children’s Memory Scale; CPT-II, Continuous Performance Test, Second Edition; CVLT-C, California Verbal Learning Test for Children; D-KEFS, Delis–Kaplan Executive Function System; KABC-II, Kaufman Assessment Battery for Children, Second Edition; NEPSY-II, Developmental Neuropsychological Assessment, Second Edition; IQ, intelligence quotient; Rey-O, Rey–Osterrieth Complex Figure Test; SB-5, Stanford Binet Intelligence Scale, Fifth Edition; VMI, Beery–Buktenica Developmental Test of Visual Motor Integration Test; WCST, Wisconsin Card Sorting Test; WIAT-III, Wechsler Individual Achievement Test, Edition; WISC-IV, Wechsler intelligence scale for children, Fourth Edition; WJ-III, Woodcock–Johnson Tests of Achievement and Cognitive Abilities, Third Edition; WJ-III, Woodcock–Johnson Tests of Cognitive Abilities, Third Edition; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence, Third Edition; WRAML-2, Wide Range Assessment of Memory and Learning, Second Edition; WRAT-IV, Wide Range Achievement Test, Fourth Edition.
Neurocognitive dysfunction in childhood cancer survivors the child by a trained professional and patient-reported outcome measures, often captured via parent-report questionnaires. In recent years, modern technologies have brought about opportunities for computerized assessments of neurocognitive functioning. According to one study, 40% of high schools that employ athletic trainers now use some form of computerized assessment for evaluation and management of sports-related concussions.29 These computerized paradigms are now being used more often with clinical populations, such as adult cancer patients30 and children diagnosed with attention-deficit/hyperactivity disorder.31 Potential advantages include availability, convenience, and accuracy of administration and scoring.29 In addition, test batteries can be customized to evaluate the specific neuropsychological functions of interest (eg, processing speed, working memory) (http://www.cogstate.com). Trials are underway to evaluate the use of computerized assessment programs with survivors of pediatric cancer.
What Are the Functional Implications? Neurocognitive dysfunction can have significant implications for functional outcomes and overall quality of life for survivors.1,2 Employability, interpersonal relationships, independent living, emotional functioning, and health status are some of the domains that may be impacted by neurocognitive late effects in survivors of pediatric brain tumors. This ultimately can translate into increased risk for poor quality of life for survivors and their families.32,33 For example, one study demonstrated that only 30% of young adults who were 10-year survivors of medulloblastoma were able to drive, live independently from their families, or find employment.34 There were also significantly lower rates of education, employment, and dating when compared with the general population. Several studies have suggested that the complex needs of pediatric brain tumor survivors may be underestimated and largely unmet. Many children spend excessive time on preparation of homework, but demonstrate difficulties in processing, storage, and integration of new information.6,35 It is clear that intellectual functioning, attention, memory, executive functioning, and a variety of other cognitive abilities are negatively impacted by CNS disease and treatment. However, questions remain about how these neurocognitive deficits interact with other medical and psychosocial factors to affect long-term functional outcomes for survivors.
39
Prevention Reduction in treatment-related toxicity has occurred with advances in neurosurgical techniques, use of neuroprotective agents, and improved radiation techniques. The overall goal of treatment is to improve outcome in tumor subtypes that have traditionally been resistant to therapies, and to reduce the toxicity of treatment in tumor subtypes that are responsive to therapies. Modern literature suggests that maximum extent of tumor resection with preservation of neurological function is associated with improved overall outcome. The use of imageguided surgery such as the intraoperative magnetic resonance imaging suite has resulted in improved extent of resection and reduction of residual tumor volume.36 There will, however, always be tumors in eloquent regions of the brain and infiltrative tumors that are less amenable to this type of approach. The use of endoscopic biopsy is an important minimally invasive method of diagnosis for the initial management of lesions in children with intraventricular and periventricular tumors and can be performed safely in conjunction with procedures to divert cerebrospinal fluid for obstructive hydrocephalus.37 Diagnostic efficacy and safety are high priorities and can preempt the need for open surgical biopsy in difficult locations. Intraoperative infusions are now used in adults and children to deliver targeting agents directly to the operative bed.38 Over the past decade, there have been advances in chemotherapeutic strategies for treatment of primary brain tumors. Specific protocols have included optimization of administration of chemotherapy, metronomic treatment,39 concomitant use of chemotherapy and radiation therapy to the CNS, and administration directly into the intrathecal/intraventricular compartment. Moreover, there are refinements in the clinical and molecular stratification of tumors that have facilitated a movement toward risk-adapted treatment planning. This is particularly true in medulloblastoma, where there are now 4 subclasses of tumor that are defined by molecular signature that directly relates to clinical and pathologic outcome indicators.40,41 Ultimately, this type of approach will lead to the identification of the next generation promising molecularly targeted therapies.42 Because of concerns over neurocognitive sequelae from radiation, there is renewed interest in reduction of total radiation dose, both for solid tumors and for primary brain tumors. The use of fractionated and conformal techniques effectively reduces toxicity to the surrounding tissue.43 With proton beam radiotherapy, there is less radiation to surrounding tissues, which theoretically has the potential to decrease the area at risk for injury and, therefore, has long-term implications for sparing of neurocognitive functioning.44,45
Strategies for Intervention
Treatment of Comorbidities
Research into strategies to evaluate, prevent, and treat the neurocognitive late effects of cancer therapy has mirrored the progress of medical therapy. Interventions and therapeutic strategies are targeted at each point along the road map of diagnosis, treatment, and survivorship.
