Neurocognitive Late Effects in Children with Cancer

Disease/treatment factors

Cranial radiation

Presence and location of a brain tumor

Surgical resection of a brain tumor

Chemotherapies known to be associated with neurotoxicity (neurocognitive, neuropathy, hearing loss, etc.)

Methotrexate

Vincristine

Carboplatin/cisplatin

Type and severity of cancer (e.g., brain tumor, leukemia, etc.)

Modality and dose intensity (IV, IO, IT)

Drug combinations such as with or without corticosteroids, leucovorin, cytarabine, asparaginase, etc.

Individual factors

Time since diagnosis/age at assessment

Age of child at disease onset

Gender

Pre-diagnosis functioning/precancer trajectory

Environmental factors (e.g., quality of school resources)

Genetic predisposition

Family functioning

Profile of Cognitive Impairment in Childhood Cancer Survivors

Common areas of dysfunction observed in survivors with a history of CRT and/or intrathecal chemotherapy include attention/concentration skills, processing speed, memory, visual-motor integration, and executive functions (e.g., planning and organizational skills, etc.) (Buizer et al. 2009; Robinson et al. 2010). Such abilities represent “core” mental processes by which children learn, store, organize and integrate, and effectively apply new knowledge and skills. In particular, changes in the underlying basic processes of attention and memory are associated with a lowered acquisition rate of new knowledge and skills relative to same age peers and, over time, impact the survivor’s IQ and academic achievement (Palmer et al. 2001). Dysfunction in attention/concentration, processing speed, and executive function skills appear to be consistently reported in studies focused on neurocognitive impact in childhood cancer survivors and warrant special attention as they can initially be easily misinterpreted as volitional nonadherence by caregivers. See Box 10.2 for common manifestations in the child’s daily life.

Box 10.2 Manifestations of Neurocognitive Dysfunction in Daily Life

Attention

Trouble sustaining focus on a task over long periods of time and may lack awareness of these episodes of disrupted attention.
Inattention may be overlooked or even mistaken for deliberate noncompliance.
A tendency to miss bits of information when somebody is talking, especially if there is a lot of noise or commotion nearby.
- May lead to inability to follow directions or understanding complex concepts.
Careless errors, incomplete homework assignments, and inconsistent performance.
May appear to have poor memory for things like schoolwork, but good memory for more personal things that are of greater interest.
Negative social impact since kids do not notice when they are making mistakes, or doing or saying something wrong, but peers may notice.

Processing Speed

Needs more time to finish tasks or to respond to a question
Trouble keeping pace with the flow of instructions, demonstrations, and explanations

Working Memory

Trouble attending to many different things or aspects of a problem at the same time
Limitation on the ability to mentally “hold” information, instructions, or ideas in mind temporarily while performing other mental operations

Planning and Organizing Skills

Trouble breaking down large projects into steps and figuring out the order in which to start
Difficulty organizing time, as they do not know how much time to allow themselves to complete an assignment or job

Quality of Life Outcomes in Survivors with Neurocognitive Impairments

The impact of neurocognitive late effects on survivors of pediatric cancer is widespread and adult survivors of childhood cancer have been found to experience long-standing economic, psychological, and social consequences (Zebrack et al. 2004). Specifically, these survivors are more likely than their siblings to require special education services, less likely to attend college, and less likely to live independently as adults (Gurney et al. 2009). In addition, survivors of childhood cancer are at increased risk of unemployment compared to their siblings and are more likely to never marry (Gurney et al. 2009). See chapter 15 (survivorship) for more details.

Survivors of pediatric cancer, and particularly those with neurocognitive late effects, experience deficits in social adjustment (Schulte and Barrera 2010). Social adjustment has been defined as the extent to which individuals are achieving socially appropriate goals (Cavell 1990). These deficits worsen with time, affecting survivors’ quality of life (Schulte and Barrera 2010). Research examining the relationship between neurocognitive processes and social adjustment is scarce in pediatric brain tumor survivors and has been identified as a gap in the literature. Typically, these constructs have been investigated independently. However, cognitive processes would be expected to have pervasive effects on a child’s perception and interpretation of social situations and behavioral responses in social interactions. For example, children with cognitive-executive deficits may have difficulty thinking about multiple social perspectives or response options when determining how to respond to social stimuli. A link between attention dysfunction and social outcomes in survivors of childhood cancer has been reported (Moyer et al. 2012; Patel et al. 2007).

Considerations in Neuropsychological Evaluation of Children with Cancer

The field of pediatric neuropsychology has developed significantly over the years and the practice currently involves work with children and families in varied clinical settings, including children with cancer. In addition to the general qualifications for neuropsychology, providers who wish to practice in a pediatric oncology setting are encouraged to specifically pursue training opportunities under the direct supervision of a licensed neuropsychologist experienced in the area.