Survivors are at risk for significant comorbidities that have been shown to impact neurocognitive functioning. This may include neurosensory deficits such as visual impairment and sensorineural hearing loss, as well as seizures, endocrine dysfunction, headaches, and peripheral neuropathy.15 It is cru-
N.J. Ullrich and L. Embry
40 cial to identify and treat any underlying health conditions that may impact overall functioning, such as underlying endocrinopathies. In addition, screening for, identification of, and correction of hearing deficits and visual impairments are important. A significant proportion of adult survivors of childhood cancer report disrupted sleep, increased daytime sleepiness, and fatigue.46 Survivors with a history of radiation therapy are more likely to be fatigued. Excessive daytime sleepiness is seen in up to 60% of children with cancer and 80% of children with tumors involving the hypothalamus, thalamus, and brainstem.47 These patients are also at risk for sleep-disordered breathing. Lastly, early identification and treatment of psychological comorbidities, such as anxiety, depression, and post-traumatic stress syndrome, in the child and in the family is important for overall quality of life as well as cognitive functioning. The overall impact of these comorbidities is often hard to decipher, but given the frequency of reported symptoms in survivor populations is important to address.
Cognitive Rehabilitation Given the prevalence of neurocognitive dysfunction in survivors of pediatric brain tumors, efforts to determine effective forms of cognitive remediation are imperative. One such study focused on acquisition of cognitive strategies to improve neuropsychological performance by completing a 4-5 month remediation program, including cognitive-behavioral interventions.48 The authors reported improved attentional skills and achievement scores over the course of the study; effect sizes were small but comparable with other intervention studies with similar population and methodology. A similar 15-week training program for improving problem solving, general cognitive skills, memory, and attention showed some positive gains from pre-intervention to postintervention in each of the domains assessed.49 However, as with the first study, participation rates were fairly low and the mode of intervention may be impractical for families with few resources or those who do not live near a large medical center that could administer the intense treatment program. These findings highlighted a need for effective short-term interventions that could be widely administered without prohibitive costs, travel requirements, or time commitments. One such intervention is home-based, computerized cognitive training programs. These programs have proven effective in improving attention and working memory in children diagnosed with attention-deficit/hyperactivity disorder50 and in a small sample of pediatric cancer survivors.51 This is notable, as some investigators believe that deficits in attention and working memory are to blame for treatment-related declines in intellectual functioning and academic performance. In fact, studies of childhood cancer survivors have shown that up to 45% of the variance in IQ scores and 70% of functional impairments at school could be attributed to these underlying processes.52,53 These results suggest that homebased, computerized cognitive training may be useful in improving survivors’ neurocognitive functioning, although more research in this area is clearly indicated.
Pharmacologic Interventions Although deficits in attention are common in survivors of primary brain tumors and manifest with behavioral issues that resemble attention deficit disorder in the general population, it is likely that the mechanism is different. At the same time, traditional stimulants have been shown to improve neurocognitive functioning among survivors. Specifically, both short-acting and long-acting doses of methylphenidate lead to improvements in measures of attention, social skills, and behavioral problems in survivors of childhood brain tumors and acute lymphoblastic leukemia, and these benefits were maintained across settings during the course of one year.54 The acetylcholinesterase inhibitor donepezil has demonstrated some promising initial results in a study of 34 adults with primary brain tumors, with improvements in attention, concentration, memory, and mood.55 These data formed the basis of a feasibility study in childhood brain tumor survivors, where it was well tolerated and demonstrated improvements in executive function and memory.56 Alternative psychostimulants, such as the dopaminergic agent modafinil, have demonstrated improved attention and memory in adult breast cancer survivors57 as well as improved cognition, mood, and symptoms of fatigue in adults with brain tumors.58,59 A randomized, placebo-controlled trial is currently underway through the pediatric cooperative group to assess efficacy of modafinil in survivors of childhood brain tumors. Thus, newer stimulant medications may also hold some possibility to improve at least some aspects of common cancer-related neurocognitive deficits.
Conclusions With newer treatments and longer overall survival leading to growing numbers of survivors, there is an increasing impact of neurological and neurocognitive toxicity related to treatment for primary brain tumors in children. As there are increasing numbers of survivors of childhood brain tumors, there is a population of patients in major need of support that includes primary prevention as well as intervention and follow-up over the lifespan with multidisciplinary care that incorporates evaluation of cognitive function. The quality of “survivorship” depends on the ability of the individual to meet developmental challenges as they move into adolescence and adulthood.
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childhood cancer: A report from the childhood cancer survivor study. Cancer 97:1115-1126, 2003 Meehan WP 3rd, d’Hemecourt P, Collins CL, et al: Computerized neurocognitive testing for the management of sport-related concussions. Pediatrics 129:38-44, 2012 Vardy J, Wong K, Yi QL, et al: Assessing cognitive function in cancer patients. Support Care Cancer 14:1111-1118, 2006 Snyder AM, Maruff P, Pietrzak RH, et al: Effect of treatment with stimulant medication on nonverbal executive function and visuomotor speed in children with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol 14:211-226, 2008 Barr RD, Simpson T, Whitton A, et al: Health-related quality of life in survivors of tumours of the central nervous system in childhood—A preference-based approach to measurement in a cross-sectional study. Eur J Cancer 35:248-255, 1999 Zebrack BJ, Chesler MA: Quality of life in childhood cancer survivors. Psychooncology 11:132-141, 2002 Maddrey AM, Bergeron JA, Lombardo ER, et al: Neuropsychological performance and quality of life of 10 year survivors of childhood medulloblastoma. J Neuro Oncol 72:245-253, 2005 Butler RW, Copeland DR: Attentional processes and their remediation in children treated for cancer: A literature review and the development of a therapeutic approach. J Int Neuropsychol Soc 8:115-124, 2002 Kuhnt D, Ganslandt O, Schlaffer SM, et al: Quantification of glioma removal by intraoperative high-field magnetic resonance imaging: An update. Neurosurgery 69:852-862, 2011 Ahn ES, Goumnerova L: Endoscopic biopsy of brain tumors in children: Diagnostic success and utility in guiding treatment strategies. J Neurosurg Pediatr 5:255-262, 2010 Pollack IF, Keating R: New delivery approaches for pediatric brain tumors. J Neuro Oncol 75:315-326, 2005 Kieran MW, Turner CD, Rubin JB, et al: A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol/Oncol 27:573-581, 2005 Ellison DW, Kocak M, Dalton J, et al: Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 29:1400-1407, 2011 Cho YJ, Tsherniak A, Tamayo P, et al: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424-1430, 2011 Packer RJ: Risk stratification of medulloblastoma: A paradigm for future childhood brain tumor management strategies. Curr Neurol Neurosci Rep 11:124-126, 2011 Kirsch DG, Tarbell NJ: Conformal radiation therapy for childhood CNS tumors. Oncologist 9:442-450, 2004 Kirsch DG, Tarbell NJ: New technologies in radiation therapy for pediatric brain tumors: The rationale for proton radiation therapy. Pediatr Blood Cancer 42:461-464, 2004 Merchant TE, Hua CH, Shukla H, et al: Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 51:110-117, 2008 Mulrooney DA, Ness KK, Neglia JP, et al: Fatigue and sleep disturbance in adult survivors of childhood cancer: A report from the childhood cancer survivor study (CCSS). Sleep 31:271-281, 2008 Rosen G, Brand SR: Sleep in children with cancer: Case review of 70 children evaluated in a comprehensive pediatric sleep center. Support Care Cancer 19:985-994, 2011 Butler RW, Copeland DR, Fairclough DL, et al: A multi-center, randomized clinical trial of cognitive rehabilitation program for childhood survivors of pediatric malignancy. J Consult Clin Psychol 76:367-378, 2008 Patel SK, Katz ER, Richardson R, et al: Cognitive and problem solving training in children with cancer: A pilot project. J Pediatr Hematol/ Oncol 31:670-677, 2009 Klingberg T, Fernell E, Olesen PJ, et al: Computerized training of working memory in children with ADHD—A randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 44:177-186, 2005
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42 51. Hardy KK, Willard VW, Bonner MJ: Computerized cognitive training in survivors of childhood cancer: A pilot study. J Pediatr Oncol Nurs 28:27-33, 2011 52. Schatz J, Kramer JH, Ablin A, et al: Processing speed, working memory, and IQ: A developmental model of cognitive deficits following cranial radiation therapy. Neuropsychology 14:189-200, 2000 53. Reddick WE, White HA, Glass JO, et al: Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors. Cancer 97:2512-2519, 2003 54. Conklin HM, Reddick WE, Ashford J, et al: Long-term efficacy of methylphenidate in enhancing attention regulation, social skills, and academic abilities of childhood cancer survivors. J Clin Oncol 28:44654472, 2010 55. Shaw EG, Rosdhal R, D’Agostino RB Jr, et al: Phase II study of donepezil
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in irradiated brain tumor patients: Effect on cognitive function, mood, and quality of life. J Clin Oncol 24:1415-1420, 2006 Castellino SM, Tooze JA, Flowers L, et al: Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: A pilot study. Pediatr Blood Cancer (in press) Kohli S, Fisher SG, Tra Y, et al: The effect of modafinil on cognitive function in breast cancer survivors. Cancer 115:2605-2616, 2009 Gehring K, Patwardhan SY, Collins R, et al: A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. J Neuro Oncol (in press) Blackhall L, Petroni G, Shu J, et al: A pilot study evaluating the safety and efficacy of modafinal for cancer-related fatigue. J Palliat Med 12: 433-439, 2009
C
Which Major Cognitive Domains Are Affected?