From a research perspective, neurocognitive and behavioral assessments are valuable to conduct in conjunction with contemporary pediatric cancer therapies to examine differences between treatments which, in cases of similar medical outcomes, may ultimately determine treatment preference. From a clinical perspective, monitoring of neuropsychological functioning in children at risk for neurocognitive impairments is valuable to provide the medical team and the child’s family with information relevant to the child’s health status, particularly with respect to the emergence of late effects across time. Importantly, information from comprehensive assessments can be used to identify any delayed sequelae and to develop a plan of care for remediation of cognitive impairments. Results from the initial neuropsychological assessment are particularly helpful in guiding the course, timing, and plan of action for the child’s transition back to academic and social environments. Subsequent assessments are helpful in tracking developmental progress, or lack of, in neuropsychological functioning. Results may also assist the family and medical team in understanding “problematic” behaviors. For example, identification of attention or memory problems may explain child’s “nonadherence” in remembering to take medications or identify emerging problems that may impact daily living skills, such as effectively managing time to complete school assignments or activities of daily living. Ongoing monitoring of the child’s neuropsychological functioning is also helpful to keep the family and medical team informed of changes across time, such as the emergence of new deficits or worsening of previously identified dysfunction.

Timing of Assessments

In general, a baseline neuropsychological evaluation is recommended following completion of primary treatments and after acute symptoms have resolved. Typically, this coincides with the child’s transition back to the school environment. The Children’s Oncology Task Force on Neurocognitive/Behavioral Complications after Childhood Cancer provided an expansion on the Children’s Oncology Group’s (COG) Long-Term Follow-Up Guidelines that offer direction on the timing of neuropsychological evaluation in pediatric cancer populations. According to these guidelines, survivors of childhood cancer should receive a baseline evaluation as they enter long-term follow-up (approximately 1–2 years post treatment), should be monitored annually for educational and vocational progress in the long-term survivorship follow-up program, and should be referred for periodic comprehensive neuropsychological reevaluations as clinically indicated (www.survivorshipguidelines.org). Typically, it is appropriate to reevaluate the patient during educational milestones and developmental transitional points (e.g., elementary to middle school, middle school to high school, and high school to college, etc.) and always when there are concerns of worsening functioning (Nathan et al. 2007). Unfortunately, not all centers have survivorship programs or staffing to provide repeated neuropsychological evaluations. Further, difficulties in securing insurance reimbursement for the neuropsychological evaluations, if done, can pose an operational barrier in providing an optimal level of care.

As described previously, children with brain tumors and ALL are at greatest risk for cognitive impairment, but the recommendation for regular monitoring of educational and vocational progress extends to children of any cancer diagnosis or treatment history. Prolonged school absences are common in children undergoing treatment for cancer which can negatively impact the child’s ability to maintain pace academically; therefore, monitoring of learning and school-related difficulties would be appropriate in these cases as well. Neuropsychological evaluations can be helpful for children in this group as well, particularly for those who are struggling at school. Please see Chap. 11 (education) for more details.

General Clinical Practices in Neuropsychological Evaluation

One of the initial steps in neuropsychological assessment is a thorough review of records, which requires sifting through all the layers of information contained in medical records which may or may not be fully relevant to the case at hand. A review of neuroimaging reports (e.g., MRI, CT scans, etc.) is helpful in formulating the approach to neuropsychological evaluation, particularly in patients with brain tumor or CNS complications, given that the particular type of neuroanatomical involvement influences decisions about the battery of tests to administer. Further, in pediatric oncology specifically, it is important to gather records about the onset and associated history of the particular cancer diagnosis, as clinical-, disease-, and treatment-related factors are known to confer varying degrees of risk for cognitive and behavioral dysfunction. Also, information regarding the patient’s specific treatment protocol is crucial in helping to attribute the various etiologies for any impairments that are identified as a result of the neuropsychological evaluation. In pediatric assessments, review of school records is essential to understand the patient’s educational exposure and to correlate any academic and behavioral difficulties with neuropsychological performances. This process may include requesting previous educational plan documentation (e.g., Individualized Education Program), progress reports, report cards, or documentation from other providers in the school setting (e.g., school psychologist).

The clinical interview is another key aspect of neuropsychological assessment and the detailed information obtained using this procedure frequently facilitates conceptualization and hypothesis generation with respect to the child’s struggles and how they manifest in daily functioning. The interview process frequently provides nuanced information regarding the severity, duration, or frequency of cognitive and behavioral symptoms that is typically not available in medical records. Incorporating details from collateral interview of parents, caregivers, teachers, other providers (e.g., therapists), etc., is also essential toward a comprehensive understanding of the child’s struggles and how these are manifested in daily life. By the end of the clinical interview, the interviewer has gathered and clarified details regarding the patient’s history across various domains (e.g., medical, developmental, family, psychosocial, educational, psychiatric, etc.).

Following the clinical interview, the pediatric neuropsychologist finalizes the specific tests to administer related to the neurocognitive functions of interest. When a comprehensive assessment is indicated, evaluation typically includes the following cognitive domains: academic achievement, attention/concentration, working memory, processing speed, language/verbal reasoning, verbal and visual learning and memory, executive functioning, daily behavioral and adaptive functioning, sensory, and gross and/or fine motor skills. As previously mentioned, particular domains known to be at risk for impairment in pediatric oncology populations should be the focus including global intellectual functioning, attention, executive functioning, processing speed, and nonverbal/visuospatial reasoning. Aspects of the neurological examination may also be administered based on the patient’s level of direct neuroanatomical involvement or sensory presentation (e.g., visual field defect secondary to tumor resection). In addition to cognitive functioning, neuropsychologists evaluate psychological, behavioral, adaptive, and personality characteristics of their patients as well as how they integrate with the patient’s neurocognitive presentation. Although generally less common in pediatric cancer populations, symptom validity testing may also be employed to provide information regarding the examinee’s level of motivation or effort during the testing process (AACN 2007).

Screening Approaches

Comprehensive neuropsychological evaluations for patients at high risk for neuropsychological impairments following cancer diagnosis and treatment are the gold standard but may not always be feasible given the practical challenges that arise in the current health-care setting. As noted earlier, comprehensive neuropsychological evaluations can be quite costly and are not always covered by insurance. In addition, full assessments can take a long time (e.g., 5 or more hours), and this is not always practical for families or within the time constraints of the clinic setting. Additionally, there may not be sufficient staffing to provide timely services to all children at high risk. In contrast, routine screening could become a fiscally responsible strategy used to target patients who are in need of more comprehensive evaluation (Krull et al. 2008b). Neurocognitive screening may range from a detailed interview to assess the child’s school, social, and learning development to administration of brief, standardized neurocognitive measures, depending on the child’s risk level. Given this context, a number of screening approaches are being evaluated (Embry et al. 2012; Krull et al. 2008a).

Regardless of whether a comprehensive or brief neurocognitive screening approach is used, test administration, scoring, and interpretation of test data are often considered the “core” components of a neuropsychological assessment and each has its standards and competencies characteristic of the process. However, with each step, it is important to consider not just the test scores but the larger context that provides the framework for the quantitative “data.” For example, in an adolescent patient preparing for their senior year, what effect could recent news of relapse have had on the testing results? The patient could potentially become depressed and these symptoms might influence how scores from some or all of the neurocognitive tests are interpreted.

Feedback

There is evidence that parents of children with cancer have a strong interest and need for information about the impact of treatment on their child’s neurocognitive functioning, both during treatment and in the years following its completion. Therefore, feedback and discussion of findings from the neuropsychological evaluation with the family are very important and frequently are dynamic processes (Trask et al. 2009). Feedback with patients and their parents in a pediatric oncology setting is typically provided in a separate face-to face session after the testing is complete, allowing clinicians to be in dialogue with parents about the assessment and recommendations.

Feedback from neuropsychological testing may at times take on a therapeutic tone during which the neuropsychologist aligns with the family in communicating the results. Feedback itself is more than simply reporting the patient’s test scores and implications of the findings, and it should also be a comprehensive clinical interaction that helps a family or patient understand their child or themselves perhaps from a new perspective. The family’s reaction and adjustment to the results provided are important to address, particularly as research suggests that parents have increased stress in managing and parenting children with higher cognitive dysfunction relative to those with more minimal neurocognitive impact (Patel et al. 2013).

Postal and Armstrong (2013) note that through the feedback session, patients and families have the opportunity to more deeply understand their diagnoses, testing scores, and expected prognosis. They also suggest that through the process of providing feedback, neuropsychologists assist patients’ understanding of particular neurocognitive syndromes in the broader real-world context. The neuropsychologist may be the first provider to integrate the patient’s medical and personal history, academic or vocational difficulties, and assessment results and conceptualize these pieces to tell a more complete story. During these sessions, it is not uncommon for additional information to arise or for the neuropsychologist to receive further clarification on an existing issue. In some cases, the written report may be finalized after these details are integrated into the documentation.