*Department of Neurology, Children’s Hospital Boston, Boston, MA. †Pediatric Brain Tumor Program, Dana-Farber Cancer Institute, Boston, MA. ‡University of Texas Health Science Center, San Antonio, TX. Address reprint requests to: Nicole J. Ullrich, MD, PhD, Department of Neurology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]
Cancer-related neuropsychological dysfunction describes a complex of neurocognitive late effects that occur over time as a result of childhood cancer and its treatment. There are multiple neurocognitive, social, and psychological issues that emerge, as children are expected to master increasingly complex tasks. The pathogenesis is not well understood. Neurocognitive late effects can be defined as problems with thinking, learning, and remembering and may include permanent disruptions in brain development.4,5 Survivors of pediatric brain tumors are especially vulnerable to these late effects, given the aggressive CNS-directed therapies required for adequate treatment of these tumors. Research has consistently demonstrated that brain tumor survivors have higher rates of neurocognitive dysfunction than survivors of nonCNS malignancies. Cognitive impairment in brain tumor survivors may occur in many different areas of functioning. These deficits can be attributed to direct insult to the brain caused by tumor type, size, and location, surgical resection, impact of cranial radiation therapy (CRT), long-term effects of systemic chemotherapy, and treatment-related complications.2,5 Late effects can increase in severity over time and in direct relation to greater treatment intensity. The most commonly affected domains and modifiers include effects on overall cognitive ability, memory, attention, and executive functions, as well as deficits in motor skills, psychosocial functioning, adaptive behaviors, and social skills, but there is no specific pattern of
entral nervous system (CNS) tumors are the most common solid tumors in children, second only to leukemia in overall incidence. Importantly, in the modern treatment era, ⬎60% of children diagnosed with a brain tumor are expected to become long-term survivors; however, survival is not without serious long-term effects, and many individuals experience significant chronic medical complications.1 Neurotoxic effects, often referred to as “late effects,” are thought to fully manifest between 2 and 5 years after completion of treatment and are often associated with pronounced and chronic impairment. Late effects may occur in a variety of domains, including physical, medical, social, emotional, behavioral, and neurocognitive functioning. Importantly, it is estimated that 40%-100% of pediatric brain tumor survivors experience deficits in cognitive function related to the tumor and/or its treatment.1-3 Development of neurocognitive dysfunction is impacted by multiple host and treatment factors, and deficits often increase over time. Importantly, many survivors and their families are unaware of the risks. This chapter will focus on neurocognitive dysfunction in childhood cancer survivors, particularly survivors of CNS tumors.
1071-9091/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2012.02.014
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36 neurocognitive dysfunction that is pathognomonic for pediatric brain tumor survivors. A recent meta-analysis comprising 39 empiric studies estimated the magnitude of general and specific neurocognitive late effects for survivors of pediatric brain tumors.5 By extracting information across 10 neurocognitive domains, the authors discovered that these children exhibited significant and pervasive impairments in multiple domains, and that survivors’ scores on measures of global cognitive ability, both verbal and nonverbal, fell nearly one standard deviation below normative means. Survivors were also found to perform poorly on measures of attention, memory, executive function, processing speed, psychomotor skills, visual-spatial skills, and language. Examination of effect sizes across studies revealed more severe deficits in attention, verbal memory, and language compared with the other domains assessed. Attention and memory are critical skills by which new knowledge is acquired.6 Impairment in these areas has significant implications for intellectual growth and development and academic performance over time, as expectations and developmental demands increase with age. In fact, recent research has suggested that many learning problems are likely the result of difficulties in attending to and retaining new information rather than the decay of previously learned material.5 The resulting level of impairment can range from mild learning problems to severely limited capabilities and overall poor quality of life.2,7-12 Brain tumor survivors treated with CRT have consistently shown evidence of greater neurocognitive dysfunction than those treated without CRT. The risk of impairment increases with higher doses of CRT, and there is a continuing pattern of decline over time.6,13 In a heterogeneous sample of 133 longterm survivors of pediatric brain tumors, 5% of individuals had such severe cognitive impairment that they were unable to complete intelligence quotient (IQ) testing.9 For those completing the assessment, the authors found several important predictors of adverse outcomes. CRT was the single most important risk factor for subsequent adverse neurocognitive functioning, accounting for an average loss of 18 fullscale IQ points (normative mean IQ score ⫽ 100; standard deviation ⫽ 15). However, other risk factors included shunt insertion because of hydrocephalus (effect estimate of 11 fullscale IQ points) and cerebral hemisphere tumor location (effect estimate of 10-15 full-scale IQ points). These authors found no association between long-term cognitive functioning and tumor grade, disease relapse, or chemotherapy.
Factors That Influence Neurocognitive Outcome There are multiple disease and host factors that influence the development of cancer-related neurocognitive dysfunction. These can be divided into tumor- and treatment-related factors, host- related factors, and environmental/psychosocial (Table 1). One way to conceptualize the impact of a brain tumor is to envision that tumor diagnosis, treatment, and follow-up occur along the spectrum of neurodevelopment.
Table 1 Risk Factors for Neurocognitive Dysfunction Tumor-Related Factors
Host Factors
Presence/absence of hydrocephalus Tumor location Tumor size Weakness/sensory deficits Cranial nerve deficits Duration of symptoms Presence/absence of seizures Need for anticonvulsants Steroid use
Age at diagnosis Age at treatment Gender Genetic polymorphisms Presence/absence of neurogenetic syndrome Pretreatment/baseline level of functioning Socioeconomic status Other medical complications/illnesses Sleep disorders Fatigue Hypertension Sensorineural hearing loss Visual impairment Endocrine dysfunction
Treatment factors Surgery Neurologic injury Motor/sensory deficits Ataxia Perioperative infarction Hemorrhage Posterior fossa syndrome Chemotherapy Neuropathy Hearing deficit Headaches Fatigue Encephalopathy Leukoencephalopathy Intrathecal chemotherapy Steroid use “Chemobrain” Radiation therapy Radiation dose Radiation field Use of radiosensitizer Radiation tissue injury White matter injury Radiation necrosis Stroke or vasculopathy Vision changes (cataracts)
Environmental/ Psychosocial factors School absences Adequacy of educational supports Access to neuropsychological assessments Hospital-based school consultation Educational/vocational supports Technical support Books on tape Assistive devices Computers Loss of socialization/peer experiences Emotional distress (patient/ sibling/family) Changes to physical appearance Psychological adjustment Self-image/psychological distress Depression/anxiety
Overall neurologic and neurocognitive function is directly impacted at each time point.
Tumor- and Treatment-related Factors The location and size of the initial tumor can impact many factors, such as symptoms at presentation, resectability, and presence/absence of neurologic deficits. These deficits can be focal, with specific relationship to the tumor location and brain regions affected, or diffuse/poorly localizable, likely
Neurocognitive dysfunction in childhood cancer survivors related to raised intracranial pressure and hydrocephalus. The impact of hydrocephalus, both in terms of degree and duration before correction, is poorly accounted.14 As many as 25% of children with a primary brain tumor experience seizures at tumor presentation.15-17 Seizure onset can occur at the time of diagnosis, can be the first sign to herald relapse of tumor, or may occur/recur many years after completion of therapy. There are several proposed causes of seizures, which include the tumor itself, surrounding areas of dysplasia, altered levels of neurotransmitters, peritumor blood products/edema, and/or scar formation.17,18 The use of necessary anticonvulsants can further contribute to cognitive dysfunction in patients who are already at risk.19 Treatment for a primary brain tumor may involve a combination of surgery, chemotherapy, radiation therapy, and stem cell transplant; specific tumor-directed therapy is tailored to the underlying tumor type and location in children. Surgical resection remains the mainstay of therapy for most primary brain tumors, both to provide histologic diagnosis and to reduce tumor burden, and is often the most important factor in overall prognosis. Deficits and long-term effects of surgery are multifactorial and depend on tumor location. Direct sequelae from surgical removal can impact neurocognitive function in a variety of ways, including development of focal weakness, sensory deficits, new cranial nerve deficits, or truncal/appendicular ataxia. Surgery may also produce local damage related to development of hemorrhage or vascular injury. Recent studies suggest that even patients treated with surgery alone are at risk for long-term effects, including ataxia, hemiparesis, and persistent neurosensory and neurocognitive deficits.2,20 One prime example of surgical toxicity is cerebellar mutism, or posterior fossa syndrome, which occurs postoperatively in 15%-25% of patients with tumors in the posterior fossa, most commonly after medulloblastoma resection.21 There is thought to be a delay of 12-48 hours after surgery, followed by a loss of verbal expression, pseudobulbar dysfunction, irritability, and ataxia. In addition, poor attention and eye contact, vomiting, incontinence, and emotional lability are common. Speech recovery ranges from days to many months. These emotional, motor, and neurocognitive effects may last months to years, and are often confounded by other aspects of cancer treatment.22 Chemotherapy, both systemic and intrathecal, can have an important impact on neurologic function; the neurologic effects of chemotherapy are seen with increasing frequency as a result of more aggressive therapy and prolonged survival. Side effects may result from direct neurotoxicity or indirect effects from metabolic encephalopathies, seizures, infections, transient ischemic attacks, ataxia, and myelopathy, as well as movement disorders. Because standard therapy often relies on combinations of chemotherapy, it is often difficult to isolate the offending agent. Drug-induced encephalopathy can be seen with chemotherapy, immunosuppressive agents, or supportive treatments, such as steroids, and the effects are often dose dependent and drug specific. Many patients now receive intrathecal therapy or high-dose chemotherapy with autologous stem cell rescue. There are a variety of experimental approaches that are being evaluated to enhance the effi-
37 cacy of conventional chemotherapy. Newer techniques are also being designed to improve access to the CNS across the blood– brain barrier and to provide more molecularly directed approaches. Neurologic effects of these new molecularly targeted agents are only beginning to be recognized in adults, but the impact on the developing nervous system is far from clear. As neurocognitive assessments are incorporated into upcoming clinical trials as important outcome measures, the effects from these specific treatments will be better documented and appreciated. Radiation therapy remains an important component of cancer treatment in children. Individuals may experience different effects depending on age, disease status, concomitant therapies, length of survival, and radiation features, such as dose, size of the field, and fractionation schema. Radiation injury can affect each level of the nervous system and can occur at the time of therapy or months or even years after completion of treatment. The most common neurologic complications related to radiation are neurocognitive dysfunction and neuroendocrine damage. Several studies have shown a progressive deterioration in IQ among children who receive whole-brain radiotherapy. For example, a craniospinal axis dose of 3600 centigray (cGy) resulted in a 20- to 30-point decline in IQ score when administered to children between the ages of 3 and 7 years.23 Cognitive deficits are typically progressive in nature, and younger children are more likely to suffer the severest damage; however, no patient, regardless of age, is free of the risk of damage.6,10,24 These long-term effects on cognitive function and growth and development emphasize the importance of examining the efficacy of reduced overall dose of therapy for diseases with high cure rates.