In addition to verbal feedback, a written neuropsychological report is the primary vehicle for summarizing and communicating the results of the evaluation to patients and their families. It serves as a reference for families in the future as a document of their children’s strengths and weaknesses, including impairments, and may be a tool for advocating for their child’s needs. Please see Education in Chap. 11 for details about services that parents can advocate for. Therefore, it is especially important to understand that the language and professional “jargon” used in a report can be a barrier to a families’ ability to interpret the results and should be used sparingly or avoided when possible. This can be the case even when parents have a university-level education (Cheung et al. 2014).

Feedback to the referring physician and the medical team involved in caring for the child is also necessary. It is important to help the team understand the child’s functioning level for various reasons, ranging from feedback about the side effects experienced as a result of the treatment protocols used to preparing providers for the possibility of inconsistent treatment adherence due to forgetfulness or disorganization or even to help the provider tailor their communications to the “developmental age” and capacity of the child. Although this multidisciplinary feedback may take place in different formats across various work settings, it is often communicated in regular team meetings or more informal one-on-one conversations. Again, the written evaluation report becomes important as a communication tool with the medical team. There is not one “typical” style of a written report; length, amount of detail, and comprehensive nature of the report will vary. It is important, however, that reports include a summary and interpretation of results, address the referral question, and provide recommendations with relevant “next steps.”

Finally, feedback provided to the school from the neuropsychological evaluation is essential. The recommendations and interventions formulated from the assessment can provide the scaffolding from which a more extensive and comprehensive educational plan can be devised. The unique insights provided from the evaluation often support a plan that is tailored to the specific needs of a student, often in the form of a 504 Accommodation Plan or Individualized Education Plan (IEP). Please see Chap. 11 on Education for more details. The plan is often best developed within the context of open communication between the family, school staff, and school administration. Without this open communication, procuring the appropriate services for children with cancer can be challenging because schools are often unaware of the specific disease-related neurocognitive and academic-related impairments experienced by this patient group. A case example of a childhood cancer survivor seen for clinical neuropsychological evaluation is presented below, as well as samples of questions typically asked in the neuropsychological interview.

Case Vignette

A right-handed, 22-year-old Hispanic and Caucasian male diagnosed at 16 years old with non-Hodgkin lymphoma of the bone and marrow is referred for a neuropsychological reevaluation by the survivorship clinic given concerns regarding his cognitive functioning and recommendations for college. The patient reported difficulties with executive functioning skills (i.e., sequencing tasks, working memory), maintaining attention, and processing speed. Memorization was also a new area of difficulty for him. These cognitive impairments were causing conflict with family members. The patient also reported significant anxious symptoms that presented physiologically (e.g., pain in his chest). He utilized spiritual coping (e.g., prayer) to manage his emotions. He reportedly drank socially but denied use of tobacco or other drugs.

He was born at 38 weeks’ gestation with no reported pre- or perinatal complications. Developmental history was notable for a diagnosis of congenital hypotonia resulting in delayed motor skills. Speech and language developed normally. Medical history was also notable for a heart murmur and visual tracking difficulties. The patient was diagnosed with attention deficit hyperactivity disorder, inattentive type, as a child.

The patient underwent 8 months of treatment including cyclophosphamide, vincristine, prednisone, triple intrathecal therapy (methotrexate, hydrocortisone, cytarabine), and intrathecal systemic chemotherapy with cytarabine and etoposide. He was taking multivitamins, calcium, and an over-the-counter medication for attention problems, but no prescribed medications.

Family medical history was notable for chronic myelogenous leukemia, Parkinson’s disease, diabetes type II, prostate cancer, multiple sclerosis, and coronary heart disease. Family mental health history was notable for severe depression, obsessive-compulsive disorder, and bipolar disorder.

Neuropsychological assessment included a clinical interview with the patient, collateral interview with the patient’s mother completed with the patient’s consent, one five-hour testing session, and feedback session. The patient required several breaks to maintain focus and he demonstrated occasional lapses in attention during the assessment. The results were considered to be a valid representation of his cognitive functioning approximately 5 years after completing treatment for non-Hodgkin lymphoma. He exhibited impairments in processing speed, sustained attention, and executive functioning (working memory, planning/organization, metacognition). He also evidenced a clinically elevated level of anxious symptoms and adaptive functioning impairments related to educational difficulties and parental conflict. The cognitive impairments significantly interfered with the patient’s ability to acquire new information and greatly impacted his learning efficiency.

As a result of the evaluation, specific recommendations were crafted to meet the patient’s educational needs in the college setting. He partnered with the office for students with disabilities at his institution for support with implementing the accommodations and interventions. Consultation for ADHD medication was also recommended for the patient at the time of the assessment given his long-standing history of attention difficulties potentially exacerbated by his previous cancer treatment.

Box 10.3 Sample Questions Asked in the Clinical Interview