Host-related Factors Overall, neurologic and neurocognitive function is also directly impacted by characteristics of the child or host. Neurodevelopment occurs over a prolonged period, during which the central nervous system is susceptible to a variety of insults. Critical features such as gender and age at diagnosis and treatment, therefore, often dictate susceptibility to treatment-related morbidities. Younger age at time of tumor diagnosis and treatment is likely the most important host factor that impacts the development and severity of neurocognitive dysfunction. However, sex of the child is also a significant variable in some treatment protocols, where girls are known to be at higher risk than boys for neurocognitive impairment.13 Comorbid conditions, such as inherited genetic syndromes, may also impact the timing and development of neurocognitive dysfunction. For example, children with neurofibromatosis type 1 may have baseline neurological and neurodevelopmental issues, which can be difficult to distinguish from tumor- and treatment-related side effects and can increase susceptibility to neurocognitive impairment resulting from treatment.25 A child’s premorbid level of cognitive, developmental, or neurological functioning may also be a significant predictor
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38 of subsequent neurocognitive dysfunction. Children with a history of neurodevelopmental disorders, such as Down syndrome, mental retardation, low birth weight, or learning disabilities, may have an even greater risk of functional impairment after cancer treatment.
Environmental Factors Lastly, there are environmental factors in the life of a child that affect neurocognitive functioning. These include socioeconomic status (SES), loss of schooling and socialization, and alterations in family psychosocial functioning. Lower SES is associated with greater cognitive decline in acute leukemia and can impact the neurocognitive outcome in brain tumor survivors.12,26 Children from families of higher SES tend to score better on measures of IQ, achievement, and adaptive functioning.27 Academic performance may also be impacted by other sociodemographic factors, such as ethnicity and parental education.13 It is likely that many children from higher SES families benefit from greater parental support, more cognitively stimulating home environments, and increased ability of parents to advocate for the unique needs of their children. Furthermore, more affluent schools may have greater resources to provide specialized services for children experiencing treatment-related neurocognitive dysfunction. A number of family characteristics are associated with the behavioral and psychological adjustment of children with chronic illnesses, including childhood cancer. For example, stress and family conflict have been consistently linked to child maladaptive behaviors. One study found that children from 2-parent households and children who had experienced fewer negative life events tended to be more emotionally well adjusted and performed better on measures of intellectual functioning.27 Although they are not directly related to disease or treatment severity, all of these factors may have differential impact on long-term neurocognitive outcomes of childhood cancer survivors.13
How/When Do We Evaluate for Cognitive Impact? Longitudinal evaluation of neurocognitive functioning for childhood cancer survivors is not yet considered standard of care,5 although many pediatric oncology programs emphasize neurocognitive assessment for high-risk patients, including those diagnosed with brain tumors. These assessments are essential in facilitating access to needed special education services and in tracking each child’s developmental trajectory over time. Estimates of the need for special education services vary by diagnosis. In one study, 25% of a heterogeneous sample of childhood cancer survivors qualified for special education in school compared with only 8% of a sibling control group.28 Other research has estimated that 40%-50% of acute lymphoblastic leukemia survivors and up to 70%80% of brain tumor survivors will require special education services at some point during their school years.13 A comprehensive neurocognitive assessment should target global intellectual functioning and academic achievement as well as the specific high-risk domains described previously. The assessment battery should be modified as needed to accommodate for other late effects of therapy, such as chronic fatigue or hearing loss. The Children’s Oncology Group consensus recommendations suggest that, at a minimum, all high-risk survivors be evaluated when they transition into a survivorship or long-term follow-up program. This should be performed regardless of patient/parent report of concern, both to detect subtle impacts on overall functioning and to serve as a baseline for future assessments, as it is known that cognitive late effects can progress over time.6 Reevaluation should factor in academic performance, any acute changes or emergence of new difficulties, and the individual child’s specific risk factors. Table 2 includes relevant domains of neurocognitive functioning that may be part of these assessments along with commonly used measurement tools. These tools include both traditional instruments that are administered to
Table 2 Neurocognitive Assessment in Children Neurocognitive Domain
Commonly Used Assessment Tools
Global cognitive functioning (IQ)
WISC-IV; WPPSI-III; WJ-III; SB-5; KABC-II; BSID-III Mental Scale
Attention
CPT-II; NEPSY-II; Trail Making Test Part A; Conners Rating Scales, Third Edition
Memory
CMS; WRAML-2; CVLT-C; Rey-O
Processing speed
WISC-IV Coding/Symbol Search; WJ-III Achievement Fluency; D-KEFS Fluency
Executive functioning
BRIEF; D-KEFS; WCST; NEPSY-II; Trail Making Test Part B; Tower of London Test
Psychomotor skills
VMI; Finger Tapping test; Grooved Pegboard; Rey-O; BSID-III Motor Scale
Academic achievement
WIAT-III; WRAT-IV; WJ-III
BSID-III, Bayley Scales of Infant Development, Third Edition; BRIEF, Behavior Rating Inventory of Executive Function; CMS, Children’s Memory Scale; CPT-II, Continuous Performance Test, Second Edition; CVLT-C, California Verbal Learning Test for Children; D-KEFS, Delis–Kaplan Executive Function System; KABC-II, Kaufman Assessment Battery for Children, Second Edition; NEPSY-II, Developmental Neuropsychological Assessment, Second Edition; IQ, intelligence quotient; Rey-O, Rey–Osterrieth Complex Figure Test; SB-5, Stanford Binet Intelligence Scale, Fifth Edition; VMI, Beery–Buktenica Developmental Test of Visual Motor Integration Test; WCST, Wisconsin Card Sorting Test; WIAT-III, Wechsler Individual Achievement Test, Edition; WISC-IV, Wechsler intelligence scale for children, Fourth Edition; WJ-III, Woodcock–Johnson Tests of Achievement and Cognitive Abilities, Third Edition; WJ-III, Woodcock–Johnson Tests of Cognitive Abilities, Third Edition; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence, Third Edition; WRAML-2, Wide Range Assessment of Memory and Learning, Second Edition; WRAT-IV, Wide Range Achievement Test, Fourth Edition.
Neurocognitive dysfunction in childhood cancer survivors the child by a trained professional and patient-reported outcome measures, often captured via parent-report questionnaires. In recent years, modern technologies have brought about opportunities for computerized assessments of neurocognitive functioning. According to one study, 40% of high schools that employ athletic trainers now use some form of computerized assessment for evaluation and management of sports-related concussions.29 These computerized paradigms are now being used more often with clinical populations, such as adult cancer patients30 and children diagnosed with attention-deficit/hyperactivity disorder.31 Potential advantages include availability, convenience, and accuracy of administration and scoring.29 In addition, test batteries can be customized to evaluate the specific neuropsychological functions of interest (eg, processing speed, working memory) (http://www.cogstate.com). Trials are underway to evaluate the use of computerized assessment programs with survivors of pediatric cancer.
What Are the Functional Implications? Neurocognitive dysfunction can have significant implications for functional outcomes and overall quality of life for survivors.1,2 Employability, interpersonal relationships, independent living, emotional functioning, and health status are some of the domains that may be impacted by neurocognitive late effects in survivors of pediatric brain tumors. This ultimately can translate into increased risk for poor quality of life for survivors and their families.32,33 For example, one study demonstrated that only 30% of young adults who were 10-year survivors of medulloblastoma were able to drive, live independently from their families, or find employment.34 There were also significantly lower rates of education, employment, and dating when compared with the general population. Several studies have suggested that the complex needs of pediatric brain tumor survivors may be underestimated and largely unmet. Many children spend excessive time on preparation of homework, but demonstrate difficulties in processing, storage, and integration of new information.6,35 It is clear that intellectual functioning, attention, memory, executive functioning, and a variety of other cognitive abilities are negatively impacted by CNS disease and treatment. However, questions remain about how these neurocognitive deficits interact with other medical and psychosocial factors to affect long-term functional outcomes for survivors.
39
Prevention Reduction in treatment-related toxicity has occurred with advances in neurosurgical techniques, use of neuroprotective agents, and improved radiation techniques. The overall goal of treatment is to improve outcome in tumor subtypes that have traditionally been resistant to therapies, and to reduce the toxicity of treatment in tumor subtypes that are responsive to therapies. Modern literature suggests that maximum extent of tumor resection with preservation of neurological function is associated with improved overall outcome. The use of imageguided surgery such as the intraoperative magnetic resonance imaging suite has resulted in improved extent of resection and reduction of residual tumor volume.36 There will, however, always be tumors in eloquent regions of the brain and infiltrative tumors that are less amenable to this type of approach. The use of endoscopic biopsy is an important minimally invasive method of diagnosis for the initial management of lesions in children with intraventricular and periventricular tumors and can be performed safely in conjunction with procedures to divert cerebrospinal fluid for obstructive hydrocephalus.37 Diagnostic efficacy and safety are high priorities and can preempt the need for open surgical biopsy in difficult locations. Intraoperative infusions are now used in adults and children to deliver targeting agents directly to the operative bed.38 Over the past decade, there have been advances in chemotherapeutic strategies for treatment of primary brain tumors. Specific protocols have included optimization of administration of chemotherapy, metronomic treatment,39 concomitant use of chemotherapy and radiation therapy to the CNS, and administration directly into the intrathecal/intraventricular compartment. Moreover, there are refinements in the clinical and molecular stratification of tumors that have facilitated a movement toward risk-adapted treatment planning. This is particularly true in medulloblastoma, where there are now 4 subclasses of tumor that are defined by molecular signature that directly relates to clinical and pathologic outcome indicators.40,41 Ultimately, this type of approach will lead to the identification of the next generation promising molecularly targeted therapies.42 Because of concerns over neurocognitive sequelae from radiation, there is renewed interest in reduction of total radiation dose, both for solid tumors and for primary brain tumors. The use of fractionated and conformal techniques effectively reduces toxicity to the surrounding tissue.43 With proton beam radiotherapy, there is less radiation to surrounding tissues, which theoretically has the potential to decrease the area at risk for injury and, therefore, has long-term implications for sparing of neurocognitive functioning.44,45
Strategies for Intervention
Treatment of Comorbidities
Research into strategies to evaluate, prevent, and treat the neurocognitive late effects of cancer therapy has mirrored the progress of medical therapy. Interventions and therapeutic strategies are targeted at each point along the road map of diagnosis, treatment, and survivorship.
Survivors are at risk for significant comorbidities that have been shown to impact neurocognitive functioning. This may include neurosensory deficits such as visual impairment and sensorineural hearing loss, as well as seizures, endocrine dysfunction, headaches, and peripheral neuropathy.15 It is cru-
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40 cial to identify and treat any underlying health conditions that may impact overall functioning, such as underlying endocrinopathies. In addition, screening for, identification of, and correction of hearing deficits and visual impairments are important. A significant proportion of adult survivors of childhood cancer report disrupted sleep, increased daytime sleepiness, and fatigue.46 Survivors with a history of radiation therapy are more likely to be fatigued. Excessive daytime sleepiness is seen in up to 60% of children with cancer and 80% of children with tumors involving the hypothalamus, thalamus, and brainstem.47 These patients are also at risk for sleep-disordered breathing. Lastly, early identification and treatment of psychological comorbidities, such as anxiety, depression, and post-traumatic stress syndrome, in the child and in the family is important for overall quality of life as well as cognitive functioning. The overall impact of these comorbidities is often hard to decipher, but given the frequency of reported symptoms in survivor populations is important to address.
Cognitive Rehabilitation Given the prevalence of neurocognitive dysfunction in survivors of pediatric brain tumors, efforts to determine effective forms of cognitive remediation are imperative. One such study focused on acquisition of cognitive strategies to improve neuropsychological performance by completing a 4-5 month remediation program, including cognitive-behavioral interventions.48 The authors reported improved attentional skills and achievement scores over the course of the study; effect sizes were small but comparable with other intervention studies with similar population and methodology. A similar 15-week training program for improving problem solving, general cognitive skills, memory, and attention showed some positive gains from pre-intervention to postintervention in each of the domains assessed.49 However, as with the first study, participation rates were fairly low and the mode of intervention may be impractical for families with few resources or those who do not live near a large medical center that could administer the intense treatment program. These findings highlighted a need for effective short-term interventions that could be widely administered without prohibitive costs, travel requirements, or time commitments. One such intervention is home-based, computerized cognitive training programs. These programs have proven effective in improving attention and working memory in children diagnosed with attention-deficit/hyperactivity disorder50 and in a small sample of pediatric cancer survivors.51 This is notable, as some investigators believe that deficits in attention and working memory are to blame for treatment-related declines in intellectual functioning and academic performance. In fact, studies of childhood cancer survivors have shown that up to 45% of the variance in IQ scores and 70% of functional impairments at school could be attributed to these underlying processes.52,53 These results suggest that homebased, computerized cognitive training may be useful in improving survivors’ neurocognitive functioning, although more research in this area is clearly indicated.
Pharmacologic Interventions Although deficits in attention are common in survivors of primary brain tumors and manifest with behavioral issues that resemble attention deficit disorder in the general population, it is likely that the mechanism is different. At the same time, traditional stimulants have been shown to improve neurocognitive functioning among survivors. Specifically, both short-acting and long-acting doses of methylphenidate lead to improvements in measures of attention, social skills, and behavioral problems in survivors of childhood brain tumors and acute lymphoblastic leukemia, and these benefits were maintained across settings during the course of one year.54 The acetylcholinesterase inhibitor donepezil has demonstrated some promising initial results in a study of 34 adults with primary brain tumors, with improvements in attention, concentration, memory, and mood.55 These data formed the basis of a feasibility study in childhood brain tumor survivors, where it was well tolerated and demonstrated improvements in executive function and memory.56 Alternative psychostimulants, such as the dopaminergic agent modafinil, have demonstrated improved attention and memory in adult breast cancer survivors57 as well as improved cognition, mood, and symptoms of fatigue in adults with brain tumors.58,59 A randomized, placebo-controlled trial is currently underway through the pediatric cooperative group to assess efficacy of modafinil in survivors of childhood brain tumors. Thus, newer stimulant medications may also hold some possibility to improve at least some aspects of common cancer-related neurocognitive deficits.
Conclusions With newer treatments and longer overall survival leading to growing numbers of survivors, there is an increasing impact of neurological and neurocognitive toxicity related to treatment for primary brain tumors in children. As there are increasing numbers of survivors of childhood brain tumors, there is a population of patients in major need of support that includes primary prevention as well as intervention and follow-up over the lifespan with multidisciplinary care that incorporates evaluation of cognitive function. The quality of “survivorship” depends on the ability of the individual to meet developmental challenges as they move into adolescence and adulthood.
References 1. Armstrong GT, Liu Q, Yasui Y, et al: Long-term outcomes among adult survivors of childhood central nervous system malignancies in the childhood cancer survivor study. J Natl Cancer Inst 101:946-958, 2009 2. Turner CD, Chordas CA, Liptak CC, et al: Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer 53:417-423, 2009 3. Moore BD 3rd: Neurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol 30:51-63, 2005 4. Mulhern RK, Palmer SL: Neurocognitive late effects in pediatric cancer. Curr Probl Cancer 27:177-197, 2003 5. Robinson KE, Kuttesch JF, Champion JE, et al: A quantitative meta-
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